Clinical trial NCT01191840
Conditions: Bacteremia
Keywords: staphylococci
Sponsor: Duke University
Start date: 2011-02-01; Completion date: 2017-03-04
Enrollment: 509 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to accurately determine the length of appropriate drug treatment for staphylococcal blood stream infection. The study seeks to address important information about the management of staphylococcal blood stream infections.

Detailed description:
To demonstrate that the clinical efficacy of algorithm-based therapy of patients with staphylococcal blood stream infection is noninferior to current standard of care.

PP (per protocol) population: randomized patients EXCLUDING those that: Received a PENS antibiotic -Did not undergo removal of intravascular catheter suspected to be infected. Note that patients with simple CoNS bacteremia may retain the catheter; all other patients should have their catheter(s) removed. -Had blood stream infection with a vancomycin-resistant staphylococcus; or a staphylococcus resistant to protocol-identified alternative drugs if these were used -Discontinued study medication prematurely for reasons other than clinical failure -Did not undergo final TOC assessment -Did not comply with all Patient Inclusion Criteria -Violated any Patient Exclusion Criteria

* Died within 3 days of randomization
* Were classified as non-evaluable

PPE Population: Patients from the PP population who did not have complicated staphylococcal infection.

Arms: arm 1: None arm 2: None
Interventions: intervention 1: Vancomycin intervention 2: Vancomycin
Intervention descriptions: intervention 1: Duration intervention 2: Duration

Protocol documents:
ICF_002.pdf: 
     
     
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Consent for Participation in a Clinical Research Study 
 
 
TITLE:   
          A Multi-Center, Randomized, Open-Label, Comparative Study to  
Assess the Safety and Efficacy of a Treatment Algorithm to 
Reduce the Use of Vancomycin in Adult Patients with Blood 
Stream Infections due to Staphylococci 
 
PROTOCOL NO: 
09-0080 
 
SPONSOR:  
 NIH 
 
 
 
 
 
INTRODUCTION 
This research study is funded through a contract with the National Institutes of Health.  
Portions of [Principal Investigator] and [his/her research team’s] salaries may be paid 
using these funds.  The study will be conducted at approximately 13 sites across the 
United States, and 1 site in Spain. The study plans to enroll approximately 500 patients 
with blood stream infection with staphylococci. 
   
It is important that you read and understand the following information. This study is 
entirely voluntary.  Please read this consent form carefully and take your time making 
your decision. As your study doctor or study staff discusses this consent form with you, 
please ask him/her to explain any words or information that you do not clearly 
understand.  We encourage you to talk with your family and friends before you decide to 
take part in this research study.  The nature of the study, risks, inconveniences, 
discomforts, and other important information about the study are listed below.   
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as 
required by U.S. Law. This Web site will not include information that can identify you. 
At most, the Web site will include a summary of the results. You can search this Web site 
at any time. 
 
PURPOSE OF THE STUDY 
You are being asked to participate in this research study because you have a blood 
infection. The infection is caused by bacteria (a germ) called Staphylococcus aureus 
bacteria (S. aureus) or coagulase negative staphylococci (CoNS). Both can cause serious 
health problems and in some people, can even lead to death.  In some instances, CoNS 
can be present in a culture but will not make you ill at all and antibiotic treatment is not 
needed. Although there are several medicines (antibiotics) used to treat S. aureus and 
CoNS, some of the antibiotics do not work because S. aureus and CoNS have developed 
resistance to them. 
You may be given the drug vancomycin to help kill the bacteria in your blood.  If you 
have an allergy or intolerance to vancomycin, and you are selected to be in the planned 
treatment group of the study, your physician may give you one of the following alternate 
equivalent antibiotic drugs to treat your infection; either an anti-staphylococcal penicillin 


     
     
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(e.g. Nafcillin and oxacillin in the U.S., or cloxacillin in Spain), a first generation 
cephalosporin, Cefazolin (to be used only for S. aureus bloodstream infections in U.S., 
not CoNS, but can be used for either S. aureus or CoNS bloodstream infections in Spain), 
or daptomycin in the U.S and Spain. Vancomycin and these alternate equivalent 
antibiotics are not experimental, and all are approved for use by the U.S. Food and Drug 
Administration, or European Medicines Agency (EMA).  If you are selected to be in 
the standard of care (SOC) group, your physician will use whichever treatments are 
normally used at your study site to treat your type of infection.  These treatments may 
prevent S. aureus and CoNS from spreading in your body. You might not need any 
antibiotic treatment.  
The purpose of this study is to accurately determine the length of appropriate drug 
treatment for staphylococcal blood stream infection.  The study seeks to address 
important information about the management of staphylococcal blood stream infections.  
 
BACKGROUND 
Blood stream infections, some of which may be intravenous catheter associated, are a 
common problem that often occurs during hospitalization. These infections are caused 
primarily by the bacteria S. aureus and CoNS and can often be treated with a short course 
of drugs (antibiotics), or need no antibiotic treatment at all. Severe and life-threatening 
problems occur in some cases. 
 
Vancomycin has been the primary drug used to treat serious infections due to resistant 
staphylococci for many years.  The overuse of vancomycin has made it less effective in 
treating staphylococci infections leading to the need to develop new ways to manage and 
monitor the use of the drug.  
 
STUDY PROCEDURES 
If you qualify and agree to participate in the study by signing this informed consent form, 
you will be randomized (like flipping a coin) to one of two different treatment groups.  
Each patient will be randomized to either a planned treatment group or a standard of care 
(SOC) treatment group.  The type of bacteria in your blood stream will be identified as 
either S. aureus or coagulase negative staphylococcus (CoNS) organism. S. aureus has 2 
classifications (uncomplicated or complicated) and CoNS has 3 categories (simple, 
uncomplicated, or complicated), which will determine the how long you are treated. You 
may not be treated with antibiotics at all if your doctor determines the blood culture 
contained a bacterial growth that will not make you ill.  Patients with complicated 
infection are not allowed into the study, but if you develop complicated infection after 
being enrolled in the study and while taking study treatment, you may continue in the 
trial.   
 
The planned treatment arm’s goal is to reduce the length of time you will receive 
antibiotic.  The entire duration of your treatment and participation will vary based on the 
infection category you have.  In the planned treatment arm, patients with S. aureus will 
be treated for about 12 to 44 days and have follow-up for up to 52 days after treatment 
ends.  If you have a CoNS blood infection, you will be treated for about 1 to 30 days, or 
your doctor may decide you do not need any antibiotic treatment if the no treatment 


     
     
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group has not been capped. Subjects who receive no antibiotic treatment based on the 
physician’s decision may be capped at 80 subjects. For a CoNS blood infection you will 
have follow-up after treatment ends, or after the day your doctor decides you don’t need 
antibiotic treatment, for up to 38 days.  
 
The entire duration of treatment and participation for patients in the SOC arm will be 
determined by the patient’s primary medical provider according to their usual length of 
treatment for the type of infection you have, including no treatment at all. 
 
If you receive antibiotic treatment, vancomycin is the preferred drug to be given in both 
treatment groups. Vancomycin will be given through an IV “intravenous” (needle) in 
your vein and the infusion will last about 60 minutes.  
   
When you have given your consent, the following will be done as part of the study: 
 
Enrollment Phase  
 Collect Medical History 
 Collect Antibiotic and other Medication History 
 Assess Vital Signs (height, weight, blood pressure, heart rate, temperature) 
 Perform Physical Exam 
 Perform Blood Tests  
 Perform urine or serum pregnancy test if you are female 
 Collect Electrocardiogram data (if performed) 
 Randomization 
 
Treatment Phase for Patients in the Hospital 
 Study Drug Administration daily, if treated 
 Assess Vital Signs daily (blood pressure, heart rate, temperature) 
 Perform Physical Exam weekly, if you are on antibiotic treatment more than a 
week  
 Perform Clinical Assessment daily 
 Perform Blood Tests weekly, if you are on antibiotic treatment more than a week 
 Collect information about Concomitant (supplemental) Antibiotics and other 
supplemental medications daily 
 Collect information about SAEs/AEs (Serious Adverse Events/ Adverse Events) 
daily 
 Collect Electrocardiogram data (if performed) 
 Perform Transesophageal or Transthoracic Echocardiogram (TEE or TTE) 
(depending on assigned treatment group).  An echocardiogram is an ultrasound of 
the heart.  
 
End of Treatment or Day of Discharge (whichever occurs first) for Patients in the 
Hospital; 
 Assess Vital Signs (blood pressure, heart rate, temperature) 
 Perform Physical Exam 


     
     
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 Perform Clinical Assessment 
 Perform Blood Tests  
 Collect information about Concomitant (supplemental) Antibiotics and other 
supplemental medications.   
 Collect information about SAEs/AEs  
 If treatment continues after discharge and/or for patients who are treated without 
being admitted to the hospital, study staff will call you 2 times per week and ask 
about study medication administration, other medications, and adverse events.  
For patients who are treated without being admitted to the hospital, tests done in 
person at a clinic visit as standard treatment may be used in the study  
 
Follow-up Phase:  Clinic visit or phone call  
 You will have approximately 2 follow-up visits in the clinic (preferred) or by 
phone.   
 Perform physical exam, if a clinic visit 
 Collect information about Concomitant (supplemental) Antibiotics 
 Collect information about SAEs/AEs  
 
TESTING and STORAGE OF Your Staphylococcal Bacteria 
Baseline staphylococcal bacteria (germs) will be taken from your first blood culture 
sample.  Your staphylococcal bacteria will be identified only by your study number, 
isolate identification, and the date it was collected. It will be saved, frozen, and shipped 
to Dr. Vance Fowler’s laboratory at Duke University.  Duke University will test your 
staphylococcal bacteria to determine the lowest amount of vancomycin required to kill 
the bacteria. Your staphylococcal bacteria may also be stored for future studies to 
determine the genetic makeup of bacteria and how disease develops. 
 
Your staphylococcal bacteria may also be shipped from Duke University to any of the 
investigational sites participating in this study to perform additional unspecified testing.  
Future testing is not part of the current study.  No human genetic testing will be 
performed as part of the current study or future studies/testing. 
 
Please initial the appropriate line to indicate whether or not you agree to allow your blood 
culture staphylococcal bacteria to be stored for future study testing as described above. 
 
_______ Yes, I agree to have my blood culture staphylococcal bacteria to be stored for 
future study testing at Duke University and the study sites. 
 
_______ No, I do not agree to have my blood culture staphylococcal bacteria to be stored 
for future study testing at Duke University and the study sites. 
 
RISKS of STUDY MEDICATION 
As a result of your staphylococcal blood stream infection you may be treated with 
vancomycin, or your doctor may decide you don’t need antibiotic treatment.  This study 
seeks to evaluate if doctors can safely shorten the duration of vancomycin therapy for 
these infections.  If the course of antibiotics is too short, possible consequences include 


     
     
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failure to eradicate the staphylococcal infection, progression of infection to other sites, or 
subsequent relapse of staphylococcal infection.  You should discuss this and the 
following risks with the study doctor and your regular health care provider. 
 
Vancomycin 
The bad effects that are rarely reported with the use of vancomycin infusion include 
kidney failure, elevated serum creatinine and blood urea nitrogen levels (indicators of 
abnormal kidney function), hearing loss, dizziness, ringing in the ears, low white blood 
cell (cells that fight infections) count, low platelet (material in blood that helps with 
clotting) count.  A few dozen cases of hearing loss have been reported.  
 
The bad effects that are infrequently reported with the use of vancomycin infusion 
include inflammation (redness swelling and pain) at the IV site, allergic reactions, fever, 
nausea, chills, and severe rashes.  
 
ALTERNATIVE TREATMENTS 
In appropriate clinical settings, vancomycin alternative drugs that are commercially 
available and FDA approved for US sites and/or EMA-approved for the site in Spain will 
also be acceptable for use in the planned treatment group.  In the standard of care group, 
your physician will use any antibiotic that is normally used at your study site for treating 
your type of infection. 
 
In the planned treatment group, vancomycin can be replaced with an intravenous anti-
staphylococcal penicillin (e.g. nafcillin, oxacillin, or cloxacillin) for patients with 
methicillin susceptible staphylococcal infections (S. aureus or CoNS) or a first generation 
cephalosporin, Cefazolin for patients with methicillin susceptible S. Aureus in U.S. or 
methicillin susceptible S. Aureus or CoNS in Spain, or daptomycin for methicillin 
resistant S. aureus infections. 
 
Your study doctor determines whether your treatment should be switched to an 
alternative drug and which one will be used.  If tests show that the alternative drugs are 
not fighting your infection, other drugs may be available to you that are outside this study 
if you are in the planned treatment group. 
 
Antistaphylococcal Penicillins 
The most common minor bad effects reported with the use of antistaphylococcal 
penicillins include mild diarrhea, nausea, pain, swelling and redness at the injection site, 
and vomiting.  
 
The severe bad effects reported with the use of antistaphylococcal penicillins include 
severe allergic reactions occurring 0.7 to 10% of the time (rash; hives; itching; difficulty 
breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); bloody 
urine or stools; chills; fever; sore throat; joint or muscle pain; pain, redness, or swelling at 
the injection site; severe diarrhea; stomach pain or cramps; vaginal irritation or discharge; 
seizures and yellowing of the eyes.          
 


     
     
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Daptomycin 
The most common minor bad effects reported with the use of the antibiotic daptomycin 
(occurring in 5-11% of patients) include constipation; diarrhea; dizziness; headache; 
nausea; pain; swelling or redness at the injection site; sore throat; trouble sleeping; 
vomiting.  
 
The severe bad effects reported with the use of the antibiotic daptomycin (occurring in 3-
6 % of patients) include severe allergic reactions (rash; hives; itching; difficulty 
breathing; chest pain; tightness in the chest; swelling of the mouth, face, lips, or tongue); 
bloody or watery stools; change in the amount of urine produced – It has been observed 
that daptomycin is less effective in patients with moderate baseline kidney failure; fever, 
muscle pain or weakness; numbness or tingling; severe or persistent diarrhea; stomach 
cramps/pain; swelling (e.g. of the hands, ankles, feet); unusual tiredness or weakness. 
 
Another condition associated with daptomycin (Cubicin) is eosinophilic pneumonia (a 
disease in which a certain type of white blood cell called an eosinophil fills the lungs).  
Symptoms include fever, cough, shortness of breath, and difficulty breathing.  In general, 
patients developed eosinophilic pneumonia 2 to 4 weeks after starting daptomycin and 
they improved when daptomycin was discontinued and steroid therapy was initiated.  
Patients who develop these signs and symptoms while receiving daptomycin should 
undergo prompt medical evaluation and daptomycin should be discontinued immediately. 
Treatment with systemic steroids is recommended. 
 
Cefazolin 
Cefazolin for Injection should not be taken by patients with known allergy to the 
cephalosporin group of antibiotics and should be taken with caution in patients with a 
history of penicillin allergy.  The severe bad effects include severe allergic reactions 
(rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, 
face, lips, or tongue); 
 
Increases or decreases in different types of white blood cells, platelets, decreased blood 
clotting, and increases in liver and kidney enzymes have been reported.  Cefazolin should 
be used with caution when patients have kidney disease and the dose of Cefazolin should 
be adjusted when the patient has severe kidney disease.   
 
The most common side effects include diarrhea, oral candidiasis (oral thrush), stomach 
cramps, loss of appetite, inflammation of the colon.  Nausea and vomiting have been 
reported rarely. Pain at the injection site has also been reported.   
 
All Antibacterial Drugs 
Clostridium difficile (C. difficile) (type of bacteria) associated diarrhea has been reported 
with the use of nearly all antibacterial drugs including vancomycin and may range in 
severity from mild diarrhea to fatal inflammation of the colon.  Treatment with 
antibacterial drugs alters the normal bacteria of the colon leading to overgrowth of C. 
difficile. 


     
     
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Risks from Additional Tests 
Electrocardiogram (ECG) 
You may have an ECG, where small sticky electrodes are applied to your chest, arms, 
shoulders and legs and the wires are connected to an ECG machine.  You will be asked to 
remain very still. The nurse or technician will record the electrical activity that is created 
by your heart and processed by the ECG machine and then printed on a special graph 
paper.  You will not experience any pain or discomfort during this test.  It takes a few 
minutes to apply the ECG electrodes, and one minute to make the actual recording.  In 
rare cases, some people may develop skin irritation from the electrode adhesive, but no 
serious allergic reactions have been reported. 
 
Transesophageal Echocardiogram (TEE)  
You may have a TEE (transesophageal echocardiogram), where a tube is placed in your 
food pipe that connects your mouth to your stomach.  You will be given a drug in your 
IV catheter to help you relax and your throat will be sprayed with a numbing drug.  The 
small tube is passed down your food pipe a short distance as you swallow to allow a view 
of your heart.  Oxygen is given as a preventive measure during the test.   
 
The actual test usually lasts 10 to 30 minutes and requires preparation and observation.  
TEE is a relatively common test and considered to be safe. You may experience 
breathing problems, abnormal or slow heart rhythm, allergic or other reactions associated 
with the drug given for relaxation, and minor bleeding from the tube being in your food 
pipe.  In extremely rare cases (1 in 10,000), TEE may cause tearing of your food pipe 
resulting in death. 
 
Transthoracic Echocardiogram (TTE) 
You may have a transthoracic echocardiogram (TTE) in which ultrasound is used to 
examine your heart. A colorless gel is applied to your chest and the echocardiogram tube 
is placed on top of it to look at images of your heart.  The echocardiogram technologist 
will record different parts of your chest to have several views of your heart.  This test 
takes 15 to 20 minutes.  There are no known risks from the clinical use of ultrasound 
during this type of testing. 
 
If you choose not to participate in this study, you will receive the same medical care, 
including antibiotics (drugs) to treat your bloodstream infection. You should discuss 
these possibilities with your doctor 
 
Women of Childbearing Age  
Being a part of this study while pregnant may expose the unborn child to significant risks. 
Therefore, pregnant women and women who are nursing their babies will be excluded 
from the study. If you are a woman of childbearing potential, a pregnancy test will be 
done (urine or blood will be collected) and it must be negative before you can enter this 
study. If sexually active, you must agree to use appropriate contraceptive measures for 
the duration of the study. Medically acceptable contraceptives include: (1) surgical 
sterilization, (2) approved hormonal contraceptives (such as birth control pills, Depo-


     
     
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Provera, or Lupron Depot), (3) two barrier methods (such as a condom or diaphragm) 
used with a spermicide, or (4) an intrauterine device (IUD). The effects of vancomycin on 
a fetus or unborn child are not fully known and exposure to the drug may involve 
unforeseeable risks to the fetus.  If you do become pregnant during this study, you must 
inform your study physician immediately. 
 
BENEFITS 
You may or may not receive any medical benefit from your participation in this study. In 
the future, other people with a similar condition may benefit from the knowledge 
obtained from this study. 
 
One potential benefit of this study depending on your assigned treatment group is that 
you may receive a shortened antibiotic course, or receive no antibiotic at all, thereby 
limiting the cost and risk associated with antibiotics. 
 
RIGHT TO WITHDRAW 
You may choose not to be in the study, or, if you agree to be in the study, you may 
withdraw from the study at any time. If you withdraw from the study, no new data about 
you will be collected for study purposes unless the data concerns an adverse event (a bad 
effect) related to the study.  If such an adverse event occurs, we may need to review your 
entire medical record.  All data that have already been collected for study purposes, and 
any new information about an adverse event related to the study, will be sent to the study 
sponsor. 
 
Your decision not to participate or to withdraw from the study will not involve any 
penalty or loss of benefits to which you are entitled, and will not affect your access to 
health care at [Institution/health care provider]. If you do decide to withdraw, we ask 
that you contact Dr. [PI] in writing and let [him/her] know that you are withdrawing 
from the study. [His/her] mailing address is [address]. 
 
If you end the study early for any reason, you will have a final visit for follow-up 
assessment.   
 
You or your legally authorized representative will be informed in a timely manner if new 
information becomes available that may affect your willingness to continue participation 
in this study. 
 
Withdrawal of Samples  
If you agree to allow your staphylococcal bacteria to be kept for research, you are free to 
change your mind at any time.  We ask that you contact Dr. [PI] in writing and let 
[him/her] know you are withdrawing your permission for your staphylococcal bacteria to 
be used for research. [His/her] mailing address is [address].  At that time, we will ask 
you to indicate in writing that you want your staphylococcal bacteria sample destroyed. 
 
INVOLUNTARY WITHDRAWAL 
You may be discontinued from participation in the study if: 


     
     
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 
Any clinical bad effect, laboratory abnormality, intercurrent illness, or other 
medical condition or situation occurs such that continued participation in the 
study would not be in  your best interest. 
 
You have an insufficient response to the study treatment 
 
NIH, Duke, or IRB terminates the study for any reason 
 
Another reason occurs (such as administrative reasons or pregnancy) 
 
You are free to withdraw from participating in the study at any time upon request. 
 
COSTS 
Any procedures, or tests, such as lab tests, TEE, and TTE, specifically required by the 
study will be performed or provided to you free of charge.  However, routine medical 
care, including drugs, tests, and procedures that are usually done for your condition (care 
you would have received whether or not you were in this study) will be charged to you or 
your insurance company.  You may wish to contact your insurance company to discuss 
this further. 
 
You will not be paid for your participation in this study. 
 
CONFIDENTIALITY 
Study records that identify you will be kept confidential as required by law. Federal 
Privacy Regulations provide safeguards for privacy, security, and authorized access.  
Except when required by law you will not be identified by name, social security number, 
address, telephone number, or any other direct personal identifier in study records 
disclosed outside of [Institution/health care provider].  For records disclosed outside of 
[Institution/health care provider], you will be assigned a unique code number.  The key 
to the code will be kept at [Institution to identify where code will be kept]. 
 
Every effort will be made to maintain the confidentiality of your study records.  Your 
medical and study records may be reviewed and copied in order to meet federal and state 
regulations.    Reviewers may include: 
  
 Representatives from Spanish regulatory authorities, for patients enrolled at the 
Spanish site 
 The National Institute of Allergy and Infectious Disease (a division of the 
National Institute of Health) or designee 
 Duke Clinical Research Institute 
o The Data Coordinating Center 
o Designated associates 
 Institutional Ethics Committee Review Board at (Institution/healthcare provider) 
 
Your study records will not be used for any purpose other than as described in this 
consent document and will not be disclosed to anyone not described in this document 
without your permission.  While the information and data resulting from this study may 


     
     
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be presented at scientific meetings or published in a scientific journal, your identity will 
not be revealed. 
 
Authorization for Use and Disclosure of Protected Health Information 
 
If you sign this consent form, you are giving your permission for the following people or 
groups to give the researchers certain information about you:   
 
 Any health care providers, professionals or agencies who have provided you 
health services or treatment, such as physicians, clinics, hospitals, home health 
agencies, diagnostics centers, laboratories, treatment or surgical centers, or 
government health agencies 
 Any agencies that provide payment for health care, such as insurers, or 
government agencies 
 
If you sign this form, this is the health information about you that the people or groups 
listed above may give to the researchers to use in this research study:  
 
 Laboratory results such as tests that measure blood counts and tests to measure 
the function of your liver, kidneys and heart 
 Radiology tests such as images of your heart 
 Electrical activity of your heart 
 Medications you have taken prior to and during the study 
 Physical assessments by care providers 
 Information about your medical history 
 Reactions you may have to treatments 
 Other treatments or assessment performed prior to and during the study 
 
This information may be shared with, used by, or seen by collaborating researchers, the 
sponsor of the research study, the sponsor’s representatives, and government agencies if 
needed to oversee the research study. Anybody who receives your information from us 
could share it with others without your permission and it would no longer be protected by 
federal privacy laws. We can use or share your information in a way that nobody can tell 
it is your information.  
 
If you want to participate in this study, you have to sign this authorization to allow access 
to your medical records. If you choose to not sign it, you are still able to receive your 
medical treatment that is not related to the study. If you do sign it, you can change your 
mind later by writing a letter that states you are taking back your permission. Mail the 
letter to [Address] or you can send us an email at [List email address] Stopping your 
authorization will prevent sharing of information in the future, but will not affect any 
information that has already been shared.   
 
 
There is no expiration date for the use of this information as stated in this authorization. 


     
     
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You will be given a copy of this authorization. If the results of this study are made public, 
information that identifies you will not be used.  
 
 
 
The purpose of collecting and sharing information is to learn about how vancomycin 
affects your blood stream infection and any bad effects you may experience as a result of 
receiving vancomycin and/or any alternative drug. 
Dr. Fowler’s Laboratory, is being used for the blood culture staphylococcal bacteria 
analysis and will only receive samples identified with a subject number, isolate 
identification and collection date/time. 
 
STUDY RECORDS RETENTION 
This consent/authorization will be retained along with your study records at 
[Institution/Health care provider]. When your doctor receives notification from the 
sponsor to dispose of the study records, the research information not already in your 
medical record will be destroyed or information identifying you will be removed from 
study results at {Institution/Health care provider} Any information in your medical 
record will be kept indefinitely 
  
 
Compensation in Case of Injury 
Immediate necessary medical care is available at [Institute name] in the event that you 
are injured as a result of your participation in this research study.  However, there is no 
commitment by [Institute name], or your [Institute name] physicians to provide 
monetary compensation to you or free medical care to you in the event of a study-related 
injury.  For questions about the study or a research-related injury, contact [Name] at 
[Phone number] during regular business hours and at [Phone number] after hours and 
on weekends and holidays. 
 
 
QUESTIONS 
If you have any questions about this study you may contact [Insert PI name and phone 
number] 
 
If you have questions regarding your rights as a participant in this study, you may contact 
[Insert name and phone number] at the [Institutional Review Board or Office of 
Risk Management]. 
 
 
 
 
 
 
THIS SPACE INTENTIONALLY LEFT BLANK 
 
 


     
     
 
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STATEMENT OF CONSENT 
"The purpose of this study, procedures to be followed, risks and benefits have been 
explained to me. I have been allowed to ask the questions I have, and my questions have 
been answered to my satisfaction. I have been told whom to contact if I have additional 
questions. I have read this consent form and agree to be in this study, with the 
understanding that I may withdraw at any time without affecting my future medical care. 
I have been told that I will be given a signed copy of this consent form." 
 
“By signing this form, I have not waived any of the legal rights I otherwise would have as 
a patient.” 
 
___________________________________ 
Printed Name of Subject 
 
 
 
 
 
 
___________________________________  
 
____________ 
Signature of Subject  
 
 
 
 
Date 
 
___________________________________  
 
 
Printed Name of Legally Authorized Representative (if applicable)  
 
___________________________________  
 
____________ 
Signature of Legally Authorized Representative 
 
Date 
(if applicable) 
 
___________________________________  
 
 
 
Relationship of Legally AuthorizedRepresentative to Subject (if applicable) 
 
___________________________________  
 
 
Printed Name of Person Obtaining Consent  
 
 
 
___________________________________  
 
____________ 
 
 
Signature of Person Obtaining Consent 
 
 
Date 
 
___________________________________  
 
 
Printed Name of Witness (if applicable) 
 
 
 
 
___________________________________  
 
____________ 
Signature of Witness (if applicable)  
 
 
Date 

Prot_001.pdf: 
Algorithm-based Treatment of Staphylococcus Septicemia 
Version 5.0  
 
05 November 2014 
 _____________________________________________________________________________________________  
 
 _____________________________________________________________________________________________  
 
TITLE: A Multi-Center, Randomized, Open-Label, Comparative 
Study to Assess the Safety and Efficacy of a Treatment Algorithm 
to Reduce the Use of Vancomycin in Adult Patients with Blood 
Stream Infections due to Staphylococci 
DMID Protocol Number: 09-0080 
DMID Funding Mechanism: Contract Number: HHSN272200900023C 
Other Identifying Numbers: EudraCT 2010-019067-10 
Principal Investigator:  Vance G. Fowler Jr., MD, MHS 
DMID Clinical Project Manager: Christine Chiou, MD 
DMID Medical Monitor: Venus Shahamatdar, MD 
Version Number: 5.0 
 
Date: 05 November 2014 
 
 
Document 
Version 
Date 
Comments 
Original 
1 
19 July 2010 
Not distributed to sites 
Amendment 1 
2 
6 January 2011 
First protocol submitted to sites 
Amendment 2 
3 
26 August 2011 
 
Amendment 3 
4 
11 July 2013 
 
Amendment 4 
5 
10 September 2014 
Not distributed to sites 
Amendment 4 
5 
05 November 2014 
Added potential cap to zero day 
subjects 
Sample size re-estimation at 250 
 
 


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STATEMENT OF COMPLIANCE 
The study will be carried out in accordance with Good Clinical Practice (GCP) as required by the 
following: 
 
United States (US) code of Federal Regulations (CFR) applicable to clinical studies 
(45 CFR Part 46, 21 CFR Part 50, and 21 CFR Part 56) 
 
ICH E6; 62 Federal Register 25691 (1997) 
 
Requirements for the conduct of clinical trials, including GCP, as implemented in the Clinical 
Trial Directive (Directive 2001/20/EC) and the GCP Directive (2005/28/EC) 
All key personnel (all individuals responsible for the design and conduct of this study) have 
completed Human Subjects Protection Training. 
 
 


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Signature Page 
The signature below constitutes the approval of this protocol and the attachments, and provides 
the necessary assurances that this trial will be conducted according to all stipulations of the 
protocol, including all statements regarding confidentiality, and according to local legal and 
regulatory requirements and applicable US federal regulations and ICH guidelines. 
 
 
Principal Investigator: 
 
Signed: 
 
Date: 
 
 
Vance G. Fowler Jr., MD, MHS 
Division of Infectious Diseases 
Duke University Medical Center 
 
 
 
DMID Clinical Project Manager: 
 
Signed: 
 
Date: 
 
 
Christine Chiou, MD 
Division of Microbiology and Infectious Diseases (DMID) 
National Institute of Allergy and Infectious Disease 
(NIAID) 
 
 
 
Co- Investigator: 
 
Signed: 
 
Date: 
 
 
G. Ralph Corey, MD 
Division of Infectious Diseases 
Duke Clinical Research Institute 
 
 
 
Site Investigator: 
 
Signed: 
 
Date: 
 
 
Name 
Title 
 
 


Algorithm-based Treatment of Staphylococcus Septicemia                                                          Version 5.0 
  
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TABLE OF CONTENTS 
STATEMENT OF COMPLIANCE ...........................................................................................................................II 
TABLE OF CONTENTS ............................................................................................................................................ I 
LIST OF ABBREVIATIONS ................................................................................................................................ VIII 
ALGORITHM BASED TREATMENT .......................................................................................................................... XIV 
1 
KEY ROLES ....................................................................................................................................................... 1 
2 
BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE ........................................................... 4 
2.1 
BACKGROUND INFORMATION ....................................................................................................................... 4 
2.1.1 
Vancomycin Overuse and Resistance ............................................................................................... 4 
2.1.2 
Management of Intravenous Catheter-associated Infections ......................................................... 4 
2.2 
RATIONALE ................................................................................................................................................... 5 
2.3 
POTENTIAL RISKS AND BENEFITS ................................................................................................................ 6 
2.3.1 
Potential Risks ....................................................................................................................................... 6 
2.3.2 
Known Potential Benefits ..................................................................................................................... 8 
3 
OBJECTIVES ..................................................................................................................................................... 9 
3.1 
STUDY OBJECTIVES ..................................................................................................................................... 9 
3.1.1 
Primary Objectives ................................................................................................................................ 9 
3.1.2 
Secondary Objective ............................................................................................................................ 9 
3.1.3 
Exploratory Analyses ............................................................................................................................ 9 
3.2 
STUDY OUTCOME MEASURES ..................................................................................................................... 9 
3.2.1 
Secondary Outcome Measures ........................................................................................................ 10 
3.2.2 
Exploratory Outcome Measures ....................................................................................................... 10 
3.2.3 
Definitions ............................................................................................................................................. 11 
3.2.4 
Committees and Helplines ................................................................................................................. 20 
4 
STUDY DESIGN .............................................................................................................................................. 21 
4.1 
NUMBER OF SITES ..................................................................................................................................... 21 
4.2 
NUMBER OF PATIENTS ............................................................................................................................... 21 
4.3 
TIMELINE FOR PATIENT ENROLLMENT ....................................................................................................... 22 
5 
STUDY ENROLLMENT AND WITHDRAWAL ............................................................................................ 23 
5.1 
PATIENT INCLUSION CRITERIA ................................................................................................................... 23 
5.2 
PATIENT EXCLUSION CRITERIA.................................................................................................................. 24 
5.3 
SOURCE OF BLOOD STREAM INFECTION ................................................................................................... 26 
5.3.1 
Baseline Infecting Pathogen .............................................................................................................. 26 
5.3.2 
Definition of Catheter-associated Blood Stream Infection ............................................................ 26 
5.3.3 
Definition of Nosocomial, Health Care-Associated and Community-Acquired Bloodstream 
Infection ............................................................................................................................................................. 27 


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5.4 
TREATMENT ASSIGNMENT PROCEDURES ................................................................................................. 28 
5.4.1 
Randomization Procedures ............................................................................................................... 28 
5.4.2 
Masking Procedures ........................................................................................................................... 28 
5.4.3 
Reasons for Withdrawal ..................................................................................................................... 28 
5.4.4 
Handling of Withdrawals .................................................................................................................... 28 
5.4.5 
Termination of Study .......................................................................................................................... 29 
6 
STUDY INTERVENTION/INVESTIGATIONAL PRODUCT ...................................................................... 30 
6.1 
ANTIBIOTIC TREATMENT AND DOSAGE ...................................................................................................... 30 
6.1.1 
Algorithm Treatment with Intravenous Vancomycin  ..................................................................... 30 
6.1.2 
Alternatives to Intravenous Vancomycin  ........................................................................................ 30 
6.2 
DURATION OF ANTIBIOTICS ........................................................................................................................ 32 
6.2.1 
Coagulase Negative Staphylococcus .............................................................................................. 32 
6.2.2 
S. aureus .............................................................................................................................................. 33 
6.3 
CRITERIA FOR CHANGE OF ANTIBIOTIC TREATMENT ................................................................................ 33 
6.3.1 
Combination Therapies ...................................................................................................................... 34 
6.3.2 
Concomitant Medications ................................................................................................................... 34 
6.3.3 
Safety Monitoring ................................................................................................................................ 34 
6.3.4 
Acquisition ............................................................................................................................................ 34 
6.3.5 
Formulation, Packaging, and Labeling ............................................................................................ 34 
6.3.6 
Product Storage and Stability ............................................................................................................ 34 
6.4 
DOSAGE, PREPARATION AND ADMINISTRATION OF STUDY INTERVENTION .............................................. 34 
6.5 
ACCOUNTABILITY PROCEDURES FOR THE STUDY INTERVENTION/INVESTIGATIONAL PRODUCT(S) ........ 35 
6.6 
ASSESSMENT OF PATIENT COMPLIANCE WITH STUDY INTERVENTION/INVESTIGATIONAL PRODUCT ...... 35 
6.7 
CONCOMITANT MEDICATIONS/TREATMENTS ............................................................................................. 35 
7 
STUDY SCHEDULE ........................................................................................................................................ 36 
7.1 
SCREENING ................................................................................................................................................ 36 
7.2 
SUBJECT CONSENT.................................................................................................................................... 36 
7.3 
RANDOMIZATION/ENROLLMENT ................................................................................................................. 36 
7.4 
SCHEDULE OF ASSESSMENTS ................................................................................................................... 36 
7.5 
EARLY TERMINATION VISIT ........................................................................................................................ 38 
7.5.1 
Replacement Procedures .................................................................................................................. 38 
8 
STUDY PROCEDURES/EVALUATIONS .................................................................................................... 39 
8.1 
ALGORITHM BASED TREATMENT ............................................................................................................... 39 
8.2 
STANDARD OF CARE TREATMENT ............................................................................................................. 40 
8.3 
SIMPLE CONS BLOOD STREAM INFECTION .............................................................................................. 41 
8.4 
FURTHER SPECIATION OF CONS .............................................................................................................. 41 
8.5 
STORAGE OF ISOLATES.............................................................................................................................. 42 
8.5.1 
Vancomycin Minimum Inhibitory Concentration (MIC) .................................................................. 42 
8.6 
CONSIDERATION OF VANCOMYCIN LEVELS ............................................................................................... 43 
8.7 
SCHEDULE OF EVENTS: SIMPLE CONS BLOOD STREAM INFECTION ....................................................... 44 
8.8 
SCHEDULE OF EVENTS: UNCOMPLICATED CONS BLOOD STREAM INFECTION ....................................... 46 
8.9 
SCHEDULE OF EVENTS – COMPLICATED CONS BLOOD STREAM INFECTION .......................................... 48 
8.10 
SCHEDULE OF EVENTS – UNCOMPLICATED S. AUREUS BLOOD STREAM INFECTION .............................. 50 
8.11 
SCHEDULE OF EVENTS – COMPLICATED S. AUREUS BLOOD STREAM INFECTION .................................. 52 


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8.12 
STANDARD OF CARE ASSESSMENTS ......................................................................................................... 54 
8.13 
SAFETY AND EFFICACY EVALUATIONS ...................................................................................................... 54 
8.13.1 
Clinical Events Committee (CEC) ................................................................................................ 54 
8.14 
LABORATORY EVALUATIONS ...................................................................................................................... 55 
8.14.1 
Clinical Laboratory Evaluations .................................................................................................... 55 
8.14.2 
Procedures to be Followed in the Event of Abnormal Laboratory Test Values or Abnormal 
Clinical Findings ............................................................................................................................................... 56 
8.14.3 
Special Assays or Procedures ...................................................................................................... 57 
8.14.4 
Specimen Preparation, Handling, and Shipping ........................................................................ 57 
9 
SPECIFICATION OF SAFETY PARAMETERS ......................................................................................... 58 
9.1 
ADVERSE EVENTS ...................................................................................................................................... 58 
9.2 
METHODS AND TIMING FOR ASSESSING, RECORDING, AND EVALUATING SAFETY PARAMETERS .......... 58 
9.2.1 
Adverse Events ................................................................................................................................... 58 
9.2.2 
Serious Adverse Events ..................................................................................................................... 59 
9.3 
REPORTING PROCEDURES ........................................................................................................................ 60 
9.3.1 
Non Serious and Serious Adverse Events ...................................................................................... 60 
9.3.2 
Reporting of Pregnancy ..................................................................................................................... 61 
9.4 
TYPE AND DURATION OF FOLLOW-UP OF PATIENTS AFTER ADVERSE EVENTS ....................................... 62 
9.5 
SAFETY OVERSIGHT .................................................................................................................................. 62 
9.6 
HALTING RULES ......................................................................................................................................... 62 
10 
CLINICAL MONITORING .......................................................................................................................... 64 
10.1 
SITE MONITORING PLAN ............................................................................................................................ 64 
11 
STATISTICAL CONSIDERATIONS ......................................................................................................... 65 
11.1 
STUDY HYPOTHESES ................................................................................................................................. 65 
11.1.1 
Primary ............................................................................................................................................. 65 
11.1.2 
Secondary ........................................................................................................................................ 65 
11.2 
SAMPLE SIZE CONSIDERATIONS ................................................................................................................ 65 
11.2.1 
Assumptions .................................................................................................................................... 65 
11.2.2 
Sample Size Calculation ................................................................................................................ 65 
11.2.3      DSMB Efficacy Review………………………………………………………………………………………..67        
11.3 
FINAL ANALYSIS PLAN ............................................................................................................................... 66 
11.3.1 
Study Population ............................................................................................................................. 66 
11.3.2 
Statistical Methods ......................................................................................................................... 67 
11.3.3 
Baseline Comparability .................................................................................................................. 67 
11.3.4 
Primary Analysis ............................................................................................................................. 68 
11.3.5 
Secondary Analysis ........................................................................................................................ 68 
11.3.6 
Sensitivity Analysis ......................................................................................................................... 69 
11.3.7 
Exploratory Analyses ..................................................................................................................... 69 
11.3.8 
Safety Assessment ......................................................................................................................... 69 
11.3.9 
Statistical Software Package ........................................................................................................ 70 
12 
SOURCE DOCUMENTS AND ACCESS TO SOURCE DATA/DOCUMENTS ................................. 71 
13 
QUALITY CONTROL AND QUALITY ASSURANCE ........................................................................... 72 
13.1 
LOCAL (SITE) PLANS FOR QUALITY ASSURANCE AND QUALITY CONTROL ............................................... 72 


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13.2 
INVESTIGATOR OBLIGATIONS ..................................................................................................................... 73 
13.2.1 
Documentation ................................................................................................................................ 73 
13.2.2 
Performance .................................................................................................................................... 74 
13.2.3 
Use of Investigational Materials .................................................................................................... 74 
13.2.4 
Electronic Case Report Forms ...................................................................................................... 74 
14 
ETHICS/PROTECTION OF HUMAN SUBJECTS ................................................................................. 75 
14.1 
ETHICAL STANDARD ................................................................................................................................... 75 
14.2 
INSTITUTIONAL REVIEW BOARD/ETHICS COMMITTEE ............................................................................... 75 
14.2.1 
Amendments to the Protocol ......................................................................................................... 76 
14.3 
INFORMED CONSENT PROCESS ................................................................................................................ 76 
Informed Consent/Assent Process (in Case of a Minor) ............................................................................ 78 
14.4 
EXCLUSION OF WOMEN, MINORITIES, AND CHILDREN (SPECIAL POPULATIONS) .................................... 78 
14.5 
PATIENT CONFIDENTIALITY ........................................................................................................................ 78 
14.6 
STUDY DISCONTINUATION ......................................................................................................................... 79 
14.7 
FUTURE USE OF STORED SPECIMENS ...................................................................................................... 79 
15 
DATA HANDLING AND RECORD KEEPING ........................................................................................ 80 
15.1 
DATA MANAGEMENT RESPONSIBILITIES .................................................................................................... 80 
15.2 
DATA CAPTURE METHODS ........................................................................................................................ 80 
15.3 
TYPES OF DATA ......................................................................................................................................... 81 
15.4 
TIMING/REPORTS ....................................................................................................................................... 81 
15.5 
STUDY RECORDS RETENTION ................................................................................................................... 81 
15.6 
PROTOCOL DEVIATIONS ............................................................................................................................ 82 
15.7 
PATIENT PRIVACY ...................................................................................................................................... 82 
16 
PUBLICATION POLICY ............................................................................................................................. 84 
17 
LITERATURE REFERENCES .................................................................................................................. 85 
 
LIST OF TABLES 
Table 1:  Algorithm Based Treatment; Definition ....................................................................... xiv 
Table 2:  Vancomycin Alternatives by Clinical Setting ................................................................ 31 
Table 3:  Sample Sizes Required for Establishing Noninferiority of the Proposed Treatment 
Algorithm to the Standard of Care ................................................................................ 66 
 


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LIST OF ABBREVIATIONS 
AE 
Adverse Event/Adverse Experience 
ALT 
Alanine Aminotransferase 
ANCOVA 
Analysis of Covariance 
ANOVA 
Analysis Of Variance 
AST 
Aspartate Aminotransferase 
BAL 
Bronchoalveolar Lavage 
BCX 
Blood Culture 
BUN 
Blood Urea Nitrogen 
CBC 
Complete Blood Count 
CD 
Compact Disc 
CDC 
Center for Disease Control and Prevention 
CEC 
Clinical Events Committee 
CFR 
Code of Federal Regulations 
cfu 
Colony-forming Units 
CIOMS 
Council for International Organizations of Medical Sciences 
CMH 
Cochran-Mantel Haenszel 
CoNS 
Coagulase Negative Staphylococcus 
CONSORT 
Consolidated Standards of Reporting Trials 
CQMP 
Clinical Quality Management Plan 
CRA 
Clinical Research Associate 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
CVC 
Central Venous Catheter 
DCRI 
Duke Clinical Research Institute 
DHHS 
Department of Health and Human Services 
DMID 
Division of Microbiology and Infectious Diseases, NIAID, NIH, 
DHHS 
DSMB 
Data and Safety Monitoring Board 
DV 
Discharge Visit 
EC 
Executive Committee 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capturing 
FDA 
Food and Drug Administration 
FWA 
Federalwide Assurance 
GCP 
Good Clinical Practice 
HACEK  
Haemophilus species, Actinobacillus actinomycetemcomitans, 
Cardiobacterium hominis, Eikenella corrodens, and Kingella 
species 


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HIPAA 
Health Insurance Portability and Accountability Act 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
IDSA 
Infectious Diseases Society of America 
IE 
Infective Endocarditis 
IEC 
Independent or Institutional Ethics Committee 
IEOT 
Inpatient End of Treatment 
IRB 
Institutional Review Board 
ITT 
Intent- to -Treat 
JAMA 
Journal of the American Medical Association 
LAR 
Legally Authorized Representative 
MDRD 
Modification of Diet in Renal Disease study 
MedDRA  
Medical Dictionary for Regulatory Activities 
MIC 
Minimum Inhibitory Concentrations 
MOP 
Manual of Operating Procedures 
N 
Number (typically refers to patients) 
NEJM 
New England Journal of Medicine 
NIAID 
National Institute of Allergy and Infectious Diseases, NIH, 
DHHS 
NIH 
National Institutes of Health 
OCRA 
Office of Clinical Research Affairs, DMID, NIAID, NIH, DHHS 
OHRP 
Office for Human Research Protections 
OHSR 
Office for Human Subjects Research 
ORA 
Office of Regulatory Affairs, DMID, NIAID, NIH, DHHS 
PB 
Privacy Board 
PDF 
Portable Document Format 
PENS 
Potentially Effective Non-study Antibiotic 
PHI 
Protected Health Information 
PI 
Principal Investigator 
PP 
Per Protocol Population 
PSB 
Protected Specimen Brush 
RBC 
Red Blood Cell 
SAE 
Serious Adverse Event/Serious Adverse Experience 
SBP 
Systolic Blood Pressure 
SGOT 
Serum Glutamic-Oxalocetic Transaminase  
SGPT 
Serum Glutamic-Pyruvic Transaminase  


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SI 
Sub-Investigator 
SOC 
Standard of Care 
TEE 
Transesophageal Echocardiogram 
TOC 
Test of Cure 
TTE 
Transthoracic Echocardiogram 
US 
United States 
WBC 
White Blood Cell 
WHO 
World Health Organization 
 
 


                                                                                                                                                                 
 
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PROTOCOL SUMMARY 
Title: 
A Multi-Center, Randomized, Open-Label, Comparative Study to 
Assess the Safety and Efficacy of a Treatment Algorithm to 
Reduce the Use of Vancomycin in Adult Patients with Blood 
Stream Infections due to Staphylococci 
Phase: 
II 
Population: 
Approximately 500 patients at least 18 years of age who have a 
blood stream infection with staphylococci 
Number of Sites: 
Thirteen sites in the United States (US) and one site in Europe 
Study Duration: 
Six years 
Patient Participation 
Duration: 
Duration of treatment varies based on algorithm or standard of 
care (SOC) and organism identified (S. aureus vs coagulase 
negative staphylococcus).  In the algorithm arm, patients will be 
treated for 14 (-/+2) days for uncomplicated S. aureus, or 28-42 
(-/+2) days if complicated S. aureus develops within the 
treatment period after randomization.  In the algorithm arm, 
simple CoNS will be treated for 0 – 3 (+1) days, uncomplicated 
CoNS will be treated for 5 (-/+1) days, or 7-28 (-/+2) days if 
complicated CoNS develops within the treatment period after 
randomization.  Duration in the SOC arm will be determined by 
the patient’s primary medical provider. 
Description of Agent or 
Intervention: 
Vancomycin or protocol-approved alternate antibiotic, with 
duration determined by clinical treatment algorithm vs SOC 
Objectives: 
 
Primary: 
 
To demonstrate that the clinical efficacy of algorithm-based 
treatment of patients with staphylococcal blood stream 
infection is noninferior to current standard of care. 
 
To evaluate the safety of algorithm-based treatment as an 
alternative to current standard of care. 
Secondary: 
 
To demonstrate that algorithm-based treatment of patients 
with staphylococcal blood stream infection can decrease 


                                                                                                                                                                 
 
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antimicrobial usage when compared to current standard of 
care (SOC).  
 
Description of Study 
Design: 
Multi-center randomized open label algorithm-based clinical trial.
Estimated Time to 
Complete Enrollment: 
It is estimated that sites will enroll 2 patients per month per site 
and that enrollment will be completed within four years. 
 
 


                                                                                                                                                                 
 
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Figure 1: Schematic of Study Design 
 
 
 
 
 
 
 
* Complicated infection is one of the protocol exclusions however, it is not reason to withdraw patient when diagnosed following randomization. 
Blood Culture Results 
Positive for  
S. Aureus or CoNS 
CoNS 
 
S aureus 
Bacteremia
Uncomplicated
Complicated 
Simple 
Complicated
Uncomplicated
Standard of Care
Algorithm Based 
Treatment
Randomized
 
S. aureus 
Bacteremia
Uncomplicated 
Complicated
Simple
Complicated
Uncomplicated
CoNS 


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Algorithm Based Treatment 
Table 1:  Algorithm Based Treatment; Definition of Clinical Classification 
Staphylococcus aureus Blood Stream Infection 
Uncomplicated 
Complicated (all other) a  
14 (-/+2) calendar days of treatment - All of the 
following: 
28-42 (-/+2) calendar days of treatment - Any of the following: 
 
Intravascular catheter source of infection (if 
present) removed within 5 days of initial blood 
culture draw.  
 
Negative follow up blood culture (drawn 24 -
72 hours following initial blood culture collection b  
 
Defervesce (Oral temperature < 38.0C) within 
72 hours of initial positive blood culture draw. 
 
Normal echocardiograma 
 
No symptoms or signs of metastatic infection such 
as vertebral osteomyelitis, endocarditis, septic 
thrombophlebitis (superficial septic thrombophlebitis 
is permitted) 
 
No indwelling intravascular prosthetic devices (e.g., 
prosthetic cardiac valve, intravascular permanent 
pacemaker/ defibrillator) c 
 
 
Positive follow-up blood culture for S. aureus  
 
Persistent fever (Oral temperature ≥ 38.0 C) for > 72 hours 
following initial positive blood culture collection 
 
Echocardiography  reveals evidence of endocarditis 
 
Symptoms or signs of metastatic infection, such as vertebral 
osteomyelitis, endocarditis, septic thrombophlebitis (superficial 
septic thrombophlebitis is permitted) 
 
 
Reminder: Complicated infection is one of the protocol 
exclusions. However, it is not reason to withdraw patient 
when diagnosed after randomization but before the 
completion of the treatment period for uncomplicated S. 
aureus. 
 
 
Coagulase negative staphylococcal Blood Stream Infection 
Simple 
Uncomplicated  
Complicated 
0-3 (+1) calendar days of 
treatment - All of the 
following: 
5 (-/+1) calendar days of treatment 
7 - 28 (-/+2) calendar days of 
treatment – Any of the following: 
 
Single blood culture 
positive for coagulase 
negative staphylococci  
 
No signs or symptoms of 
local infection  
 
Negative follow up blood 
culture (drawn 24 -168 
hours following initial 
blood culture collection  
 
No symptoms or signs of 
metastatic infection, such 
as vertebral 
osteomyelitis, 
endocarditis, septic 
thrombophlebitis 
(superficial septic 
thrombophlebitis is 
permitted) 
 
No indwelling 
intravascular prosthetic 
devices (see above) 
EITHER:   
 
≥ 2 sets blood cultures positive for coagulase 
negative staphylococci from samples drawn ≤ 24 
hours apart (e.g. 23:50 hours Tues. night and 
14:00 Wed. afternoon). 
Or  
 
Single set of blood cultures positive for coagulase 
negative staphylococci  PLUS signs/ symptoms 
of infection at catheter site (e.g., focal pain, 
induration, erythema, drainage, etc). 
PLUS ALL of the following  
 
Removable focus (intravascular catheter) 
removed, if present, within 5 days of initial blood 
culture draw. 
 
Negative follow up blood culture (drawn 24 -
168 hours following initial blood culture collection 
 
No symptoms or signs of metastatic infection, 
such as vertebral osteomyelitis, endocarditis, 
septic thrombophlebitis (superficial septic 
thrombophlebitis is permitted) 
 
No indwelling intravascular prosthetic devices 
(see above. 
 ≥ 2 sets blood cultures positive for 
CoNS from samples drawn > 24 
hours apart. 
 Symptoms or signs of metastatic 
infection, such as vertebral 
osteomyelitis, endocarditis, septic 
thrombophlebitis (superficial septic 
thrombophlebitis is permitted).  
 
Reminder: Complicated 
infection is one of the protocol 
exclusions. However, it is not 
reason to withdraw patient 
when diagnosed after 
randomization but before 
completion of the treatment 
period for the baseline clinical 
classification of bacteremia (i.e. 
simple or uncomplicated 
CoNS).  
  
a. 
Echocardiography (TEE preferred) mandated for algorithm S. aureus patients 
b. 
Follow-up blood cultures should be drawn 24-72 hours after the index culture; however, if this is not feasible, for example 
because the index cultures did not turn positive until >72 hours has elapsed, then follow-up cultures should be obtained 
within 24 hours of randomization  
c. 
Coronary artery stents, inferior vena cava (IVC) filters, non-hemodialysis grafts > 90 days following implantation, 
hemodialysis grafts not used within past 12 months and not previously infected, synthetic hernia repair mesh, and non-
arthroplasty orthopedic prostheses including pins or plates permitted 


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1 
KEY ROLES 
 
Individuals: 
Protocol Champion:  Christine Chiou, MD 
National Institute of Allergy and Infectious Diseases 
Christine Chiou MD 
BMB DMID NIAID 
5601 Fisher Lane 7E38 
Rockville MD 20852 
Email: cchiou@niaid.nih.gov 
Phone: 240 292 4181 
 
Principal Investigator:  Vance G. Fowler Jr., MD, MHS 
Duke Clinical Research Institute  
2400 Pratt Street 
Durham, NC 27705 
Phone: 919-684-6854 
 
Co- Investigator: G. Ralph Corey, MD 
Duke Clinical Research Institute  
Phone: 919-668-7174 
 
DMID Medical Monitor (Safety):  Venus Shahamatdar, MD 
OCRA/DMID/NIAID/NIH 
5601 Fishers Lane, 7E54 
Bethesda, Maryland 20892-9826 
Phone:  240-627-3369 
Email: venus.shahamatdar@nih.gov 
 
 
Clinical Medical Monitor:    Thomas Holland, MD 
Duke University Medical Center 
Durham, NC  27705 
Study Pager:  919–970-1232 
 
Statistician: Shein Chung-Chow, PhD 
Duke Clinical Research Institute 
Phone: 919- 668-7523 
 
Database Management: Jacqueline Huvane, PhD 
Project Manager 
Duke Clinical Research Institute 
Phone: 919-668-8282 


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2 
Institutions:  
 
Fundació Clinic Privada per  
a la Recera 
Hospital Clinic I Provincial de Barcelona 
Servicio de Enfermedades Infecciosas 
c/Villarroel, 170,  
Barcelona, 08036, Spain 
 
 
 
PI: Jose M. Miro, MD, PhD 
Telephone: +34.93.227.5707 
Fax: +34.93.451.5272 
E-mail:  miro97@fundsoriano.es  
 
University of Alabama 
1900 University Boulevard, THT 229 
Birmingham, AL 35294 
 
PI:  John Baddley, MD 
Phone:  205-934-5191 
Fax: 205-934-5155 
E-mail:  jbaddley@uab.edu 
 
Duke University Medical Center 
Department of Infectious Diseases 
315 Trent Drive  
Durham, NC  27710 
 
 
PI:  Vivian Chu, MD 
Phone: 919-668-7174 
Fax: 919-681-7494 
E-mail:  vivian.chu@duke.edu  
 
Greenville Hospital System 
890 W. Faris Road, St. 520 
Greenville, SC  29605 
 
PI:  John Schrank, Jr., MD 
Phone:  864-455-4851 
Fax: 864-455-1225 
E-mail:  jschrank@ghs.org 
 
University of Nebraska Medical Center 
987835 Nebraska Medical Center 
Omaha, NE  68198-7835 
 
PI:  Mark E. Rupp, MD 
Phone: 402-559-5276 
Fax: 402-559-8300 
E-mail:  merupp@unmc.edu 
 
 
 
MD Anderson Center 
1515 Holcombe Blvd 
Houston, TX 77030 
 
PI:  Issam Raad, MD 
Phone:  713-792-7943 
Fax: 713-792-8233 
E-mail:  iraad@mdanderson.org 
 
 
 
Denver Health Medical Center 
660 Bannock Street 
Denver, CO 80228 
 
PI:  Timothy Jenkins, MD 
Phone:  303-602-5041 
Fax: 303-602-5055 
E-mail:  timothy.jenkins@dhha.org 
 
 
 
 


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Medical University of South Carolina 
135 Rutledge Ave 
Charleston, SC 29425 
PI:  Dannah Wray, MD 
Phone:  843-792-4541 
Fax: 843-792-6680 
E-mail:  wraydw@musc.edu 
 
Henry Ford Hospital 
2799 West Grand Blvd 
Detroit, MI 48202 
 
PI:  Marcus Zervos, MD 
Phone:  313-916-2573 
Fax: 1-313-916-2993 
E-mail:  mzervos1@hfhs.org 
 
David Geffen School of Med. at UCLA 
757 Westwood Blvd 
Los Angeles, CA 90095 
 
PI:  Zachary Rubin, MD 
Phone:  310-794-0187 
Fax: 310-319-4141 
E-mail:  zrubin@mednet.ucla.edu 
 
Albert Einstein College of Medicine 
Montefiore Hospital 
111 E. 210th St. 
Bronx, NY 10467 
 
PI:  Paul Riska, MD 
Phone:  718-920-6494 
Fax: 718-231-9187 
E-mail:  priska@montefiore.org 
 
Brody School of Med at East Carolina 
University 
2300 Beasley Drive 
Greenville, NC 27834 
 
PI:  Paul Cook, MD 
Phone:  252-744-4500 
Fax: 252-744-3472 
E-mail:  cookp@ecu.edu 
 
Carolina Medical Center 
1350 South Kings Drive 
Charlotte, NC 28207 
 
PI:  James Horton, MD 
Phone:  704-355-3823 
Fax: 704-446-7641 
E-mail:  james.horton@carolinashealthcare.org 
 
UMass Memorial Medical Center 
55 North Lake Avenue 
Worcester, MA 01655 
 
PI:  Jennifer Daly, MD 
Phone:  508-856-3158 
Fax: 508-856-4060 
E-mail:  Jennifer.daly@umassmemorial.org 
 
 


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2 
BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE 
2.1 
Background Information 
2.1.1 
Vancomycin Overuse and Resistance 
Antimicrobial resistance represents an urgent unmet global medical need. Although sepsis 
(blood stream infection) is a leading cause of death in the United States (US), the number of 
treatment options for infected patients is decreasing. This decrease is driven in part by rising 
rates of antimicrobial resistance among many pathogenic bacteria. Simultaneously, the pipeline 
of new antibiotics is dwindling just as the clinical need for these novel treatments is 
expanding.1,2 This dual threat of increasing antimicrobial resistance and decreasing numbers of 
anti-infectives under development underscores the need to identify new strategies to maximize 
the clinical utility of existing antibiotics through more rational utilization of this precious national 
resource. 
For more than three decades, vancomycin has been the mainstay antibiotic for the treatment of 
serious infections due to resistant staphylococci. This reliance on vancomycin has led to 
significant overuse. For example, in 1995, over 14,000 kilograms of vancomycin were used in 
the US and Western Europe alone.3  This overuse of vancomycin has ultimately contributed to a 
diminished clinical utility of the antibiotic in staphylococci. Several reports have documented 
increasing resistance to vancomycin in clinical isolates of S. aureus4,5,6,7   and coagulase 
negative staphylococci8,9,10,11,12,13 as well as rising vancomycin minimum inhibitory 
concentrations (“MIC creep”) among large surveys of clinical strains of staphylococci8..  
Nowhere is the challenge of vancomycin overuse more pervasive than among hospitalized 
patients with suspected or confirmed blood stream infection. Sepsis is a leading cause of 
nosocomial mortality and staphylococci are the leading cause of sepsis in the US.14,15 
Mortality among patients with untreated blood stream infection exceeds 80%.16  As a result, 
many patients with staphylococcal blood stream infection require antibiotic therapy, often with 
vancomycin. However, every patient with staphylococci isolated from blood cultures may not 
require prolonged treatment with vancomycin. 
2.1.2 
Management of Intravenous Catheter-associated Infections 
Intravenous catheter-associated blood stream infection is a frequent nosocomial complication. 
Caused primarily by staphylococci (S. aureus and coagulase negative staphylococcus [CoNS]), 
these infections can often be treated with a short course of antibiotics. However, in a minority of 
cases severe, even life-threatening complications occur, including but not limited to: infective 
endocarditis, septic arthritis, deep tissue abscess, vertebral osteomyelitis, epidural abscess, 
septic thrombophlebitis, psoas abscess, and meningitis.17,18,19  
Catheter removal is a critical component in the treatment of catheter-related infections.20  
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where the intravenous catheter needs to be left in place. Therefore, treatment of 
catheter-associated infections becomes complicated in terms of the decision to remove the 
catheter as well as in determining the drug of choice and the duration of treatment. 
In 2001, the Infectious Diseases Society of America (IDSA) published guidelines for the 
management of catheter-associated infections.20   Guidelines were revised in 2009.21  Catheter 
removal was recommended in most cases of non-tunneled catheter-associated infections 
following completion of blood cultures and other appropriate diagnostic tests. It was also 
recommended that intravenous therapy be initiated on the basis of clinical clues, the patient’s 
condition, and the potential pathogen involved. Unfortunately, these clinical clues are far from 
perfect in establishing a diagnosis of catheter-associated infection because of their poor 
specificity and sensitivity.21  For example, in a recent prospective cohort study of patients with 
central venous catheter-associated S. aureus blood stream infection, we demonstrated that the 
sensitivity of physical examination findings for ultrasonogram-confirmed catheter-associated 
thrombosis was only 24%.19  Blood cultures that yield CoNS or S. aureus increase the suspicion 
for catheter-associated infections, but do not exclude additional sites of infection, such as 
endocarditis, septic thrombophlebitis, or septic arthritis. 
Additionally, management of staphylococcal bloodstream infection may differ according to 
whether the infection is nosocomial, health care-associated, or community acquired.  This trial 
will enroll patients with staphylococcal infections from these various settings, to better delineate 
appropriate management of staphylococcal bacteremia across all settings encountered in 
clinical practice. 
2.2 
Rationale 
Accurately differentiating patients with severe staphylococcal blood stream infection requiring 
extended courses of vancomycin from those patients whose condition could safely receive brief 
durations of therapy could allow clinicians to treat patients appropriately while simultaneously 
limiting unnecessary vancomycin use. In this clinical trial, we will describe treatment algorithms 
based upon clinical, echocardiographic, and laboratory features to identify which patients may 
safely and successfully undergo shortened antibiotic therapy. 
The purpose of this clinical trial is to accurately determine the complication potential and thus 
the length of appropriate therapy for staphylococcal blood stream infection, allowing careful 
stewardship of our remaining antibiotic resources. In addition, the current protocol seeks to 
address important aspects of the management of staphylococcal blood stream infections. 
This study is particularly important since there are no clearly defined universally accepted 
guidelines for the treatment duration of patients with blood stream staphylococcal infections. 


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2.3 
Potential Risks and Benefits 
2.3.1 
Potential Risks 
This clinical trial compares the efficacy and safety of algorithm-based antibiotic therapy to 
standard therapy for the treatment of staphylococcal bacteremia. The primary potential risk of 
the study is that the duration of antibiotic therapy is inappropriately short. For example, patients 
randomized to algorithm-based therapy may receive shorter courses of antibiotic therapy than 
required, while patients in the standard treatment arm may receive longer courses of antibiotic 
therapy than necessary. If the course of antibiotics is too short, possible consequences include 
failure to eradicate the staphylococcal infection, progression of infection to other sites, or 
subsequent relapse of staphylococcal infection.   
All antibiotics used in this trial are commercially available; however, a second risk is that 
antibiotic therapy will lead to adverse events (AEs) related to the antimicrobial therapy.  The 
package insert should be consulted prior to prescription and dosing of any of the protocol-
approved, commercially-available antibiotics to be provided to patients as part of this clinical 
study.  A summary of major AEs associated with these antibiotics is provided below.  Please 
consult the relevant package insert for a more detailed description of these AEs. 
All Antibacterial Agents: 
 
Clostridium Difficile Associated Diarrhea (CDAD) - CDAD has been reported with use of 
nearly all antibacterial agents and may range in severity from mild diarrhea to fatal 
colitis.  Treatment with antibacterial agents alters the normal flora of the colon leading to 
overgrowth of C. difficile.  If CDAD is suspected or confirmed, ongoing antibiotic use not 
directed against C. difficile may need to be discontinued.  Appropriate fluid and 
electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and 
surgical evaluation should be instituted as clinically indicated.   
Vancomycin: 
 
Contraindications – Vancomycin hydrochloride is contraindicated in patients with known 
hypersensitivity to this antibiotic  
 
Nephrotoxicity – Rarely, renal failure, principally manifested by increased serum 
creatinine or blood urea nitrogen (BUN) concentrations, especially in patients given large 
doses, has been reported. 
 
Ototoxicity – A few dozen cases of hearing loss associated with vancomycin 
hydrochloride have been reported.  Most of these patients had kidney dysfunction or a 
pre-existing hearing loss, or were receiving concomitant treatment with an ototoxic drug.  
Vertigo, dizziness, and tinnitus have been reported rarely. 
 
Hematopoietic – Reversible neutropenia, usually starting one week or more after onset 
of therapy with vancomycin hydrochloride or after a total dosage of more than 25 g, has 
been reported for several dozen patients.  Neutropenia appears to be promptly 


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reversible when vancomycin hydrochloride is discontinued.  Thrombocytopenia has 
rarely been reported.   
 
Phlebitis – Inflammation at the injection site has been reported 
 
Gastrointestinal – Onset of pseudomembranous colitis symptoms may occur during or 
after antibiotic treatment 
 
Miscellaneous – Infrequently, patients have been reported to have had anaphylaxis, 
drug fever, nausea, chills, eosinophilia, rashes (including exfoliative dermatitis), Stevens-
Johnson syndrome, toxic epidermal necrolysis, and rare cases of vasculitis in 
association with the administration of vancomycin. 
 
Anti-Staphylococcal Penicillins (e.g. penicillin, nafcillin, oxacillin, cloxacillin): 
 
Contraindications – A history of a hypersensitivity (anaphylactic) reaction to any penicillin 
is a contraindication.   
 
Nervous System Reactions – Neurotoxic reactions similar to those observed with 
penicillin G may occur with large intravenous doses of anti-staphylococcal penicillins, 
especially with patients with renal insufficiency. 
 
Urogenital Reactions – Renal tubular damage and interstitial nephritis have been 
associated infrequently with administration of anti-staphylococcal penicillins.  
Manifestations of this reaction may include rash, fever, eosinophilia, hematuria, 
proteinuria, and renal insufficiency.   
 
Gastrointestinal Reactions – Pseudomembranous colitis has been reported with the use 
of anti-staphylococcal penicillins.  The onset of pseudomembranous colitis symptoms 
may occur during or after antibiotic treatment.   
 
Metabolic Reactions – Hepatotoxicity, characterized by fever, nausea, and vomiting 
associated with abnormal liver function tests, mainly elevated SGOT levels, has been 
associated with the use of anti-staphylococcal penicillins.  
Cubicin® (daptomycin) 
 
Contraindications - CUBICIN® is contraindicated in patients with known hypersensitivity 
to daptomycin. 
 
Eosinophilic Pneumonia – Eosinophilic pneumonia has been reported in patients 
receiving CUBICIN®.  In reported cases associated with CUBICIN®, patients developed 
fever, dyspnea with hypoxic respiratory insufficiency, and diffuse pulmonary infiltrates.  
In general, patients developed eosinophilic pneumonia 2 to 4 weeks after starting 
CUBICIN® and improved when CUBICIN® was discontinued and steroid therapy was 
initiated.  Recurrence of eosinophilic pneumonia upon re-exposure has been reported.  
Patients who develop these signs and symptoms while receiving CUBICIN® should be 
discontinued immediately.  Treatment with systemic steroids is recommended. 
 
Severe Adverse Events – Those reported with the use of the antibiotic daptomycin 
(occurring in 3-6 % of patients) include severe allergic reactions (rash; hives; itching; 
difficulty breathing; chest pain; tightness in the chest; swelling of the mouth, face, lips, or 
tongue); bloody or watery stools; change in the amount of urine produced; fever, muscle 


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pain or weakness; numbness or tingling; severe or persistent diarrhea; stomach 
cramps/pain; swelling (e.g. of the hands, ankles, feet); unusual tiredness or weakness. 
 
Miscellaneous – The most common minor adverse effects reported with the use of the 
antibiotic daptomycin (occurring in 5-11% of patients) include constipation; diarrhea; 
dizziness; headache; nausea; pain; swelling or redness at the injection site; sore throat; 
trouble sleeping; vomiting.  
Cefazolin 
 
Contraindications – Cefazolin for Injection is contra-indicated in patients with known 
allergy to the cephalosporin group of antibiotics. 
 
Warnings - Before therapy with Cefazolin is instituted, careful inquiry should be made to 
determine whether the patient has had previous hypersensitivity reactions to cefazolin, 
cephalosporins, penicillins, or other drugs.  If this product is given to penicillin-sensitive 
patients, caution should be exercised because cross-hypersensitivity among beta-lactam 
antibiotics has been clearly documented and may occur in up to 10% of patients with a 
history of penicillin allergy. 
 
Gastrointestinal - Diarrhea, oral candidiasis (oral thrush), vomiting, nausea, stomach 
cramps, and anorexia.  Nausea and vomiting have been reported rarely. 
 
Allergic - Anaphylaxis, eosinophilia, itching, drug fever, skin rash, Stevens-Johnson 
Syndrome. 
 
Hematologic - Neutropenia, leukopenia, thrombocytopenia, thrombocythemia 
 
Hepatic and Renal - Transient rise in SGOT, SGPT, and alkaline phosphatase levels has 
been observed without clinical evidence of renal or hepatic impairment. 
 
Local Reactions - Rare instances of phlebitis have been reported at the site of injection. 
 
Other Reactions - Genital and anal pruritus (including vulvar pruritus, genital moniliasis, 
and vaginitis) 
 
2.3.2 
Known Potential Benefits 
One potential benefit is for improved overall patient care in the algorithm-based treatment arm. 
By making use of a careful, systematic approach to a common clinical problem, infection 
severity may be accurately identified. In this way, patients with complicated staphylococcal 
bacteremia may appropriately receive extended courses of antibiotic treatment, while those with 
simple or uncomplicated staphylococcal bacteremia may safely receive abbreviated antibiotic 
courses, thereby limiting the cost and risk associated with parenteral antibiotics. That is, an 
individual patient in the study may safely receive a shorter course of treatment than s/he would 
have otherwise, thereby reducing risk of treatment-related adverse effects and decrease 
resistance.  Additionally, there is potential benefit in that the information gained from this study 
will support future studies leading to improved care for patients requiring antibiotic treatment. 


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3 
OBJECTIVES 
3.1 
Study Objectives 
3.1.1 
Primary Objectives 
To demonstrate that the clinical efficacy of algorithm-based treatment of patients with 
staphylococcal blood stream infection is noninferior to current standard of care (SOC). 
 
To evaluate the safety of algorithm-based treatment as an alternative to current SOC. 
3.1.2 
Secondary Objective 
To demonstrate that algorithm-based treatment of patients with staphylococcal blood stream 
infection can decrease antimicrobial usage when compared to current SOC. 
 
3.1.3 
Exploratory Analyses 
The exploratory analyses include comparisons of the treatment effects for the endpoints, cure 
rate, days of antibiotic use and days to discontinuation using survival analysis methods for the 
following diagnostics subgroups in the ITT and PP populations, respectively: 
1.  Cohort of Coagulase Negative Staphylococcus 
2.  Sub-cohort within Coagulase Negative Staphylococcus and simple case 
3.  Sub-cohort within Coagulase Negative Staphylococcus and uncomplicated case 
4.  Cohort of S. aureus Bacteremia 
5.  Sub-Cohort within S. aureus Bacteremia and uncomplicated case 
 
In addition, potential associations between vancomycin MIC values and clinical outcomes (e.g., 
cure rates, duration of bacteremia on treatment, and incidence of development of new 
complicated staphylococcal infection) will be assessed as part of exploratory efficacy analyses.  
 
3.2 
Study Outcome Measures  
The primary analyses are 1) to compare cure rate at Final Test of Cure (TOC) evaluation, 
between the proposed treatment algorithm and the SOC treatment and 2) to evaluate the safety 
of algorithm-based treatment as an alternative to current SOC. Final TOC evaluation will occur 
at different time points for S. aureus and CoNS to reflect the different clinical characteristics of 
infections with each organism. Final TOC for CoNS infections will be evaluated at 28  4 days 
following last dose of antibiotic. Final TOC evaluation for S. aureus infections will be evaluated 
at 42  4 days following last dose of antibiotic.  The secondary analysis is to compare the days 
of antibiotic use between the proposed treatment algorithm and the SOC treatment.  
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Primary safety and efficacy analysis will be conducted in the Intent-to-Treat (ITT) population 
by evaluating the difference in cure rates at final TOC by treatment group and calculating 95% 
confidence intervals around the difference in cure rates among study patients randomized to 
algorithm-based treatment vs cure rates among study patients randomized to standard 
treatment.  Safety analysis will include analysis of all AEs leading to study drug withdrawal and 
all SAEs. In addition, if patient changes from vancomycin or a protocol-approved study antibiotic 
to another protocol-approved study antibiotic due to AE associated with study drug, incidence 
rates will be calculated from these data. 
3.2.1 
Secondary Outcome Measures 
The secondary outcome measure is antibiotic days by treatment group. 
Secondary outcome analysis will be conducted in the PP population by evaluating the 
difference in antibiotic days (vancomycin or approved vancomycin alternative) by treatment 
group and calculating 95% confidence intervals around the difference in antibiotic days among 
study patients randomized to algorithm-based treatment vs among study patients randomized to 
standard treatment. The patients identified with a complicated staphylococcal infection after 
randomization but prior to the completion of study treatment for their baseline clinical 
classification of bacteremia (i.e. Simple CoNS, Uncomplicated CoNS, Uncomplicated S. aureus) 
will be excluded in the duration of treatment analysis as the duration of treatment for both 
Algorithm-based and Standard treatment groups will be identical   Antibiotic days will also be 
compared by treatment group for the various diagnostic subgroups in the ITT and PP 
populations as described in the exploratory outcome measures below.  
 
3.2.2 
Exploratory Outcome Measures 
The exploratory outcome measures include:  
a. cure rate, days of antibiotic use and days to discontinuation using survival analysis 
methods for the following diagnostics subgroups in the ITT and PP populations, 
respectively: 
1.  Cohort of Coagulase Negative Staphylococcus 
2.  Sub-cohort within Coagulase Negative Staphylococcus and simple case 
3.  Sub-cohort within Coagulase Negative Staphylococcus and uncomplicated 
case 
4. Cohort of S. aureus Bacteremia 
5. Sub-Cohort within S. aureus Bacteremia and uncomplicated case; 
b.) vancomycin MIC values to investigate potential associations to clinical outcomes (e.g., 
cure rates, duration of bacteremia on treatment, and incidence of development of new 
complicated staphylococcal infection).  
 


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3.2.3 
Definitions 
3.2.3.1 
Definition of primary efficacy endpoint 
Outcome at early and final TOC will be assessed as either “Success”, “Failure”, or “Non-
Evaluable”. 
Success: 
Patients will be classified as “Success” at the respective TOC visit if they meet all of the 
following Criteria: 
 
Were judged “Cure” by the Site Principal Investigator (PI) or designated Sub-Investigator 
(SI) at the respective TOC visit (see Section 3.2.3.8 below for definition of “Cure”). 
 
Exhibited none of the criteria for “Failure” or “Non-Evaluable” outcomes.  
Failure: 
Patients will be classified as “Failure” at or before final TOC if they meet any of the following 
Criteria*: 
 
Were judged “Failure” at early or final TOC by the Site PI or designated SI 
 
Treatment was changed due to Unsatisfactory Clinical Response defined as failure to 
resolve clinical manifestations of infection (e.g. fever, elevated WBC count). 
 
Had persisting or relapsing infection (Section 3.2.3.2 and Section 3.2.3.3,   respectively). 
 
Identification of a New Complicated Staphylococcal Infection (Section 3.2.3.5) defined as 
not known to be present at both randomization and at the completion of study treatment 
for their baseline clinical classification of bacteremia but is discovered at any time after 
the completion of the study treatment up to the final TOC.  These patients will be 
retained in their original group and counted as treatment failures.  
 
Died prior to early or final TOC evaluation. 
 
* if patients fail prior to the  final TOC visit, final TOC assessments can be conducted at the time 
of failure and the patient can be classified as completing the study at that time. 
 
Non-Evaluable: 
Patients will be classified as “Non-evaluable” at or before final TOC if they meet the following 
Criteria*: 
 
 
Failure for Administrative Reasons (e.g., patient withdraws consent for study 
participation; patient discontinues medical treatment against medical advice; patient 
withdrawn from the study; patient lost to follow-up) in patients who do not fail for other 
reasons. 
 


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All non-evaluable patients will be considered failures for the ITT analysis, will be considered 
missing for the sensitivity analysis and will be excluded from the PP population. 
 
* if patients are determined non-evaluable prior to the  final TOC visit, safety and outcome  data 
will be collected at the time that the patient is determined non-evaluable and the patient can be 
classified as terminating the study at that time. 
ITT Population:  All patients randomized into the study will be analyzed in the ITT population 
analysis.   
 
PP Population: Patients meeting any of the following criteria will be EXCLUDED from PP 
analysis: 
 
 
Received a PENS antibiotic 
 
 
Did not undergo removal of intravascular catheter suspected to be infected.  Note that 
patients with simple CoNS bacteremia may retain the catheter; all other patients should 
have their catheter(s) removed. 
 
 
Had blood stream infection with a vancomycin-resistant staphylococcus; or a 
staphylococcus resistant to protocol-identified alternative drugs if these were used 
 
 
Discontinued study medication prematurely for reasons other than clinical failure 
 
 
Did not undergo final TOC assessment 
 
 
Did not comply with all Patient Inclusion Criteria as listed in 5.1. 
 
 
Violated any Patient Exclusion Criteria as listed in 5.2. 
 
 
Died within 3 days of randomization 
  
 
Were classified as non-evaluable per the definition above 
 
PPE Population: Patients from the PP population who did not have complicated staphylococcal 
infection. 
3.2.3.2 Persisting infection 
Persisting infection is defined as a staphylococcus that represents the same bacterial strain as 
the Baseline Infecting Pathogen (based on bacterial speciation, antibiotic susceptibility testing, 
and/or genotyping tests, as appropriate) plus either a) or b). 
 
a) 
is repeatedly isolated from the bloodstream or other sterile body site for > 7 days 
despite appropriate surgical debridement as necessary, and appropriate antibiotic 
treatment as documented by culture susceptibility data; or  


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 
b) 
patient exhibits ongoing signs and symptoms of acute infection without significant 
clinical response for > 7 days. 
Workup for persisting infection will consist of the follow-up blood cultures per protocol, along 
with symptom- and sign-based evaluation (eg. MRI of spine for new back pain, arthrocentesis 
for concern of septic arthritis, etc).  
3.2.3.3 Relapsing infection    
Relapsing infection is defined as a staphylococcus that:  
 
represents the same bacterial strain as the Baseline Infecting Pathogen (based on 
bacterial speciation, antibiotic susceptibility testing, and/or genotyping tests, as 
appropriate); 
 
is documented by a culture yielding staphylococcus obtained 3 days or more after the 
most recent documented positive cultures, is separated by at least 1 set of negative 
blood cultures drawn on a separate calendar day and is accompanied by resolution of 
clinical signs and symptoms of staphylococcal infection for at least 3 days.  
 
is judged by the Site PI not to represent a Contaminant. 
For the purposes of defining a relapsing infection, a contaminant will include CoNS isolated from 
the bloodstream after the collection of the index blood culture if:  
 
only a single blood culture per day is positive for CoNS;  
 
it is judged by the site PI to represent a contaminant; and 
 
patient treatment is not altered by the identification of the culture result 
 
The following organisms will be considered contaminants if grown from only one blood culture 
(either alone or in addition to a clinically significant staphylococcus isolated from the same blood 
culture): Propionibacterium species, Micrococcus species, viridans-group streptococcus, 
Corynebacterium species, Bacillus species other than B. anthracis 22 , or enterococcus 
species23. All isolates of Staphylococcuswill be considered clinically significant. 
    
3.2.3.4 Polymicrobial Bacteremia 
Polymicrobial bacteremia.  Polymicrobial bacteremia is defined as a blood culture that grows 
an organism in addition to the baseline infection pathogen.  
3.2.3.5 New Complicated Staphylococcal Infection  
A complicated staphylococcal infection will be defined as “New” if it is not known to be present 
at both randomization and at completion of treatment for the baseline clinical classification of 
bacteremia but is discovered at any time after the completion of the study treatment up to the 


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final TOC.  These patients will be retained in their original group and counted as treatment 
failures. 
3.2.3.6 Complicated Staphylococcal Infection  
The presence of any one of the following conditions will be defined, by category (e.g., 
endocarditis), as a complicated staphylococcal infection. 
 
Positive Follow-up Blood Cultures- Either of the following: 
 
Follow-up blood culture positive for S. aureus (follow up blood culture drawn 
24 - 72 hours following initial blood culture collection showing S. aureus. 
 
≥ 2 sets blood cultures positive for CoNS from samples drawn > 24 hours apart 
 
Persistent fever 
 
Oral temperature ≥ 38.0 C for > 72 hours following initial positive blood culture draw for 
staphylococcus 
 
Meningitis - Either of the following: 
 
Positive Cerebrospinal Fluid (CSF) culture for Staphylococcus  
 
CSF yields either pleocytosis (> 10 neutrophils/mm3) or Gram positive cocci on CSF 
Gram Stain in a patient with documented staphylococcal blood stream infection  
 
Brain abscess - Either of the following:  
 
Culture of abscess contents yields Staphylococcus; or 
 
Abscess visualized by radiographic imaging.  
 
Epidural abscess - Either of the following: 
 
Culture of abscess contents yields Staphylococcus; or 
 
Abscess visualized by radiographic imaging.  
 
Intracranial hemorrhage secondary to mycotic aneurysm  
 
Abnormalities visualized by radiographic imaging or direct operative inspection. 
Endocarditis (Modified Duke Criteria)  
Definite Infective Endocarditis: 


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Pathologic Criteria 
 
Microorganisms demonstrated by culture or histologic examination of a 
vegetation, a vegetation that has embolized, or an intracardiac abscess 
specimen; or  
 
Pathologic lesions; vegetation or intracardiac abscess confirmed by histologic 
examination showing active endocarditis  
Clinical Criteria 
 
2 major criteria; or  
 
1 major criterion and 3 minor criteria; or  
 
5 minor criteria  
Possible Infective Endocarditis:  
 
1 major criterion and 1 minor criterion; or  
 
3 minor criteria  
 
Modified Duke Criteria for the Diagnosis of Infective Endocarditis: 
Major Criteria  
 
 
Blood culture positive for IE  
 Typical microorganism consistent with IE from 2 separate blood cultures:  
 Viridans streptococci, Streptococcus bovis, HACEK1 group, S. aureus; or  
 Community-acquired enterococci, in the absence of a primary focus; or  
 Microorganisms consistent with IE from persistently positive blood cultures, 
defined as follows:  
 
At least 2 positive blood culture samples drawn > 12 hours 
apart; or  
 
All of 3 or a majority of > 4 separate cultures of blood (with first 
and last sample drawn at least 1 hour apart)  
 
Single positive blood culture for Coxiella burnetii or antiphase 
titer of > 1:800  
 
Evidence of endocardial involvement  
                                                
1 Haemophilus species, Actinobacillus actinomycetemcomitans, Cardiobacterium hominis, Eikenella 
corrodens, and Kingella species 


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 
Echocardiogram positive for IE (TEE recommended in patients with prosthetic 
valves), rated at least “possible IE” by clinical criteria, or complicated IE 
[paravalvular abscess, echocardiogram (TEE preferred) is mandated in algorithm 
patients with uncomplicated S. aureus bacteremia ]; TTE as first test in other 
patients), defined as follows:  
 
Oscillating intracardiac mass on valve or supporting structures, in the 
path of regurgitant jets, or on implanted material in the absence of an 
alternative explanation; or   
 
Abscess; or  
 
New partial dehiscence of prosthetic valve  
 
New valvular regurgitation (worsening or changing of pre-existing murmur not 
sufficient)  
Minor Criteria  
 
Predisposition, predisposing heart condition or injection drug use 
 
Fever, temperature >38ºC 
 
Vascular phenomena, major arterial emboli, septic pulmonary infarcts, mycotic 
aneurysm, intracranial hemorrhage, conjunctival hemorrhages, and Janeway’s 
lesions 
 
Immunologic phenomena, glomerulonephritis, Osler’s nodes, Roth’s spots, and 
rheumatoid factor  
Microbiological evidence: positive blood culture but does not meet a major criterion as noted 
above or serological evidence of active infection with organism consistent with IE.  
 
Visceral Abscess (eg. Liver, spleen, kidney, etc.) - Either of the following: 
 
Abscess visualized on radiographic exam or 
 
Isolation of Staphylococcus from culture of abscess contents. 
 
Pneumonia – All of the following: 
 
Pulmonary infiltrate consistent with pneumonia in patients with S. aureus bacteremia and 
 
S. aureus in pleural fluid, needle aspirate biopsy, or growth from bronchoalveolar lavage 
(BAL)/protected specimen brush (PSB)  
and 
 
Clinical evidence of pneumonia (eg. Increased O2, increased respiratory rate, cough, 
mechanical ventilation, purulent sputum, etc) 
Osteomyelitis - Either of the following: 
 
Radiographic evidence of bone lesion consistent with osteomyelitis;  or 


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 
Culture of bone yields staphylococcus. 
Pyomyositis – Either of the following: 
 
Radiographic evidence consistent with pyomyositis;  or  
 
Culture of abscess contents yields staphylococcus. 
Septic Arthritis – Either of the following: 
 
Staphylococcus in culture of synovial fluid; or  
 
Positive Gram stain of synovial fluid for Gram positive cocci AND synovial fluid cell count 
≥20,000 WBC/mL without alternate explanation 
Septic Thrombophlebitis: 
 
Positive follow-up blood cultures, and either of the following: 
 
Palpable venous cord; or  
 
Evidence of thrombosis on radiologic exam 
3.2.3.7 Potentially Effective Non-Study (PENS) Antibiotics  
PENS antibiotic is defined as any antibiotic course not indicated by the study protocol with 
potential efficacy against a patient’s infecting staphylococcal bloodstream pathogen, that is 
received by the patient from the time of collection of the baseline blood culture until final 
TOC evaluation, and that may have influenced patient outcome.  Please see the caveat 
below regarding empiric administration of more than one agent.  A PENS antibiotic may be 
either an antibiotic not specifically indicated by the protocol (e.g., linezolid for patients in the 
algorithm arm) or a protocol-approved antibiotic received outside of the protocol indications 
(e.g., a one-week course of I.V. vancomycin received 2 weeks after completion of protocol-
approved antibiotic regimen).  For patients in the SOC arm, in which the primary provider has 
unrestricted choice of antibiotics, any antibiotic given expressly as initial treatment for the 
patient's staphylococcal infection will not be considered a PENS antibiotic.  As an example of a 
potential PENS antibiotic, a patient who completed his/her study treatment for the baseline 
staphylococcal bacteremia, but received a clinically significant course of doxycycline prior to 
final TOC evaluation for an episode of bronchitis would be judged to have received a PENS 
antibiotic if his/her initial staphylococcal isolate(s) were susceptible to doxycycline. Potential 
episodes of PENS will primarily be identified by Site Investigators and will be triggered for 
blinded adjudication.  Designation of PENS will be established by blinded review of study 
documents by the Clinical Events Committee (CEC). 
 
 The following will not be considered to represent PENS antibiotics: 
1. 
Protocol-approved alternative antibiotics (Table 2) administered according to study 
designation (e.g., per algorithm or per Standard Treatment). 


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2. 
For patients in the SOC arm, in which the primary provider has unrestricted choice of 
antibiotics, any antibiotic given expressly as initial treatment for the patient's staphylococcal 
bloodstream infection. 
3. 
In the instance of empiric administration simultaneously of more than one antibiotic with 
potential antistaphylococcal efficacy (e.g., vancomycin and piperacillin/tazobactam), the 
nonstudy agent will not be considered a PENS antibiotic from the time of collection of the 
baseline blood culture until randomization. . The rationale for this accommodation is to 
ensure that the study protocol remains consistent with Guidelines for empiric treatment of 
sepsis suspected to be due to Multi-Drug Resistant Pathogens.24Even though the nonstudy 
agent will not be considered a PENS, it may be counted towards antibiotic days per Section 
6.2.  
4. 
Patients who developed their index bacteremia after at least 7 days of prophylaxis with 
oral antibiotics have by definition failed prophylaxis and the oral antibiotic regimen can be 
deemed non-effective for the index bacteremia.  Oral antibiotics that have failed as 
prophylaxis in this manner will not be considered a PENS or count towards antibiotic days 
unless continuing or re-starting after randomization. 
 
3.2.3.8 Assessment of Cure by Site PI or designated SI 
“Cure” as defined by Site PI or designated SI is one criterion for Establishing Primary Efficacy 
Endpoint (see Section 3.2.3.1). Assessments of cure will occur at the early and final TOC for 
both algorithm-treated and Standard Care-treated patients. Patients will be defined by Site PI as 
“Cure” at the respective TOC visit if all of the following criteria are met: 
Simple CoNS bacteremia 
 Resolution of bacteremia as demonstrated by negative follow-up blood culture 
 Clinical resolution of signs and symptoms of staphylococcal blood stream infection; 
and 
 No development of a) persisting infection; b) relapsing infection; or c) New 
Complicated Staphylococcal Infection, up to the respective TOC evaluation 
Uncomplicated CoNS bacteremia 
 Resolution of bacteremia as demonstrated by negative follow-up blood culture 
 Clinical resolution of signs and symptoms of staphylococcal blood stream infection; 
and 
 No development of a) persisting infection; b) relapsing infection; or c) New 
Complicated Staphylococcal Infection, up to the respective TOC evaluation 
Complicated CoNS bacteremia 


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New Complicated Staphylococcal Infection is reason for Failure when identified after the 
completion of study treatment for the baseline clinical classification of bacteremia for patients 
with Simple and Uncomplicated CoNS bacteremia.  We anticipate that complicated CoNS 
bacteremia will be relatively uncommon in the trial.  However, some patients with CoNS 
bacteremia with no apparent complications at randomization will be found to have complicated 
infection after randomization but before the completion of study treatment for their baseline 
clinical classification of bacteremia. These patients will remain in the trial, be categorized as 
Complicated CoNS bacteremia, and will be treated per Protocol.  For such patients, “Cure” will 
be defined as - 
 Resolution of bacteremia as demonstrated by negative follow-up blood culture 
 Clinical resolution of signs and symptoms of staphylococcal blood stream infection; 
and 
 No development of a) persisting infection; b) relapsing infection; or c) additional sites 
of complicated staphylococcal infection, up to the respective TOC evaluation 
Uncomplicated S. aureus bacteremia  
 Resolution of bacteremia as demonstrated by negative follow-up blood culture 
 Clinical resolution of signs and symptoms of staphylococcal blood stream infection; 
and 
 No development of a) persisting infection; b) relapsing infection; or c) New 
Complicated Staphylococcal Infection, up to the respective TOC evaluation 
Complicated S. aureus bacteremia  
New Complicated Staphylococcal Infection is reason for Failure when identified after completion 
of all diagnostic tests and completion of the study treatment period for patients with 
uncomplicated S. aureus bacteremia. We anticipate that complicated S. aureus bacteremia will 
be relatively uncommon in the trial. However, some patients with S. aureus bacteremia with no 
apparent complications at randomization will be identified by the study evaluation (blood 
cultures, echocardiography) after randomization but on or before  completion of the treatment 
period for the baseline clinical classification of bacteremia. These patients will remain in the trial, 
will be categorized as Complicated S. aureus bacteremia, and will be treated per Protocol.  For 
such patients, “Cure” will be defined as - 
 Resolution of bacteremia as demonstrated by negative follow-up blood culture 
 Clinical resolution of signs and symptoms of staphylococcal blood stream infection; 
and 
 No development of a) persisting infection; b) relapsing infection; or c) additional sites 
of complicated staphylococcal infection, up to the respective TOC evaluation 


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3.2.4 
Committees and Helplines 
There are 3 committees and 2 help lines.  The responsibilities for each committee/helpline are 
listed below and will be referenced throughout the protocol. 
3.2.4.1 Clinical Event Committee (CEC)    
The CEC will consist of 3 physicians with expertise in infectious diseases who are not involved 
in study conduct. The CEC will develop a charter and will adjudicate events on at least a yearly 
basis.  All CEC members will be blinded to randomization and treatment category. 
The CEC Review Committee will be responsible for defining the presence and significance of 
potentially effective nonstudy (PENS) antibiotics received from the time of collection of the 
baseline blood culture until final TOC based upon review of all available culture, susceptibility, 
and antibiotic administration data. In addition, the CEC will evaluate clinical outcomes and 
antibiotic days in at least 10% of randomly selected patients. The DSMB will review CEC 
adjudication decisions. 
3.2.4.2 Executive Committee (EC) 
The Executive Committee is comprised of study leadership in NIAID and DCRI.  This committee 
is responsible for protocol development and oversight of study progress.  The Executive 
Committee will meet monthly or more frequently during study start up.  As study progresses, 
committee meeting schedule will be reassessed based on need.   
3.2.4.3 Data Safety Monitoring Board (DSMB)   
The DSMB is an independent body appointed and managed by DMID.  The DSMB is charged 
with monitoring patient safety throughout the trial according to their charter. Refer to Section 9.5 
for details regarding DSMB responsibilities and meeting frequency.   
3.2.4.4 Coordinating Center Physician Helpline   
The physician help line was developed to help sites with inclusion/exclusion questions or 
patients treatment on a medical level.  You may reach the DCRI infectious disease physician on 
call by paging 919-970-1232.  
3.2.4.5 Safety Surveillance Helpline   
The Safety Surveillance helpline is to help answer site questions regarding SAE reporting.  
DCRI Safety Surveillance helpline is 919-668-8624, or at 866-668-7799 (within the US only).  
 


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4 
STUDY DESIGN 
Study patients will be identified by the site staff through daily review of the positive blood culture 
results in the clinical microbiology laboratory of each participating site followed by reviewing 
each potential patient’s medical chart. If the patient has a documented  blood stream infection 
(defined in Section 5.3) and appears to meet enrollment criteria, then the patient (or his/her 
legally authorized representative [LAR]) will be asked to sign an informed consent form (ICF). 
The study will be explained to the patients or their LAR and then they will be asked to sign the 
informed consent document after they have had all their questions answered and have been 
given adequate time to consider consenting. Once consented and speciation and clinical 
classification are confirmed, the patient will be randomized to algorithm-determined treatment or 
SOC treatment. 
During their treatment, patients will be evaluated every day while they are inpatients until the 
Inpatient End of Treatment (IEOT) ± 2 days. Patients discharged while still on study treatment 
will have a Discharge Visit (DV) up to 2 days prior to or on the day of discharge. Some CoNS 
patients may be treated solely as outpatients.  These patients will only have IEOT/DV visit 
procedures performed if they have an in-person clinic visit as part of their treatment plan 
between the enrollment visit and the end of treatment.  Subjects on treatment as outpatients, or 
continuing treatment after discharge, will be monitored for compliance with study antibiotics by 
twice-weekly telephone calls from site study personnel during study treatment; and then by a 
telephone call on the day study treatment is scheduled to end (± 2 days).  All subjects will 
undergo an early TOC assessment by telephone call or clinic visit at 14 - 4 + 10 days for CoNS 
or 21 - 4 + 10 days for S. aureus after completion of study antibiotic treatment. In-clinic 
evaluation is preferred but not mandatory for the TOC assessments.  
All subjects will undergo a final TOC assessment by telephone call or clinic visit at 28 – 4 + 10 
days for CoNS or 42 - 4 + 10 days for S. aureus after completion of study antibiotic treatment. 
Subjects who, at the time of the phone call(s) or clinic visit(s), state that they have any signs or 
symptoms of potentially continuing infection will be referred to their primary care physicians for 
further evaluation as needed, with a subsequent follow-up call made to the patient to establish 
the results of that evaluation. 
4.1 
Number of Sites 
A total of Fourteen sites will participate in the clinical trial; thirteen in the US and one in Spain. 
4.2 
Number of Patients  
It is anticipated that 500 patients will need to be enrolled in the study based on the sample size 
calculations described in Section 11.2.  


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Simple CoNS subjects who do not receive any study drug (i.e. the “zero days” subjects), may be 
capped at approximately 80 subjects to allow for enrollment of additional uncomplicated CoNS 
and S. aureus subjects.  
 
A blinded sample-size re-estimation was performed after 250 patients were enrolled in the study 
and was assessed by the DSMB per Section 11.2.   
DSMB’s recommendation for sample size increase was made based on a conservative 
sensitivity analysis approach to account for variability associated with the observed difference in 
cure rates at interim. This recommendation will be confirmed at the next blinded sample size re-
estimation at 350 subjects enrolled.   
Total patient target may be adjusted if the DSMB determines that the study will be sufficiently 
powered at that patient number.   
4.3 
Timeline for Patient Enrollment 
It is estimated that each site will enroll 2 patients or more per month, and enrollment will be 
completed within four years. This estimate is based upon the extensive experience of the 
investigators in conducting similar randomized, controlled multicenter trials in staphylococcal 
blood stream infection.25, 26  The difficulty of enrolling patients into staphylococcal blood stream 
infection trials is well known.227  The primary challenge for such trials is the high numbers of 
patients screened. For example, over 2000 patients were screened in more than 44 sites in four 
countries for three years to enroll 235 patients for the daptomycin S. aureus blood stream 
infection and endocarditis trial, and more than 2639 patients were screened to enroll 73 patients 
in the dalbavancin vs standard therapy catheter-associated blood stream infection trial.228  
Enrollment is further challenged by the need to exclude hemodialysis-dependent patients from 
the trial due to difficulty in calculating vancomycin days in this patient population. 
 


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5 
STUDY ENROLLMENT AND WITHDRAWAL 
The study population will consist of patients at least 18 years of age, who have a positive blood 
culture for  S. Aureus or CoNS. Patients who fulfill all of the inclusion criteria and none of the 
exclusion criteria listed below will be eligible for randomization. 
5.1 
Patient Inclusion Criteria 
A patient must fulfill all of the following criteria prior to randomization: 
1. Provide signed and dated informed consent (the patient’s LAR can provide a signed 
informed consent for the patient if allowed by local IRB/IEC policy). 
2. Is ≥ 18 yrs of age. 
3. If subject has an intravenous catheter in place, then the subject and his/her primary 
health care provider must agree to have the catheter removed within 5 days of initial 
blood culture draw, with the exception of those subjects who meet criteria for simple 
CoNS bacteremia as defined in Table 1.  The catheter may be retained in those subjects 
with simple CoNS bacteremia.  
4. Has blood stream infection defined as at least one blood culture positive for S. Aureus or 
CoNS. In most cases, vancomycin (or other study drug alternative) will have been 
started prior to randomization.  Enrollment windows depend on clinical classification as 
follows:  
a. identification of CoNS and classification as simple per Table 1 – must be 
randomized within 3 calendar days of the start of treatment effective for the 
baseline infecting pathogen 
b. identification of CoNS and classification as uncomplicated per Table 1 – must be 
randomized within 4 calendar days of the start of treatment effective for the 
baseline infecting pathogen 
c.  identification of S. Aureus – must be randomized within 12 calendar days of the 
start of treatment effective for the baseline infecting pathogen .  
5. This criterion has been removed. 
6. Women of child bearing potential must have a negative urine and/or serum pregnancy 
test. 
7. All patients of reproductive potential must be abstinent or agree to use double-barrier 
contraception while receiving study (algorithm-based or SOC) treatment. 


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5.2 
Patient Exclusion Criteria 
All patients meeting any of the exclusion criteria at randomization will be excluded from study 
participation. 
1. Has known or suspected complicated staphylococcal infection at the time of 
randomization. 
2. Weigh ≥ 200 kg. 
3. Has non-removable intravascular foreign material at the time a positive blood culture 
was drawn (e.g., intracardiac pacemaker or cardioverter/defibrillator wires, hemodialysis 
access grafts, cardiac prosthetic valve, valvular support ring). Exception: coronary 
stents, inferior vena cava (IVC) filters in place >6 weeks, patients with pacemakers 
whose baseline infecting pathogen is a CoNS, vascular stents in place for > 6 weeks, 
non-hemodialysis grafts in place >90 days and hemodialysis grafts not used within past 
12 months and not previously infected are eligible for randomization.  Arthroplasties and 
other extravascular devices, e.g. synthetic hernia repair mesh, and non-arthroplasty 
orthopedic prostheses including pins or plates, are acceptable as long as there are no 
signs or symptoms of foreign material-related infection at the time of randomization.  
4. This criterion has been removed. 
5. Has a moribund clinical condition such that there is a high likelihood of death or cardiac 
surgery during the next three days. 
6. Has shock or hypotension (supine systolic blood pressure < 80 mmHg) or oliguria (urine 
output < 20 mL/h) unresponsive to fluids or pressors within four hours. 
7. Has received an investigational antibacterial agent with antistaphylococcal activity within 
30 days prior to randomization. 
8. Has a documented history of significant allergy or intolerance to all protocol-approved 
antibiotics anticipated to be effective for their infection. 
9. Has an infecting pathogen with confirmed reduced susceptibility to vancomycin 
(MIC > 2 µg/mL), if known.  Note: If reduced susceptibility to vancomycin is discovered 
after enrollment, the patient will be treated with daptomycin (if pathogen is susceptible).  
Patient will remain in study as appropriate and be evaluated in the ITT analysis, but will 
be excluded from PP analyses. 
10. For S. Aureus patients, is severely neutropenic (absolute neutrophil count 
< 0.100x103/mm3) or is anticipated to develop severe neutropenia (absolute neutrophil 
count < 0.100x103/ mm3) during the study treatment period due to prior or planned 
chemotherapy.  CoNS patients with neutropenia are eligible to be enrolled. 


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11. This criterion has been removed. 
12. Has previously known HIV infection with a nadir CD4+ count of < 100 cells/mm3 within 
the past 12 months. 
13. Is considered unlikely to comply with study procedures or to return for scheduled post-
treatment evaluations. 
14. Is pregnant or trying to get pregnant, nursing, or lactating. 
15. Has known or suspected septic arthritis, osteomyelitis, pneumonia or other metastatic 
focus of infection.  CoNS patients with pneumonia and not being treated, or anticipated 
to start treatment, with antibiotics effective for the baseline infecting pathogen can be 
included. 
16. Has polymicrobial blood stream infection including at least one non-staphylococcal 
species, except AFTER consultation with the Clinical Medical Monitor at DCRI. Note that 
it is possible that a subject may not have a known polymicrobial bloodstream infection at 
the time of randomization, but additional pathogen(s) can subsequently be isolated from 
the initial blood culture.  These patients will be eligible to remain in the trial.  Please also 
note that patients with S. aureus plus CoNS will follow the treatment pathway for S. 
aureus. 
17. This criterion has been removed. 
18. Is hemodialysis dependent or has end stage renal disease (CrCl < 30 cc/min). 
19. Developed S. aureus blood stream infection within 72 hours of percutaneous coronary 
revascularization  
20. Received of any of the following antibiotics for 7 or more of the 10 calendar days 
immediately preceding the calendar day that the initial positive blood culture was drawn:  
a. 
If methicillin susceptibility of the isolate is unknown at the time of enrollment: 
vancomycin; daptomycin; telavancin; tigecycline; linezolid (in either oral or IV 
administration); quinupristin/dalfopristin; piperacillin/tazobactam; penicillin; nafcillin; 
oxacillin; cloxacillin; cefazolin, ceftriaxone, ceftaroline, dalbavancin, oritavancin, and 
tedizolid levofloxacin or equivalent fluroquinolone (in either oral or IV administration) 
Note: ciprofloxacin is not an exclusion criteria.   
b. 
 If the staphylococcal isolate is known to be methicillin resistant: vancomycin; 
daptomycin; telavancin; tigecycline; linezolid (in either oral or IV administration), 
quinupristin/dalfopristin, dalbavancin, oritavancin, and tedizolid ceftaroline. 
Note: patients who have developed bacteremia after at least 7 days of prophylaxis 
with oral antibiotics have by definition failed prophylaxis and the oral antibiotic can be 
deemed non-effective for the index bacteremia.  Oral antibiotics that have failed as 


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prophylaxis in this manner will not be considered exclusionary or count towards the 
number of antibiotic days but must be stopped upon randomization.   
21. Has previously participated in this study. 
 
5.3 
Source of Blood Stream Infection 
5.3.1 
Baseline Infecting Pathogen 
 
The staphylococcus reported by the local microbiology laboratory isolated from a blood culture 
meeting the parameters of inclusion criterion # 4 that triggered evaluation for study participation 
will be defined as the Baseline Infecting Pathogen.  
 
5.3.2 
Definition of Catheter-associated Blood Stream Infection 
The current protocol will evaluate an algorithm-based treatment strategy for the treatment of 
staphylococcal blood stream infection, many of which will be catheter-associated infections. 
Definitions of these conditions are provided below. Ideally, the studies in this condition could be 
limited to confirmed catheter-associated staphylococcal blood stream infection. However, based 
on our previous published experience18,19,25,26,29,30,31 and on the experiences of previous trials27,28   
enrollment of patients with confirmed catheter-associated infections is extremely difficult. There 
are several important issues contributing to this fact. First, catheters have already been 
removed from many of these patients by the time that the blood cultures have turned positive 
and they are being screened for study participation. Thus, catheter-culture techniques are no 
longer possible. Second, not all centers perform quantitative catheter or blood cultures. Thus, 
these important data are not available. 
Because the presence of catheter-associated blood stream infection is difficult to confirm, we 
are also including patients who do not have a catheter, as well as patients who do have a 
catheter and in whom this infection is suspected clinically, but confirmation is not possible. The 
inclusion of patients with suspected catheter-associated staphylococcal blood stream infection 
serves two important purposes. First, it avoids the prohibitively high screen:enroll ratios 
experienced by recent clinical trials requiring confirmed infection27,28.  Second, it strengthens the 
clinical relevance of this study by better reflecting current clinical practice. In this way, the study 
findings will be more generalizable to routine clinical care. 
Note that “catheter” refers to any type of intravascular catheter, including peripheral catheters, 
peripherally-inserted central catheters (PICC); central venous catheters (short-term central 
venous catheters, vascath); cuffed, tunneled central lines (eg, Perm-cath, Hickman catheters), 
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Confirmed catheter-associated staphylococcal blood stream infection will be defined as 
the isolation of staphylococci in a patient with 1) “an intravascular device and ≥ 1 positive blood 
culture of blood samples obtained from the peripheral vein, clinical manifestations of infection 
(e.g., fever, chills, and/or hypotension), and no apparent source for bloodstream infection (with 
the exception of the catheter); and 2) at least one of the following: “a positive result of 
semiquantitative (> 15  colony forming units [cfu] per catheter segment) or quantitative 
(> 102 cfu per catheter segment) catheter culture, whereby the same organism (species and 
antibiogram) is isolated from a catheter segment and a peripheral blood sample; simultaneous 
quantitative cultures of blood samples with a ratio of > 5:1 (central venous catheter [CVC] vs 
peripheral); or a differential time to positivity (i.e., a positive result of culture from a CVC is 
obtained at least 2 hours earlier than is a positive result of culture from peripheral blood).20  
Suspected catheter-associated staphylococcal blood stream infection will be defined as 
the isolation of staphylococci in a patient with an intravascular device, or a patient who has had 
an intravascular device removed within 5 days  of initial blood culture drawn, and clinical 
suspicion of catheter-associated infection, but without any quantitative or semiquantitative 
culture confirmation as present in patients with confirmed infection. 
5.3.3 
Definition of Nosocomial, Health Care-Associated and Community-
Acquired Bloodstream Infection 
The protocol will also evaluate the management of bloodstream infections from diverse settings, 
including those that are nosocomial, non-nosocomial but health care-associated, and those that 
are community-acquired.  In accordance with accepted practice32, these terms are defined as 
follows:  
Nosocomial bloodstream infection will be defined as a positive blood culture obtained from a 
patient who has been hospitalized for 48 hours or longer.  If a patient has been transferred from 
another hospital, the duration of inpatient stay will be calculated from the date of the first 
hospital admission. 
Health care-associated bloodstream infection will be defined as a positive blood culture 
obtained from a patient at the time of presentation, or within 48 hours of presentation, if the 
patient also fulfills any of the following criteria: 
 
 
Received intravenous therapy at home; received wound care or specialized nursing care 
through a health care agency, family, or friends; or had self-administered intravenous 
medical therapy in the 30 days before the bloodstream infection. 
 
 
Attended a hospital or hemodialysis clinic or received intravenous chemotherapy in the 30 
days before the bloodstream infection. 
 
 
Was hospitalized in an acute care hospital for 2 or more days in the 90 days before the 
bloodstream infection. 


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 
Resided in a nursing home or long-term care facility. 
Community-acquired bloodstream infection will be defined as a positive blood culture 
obtained at the time of presentation, or within the 48 hours after presentation, for patients who 
do not fit the criteria for a health care-associated infection. 
5.4 
Treatment Assignment Procedures 
5.4.1 
Randomization Procedures 
Randomization will be 1:1 Algorithm vs SOC in permuted randomized blocks by site. The 
randomization plan will be generated by a Duke Clinical Research Institute (DCRI) statistician.  
Site personnel will randomize patients through an automated system. The subject will be 
assigned a randomization number, which will be a combination of a two-digit site number and a 
four-digit patient number starting with 0001 and continuing sequentially.      
 
5.4.2 
Masking Procedures 
The study personnel will not be blinded to study intervention group.  However, CEC adjudicators 
will be blinded to treatment assignment. The CEC Coordinator will ensure that the data is 
blinded when provided to CEC members for review and adjudication.   
5.4.3 
Reasons for Withdrawal 
A study patient will be discontinued from participation in the study for the following reasons: 
 
The patient develops a serious adverse event (SAE) possibly related to study drug or 
algorithm, and continuation in the study would jeopardize best clinical practice.  
 
Patient withdraws consent at any time during the study. 
 
Physician caring for the patient (not necessarily a study investigator) feels withdrawal is 
in the patient’s best interest. 
 
Pregnancy 
 
Administrative reasons necessitating discontinuation (such as patient discontinues 
medical treatment against medical advice; patient lost to follow-up). 
Complicated infection is a protocol exclusion; however, it is not reason to withdraw the patient 
when diagnosed after randomization.  
5.4.4 
Handling of Withdrawals 
A premature discontinuation occurs when an enrolled patient ceases participation in the study, 
regardless of circumstances, prior to the final TOC. All patients prematurely discontinuing from 


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the study, regardless of cause, must receive a final evaluation at the time of withdrawal, will be 
classified as non-evaluable, and will be analyzed as a “Failure” in the efficacy analyses.  The 
reason(s) for early discontinuation should be reflected in the source documentation and on the 
Study Termination Record of the eCRF. If a patient withdrawing from the study has an ongoing 
AE at the time of withdrawal, the AE will be followed for 72 hours after the last dose of study 
treatment; an ongoing SAE will be followed until resolved or stabilized.  
5.4.5 
Termination of Study  
The Executive Committee shall have the right to terminate this study at its discretion with written 
notice to the institution and the site investigator. The investigator or institution shall have the 
right to terminate this study at its discretion with written notice to the Executive Committee or its 
designee.  DMID/NIAID shall also have the right to terminate the study at any time. 
Possible reasons for termination of the study include, but are not limited to: 
Unsatisfactory enrollment with respect to quantity or quality 
Inaccurate or incomplete data collection 
Falsification of records 
Failure to adhere to the protocol 
At the request of a local IRB 
 
A situation may arise that could lead a local IRB to suspend or terminate a study at their site.    
If the reason for the suspension or termination is specific to that site, it will not impact the status 
of the study at other sites. 


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6 
STUDY INTERVENTION/INVESTIGATIONAL PRODUCT 
6.1 
Antibiotic Treatment and Dosage 
6.1.1 
Algorithm Treatment with Intravenous Vancomycin  
Vancomycin will be reconstituted with 20mL of sterile water for injection USP or 0.9% Sodium 
Chloride, diluted with 200mL of diluent (5% dextrose or 0.9% Sodium Chloride, or as per 
standard practice at each participating site, and administered as an IV infusion over 60 minutes 
every 12 hours or as per local practice to achieve desired vancomycin trough levels. 
Vancomycin will be dosed by local standard practice, but it is recommended that it be dosed to 
achieve a goal trough of 15 - 20 mcg/ml in accordance with published guidelines.33 Trough 
levels are not required, but if done should be checked within thirty minutes prior to the infusion 
of the fourth dose, and again prior to the fourth dose after any changes in dose. Toxicity to 
vancomycin intravenous will be monitored by performing hematology and chemistry tests 
outlined in Section 8.15, and  as clinically indicated to conform to published guidelines.33   
6.1.2 
Alternatives to Intravenous Vancomycin  
In the appropriate clinical settings, vancomycin alternative agents that are commercially 
available, approved by the study protocol, and FDA-approved for US sites and/or 
EMEA-approved for the site in Spain will also be acceptable for use in the algorithm arm. For 
patients in the SOC arm, the primary provider has unrestricted choice of antibiotics.  It is 
preferable that all patients be treated with vancomycin.  However, vancomycin alternatives may 
be used if the bloodstream staphylococcal isolate is methicillin-susceptible, if the isolate has 
reduced susceptibility to vancomycin, or if the patient develops, or has an existing, intolerance 
or allergy to vancomycin, as outlined below.  In addition, any antibiotic may be utilized in SOC 
patients in order to follow standard clinical practice. 
Appropriate settings for vancomycin alternatives include the following: 
 
Replacement of vancomycin with intravenous antistaphylococcal penicillin (e.g., 
penicillin, nafcillin, oxacillin, cloxacillin) or first generation cephalosporin (cefazolin) 
for patients with methicillin susceptible staphylococcal infections.  
 
Use of daptomycin (US) or Cubicin (Spain) (dosed per standard of care in patients in 
the SOC arm and at 6mg/kg IV once daily, or according to patient renal function per 
package insert, for patients in the algorithm arm) when methicillin-resistant 
staphylococcal bloodstream infection has been identified and if vancomycin cannot 
be used due to the development of vancomycin allergy or intolerance, reduced 
vancomycin susceptibility (vancomycin MIC ≥ 2 µg/ml for S. aureus), AE/SAE 
potentially related to vancomycin, or other extenuating circumstances that would 
require withdrawal of the patient from the trial (these circumstances should be 
discussed with the Clinical Medical Monitor who will subsequently discuss with the 
DMID Medical Monitor).   


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For these clinical settings, dosing recommendations for each vancomycin alternative agent is 
provided in Table 2:  
Table 2:  Vancomycin Alternatives by Clinical Setting* 
Antibiotic 
Dosing 
Comments 
Vancomycin alternative antibiotics for methicillin susceptible staphylococci 
US - Nafcillin, oxacillin 
Spain – Cloxacillin 
2 gm q 4h IV, or 
equivalent dosing 
through continuous 
infusion, in algorithm 
arm (dosing per SOC 
in SOC arm)  
Preferred agents for MSSA and 
susceptible CoNS.  If penicillin-allergic 
or intolerant, may use vancomycin 
instead 
Penicillin 
4 million units q4h IV 
or equivalent dosing 
through continuous 
infusion, in algorithm 
arm (dosing per SOC 
in SOC arm) 
Cefazolin 
1.5 gm q 6h IV or 
equivalent, e.g. 2 gm q 
8h IV**, renally dose-
adjusted per package 
insert 
In the US, may use for S. aureus only, 
per FDA indication.  In Spain, may use 
for any methicillin-susceptible 
staphylococci 
Vancomycin alternative antibiotics for methicillin resistant staphylococci  
US - Daptomycin***  
Spain – Cubicin 
6 mg/kg IV q 24h in 
algorithm arm (dosing 
per SOC in SOC arm) 
Use only if unable to give vancomycin 
due to allergy, intolerance, elevated 
vancomycin MIC, or AE/SAE 
*any antibiotic may be utilized in SOC patients in order to follow standard clinical practice  
**recommended dose per package insert is 1-1.5 g q 6h IV, which is equivalent to the 2 gm q 8h IV 
recommended by current guidelines, and less than the 12 g/day maximum dose allowed per package 
insert  
***FDA-Approved for S. aureus bacteremia and right-sided endocarditis, including infections 
caused by methicillin resistant S. aureus. 
 


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6.2 
Duration of Antibiotics 
All vancomycin alternatives will be considered in calculating antibiotic days. In the event that two 
antibiotics are used in empiric treatment of presumed staphylococcal sepsis, when both drugs 
are administered concomitantly only the duration of vancomycin will be considered when 
calculating antibiotic days.  In the rare event that two antibiotics are administered concomitantly 
and neither is vancomycin, the effective antistaphylococcal antibiotic will be considered when 
calculating antibiotic days (per Section 6.3.1 use of combination antistaphylococcal treatment is 
not permitted in either treatment group).  In the event that two antibiotics with documented 
efficacy based on the susceptibility profile of the bloodstream isolate are added sequentially, 
including as part of empiric therapy, the total duration of effective antistaphylococcal treatment 
with one or more agent will be used for calculations. 
The following sections clarify durations of antibiotics for algorithm-treated patients only.  
Patients in the SOC treatment arm will be managed according to the judgment of the primary 
treating physician.  If patients were given empiric treatment prior to speciation and susceptibility 
testing and the empiric treatment was found not to be effective for the baseline infecting 
pathogen, those days will not be counted towards duration of treatment or as antibiotic days.   
Similarly, if patients were given oral prophylaxis with antibiotics for at least 7 days and 
developed the index bacteremia regardless, these oral antibiotics will not be counted towards 
antibiotic days prior to randomization. 
6.2.1 
Coagulase Negative Staphylococcus  
Patients randomized to Algorithm-based treatment will be treated according to the type of 
staphylococcal infection present.  Patients with CoNS blood stream infection will be categorized 
into simple or Uncomplicated treatment groups. In some cases, complicated staphylococcal 
infections may develop after randomization in patients with CoNS blood stream infection. 
Simple:  Patients randomized to Algorithm-based treatment who meet criteria for simple 
coagulase negative staphylococcal blood stream infection (as defined in Table 1) may have 
received up to 3 (+1) calendar days of vancomycin, or protocol approved alternative.  Upon 
randomization to Algorithm-based treatment, antibiotic treatment for the index bacteremia in 
patients who meet criteria for simple CoNS must be discontinued.  If the patient has not 
received any antibiotic treatment for the index bacteremia prior to randomization, no treatment 
will be started.  In the simple CoNS algorithm patients who do not receive any antibiotic 
treatment, End Of Therapy will be defined as the day that the patient was randomized 
Uncomplicated:  Algorithm patients meeting criteria for uncomplicated CoNS blood stream 
infection (as defined in Table 1) will receive 5 (-/+1) calendar days of vancomycin or protocol-
approved vancomycin alternative as defined in Section 6.1.2.  
Complicated:  Algorithm patients who develop complicated CoNS blood stream infection after 
randomization but before the completion of study treatment for their baseline bacteremia clinical 


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classification (i.e. Simple CoNS, Uncomplicated CoNS) will receive 7 - 28 (-/+2) calendar days 
of treatment with vancomycin or a protocol-approved vancomycin alternative antibiotic. This 
wide range of possible treatment durations reflects the heterogeneity of complicated coagulase 
negative staphylococcal infections. For example, a patient with CoNS blood stream infection on 
2 separate calendar days but without signs of metastatic infection may be treated for as few as 
7 days, whereas endocarditis would be treated for up to 28 days. Precise duration of treatment 
will be determined by local standard practice. 
6.2.2 
S. aureus 
Uncomplicated:  Algorithm patients meeting criteria for Uncomplicated S. aureus infection (as 
defined in Table 1) will receive 14(-/+2) calendar days of treatment with vancomycin or one of 
the protocol-approved alternatives defined in Section 6.1.2. 
Complicated:  Patients who develop complicated S. aureus infection after enrollment and before 
the completion of study treatment for the baseline bacteremia clinical classification will receive 
28 – 42 (-/+2) calendar days of treatment with vancomycin or one of the acceptable alternatives 
as defined in Section 6.1.2. As with coagulase negative staphylococcal infections, there is 
considerable heterogeneity of S. aureus infections leading to different durations of treatment. 
For example, complicated bacteremia without endocarditis could be treated for 28 days, 
whereas endocarditis would be treated for 42 days. 
6.3 
Criteria for Change of Antibiotic Treatment 
Changes in antibiotic treatment in the standard of care (SOC) treatment arm will be based upon 
local SOC. The number of days of antibiotic use will include vancomycin or alternatives taken 
starting the day the baseline blood culture sample was collected..  Replacements for 
vancomycin will continue to count for total antibiotic days for secondary analysis.  As stated 
above, however, if patients were given empiric treatment prior to speciation and susceptibility 
testing and the empiric treatment was found not to be effective for the baseline infecting 
pathogen, those days will not be counted towards duration of treatment or as antibiotic days.  
Similarly, if patients were given oral prophylaxis with antibiotics for at least 7 days and 
developed the index bacteremia regardless, these oral antibiotics will not be counted towards 
duration of treatment or antibiotic days prior to randomization. 
Algorithm-based group changes in treatment will be allowed in the following circumstances: 
a. replacing vancomycin (or alternative drug) with anti-staphylococcal penicillin or first-
generation cephalosporin (cefazolin) for patients infected with methicillin susceptible 
staphylococci 
b. replacing antistaphylococcal antibiotic with daptomycin due to intolerance, allergic 
reaction, drug resistance, or adverse effect;  


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c. other reasons for changing treatment to one of the protocol identified alternative 
antibiotics will be allowed if approved by the coordinating center helpline physician.  
6.3.1 
Combination Therapies 
Use of combination antistaphylococcal treatment (e.g., addition of gentamicin and/or rifampin to 
vancomycin) is not permitted in the algorithm group. 
6.3.2 
Concomitant Medications 
Empiric treatment for Gram-negative pathogens is allowable. These agents will not be counted 
when calculating antibiotic days unless: 1) susceptibility testing of the bloodstream 
staphylococcal isolate reveals that the staphylococcus is susceptible to the antibiotic, and 2) the 
patient is not receiving other protocol approved antistaphylococcal treatment (e.g., 
methicillin-susceptible staphylococcal bloodstream isolate from a patient receiving empiric 
beta-lactam treatment for gram-negative infection). Aminoglycosides, including gentamicin, are 
prohibited for combined treatment of staphylococcal blood stream infection as addressed above.  
Aminoglycosides are prohibited for treatment of suspected or confirmed Gram-negative 
bacterial infections unless: 1) no other alternatives are available, and 2) its use for the treatment 
of a Gram-negative bacterial infection is approved by the coordinating center helpline physician.      
6.3.3 
Safety Monitoring 
Clinical and laboratory evaluations of safety will be carried out as specified in the Schedule of 
Events in Sections 8.8-8.12 and in Section 8.14.1. 
6.3.4 
Acquisition 
All drugs will be provided by the local hospital pharmacy. 
6.3.5 
Formulation, Packaging, and Labeling 
Formulation, packaging, and labeling of vancomycin and vancomycin alternatives will be as per 
marketed drug and available from the local hospital pharmacy stock. 
6.3.6 
Product Storage and Stability 
All drugs will be provided from the local hospital pharmacy, where they will be stored and 
prepared according to product labeling. Only drugs that have not expired will be administered to 
study patients. 
6.4 
Dosage, Preparation and Administration of Study Intervention 
If done, recommended vancomycin trough levels for the algorithm arm will be consistent with 
published treatment guidelines (e.g., vancomycin trough levels of 15 - 20 ug/mL).32   


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Refer to manufacturer package insert for dosage, preparation and administration instructions for 
study medication.  The local pharmacy or site study staff will prepare study drug according to 
manufacturer package insert 
6.5 
Accountability Procedures for the Study 
Intervention/Investigational Product(s) 
Study drug will be accounted for by local pharmacy standard practices and procedures.  
Pharmacies will be required to keep a drug accountability log per pharmacy procedures. 
6.6 
Assessment of Patient Compliance with Study 
Intervention/Investigational Product  
Dose and frequency of study drug will be captured in the EDC system. Protocol compliance will 
be assessed during on-site monitoring visits and periodically by viewing data. Noncompliance 
issues will be documented and addressed with the site PI.  After discharge, or during outpatient 
treatment for CoNS patients who were not admitted, site study personnel will contact patients 
actively taking study drug 2 times per week to assure they are compliant with prescribed dose.  
6.7 
Concomitant Medications/Treatments 
Concomitant medications will be recorded in the Electronic Data Management system (EDC).  
After discharge, or during outpatient treatment for CoNS patients who were not admitted, study 
staff will contact patients 2 times per week and inquire about concomitant medication usage and 
enter into the EDC system. The exception to this is patients who are assigned to the 5-day 
treatment algorithm who will be called for this information every other weekday (to avoid the 
need for weekend calls). The information reported to study staff by the patient during these 
contacts will be considered source.  Antibiotics will be captured from the day of baseline blood 
culture collection to trial termination; all other drug classes below will be captured only from 
randomization through end of treatment. 
The following classes of concomitant medications will be captured: 
 
Antimicrobials  
 
Aspirin 
 
Anticoagulants 
 
Statins 


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7 
STUDY SCHEDULE 
7.1 
Screening  
Site personnel will follow local site procedures to obtain permission to monitor blood culture 
results daily. The investigator or designee will evaluate the patient’s eligibility to enter the study 
based on the bacteriology results, clinical signs and symptoms, the clinician’s judgment and the 
inclusion/exclusion criteria. 
Patients who meet all inclusion criteria and none of the exclusion criteria will be eligible to be 
randomized and will receive either algorithm (defined in Section 8.2) or SOC (defined in Section 
8.3) treatment.  
7.2 
Subject Consent 
All patients (or the patient’s LAR) must sign and date the current approved Informed Consent 
Form (ICF) before any study related procedures or tests are performed or any data is entered 
into the EDC system.   A patient may be consented at the time of report of gram positive cocci in 
clusters i.e. positive for staphylococcal infection, if all other available data indicates that the 
patient is eligible for the study.  Patients cannot be randomized, however, until all inclusion 
criteria have been met and all exclusion criteria have been assessed and it is determined that 
the patient does not meet any of the exclusion criteria. 
7.3 
Randomization/Enrollment 
Treatment assignment will be by randomization (see Section 5.4.1). Refer to Schedule of 
Events sections 8.7, 8.8 and 8.10 for Enrollment procedures. 
7.4 
Schedule of Assessments 
 For patients assigned to algorithm-based treatment and the standard of care-based treatment, 
the Schedule of Events tables are provided in Sections 8.7 through 8.11. Patients will be seen 
at the Enrollment visit and, if hospitalized, daily until the Inpatient End of Treatment visit (IEOT) 
± 2 days. Patients discharged while still on treatment will have a Discharge Visit (DV) up to 2 
days prior to or on the day of discharge.  Some CoNS patients may be treated solely as 
outpatients.  These patients will only have IEOT/DV visit procedures performed if they have an 
in-person clinic visit as part of their treatment plan between the enrollment visit and the end of 
treatment.  Subjects on treatment as outpatients, or continuing treatment after discharge, will 
then be monitored for compliance with study antibiotics and for concomitant medication and 
adverse event information by twice-weekly telephone calls from site study personnel during 
study  treatment. Site study personnel will call the patient on the day study treatment is 
scheduled to end (± 2 days) to confirm actual drug discontinuation date, and to collect 


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concomitant medication and adverse event information. If the site study personnel are unable to 
contact the subject via telephone, required data obtained from the medical records is acceptable 
but not preferred.  The site should document all attempts to contact the subject in the study 
records. 
 
All subjects will undergo an early TOC assessment by clinic visit, which is preferred, or by 
telephone call at 14 - 4 + 10 days for CoNS or 21 - 4 + 10 days for S. aureus after completion of 
study antibiotic treatment. All subjects will undergo a final TOC assessment by clinic visit, which 
is preferred, or by telephone call at 28 - 4 + 10 days for CoNS or 42 - 4 + 10 days for S. aureus 
after completion of study antibiotic treatment. . If the site study personnel are unable to contact 
the subject via telephone, required data obtained from the medical records is acceptable but not 
preferred.  The site should document all attempts to contact the subject in the study records. 
Subjects who, at the time of the phone call(s) or clinic visit(s), state that they have any signs or 
symptoms of potentially continuing infection will be referred to their primary care physicians for 
further evaluation as needed, with a subsequent follow-up call made to the patient to establish 
the results of that evaluation. 
 
If a patient is readmitted to the hospital after treatment ends, the patient or family member 
should notify study staff of the reason for readmission. Patients readmitted before final TOC 
assessment for infection due to a staphylococcus that is identical to the Baseline Infecting 
Pathogen on the basis of speciation, antimicrobial susceptibility testing, and/or genotyping will 
be considered treatment failures and discontinued from the study.  If bacterial genetic testing is 
not done, the patient will be considered a treatment failure and discontinued from the study.  If 
patient was admitted for reasons other than staphylococcal infection, study staff will continue to 
contact patient or family member with patient’s permission to obtain follow-up information for the 
duration of the study. If the patient dies before final TOC, a family member should notify the 
study staff of the reason for death, if otherwise unknown.  If a patient is lost to follow up prior to 
final TOC, all attempts should be made by study staff to determine if the patient died prior to 
final TOC since death is an important patient outcome.    
 
If patients fail or are determined non-evaluable prior to the scheduled final TOC visit, all 
applicable TOC assessments can be conducted at the time of failure or non-evaluable 
determination and the patient can be classified as completing (failure) or terminating (non-
evaluable) the study at that time. 
 
A Schedule of Events for complicated infection is provided in the protocol and applies only to 
those patients diagnosed with complicated infection, as defined in Section 3.2.3.6, after 
randomization but before completion of study treatment for the baseline bacteremia clinical 
classification. 


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7.5 
Early Termination Visit 
If patient terminates the study early for any reason, the TOC assessment should be performed 
at the time of termination. Only safety and outcome data will be collected during early 
termination visits for patients terminating early due to administrative reasons.  These patients 
will be classified as ‘Non-Evaluable’ per Section 3.2.3.1.  All TOC data will be collected for 
patients terminating early due to an outcome of ‘Failure’. 
7.5.1 
Replacement Procedures 
Patients who discontinue after randomization will not be replaced. 
 


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8 
STUDY PROCEDURES/EVALUATIONS 
 
8.1 
Algorithm Based Treatment 
Algorithm based treatment will be based upon the clinical classification of staphylococcal 
infection present.  Patients with CoNS infections will be categorized into Simple or 
Uncomplicated treatment groups and all eligible S. aureus patients will have Uncomplicated 
infections.  In some cases, complicated staphylococcal infections may develop or be discovered 
after enrollment.   Definitions of the different categories are listed in Table 1. 
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8.2 
Standard of Care Treatment 
For the purposes of this trial, Standard of Care treatment will consist of routine care as provided 
by the patient's primary provider.  Therefore there will not be a mandatory treatment regimen, 
such as that advocated by the IDSA guidelines.  The goal in this trial is not to compare 
algorithm-based care to published guidelines (which are in any event often not followed 44 ), as 
the algorithm-based recommendations mimic the guideline recommendation by design.  
Instead, the goal of this trial is to compare algorithm-based care to routine care as it is currently 
practiced.  Thus, for example, a patient in the SOC group may or may not have treatment 
guided by an infectious disease consultant.  Additionally, for those patients in the SOC group, 
selection of the antibiotic for treatment of the staphylococcal infection will be at the discretion of 
the primary provider.  Standard practices for treatment of staphylococcal bloodstream infection 
are outlined below but are not mandatory for those patients on the SOC group.  
It is important to point out that the current protocol does not deprive patients of standard 
treatment. Thus, patients with complicated infections in both the algorithm-based treatment 
group and those receiving SOC treatment will have identical durations of antibiotic treatment. 
Instead, the algorithm-based treatment strategy uses clinically rational, evidence-based 29,30 
criteria to identify patients without complicated infection and justify the decision to stop 
unnecessary antibiotics in these patients. In this way, the algorithm-based treatment strategy 
will reduce overall antibiotic use without compromising patient care. 
While there are no absolute guidelines for treatment of staphylococcal blood stream infection, 
there are some general practices followed in most centers to treat these infections. These 
standard practices are outlined below. 
 In the absence of extenuating circumstances, patients with methicillin-susceptible 
staphylococcus should be treated with an antistaphylococcal penicillin or first-
generation cephalosporin in place of vancomycin. 
 
Standard general practices for duration of antibiotic treatment for S. aureus blood stream 
infection2 
*Uncomplicated: 14 to 28 days 
*Complicated: 28 to 42 days 
 
                                                
 
 


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Standard general practices for durations of antibiotic treatment for CoNS blood stream 
infection2 
*Simple: 4 days 
*Uncomplicated: 10 days 
*Complicated: 7 to 28 days 
*As defined in Table 1.   
8.3 
Simple CoNS Blood Stream Infection 
We anticipate that a significant portion of the blood cultures included in this group will represent 
contaminants rather than clinically significant blood culture results. However, the clinical 
interpretation of a blood culture result as a contaminant generally occurs 36 – 48 hours after the 
initial blood culture was obtained, when Gram positive cocci in clusters have been isolated, but 
not yet speciated. During this period, many patients are treated with empiric vancomycin or 
other effective vancomycin alternative due to the adverse impact of delayed effective 
antimicrobial treatment on the outcome of patients with S. aureus bloodstream infection.34  To 
account for this clinical reality, our treatment algorithm has allowed for a range of treatment 
days.   If a patient has been taking study antibiotic empirically before enrollment in the trial, the 
number of  treatment days will be counted beginning at the day that empirical treatment with an 
antibiotic effective for the baseline infecting pathogen was started, and no earlier than the time 
bacteremia was suspected i.e. the day that the index blood culture was drawn.  In this way, 
patients with simple CoNS blood stream infection randomized to the algorithm-based treatment 
arm will have antibiotics appropriately discontinued, while those for whom parenteral antibiotics 
are appropriate will be treated accordingly. Importantly, this design avoids the counterproductive 
scenario of recipients of algorithm-based treatment being mandated to receive antibiotics that 
they would otherwise not receive. 
8.4 
Further Speciation of CoNS 
The decision to treat CoNS isolated from the blood stream can be influenced by the species of 
the organism. For example, the isolation of Staphylococcus lugdunensis from the blood stream 
is virtually always clinically significant and requires treatment34.  However, the cost-effectiveness 
of routine speciation of CoNS from blood cultures is controversial, and thus CoNS speciation is 
not performed at all medical centers. In the current trial, CoNS speciation is performed at some, 
but not all participating sites. For this reason, CoNS speciation is preferred and should be 
requested for enrolled subjects but is not mandated. However, susceptibility testing is required 
for the baseline infection pathogen for all subjects, as this is critical for evaluating PENS 
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The interpretation of different species of staphylococci from different sets of blood cultures is an 
important consideration.  Only the initial isolate in the discordant pairs will be considered as 
clinically significant except in the following circumstances: 1) at least one of the isolates is S. 
lugdunensis. In this situation, S. lugdunensis will be considered clinically significant; 2) one 
staphylococcal isolate is grown from a blood culture obtained from venipuncture and the second 
staphylococcal isolate of a different species is grown from a blood culture obtained from an 
indwelling venous catheter. In this setting the peripheral culture will be considered as clinically 
significant; 3) any other clinical setting which the site investigator and/or the patient’s primary 
physician considers relevant in the determination of a clinically significant organism. 
In situations where S. aureus and at least one culture of CoNS staphylococci are isolated from 
two different sets of blood cultures, the patient will receive the S. aureus treatment. 
8.5 
Storage of Isolates 
An important strength of this proposal is the planned storage of baseline staphylococcal 
bloodstream isolates from patients enrolled in the trial who provided consent for future use of 
their samples. These isolates will be saved, frozen at -70°C to -80°C, and shipped to Dr. 
Fowler’s laboratory at Duke University. Alternatively, isolates may be lyophilized. The availability 
of these isolates will allow for additional analyses (e.g., vancomycin MIC determination [see 
Section 8.6.1], genotyping, and pathogenesis studies). With the subject’s (or LAR’s) consent, 
subcultures of isolates may be sent from Dr. Fowler’s laboratory to study PIs upon request for 
future testing.  No human genetic testing will be performed as part of the current study or future 
studies/testing.  Dr. Fowler’s laboratory personnel have extensive experience in linking 
individual study data with bacterial isolates,36,37,38,39 as well as shipping and receipt of pathogens 
according to appropriate regulations.  All shipments will be documented. 
Isolates will be labeled with patient number and date of sample and stored at -80°C in Dr. 
Fowler’s laboratory until required for analysis. Additional details regarding collection, labeling, 
and storage of isolates will be contained in the Manual of Procedures (MOP). 
8.5.1 
Vancomycin Minimum Inhibitory Concentration (MIC) 
A growing body of evidence suggests that higher vancomycin MICs – even within levels 
interpreted as susceptible for staphylococci - in staphylococcal blood stream isolates may be 
associated with a worse overall clinical outcome. 40  However, the clinical significance of these 
findings is not yet fully established. Thus, vancomycin MIC values are not routinely made 
clinically available at all of the participating sites in this trial. In order to uniformly address the 
potential impact of bacterial vancomycin MIC values on the clinical outcome of patients treated 
with this antibiotic, all baseline bloodstream isolates from enrolled patients will be retained by 
the participating sites and shipped to Dr. Fowler’s laboratory. Once in Dr. Fowler’s lab, 
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Potential associations between vancomycin MIC values and clinical outcome will then be 
assessed as part of Exploratory Efficacy analyses.  
8.6 
Consideration of Vancomycin Levels 
In accordance with consensus guidelines published in 7/2009, vancomycin should be dosed to 
attain target troughs of 15-20 mcg/ml.32 Trough levels should be obtained just prior to the fourth 
dose, at steady-state conditions. However, in light of ongoing controversy regarding the efficacy 
of this practice, it will not be mandatory to follow this suggested vancomycin monitoring 
schedule.  If vancomycin levels are obtained as part of clinical care, the results will be collected 
as part of study data.


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8.7 
Schedule of Events: Simple CoNS Blood Stream Infection 
If Randomized to Algorithm, the total treatment period is 0 – 3 (+1) Days 
 
Baseline 
Enrollment 
Treatmentm,n,o 
Follow-up 
Daya 
 
 
Daily to 
IEOT/D
Vb 
IEOT/D
Vb 
Early TOCc 
Assessment 
14-4+10 daysd 
Final TOC 
Assessment 
28-4 + 10 
dayse 
Informed Consent  
 
X 
 
 
 
 
Medical History 
 
X 
 
 
 
 
Antibiotic / Medication 
History 
 
X 
 
 
 
 
Vital Signsf  
 
X 
X 
X 
 
 
Physical Exam (PE) 
 
X 
 
X 
X 
X 
Height, Weightg 
 
X 
 
 
 
 
Clinical Assessmenth 
 
X 
X 
X 
 
 
Blood Culture 
Xa 
X 
48-168 hours after initial positive 
blood culture was collected 
 
 
CBC with differential,  
Comprehensive metabolic 
panelj  
 
Xp 
 
Xp 
 
 
Pregnancy Test (urine or 
serum) 
 
X 
 
 
 
 
Randomization 
 
Xa 
 
 
 
 
Study Medication 
Administration  
(X)o 
(X)o 
X 
X 
 
 
Concomitant Antibioticsk 
 
 
X 
X 
X 
X 
Safetyl 
 
 
X 
X 
X 
X 


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a. 
Patients must have at least one blood culture positive for CoNS and classification of simple 
and have received no more than 3 calendar days of medication effective for their baseline 
infecting pathogen prior to randomization. Baseline bloodstream isolates will be collected 
and stored for shipment until the end of the study, or earlier if requested. 
b. 
Inpatient End of Treatment (IEOT) or Discharge Visit (DV), whichever occurs first. The IEOT 
can be ± 2 days; the DV can be done up to two calendar days prior to discharge. Some 
CoNS patients may be treated solely as outpatients.  These patients will only have IEOT/DV 
visit procedures performed if they have an in-person clinic visit as part of their treatment 
plan between the enrollment visit and the end of treatment.  Subjects on treatment as 
outpatients, or continuing treatment after discharge, will receive a phone call from the site 
on  the day treatment is scheduled to end (± 2 days) to confirm drug discontinuation date, 
and collect con med and AE information. In the simple CoNS algorithm patients who do not 
receive any antibiotic treatment for their index bacteremia, End Of Therapy will be defined 
as the day that the patient was randomized. 
c. 
Test of Cure (TOC). If patients fail or are determined non-evaluable prior to the scheduled 
TOC visit, all applicable final TOC assessments can be conducted at the time of failure or 
non-evaluable determination and the patient can be classified as completing (failure) or 
terminating (non-evaluable) the study at that time. 
d. 
14 - 4 + 10 days after last dose of study drug, by clinic visit (preferred) or telephone call 
(required data obtained from the medical records is acceptable but not preferred). Perform 
PE only if clinic visit. 
e. 
28 - 4 + 10 days after last dose of study drug, by clinic visit (preferred) or telephone call 
(required data obtained from the medical records is acceptable but not preferred).  Perform 
PE only if clinic visit. 
f. 
Vital signs are blood pressure, heart rate and temperature; record the most clinically 
significant measurement for that date.   
g. 
Record weight and height at enrollment only. Use weight and height from admission; if none 
available measure at enrollment.  
h. 
Clinical Assessment is done by PI or designated SI and involves clinical judgment based 
upon all clinical aspects of care (e.g. labs, ECG and/or ECHO if clinically indicated, clinical 
symptoms). 
i. 
If repeat culture is positive, patient meets criteria for complicated infection and will be 
managed according to table 8.9. 
j. 
CBC with differential and comprehensive metabolic panel includes the tests listed in 
Section 8.14.1.  If these tests were not run as standard of care prior to randomization, they 
should be requested at the time of randomization 
k. 
Empiric treatment for Gram-negative pathogens is allowable; these agents will not be 
counted when calculating antibiotic days unless susceptibility testing of the bloodstream 
staphylococcal isolate reveals that the staphylococcus is susceptible to the antibiotic and 
the patient is not receiving other antistaphylococcal treatment (e.g., methicillin-susceptible 
staphylococcal bloodstream isolate from a patient receiving empiric beta-lactam treatment 
for gram-negative treatment).  
l. 
Collect all AEs leading to study drug withdrawal and all SAEs. 
m. Suggest to measure trough vancomycin levels prior to 4th dose and at steady state. 
n. 
For subjects on treatment as outpatients, or continuing treatment after discharge, study 
staff will call patient twice per week and on the scheduled end of treatment day (± 2 days) to 
confirm drug discontinuation date, concomitant medication usage, and AE information. 
o. 
If empiric treatment was started prior to randomization and this treatment is effective for the 
baseline infecting pathogen, these treatment days will count towards the total treatment 
duration.  In patients randomized to algorithm in the simple CoNS group, antibiotic 
treatment for the index bacteremia must be discontinued upon randomization.  If the patient 
has not received any antibiotic treatment for the index bacteremia prior to randomization, no 
treatment will be started.   
p. 
Labs within 14 days of enrollment. Differential required only at Enrollment.  For 
comprehensive metabolic panel AST (SGOT) is not required. 
 
 


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8.8 
Schedule of Events: Uncomplicated CoNS Blood Stream 
Infection 
If Randomized to Algorithm, the total treatment period is 5 (-/+1) Days 
 
Baseline 
Enrollment 
Treatmentm,n,o 
Follow-up 
Daya 
 
 
Daily to 
IEOT/DVb 
IEOT/DVb 
Early TOCc 
Assessment 
 14-4+10 daysd 
Final TOCc  
Assessment  28-
4+10 days e 
Informed 
Consent 
 
X 
 
 
 
 
Medical 
History 
 
X 
 
 
 
 
Antibiotic / 
Medication 
History 
 
X 
 
 
 
 
Vital Signsf 
 
X 
X 
X 
 
 
Height/Weightg 
 
X 
 
 
 
 
Physical Exam 
 
X 
 
X 
X 
X 
Clinical 
Assessmenth 
 
X 
X 
X 
 
 
Blood Culture 
Xa 
X 
48- 168 hours after initial positive blood culture 
was collected 
 
 
CBC with 
differential,  
Comprehensive 
metabolic 
panelj    
 
Xp 
 
Xp 
 
 
Pregnancy Test 
(urine or 
serum) 
 
X 
 
 
 
 
Randomization 
 
X 
 
 
 
 
Study 
Medication 
Administration 
(X)o 
(X)o 
X 
X 
 
 
Concomitant 
Antibioticsk 
 
 
X 
X 
X 
X 
Safetyl 
 
 
X 
X 
X 
X 


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a. 
Patients must have at least one blood culture positive for CoNS, meet the classification for 
uncomplicated, and have received  no more than 4 calendar days of medication effective for 
their baseline infecting pathogen prior to randomization. Baseline bloodstream isolates will 
be collected and stored for shipment until the end of the study, or earlier if requested. 
b. 
Inpatient End of Treatment (IEOT) or Discharge Visit (DV), whichever occurs first. The IEOT 
can be ± 2 days; the DV can be done up to two calendar days prior to discharge Some CoNS 
patients may be treated solely as outpatients.  These patients will only have IEOT/DV visit 
procedures performed if they have an in-person clinic visit as part of their treatment plan 
between the enrollment visit and the end of treatment.   
c. 
Test of Cure (TOC). If patients fail or are determined non-evaluable prior to the scheduled 
TOC visit, all applicable final TOC assessments can be conducted at the time of failure or 
non-evaluable determination and the patient can be classified as completing (failure) or 
terminating (non-evaluable) the study at that time. 
d. 
14 - 4 + 10 days after last dose of study drug, by clinic visit (preferred) or telephone call 
(required data obtained from the medical records is acceptable but not preferred). Perform 
PE only if clinic visit. 
e. 
28 - 4 + 10 days after last dose of study drug, by clinic visit (preferred) or telephone call 
(required data obtained from the medical records is acceptable but not preferred). Perform 
PE only if clinic visit. 
f. 
Vital signs are blood pressure, heart rate and temperature; record the most clinically 
significant measurement for that date.   
g. 
Record height and weight at enrollment only.  Use height and weight from admission; if 
none available, measure at enrollment.  
h. 
Clinical Assessment is done by PI or designated SI and involves clinical judgment based 
upon all clinical aspects of care (e.g. labs, ECG and/or ECHO if clinically indicated, clinical 
symptoms).  
i. 
If repeat cultures positive, patient meets criteria for complicated infection and will be 
managed according to table 8.9. Blood cultures will be repeated every 1-2 days until all 
cultures obtained within the past 48 hours have remained negative. 
j. 
CBC with differential and comprehensive metabolic panel includes the tests listed in 
Section 8.14.1.  If these tests were not run as standard of care prior to randomization, they 
should be requested at the time of randomization 
k. 
Empiric treatment for Gram-negative pathogens is allowable; these agents will not be 
counted when calculating antibiotic days unless susceptibility testing of the bloodstream 
staphylococcal isolate reveals that the staphylococcus is susceptible to the antibiotic and 
the patient is not receiving other antistaphylococcal treatment (e.g., methicillin-susceptible 
staphylococcal bloodstream isolate from a patient receiving empiric beta-lactam treatment 
for gram-negative treatment).   
l. 
Collect AEs leading to study drug withdrawal and all SAEs.  
m. Suggest to measure trough vancomycin levels prior to 4th dose and at steady state. 
n. 
For subjects on treatment as outpatients, or continuing treatment after discharge, study 
staff will call patient twice per week and on the scheduled end of treatment day (± 2 days) to 
confirm drug discontinuation date, concomitant medication usage, and AE information. 
o. 
If empiric treatment was started prior to randomization and this treatment is effective for the 
baseline infecting pathogen, these treatment days will count towards the total treatment 
duration. 
p. 
Labs within 14 days of enrollment. Differential required only at Enrollment.  For 
comprehensive metabolic panel AST (SGOT) is not required. 
 
 
 


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8.9 
Schedule of Events – Complicated CoNS Blood Stream 
Infection 
 
Reminder: Complicated infection is an enrollment exclusion; however, it is not reason to withdraw a 
patient when diagnosed after randomization.  This schedule of events applies only to those patients 
diagnosed with complicated infection after randomization but before completion of study treatment 
for the baseline bacteremia clinical classification. Complicated CoNS identified after completion of 
study treatment for the baseline bacteremia clinical classification will be considered a “New 
Complicated Staphylococcal Infection” will be retained in their original group and counted as a 
Treatment Failure. 
 
If Randomized to Algorithm, the total treatment period is 7-28 (-/+2) Days 
 
 
Treatment,j,k 
Follow-up 
Day  
Daily to 
IEOT/DVa 
Weekly to 
IEOT/DVa 
IEOT/DVa  
Early TOCb 
Assessment 
14+/-4 daysc 
Final TOCb 
Assessment 
28- 4 + 10 daysd 
Vital Signse 
X 
 
X 
 
 
Physical Exam 
 
X 
X 
X 
X 
Clinical 
Assessmentf 
Xl 
 
X 
 
 
Blood Cultureg   
  
Repeat every 1-2 days until all 
negative for 48 hours. 
 
 
CBC with 
differential,  
Comprehensive 
metabolic panel    
 
Xk 
Xk 
 
 
Study 
Medication 
Administration
h 
X 
 
X 
 
 
Concomitant 
Antibioticsj 
X 
 
X 
X 
X 
Safetyi 
X 
 
X 
X 
X 


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a. 
Inpatient End of Treatment (IEOT) visit or Discharge Visit (DV), whichever comes first. The 
IEOT visit can be ± 2 days; the DV can be done up to two calendar days prior to /discharge. 
b. 
Test of Cure (TOC). If patients fail or are determined non-evaluable prior to the scheduled 
TOC visit, all applicable final TOC assessments can be conducted at the time of failure or 
non-evaluable determination and the patient can be classified as completing (failure) or 
terminating (non-evaluable) the study at that time. 
c. 
14 - 4 + 10 days after last dose of study drug by clinic visit (preferred) or telephone call 
(required data obtained from the medical records is acceptable but not preferred).  Perform 
PE only if clinic visit. 
d. 
28 - 4 + 10 days after last dose of study drug by telephone call or clinic visit (preferred) or 
telephone call (required data obtained from the medical records is acceptable but not 
preferred).  Perform PE only if clinic visit. 
e. 
Vital signs are blood pressure, heart rate and temperature; record the most clinically 
significant measurement for that date.  
f. 
Clinical Assessment is done by PI or designated SI and involves clinical judgment based 
upon all clinical aspects of care (e.g. labs, ECG and/or ECHO if clinically indicated, clinical 
symptoms).  
g. 
Blood culture(s) will be repeated every 1-2 days until all cultures obtained within the past 
48 hours have remained negative.  
h. 
Empiric treatment for Gram-negative pathogens is allowable; these agents will not be 
counted when calculating antibiotic days unless susceptibility testing of the bloodstream 
staphylococcal isolate reveals that the staphylococcus is susceptible to the antibiotic and 
the patient is not receiving other antistaphylococcal treatment (e.g., methicillin-susceptible 
staphylococcal bloodstream isolate from a patient receiving empiric beta-lactam treatment 
for gram-negative treatment).   
i. 
Collect AEs leading to study drug withdrawal and all SAEs.  
j. 
Suggest to measure trough vancomycin levels prior to 4th dose and at steady state. If on 
treatment after discharge, study staff will call patient 2 times per week and on the scheduled 
end of treatment day (± 2 days)   to confirm drug discontinuation date, concomitant 
medication usage, and AE information. Clinical assessments performed daily while inpatient 
and on treatment  
k. 
Labs within 14 days of enrollment. Differential required only at Enrollment.  For 
comprehensive metabolic panel AST (SGOT) is not required. 
 
 
 
  
 
 


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8.10 Schedule of Events – Uncomplicated S. aureus Blood 
Stream Infection 
 
If Randomized to Algorithm, the total treatment period is 14 (-/+2) Days  
 
 
Baseline 
Enroll
ment 
Treatmentn,o,p 
Follow-up 
Day a 
 
 
Daily to 
IEOT/DVb 
 
Weekl
y to 
IEOT/
DVb 
IEOT/
DVb 
Early TOCc 
Assessment 
21-4 + 10 
daysd 
Final TOCc 
Assessment
42-4+10 
dayse 
Informed 
Consent 
 
X 
 
 
 
 
 
Medical History 
 
X 
 
 
 
 
 
Antibiotic / 
Medication 
History 
 
X 
 
 
 
 
 
Vital Signsf 
 
X 
X 
 
X 
 
 
Height/Weightg 
 
X 
 
 
 
 
 
Physical Exam 
 
X 
 
X 
X 
X 
X 
Clinical 
Assessmenth 
 
X 
Xq 
 
X 
 
 
Blood Culturea   
X 
X   
24-72 hours following 
initial blood culture 
collection 
 
 
 
 
CBC with 
differential,  
Comprehensive 
metabolic panelj 
 
Xr 
 
Xr 
Xr 
 
 
Pregnancy Test 
(urine or serum) 
 
X 
 
 
 
 
 
Echocardiogra
m (Algorithm  
Only)k 
 
 
Within 10 
calendar 
days of start 
of treatment 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
Study 
Medication 
Administration 
(X)p 
(X)p 
X 
 
X 
 
 
Concomitant 
Antibioticsl 
 
X 
X 
 
X 
X 
X 
Safetym 
 
X 
X 
 
X 
X 
X 


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a. 
Patients must have at least one blood culture positive for S. aureus and have received no 
more than 12 days of treatment effective for their baseline infecting pathogen prior to 
randomization. Baseline bloodstream isolates will be collected and stored for shipment until 
the end of the study, or earlier if requested. 
b. 
Inpatient End of Treatment (IEOT) or Discharge Visit (DV), whichever occurs first. The IEOT 
can be ± 2 days; the DV can be done up to two calendar days prior to discharge 
c. 
Test of Cure (TOC). If patients fail or are determined non-evaluable prior to the scheduled 
TOC visit, all applicable final TOC assessments can be conducted at the time of failure or 
non-evaluable determination and the patient can be classified as completing (failure) or 
terminating (non-evaluable) the study at that time. 
d. 
21 - 4 + 10 days after last dose of study drug, by clinic visit (preferred) or telephone call 
(required data obtained from the medical records  is acceptable but not preferred). Perform 
PE only if clinic visit. 
e. 
42 - 4 + 10 days after last dose of study drug, by clinic visit (preferred) or telephone call 
(required data obtained from the medical records is acceptable but not preferred).  Perform 
PE only if clinic visit. 
f. 
Vital signs are blood pressure, heart rate and temperature; record the most clinically 
significant measurement for that date.   
g. 
Record weight at Enrollment only. Use height and weight from admission; if none available, 
measure at enrollment. 
h. 
Clinical Assessment is done by PI or designated SI and involves clinical judgment based 
upon all clinical aspects of care (e.g. labs, ECG, TTE, TEE, clinical symptoms). 
i. 
Blood culture(s) will be repeated every 1-2 days until all cultures obtained within the past 
48 hours have remained negative. If repeat culture is positive, patient meets criteria for 
complicated infection and will be managed according to algorithm 8.11. 
j. 
CBC with differential and comprehensive metabolic panel includes the tests listed in 
Section 8.14.1.  If these tests were not run as standard of care prior to randomization, they 
should be requested at the time of randomization 
k. 
Echocardiography (TEE preferred) mandated for algorithm S. aureus within 10 calendar 
days of start of study treatment. 
l. 
Empiric treatment for Gram-negative pathogens is allowable; these agents will not be 
counted when calculating antibiotic days unless susceptibility testing of the bloodstream 
staphylococcal isolate reveals that the staphylococcus is susceptible to the antibiotic and 
the patient is not receiving other antistaphylococcal treatment (e.g., methicillin-susceptible 
staphylococcal bloodstream isolate from a patient receiving empiric beta-lactam treatment 
for gram-negative treatment). 
m. Collect AEs leading to study drug withdrawal and all SAEs. 
n. 
Suggest to measure trough vancomycin levels prior to 4th dose and at steady state.  
o. 
If on treatment after discharge study staff will call patient 2 times per week and on the 
scheduled end of treatment day (± 2 days) to confirm drug discontinuation date, 
concomitant medication usage, and AE information. 
p. 
If empiric treatment was started prior to randomization and this treatment is effective for the 
baseline infecting pathogen, these treatment days will count towards the total treatment 
duration. 
q. 
Clinical assessments performed daily while inpatient and on treatment 
r. 
Labs within 14 days of enrollment. Differential required only at Enrollment.  For 
comprehensive metabolic panel AST (SGOT) is not required. 
 


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8.11 Schedule of Events – Complicated S. aureus Blood Stream 
Infection 
Reminder: Complicated S. aureus blood stream infection is an enrollment exclusion; however, it is 
not reason to withdraw patient when diagnosed after randomization. This schedule of events applies 
to those patients diagnosed with complicated infection after randomization but prior to completion 
of study treatment for the baseline bacteremia clinical classification.  Patients with Complicated S. 
aureus blood stream infection identified after completion of study treatment for the baseline 
bacteremia clinical classification will be defined as having a New Complicated Staphylococcal 
infection will be retained in their original group and counted as a Treatment Failure. 
 
If Randomized to Algorithm, the total treatment period is 28-42 (-/+2) Days  
 
TREATMENT k,l  
FOLLOW-UP 
Day 
Daily to 
IEOT/DVa 
Weekly to 
IEOT/DVa 
IEOT/DVa 
Early 
TOCb 
Assessment
21-4+10 
daysc 
Final TOCb 
Assessment 
42-4+10 
daysd 
Vital Signse   
X 
 
X 
 
 
Physical Exam 
 
X 
X 
X 
X 
Clinical 
Assessmentf 
Xj 
 
X 
 
 
Blood Cultureg 
Repeat every 1-2 days until negative for 48 
hours. 
 
 
CBC with 
differential,  
Comprehensive 
metabolic panel 
 
Xm 
Xm 
 
 
Echocardiogram 
(Algorithm 
only)h 
Within 10 
calendar days 
of start of 
treatment 
 
 
 
 
Study 
Medication 
Administration  
X 
 
X 
 
 
Concomitant 
Antibioticsi 
X 
 
X 
X 
X 
Safetyj 
X 
 
X 
X 
X 


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a. 
Inpatient End of Treatment (EOT) or discharge, whichever occurs first. The IEOT can be ± 2 
days; the DV can be done up to two calendar days prior to discharge. 
b. 
Test of Cure (TOC). If patient fails or is determined non-evaluable prior to the scheduled 
TOC visit, all applicable final TOC assessments can be conducted at the time of failure or 
non-evaluable determination and the patient can be classified as completing (failure) or 
terminating (non-evaluable) the study at that time. 
c. 
21 - 4 + 10 days after last dose of study drug, by clinic visit (preferred) or telephone call 
(required data obtained from the medical records is acceptable but not preferred). Perform 
PE if clinic visit. 
d. 
42 -  4 + 10 days after last dose of study drug, by clinic visit (preferred) or telephone call.  
Perform PE if clinic visit. 
e. 
Vital signs are blood pressure, heart rate and temperature; record the most clinically 
significant measurement for that date. 
f. 
Clinical Assessment is done by PI or designated SI and involves clinical judgment based 
upon all clinical aspects of care (e.g. labs, ECG, TTE, TEE, clinical symptoms).  
g. 
Blood culture(s) will be repeated every 1-2 days until all cultures obtained within the past 
48 hours have remained negative. 
h. 
Echocardiography (TEE preferred) mandated for algorithm s. aureus within 10 calendar days 
of the start of treatment. 
i. 
Empiric treatment for Gram-negative pathogens is allowable; these agents will not be 
counted when calculating antibiotic days unless susceptibility testing of the bloodstream 
staphylococcal isolate reveals that the staphylococcus is susceptible to the antibiotic and 
the patient is not receiving other antistaphylococcal treatment. 
Clinical assessments 
performed daily while inpatient and on treatment (e.g., methicillin-susceptible 
staphylococcal bloodstream isolate from a patient receiving empiric beta-lactam treatment 
for gram-negative treatment). 
j. 
Collect AEs leading to study drug withdrawal, and all SAEs . 
k. 
Suggest to measure trough vancomycin levels prior to 4th dose and at steady state.  
l. 
If on treatment after discharge study staff will call patient 2 times per week and on the 
scheduled end of treatment day (± 2 days) to confirm drug discontinuation date, 
concomitant medication usage, and AE information.  
m. Labs within 14 days of enrollment. Differential required only at Enrollment.  For 
comprehensive metabolic panel AST (SGOT) is not required. 
 
 
 
 
 


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8.12 Standard of Care Assessments 
Both the Standard of Care and Algorithm treatment arm will have the same assessments 
and data collected with the exception of the echocardiography.  The echocardiogram 
(TEE preferred) is not obligatory in the Standard of Care treatment group but is 
mandatory in the Algorithm group for patients with cultures positive for S. aureus. Refer 
to Sections 8.7 through 8.11 for the Schedule of Events for all subjects, based on the 
subject’s infecting pathogen and clinical classification.  
 
8.13 Safety and Efficacy Evaluations 
Efficacy will be determined based upon the patient’s clinical and bacteriologic results on 
the days designated by the group to which the patient is randomized. Safety will be 
evaluated by collecting and comparing all AEs leading to study drug withdrawal, and all 
SAEs, in the algorithm-based treatment and SOC treatment. 
The DMID Medical Monitor will review all SAEs on an ongoing basis and will also review 
all occurrences of persisting and relapsing infection.  In addition, the DSMB will meet 
and review reported AEs and SAEs as outlined in their charter. 
8.13.1 
Clinical Events Committee (CEC) 
In addition to the investigator evaluation of clinical outcomes, a CEC consisting of three 
adjudicators will be established. These three CEC adjudicators are Board Certified 
Infectious Diseases Physicians with particular expertise in bacterial infections. They will 
be responsible for: 1) establishing the presence and significance of PENS antibiotics; 2) 
evaluating patient outcome in a randomly selected cohort of study patients; and 3) 
adjudicate death for attribution.    
All investigator identified potential PENS occurrences will be reviewed by the CEC using 
source documents and specifically designed study documents will be completed by the 
Site Study Coordinator.   
Outcomes will be defined as "Success,”  "Failure", or “Non-evaluable” for the ITT 
population and as “Success”, or “Failure“ for the PP population, using definitions in 
Section 3.2.3.1 and 3.2.3.2, and will be assessed at a TOC telephone call or clinic visit 
at TOC assessment. Outcome assignment will be based on relevant hospital records, 
outpatient records, and study coordinator data. At least 50 patients or ~ 12 patients per 
year for the 4 years of study enrollment will be adjudicated to address the potential 
confounding effect of open label design. If there is a disagreement in outcome between 
the CEC committee and site PI/SI, then the CEC decision on outcome will be used in the 
final analysis.  For example, if PI/SIs assessment is cure and CECs assessment is 
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The CEC charter will be developed, and the committee and the process will be defined 
in the charter.  The committee chair will be responsible for ensuring accuracy and 
compliance with the charter.  Five percent of all the cases reviewed in the first session 
will be reviewed again as a quality control effort to evaluate internal consistency of the 
group interpretation; any inconsistencies will be resolved by the group under the 
direction of the adjudication chair. 
8.14 Laboratory Evaluations 
8.14.1 
Clinical Laboratory Evaluations 
Baseline blood culture(s) will have been drawn and a positive result of S. Aureus or 
CoNS reported, prior to randomization. Blood and urine specimens for laboratory 
determinations will be collected at the Enrollment visit and at intervals determined on the 
Schedule of Events in Sections 8.7 through 8.11, based on the subject’s baseline 
pathogen and clinical classification..  
Specimens will be submitted for analysis as per the instructions of the individual hospital 
laboratory. These laboratories will be intended to evaluate both 1) potential AEs and 2) 
therapeutic response.  Hematologic and chemistry laboratories will be obtained to 
evaluate for possible AEs.  Blood cultures will be obtained to monitor therapeutic 
response.  The following parameters will be measured:   
 
Hematology: hemoglobin, hematocrit, WBC count (with differential), and platelet 
count, at Enrollment, then according to the Schedule of Events in Sections 8.7-8.11, 
and then as clinically indicated. 
 
Chemistry: alkaline phosphatase, BUN (reported only if done), calcium(reported only 
if done), creatinine, glucose, potassium, ALT (SGPT), sodium, total bilirubin, 
obtained collectively within a comprehensive metabolic panel at Enrollment, then 
according to the Schedule of Events  in Sections 8.7-8.11, and then as clinically 
indicated. 
 
Urine or serum pregnancy screen at Enrollment only. 
 
Blood cultures at Baseline, then as specified by the Schedule of Events in Sections 
8.7-8.11, and then as clinically indicated. 
 
Creatinine clearance will be calculated at the enrollment visit using the Cockcroft-
Gault or Modification of Diet in Renal Disease study (MDRD) formula and should be 
noted in the source documentation. 
 
Transesophageal Echocardiogram (TEE) or Transthoracic Echocardiogram (TTE) is 
mandated only for algorithm patients with cultures positive for S. aureus. The TEE is 
preferred.  
 
Electrocardiograms (ECG) are not mandated and will only be performed if part of 
clinical assessment.  


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 
It will not be mandatory to obtain vancomycin levels, but if these are obtained, the 
results will be collected as part of study data. 
 
8.14.1.1 Echocardiogram 
 
Echocardiography will be performed on all algorithm subjects with a baseline blood 
culture positive for S. aureus . The TEE is preferred over the TTE. The echocardiogram 
will be interpreted by the site’s echocardiographer as per standard clinical practice 41 and 
the interpretation must be kept in the investigator’s file.  In addition, the de-identified 
echo study recorded on CD will be sent to DCRI and be reinterpreted by an experienced 
echocardiographer at the DCRI Echocardiography Core Laboratory.  The 
echocardiographer will be blinded to the clinical details of the patient.  
 
The following selection criteria will be used to determine which study is reinterpreted: 
a. 
If a single protocol required echocardiogram is performed, it will be sent for 
reinterpretation.  
b. 
If multiple echocardiograms are performed then the study that is the most 
diagnostic for endocarditis will be sent for reinterpretation.  
c. 
If multiple echocardiograms are performed, but none are diagnostic, then the 
first study following the initial diagnosis of S. aureus bacteremia will be sent for 
reinterpretation.  If both a TTE and TEE have been performed, and none are 
diagnostic, then the first TEE following initial diagnosis of S. aureus bacteremia 
will be sent for reinterpretation. 
 
 A comparison between the site and central echocardiogram readings will be performed.  
If there are discrepancies, then only the site interpretation will be reported on the eCRF 
and used for clinical decision-making at the study site.  Patient outcome at final TOC for 
those patients randomly selected for CEC adjudication of outcome, will also be assessed 
by the CEC using the interpretation of the Echocardiography Core Laboratory to ensure 
that no bias is introduced by the fact that the onsite clinicians interpreting the 
echocardiogram know the clinical condition of the patient.  See Section 8.13.1. 
Echocardiography may also be performed for clinical assessments and read by site 
echocardiographer per standard clinical practice, but a CD recording should not be 
submitted as it will not be reinterpreted by the central Core Laboratory. 
8.14.2 
Procedures to be Followed in the Event of Abnormal Laboratory 
Test Values or Abnormal Clinical Findings 
If the following abnormal laboratory values are found, they will be followed at least 
weekly until resolution or until stable: 
1) WBC <2000/mm3 


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2) renal impairment, as defined by an increase in creatinine by at least 50% or 
0.5 mg/dL over baseline value, whichever is greater 
3) platelet count <60,000/mm3 
4) AST or ALT >5x upper limit of normal if the patient is on an antistaphylococcal 
penicillin. 
Other abnormal laboratory test values will be managed according to routine clinical care.   
TEE/TTE results consistent with infective endocarditis will be managed according to the 
cohort to which the subject was randomized; other TEE/TTE abnormalities will be 
managed according to routine clinical care. 
 
8.14.3 
 Special Assays or Procedures 
Baseline staphylococcal bloodstream isolates will be analyzed as part of this protocol to 
determine vancomycin minimum inhibitory concentration. In addition, the baseline 
bloodstream isolates will be stored for potential future additional studies if patients 
agree.  There is a section in the ICF for patients to indicate if they choose to “opt out” of 
storage for future testing. 
8.14.4 
 Specimen Preparation, Handling, and Shipping 
All baseline staphylococcal isolates from study patients will be shipped to Dr. Fowler’s 
laboratory for storage until required for additional analyses. The bloodstream 
staphylococcal isolate from the initial positive blood culture of each study patient will be 
stored, frozen at -70°C to -80°C or lyophilized and batch shipped to Dr. Fowler’s 
laboratory at Duke University at the following address: 
Vance G. Fowler, Jr. MD, MHS 
Division of Infectious Diseases  
Department of Medicine  
Room 1546, Stead Bldg  
Duke University Medical Center  
Durham, NC 27710  
(Lab) 919-668-3369  Office: 919-613-5678 
Additional details regarding collection, storage, packing and shipping of isolates will be 
contained in the Manual of Operating Procedures (MOP). 


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9 
SPECIFICATION OF SAFETY PARAMETERS 
9.1 
Adverse Events  
Site investigator is responsible for monitoring the safety of patients enrolled into the 
study at the study sites. All adverse events should be documented in the patient’s 
medical record and managed as standard practice. All AEs should be followed by the 
site until satisfactory resolution or until the investigator deems the event to be chronic 
and/or the patient to be stable. At each visit the study staff, with investigator oversight, 
will review the patient’s medical record and determine if there have been any AEs 
leading to study drug withdrawal or serious adverse events (SAEs) and will then collect 
all pertinent information for entry into the eCRF. All AEs leading to study drug 
withdrawal, and all SAEs will be documented by the sites and will be reviewed by the 
Data Safety Monitoring Board (see Section 9.5)  
9.2 
Methods and Timing for Assessing, Recording, and 
Evaluating Safety Parameters 
9.2.1 
Adverse Events 
An AE is any untoward medical occurrence in a patient or clinical investigation where a 
patient is administered a pharmaceutical product. An AE can therefore be any 
unfavorable and unintended sign (including abnormal laboratory finding), symptom, or 
disease temporally associated with the use of a medicinal (investigational) product. AEs 
also include any worsening (i.e., any clinically significant change in frequency and/or 
intensity) of a pre-existing condition that is temporally associated with the use of the 
study drug (vancomycin or protocol permitted alternative drug) and abnormal laboratory 
findings considered by the reporting investigator to be clinically significant. 
All SAEs, and AEs leading to study drug withdrawal, must be graded for severity and 
relationship to study drug. 
Severity of Event:  Clinicians will use the following guidelines to quantify intensity of the 
event reported.  
 
Mild: events require minimal or no treatment and do not interfere with the patient’s 
daily activities. 
 
Moderate: events result in a low level of inconvenience or concern with the 
therapeutic measures. Moderate events may cause some interference with 
functioning. 
 
Severe: events interrupt a patient’s usual daily activity and may require systemic 
drug therapy or other treatment. Severe events are usually incapacitating. 


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 
Life threatening:  any adverse drug experience that places the patient or subject, in 
the view of the investigator, at immediate risk of death from the reaction as it 
occurred, i.e., it does not include a reaction that had it occurred in a more severe 
form, might have caused death. 
Changes in the severity of an AE should be documented but only the most severe level 
of intensity is to be captured on the eCRF. AEs characterized as intermittent require 
documentation of onset and duration of each episode. If the AE is deemed “Life 
Threatening” or meets any other criteria in Section 9.2.2, then the event is reported as a 
“Serious Adverse Event” (see section 9.2.2 for definition and Section 9.3.1 for reporting 
requirements). 
Relationship to Study Intervention:  The investigator should use the following 
definitions when assessing causality of an AE to study medication: 
 
Not associated:  an AE that has no or little temporal relationship to trial drug or has a 
definite alternative etiology (only SAEs of this category will be recorded on the 
eCRFs). 
 
Associated:  an AE commonly associated with this drug class; or that has a temporal 
relationship to study medication and/or reappeared on re-challenge; and/or no 
alternative etiology exists or is apparent (only AEs leading to study drug withdrawal 
and SAEs of this category will be recorded on the eCRFs). 
Lack of efficacy will not be reported as associated to study drug but may satisfy the 
definition of treatment failure.  
9.2.2 
Serious Adverse Events 
An SAE is any AE that results in any of the following outcomes: 
 
Death 
 
Life-threatening  
 
Persistent or significant disability or incapacity 
 
Inpatient hospitalization or prolongation of existing hospitalization 
 
Congenital abnormality or birth defect 
 
Important medical event 
Life-threatening means that the patient or subject was, in the view of the investigator, at 
immediate risk of death from the AE as it occurred. It does not include an AE that, had it 
occurred in a more severe form, might have caused death. 
Persistent or significant disability/incapacity means that the event resulted in 
permanent or significant and substantial disruption of the patient’s ability to carry out 
normal life functions. 


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Important medical event is any medical event that may not result in one of the above 
outcomes, but may jeopardize the health of the study participant or require medical or 
surgical intervention to prevent one of the outcomes listed in the above definition of 
SAEs.  
9.3 
Reporting Procedures 
9.3.1 
Non Serious and Serious Adverse Events 
 
Sites will record all AEs leading to study drug withdrawal, and all SAEs, occurring from 
study drug initiation (time of first dose of study drug) for all treatment subjects through 
final TOC assessment regardless of their association to study drug on the AE eCRF.   In 
the case of subjects with simple CoNS who do not receive any study drug (i.e. the “zero 
days” subjects), sites will record all SAEs occurring from randomization through final 
TOC assessment. 
All AEs leading to study drug withdrawal, and all SAEs, will be followed by the site until 
satisfactory resolution or until the investigator deems the event to be chronic and/or the 
patient to be stable regardless if the patient is continuing the study.   
All SAEs will be reported by completing the AE/SAE eCRF page in INFORM within 
24 hours of knowledge of the event. The initial report must be as complete as possible, 
including details of the SAE, and provide an investigator assessment of severity and the 
causal relationship between the event and the investigational product. Information not 
available at the time of the initial reporting must be documented on SAE eCRF page in 
Inform within 24 hours of knowledge of the information.  
DCRI Safety Surveillance, the DMID Medical Monitor and the DMID Pharmacovigilance 
designee will receive a real-time automated SAE email notification when data is entered 
or changed on the SAE eCRF in InForm. DCRI Safety Surveillance will be responsible 
for reviewing SAE eCRF data, querying sites within InForm for additional or missing SAE 
data, and generating SAE reports. SAEs confirmed to meet protocol specific reporting 
criteria will be forwarded to DMID Pharmacovigilance within 1 business days of receipt. 
DMID Pharmacovigilance will process all SAE reports and forward to the DMID Medical 
Monitor. DMID Pharmacovigilance will forward any additional SAE queries to DCRI 
Safety Surveillance to be entered into InForm clinical database. 
Questions about SAE reporting can be referred to DCRI Safety Surveillance at 
919-668-8624, or at 866-668-7799 (North America only). 
Other supporting documentation of the event may be requested by DCRI Safety 
Surveillance and should be provided as soon as possible. 
All SAEs and all AEs leading to study drug withdrawal will be followed by the site until 
satisfactory resolution or until the investigator deems the event to be chronic and/or the 
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or stabilized or until the trial database lock. For any ongoing SAE after database lock, 
the sites will be instructed to forward follow-up information directly to DMID 
Pharmacovigilance. If the event resolves during the study or follow-up period, a 
resolution date should be documented on the AE eCRF. 
 
9.3.2 
Reporting of Pregnancy 
Pregnant patients are excluded from enrolling in this trial and participants are strongly 
discouraged from becoming pregnant while enrolled in the trial. If a study participant 
does become pregnant during the course of the study, the site will follow the pregnancy 
through 8 weeks post-live delivery or elective or natural termination of the pregnancy, 
whichever occurs first.  If an SAE occurs in conjunction with the pregnancy the SAE 
must be reported as described in section 9.3.1 above. 
Upon notification of pregnancy the site will obtain a Pregnancy Outcome Tracking (POT) 
form from DCRI Safety Surveillance by calling 919-668-8624, or at 866-668-7799 
(North America only). The form should be completed with as much information as is 
available and faxed to DCRI Safety Surveillance at the number provided on the form. 
The site will provide updated information on the POT as it becomes available through 
the final outcome of the pregnancy and for  8 weeks after delivery via fax to DCRI 
Safety Surveillance as above. 
DCRI Safety Surveillance will forward all Pregnancy Outcome Tracking forms to DMID 
Medical Monitor and DMID Pharmacovigilance designee within 1-2 business days of 
receipt 
Vancomycin is an approved drug, and thus, the risk to the fetus and newborn known 
slightly better than an unapproved drug, but is still not well defined.  It is not known if 
vancomycin can affect reproduction capacity (Baxter Healthcare Corporation, 
Vancomycin Hydrochloride Injection Package insert revised February 2009).  In one 
controlled clinical study, vancomycin was administered to pregnant women.  One infant 
had conductive hearing loss, but this was not attributed to vancomycin.  The size of the 
trial is not reported in the package insert. 
Sexually active female participants must use an effective method of birth control during 
the study. Non-estrogen-containing birth control medications or double-barrier 
contraception will be recommended for all female participants of childbearing potential. 
The ICF must indicate that the investigator has reviewed information about pregnancy 
prevention for all women of childbearing potential. A serum or urine -HCG will be 
performed at enrollment. 
The consent form will include what is known about mutagenic and teratogenic effects of 
vancomycin from reproductive toxicity studies in animals, with the statement that this 
information has had limited predictive value for effects in humans. The consent form will 


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indicate that exposure to vancomycin may involve unforeseeable risks to a fetus. The 
ICF must include names and telephone numbers for study contacts that the participant 
can call if she becomes pregnant, suspects she may be pregnant, has missed her period 
or it is late, or has had a change in her usual menstrual cycle. Any participant who 
becomes pregnant during the study will be withdrawn immediately and referred for 
obstetrical care.  
The primary physician caring for the patient will oversee any changes to treatment, for 
example changing antibiotics, as appropriate.  Vancomycin is classified as a FDA 
Category C in pregnancy, whereas daptomycin is FDA Category B.  Thus, daptomycin is 
the recommended antibiotic in this study for staphylococcal bacteremia in pregnant 
patients, unless individual circumstances intervene. 
9.4 
Type and Duration of Follow-up of Patients after Adverse 
Events 
Any clinical findings in the final examination, including clinically significant laboratory 
abnormalities, must be followed, whether the patient completes the study or discontinues 
prematurely for any reason, until satisfactory resolution or until the investigator deems 
the event to be chronic and/or the patient to be stable.  See Section 9.3.1 for detailed 
information regarding follow-up timelines of SAE and AEs. 
9.5 
Safety Oversight  
An independent DSMB will be established by NIAID to monitor safety data.  The DSMB 
will operate under the rules of a DMID-approved charter that will be written at the 
organization meeting of the DSMB.  At this time, each data element that the DSMB 
needs to assess safety will be clearly defined.  There will be several safety data reviews 
during the conduct of the study, which will take place, at a minimum, after approximately 
125, 250, and 350 patients have enrolled and completed the final TOC visit. In addition 
the DSMB may hold more frequent meetings if determined necessary for any reason and 
the DSMB will also be involved in the planned sample size re-estimation outlined in 
Section 11.2.3.  The DSMB will advise DMID of its recommendations.  The DMID and 
DSMB will also review periodic reports generated from CEC adjudication meetings.  
Either the study Executive Committee, DMID or the investigator may terminate the study 
at any time based on safety concerns. 
9.6 
Halting Rules 
The Data and Safety Monitoring Board (DSMB) will define halting rules in their charter. 
 
The DSMB will consider stopping the trial if one or more of the following conditions 
occur: 


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1. In the patients with simple or uncomplicated bacteremia, there is evidence that the 
incidence of SAEs in the algorithm group is >= 20% higher than the standard of care 
group (SOC) and is not by chance alone (defined as P-value <0.05). 
 
2.  In patients with simple or uncomplicated infections, the incidence of persisting and/or 
relapsing infections is >= 20% higher in the algorithm group than the SOC group and is 
not by chance alone (defined as P-value <0.05).   
 
See section 3.2.3.2 and 3.2.3.3 for definitions of persisting and relapsing infection.  
 
3. In all randomized patients, there is ≥ 20% difference in the death rate between the 
SOC and algorithm group and is not by chance alone (defined as P-value <0.05). 
 
To assure adequate data is available, halting rule analysis will be performed prior to 
DSMB meetings after 125, 250 and 350 patients have enrolled and completed the Test 
of Cure visit.  The DSMB will evaluate the halting rule results during regularly scheduled 
DSMB meetings and will decide if the trial may proceed or should be stopped during 
each meeting. 


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10 
CLINICAL MONITORING 
10.1 Site Monitoring Plan  
A universal monitoring plan was developed by DCRI. The monitoring plan will be 
updated as needed to address the changing needs of the study. The DCRI Lead CRA or 
designee will train both the DCRI and Aptiv Solutions (formerly SRA International) 
monitors on all versions of the clinical monitoring plan to assure consistency in 
monitoring activities.  
The investigator will make available to the CRA the eCRFs, source documents, patients’ 
medical records, signed consent forms, and all other study related documents. The 
investigator will be responsible for reviewing eCRFs, providing missing or corrected 
data, approving all changes performed on his/her data, and signing the appropriate 
eCRF(s). 
 


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11 
STATISTICAL CONSIDERATIONS 
11.1 Study Hypotheses 
11.1.1 
 Primary 
The primary study objective is to demonstrate that the clinical efficacy of algorithm-
based treatment of patients with staphylococcal blood stream infection is noninferior to 
current SOC. Based on the primary study endpoint of clinical outcome (cure rate), a non-
inferiority hypothesis will be tested using a two-sided alpha of 0.05; a non-inferiority 
margin of 15%, at least 80% power, an assumed cure rate of 75%, and an estimated 
drop-out rate of 28%. Note that non-inferiority is sometimes considered a one-sided 
equivalence. 42 
11.1.2 
 Secondary 
The secondary study objective is to demonstrate that algorithm-based treatment of 
patients with staphylococcal blood stream infection can decrease antibiotic days when 
compared to current SOC. Based on the number of days of antibiotic use, a superiority 
hypothesis will be tested at the 5% level of significance. 
11.2 Sample Size Considerations 
11.2.1 
Assumptions 
With a sample size of 500 patients (i.e., 362 patients after 28% dropout), we would have 
at least 90% power for establishing non-inferiority based on two-sided test at 5%  
assuming that (1) equal cure rate of 75% and (2) a non-inferiority margin of 15%. See 
Table 3 below.  In order to validate these assumptions, and to confirm the appropriate 
target number of patients, a blinded sample size re-estimation was performed after 250 
patients were enrolled and completed the TOC visit DSMB’s recommendation for sample 
size increase was made based on a conservative sensitivity analysis approach to 
account for variability associated with the observed difference in cure rates at interim. 
This recommendation will be confirmed at the next blinded sample size re-estimation 
when 350 patients have been enrolled and completed the TOC visit..  The sample size 
re-estimation will be reviewed by the DSMB.  If the sample size re-estimation performed 
at 350 patients enrolled confirms that at least 80% power can be achieved, the total 
patient target may adjusted  In the unlikely event that at least 80% power cannot be 
achieved with 500 patients enrolled, the DSMB will provide recommendations and the 
Executive Committee will determine an appropriate course of action. 
11.2.2 
Sample Size Calculation 
Sample size calculation was performed based on the primary study endpoint of clinical 
outcome (cure rate). The proposed study is powered to establish non-inferiority in clinical 


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outcome (cure rate) between the proposed treatment algorithm group and the SOC 
group43.  
Table 3:  Sample Sizes Required for Establishing Noninferiority of the Proposed 
Treatment   Algorithm to the Standard of Care 
 
 
 
Sample Size 
Required 
 
        Cure  
Rate  
      80% 
Power 
     90% 
Power 
 
   Margin  
Equal Cure   
Rate of both 
Treatments 
One-sided* 
Test at 
2.5% 
Two-sided** 
Test at 
5% 
One-sided 
Test at  
2.5%       
Two-sided 
Test at 
5% 
 
75% 
590 
644 
790 
812 
10% 
80% 
504 
550 
674 
694 
 
85% 
402 
438 
536 
552 
 
75% 
262 
286 
352 
362**** 
15% 
80% 
224 
244 
300 
308 
 
85% 
178 
196 
240 
246 
Note:   
* One-sided test for noninferiority at the 2.5% level of significance.  
** One side of a two-sided test for equivalence at the 5% level of significance (i.e., each 
side is 2.5%). 
*** Sample sizes are not adjusted for dropouts. 
**** the original sample size of 500 patients (362 patients after a 28% predicted 
dropout) was intended to achieve 90% power.  The blinded sample size re-estimation 
will be performed with the goal of achieving at least 80% power. 
 
 
11.2.3 
 DSMB Efficacy Review 
No interim analysis for efficacy is planned. DSMB safety reviews are outlined in Section 
9.5. 
11.3 Final Analysis Plan 
11.3.1 
Study Population 
The primary analysis will be performed based on both the ITT population and the PP 
population.  
The ITT population is defined as all randomized patients.  
The PP population includes randomized patients EXCLUDING those that meet any of 
the following criteria: 


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a) Received a PENS antibiotic 
b) Did not undergo removal of intravascular catheter suspected to be infected.  Note 
that patients with simple CoNS bacteremia may retain the catheter; all other 
patients should have their catheter(s) removed. 
c) Had blood stream infection with a vancomycin-resistant staphylococcus; or a 
staphylococcus resistant to protocol-identified alternative drugs if these were 
used 
d) Discontinued study medication prematurely for reasons other than clinical failure  
e) Did not undergo final TOC assessment 
f) Did not comply with all Patient Inclusion Criteria as listed in 5.1. 
g) Violated any Patient Exclusion Criteria as listed in 5.2. 
h) Died within 3 days of randomization. 
i) 
Were classified as non-evaluable 
 
PPE Population: Patients from the PP population who did not have complicated 
staphylococcal infection. 
Patients who discontinue after randomization will not be replaced. 
 
11.3.2 
Statistical Methods 
 
For continuous variables, descriptive statistics such as the number of patients, mean, 
standard deviation, median, minimum, and maximum will be generated. For discrete 
variables, the number and percentage of patients in each category will be provided. 
Unless otherwise noted, any tests of hypotheses are two-sided and the nominal level of 
significance will be 0.05. No intra-block correlation will be assumed in statistical analysis 
of the collected data.  
 
Missing efficacy data will be handled as follows: subjects who had missing values in 
efficacy variable at final TOC will be considered as treatment failure for both the ITT 
analyses and the PP analyses. For assessment of the primary endpoint, missing values 
will be counted as missing, and will be imputed by early TOC for the sensitivity analysis. 
11.3.3 
Baseline Comparability 
Patient disposition in terms of the number and percent of patients enrolled by site will be 
tabulated. The number of patients randomized, number completing the study, and 
reasons for discontinuation will be summarized by treatment group within each cohort. 
Patient demographics and baseline characteristics such as age, weight, route of 
acquisition of infection (nosocomial, health-care associated and community-acquired) 
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each cohort. All comparisons will be performed by use of the CMH test for categorical 
variables and two-way ANOVA for continuous variables. 
 
11.3.4 
Primary Analysis 
The primary efficacy analysis is to compare cure rate between the proposed treatment 
algorithm and the overall SOC treatment.  
Point estimates and the corresponding 95% confidence intervals for the cure rate in 
each treatment will be calculated. The large sample z-test for comparing the two 
proportions will be performed to test the inferiority with the pre-specified non-inferiority 
margin. The CMH test and ANOVA or ANCOVA will also be performed to compare the 
difference of the intrinsic differences in the clinical experiences and practices at each 
site, characteristics of enrolled patients (including route of acquisition of infection), and 
variations in administering antibiotic dosing schemas as appropriate.  Such variations 
may relate to site-specific practices involving vancomycin dosing, for example, whether 
troughs are followed or utilized.  If there is statistically significant difference for the above 
parameters among the sites detected, the logistic regression model with the confounding 
factor of site and the above parameters, which had significant difference among sites, 
will be used to comparing the cure rate between treatments. 
 
Because safety will also be assessed as a primary endpoint in this trial, safety will be 
evaluated by comparing all SAEs in the algorithm-based treatment and SOC treatment.   
 
11.3.5 
Secondary Analysis 
The secondary analysis is to compare the days of antibiotic use between the proposed 
treatment algorithm and the SOC treatment for the PP population. 
Patients in the simple or uncomplicated cohort who develop New Complicated 
staphylococcal infections after the completion of study treatment for their baseline 
clinical classification of bacteremia will be retained in their original group and counted as 
failure. They will be included in the PP analyses as treatment failures and their antibiotic 
days for their original grouping (e.g., the clinical group to which they had been assigned 
before being defined as having complicated infection) will be included in the Secondary 
analysis. 
 
Patients in the simple or uncomplicated cohort who develop complicated staphylococcal 
infection after randomization but prior to the completion of effective treatment for their 
baseline clinical classification of bacteremia should remain in the PP analysis. Cure will 
be determined at their TOC visit.  These patients will be regrouped in the complicated 
bacteremia population of the algorithm and will be excluded in the duration of treatment 
analysis.   
 


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Point estimates and the corresponding 95% confidence intervals for the difference in the 
days of antibiotic use between the proposed treatment algorithm and the SOC will be 
calculated. If statistically significant differences for the parameters among the sites are 
detected, ANCOVA will be performed to compare the days of antibiotic use between 
treatments with the confounding factor of site and the above parameters that have 
significant differences among sites.  
 
 
11.3.6 
Sensitivity Analysis 
Sensitivity Analysis will be performed in the same manner as primary efficacy analyses 
to count the missing values as “missing” and the missing outcomes will be imputed by 
early TOC. 
 
11.3.7 
Exploratory Analyses 
The exploratory analyses include comparisons of the treatment effects for the endpoints 
cure rate, days of antibiotic use and days to discontinuation using survival analysis 
methods for the following diagnostics subgroups in the ITT and PP populations, 
respectively: 
1.  Cohort of Coagulase Negative Staphylococcus 
2.  Sub-cohort within Coagulase Negative Staphylococcus and simple case 
3.  Sub-cohort within Coagulase Negative Staphylococcus and uncomplicated case 
4. Cohort of S. aureus Bacteremia 
5. Sub-Cohort within S. aureus Bacteremia and uncomplicated case 
 
In addition, potential associations between vancomycin MIC values and clinical outcomes 
(e.g., cure rates, duration of bacteremia on treatment, and incidence of development of 
new complicated staphylococcal infection) will be assessed as part of exploratory efficacy 
analyses.  
11.3.8 
Safety Assessment 
Because safety will also be assessed as a primary endpoint in this trial, safety will be 
evaluated by comparing all SAEs in the algorithm-based treatment and SOC treatment.  
Collected AEs will be tabulated and ordered by decreasing frequency for all patients. 
Separate tabulations will list events according to seriousness, severity, and possible 
association with study drug. If appropriate, the incidence of AEs will be compared by 
Fisher’s exact test. Special attention will be given to patients who discontinued treatment 
because of AEs as well as those who had an SAE. 


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For the clinical laboratory data, descriptive statistics (with classes for below, within, and 
above the normal range) will be generated for all tests performed during the study. The 
McNemar test or Stuart-Maxwell test may be performed to determine whether a 
significant shift in laboratory data occurred after treatment began. Vital signs will also be 
analyzed. Results will be summarized for each time point and for changes in each 
variable from Enrollment visit and during each interval between assessments. 
Extent of exposure to study medication will be presented in terms of treatment duration 
and mean daily dose. 
A summary table will be provided for dose compliance. 
11.3.9 Statistical Software Package 
Statistical analyses will be performed using Version 9.2 (or newer version) of SAS® on a 
UNIX operating system at DCRI. 


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12 
SOURCE DOCUMENTS AND ACCESS TO SOURCE 
DATA/DOCUMENTS 
During monitoring visits, the site will make their computer and/or high speed Internet 
access available to the CRAs, so that they may verify the data entries with the source 
documentation. At the conclusion of the study, each enrolling site will be provided with a 
compact disc (CD) containing PDF files of both the individual patient's data and the audit 
trail (changes made to the database). This will be maintained at the site according to the 
requirements for records retention. 
All data collected in the context of this study will be stored and evaluated in such a way 
as to guarantee patient confidentiality in accordance with the legal stipulations applying 
to confidentiality of data. Study records and regulatory documents will be retained at the 
study site, along with adequate source documentation, according to NIH requirements. 
All source documents must be available for monitor review.  The source document is the 
first place information is documented.  Source documents include but are not limited to 
patient charts, lab reports, medication administration records, echocardiograms, etc. All 
study records must be available for inspection by Duke Clinical Research Institute, 
DMID, or their authorized representatives, and the NIH. 


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13 
QUALITY CONTROL AND QUALITY ASSURANCE 
The DCRI will submit a protocol specific CQMP template to DMID for review and 
acceptance.  This template will be provided to sites who will enter site specific 
information onto the CQMP and implement the quality management activities.  The 
CQMP policy describes elements to assist sites, conducting DMID-supported clinical 
research with developing, implementing, and evaluating such a plan.  DMID makes 
available through the NIAID public website adaptable sample quality management plan 
templates and tools to meet the specific site/protocol needs.   
https://www.dmidcroms.com/CRS/QM/SitePages/Qualitymanagement.aspx  
13.1 Local (site) plans for Quality Assurance and Quality 
Control 
See Section 10.1 for details on the DCRI site monitoring plan. 
 
All sites conducting research under the sponsorship of the DMID are required to have a 
plan in place for assuring the quality of the research being conducted.   
 
Each site should have a quality management plan which describes: 
 
How data will be evaluated for compliance with the protocol and for accuracy 
in relations to source documents. 
 
The documents to be reviewed (eg. CRFs, clinic notes) who is responsible, 
and the frequency for reviews should be identified, either in a formal quality 
management plan or in their SOPs. 
 
Site study staff will receive protocol and Good Clinical Practice training during 
the investigator meeting. This training will be reinforced during initiation visits, 
interim monitoring visits, and via phone as needed. In addition, site will be 
trained on entry of data into the EDC system (Inform) via web cast and during 
the investigator meeting.  Site will describe clinic training requirement of staff 
in their formal quality management plan and/or SOPs. Documentation of all 
training must be made available to DMID or designee upon request. 
 
The following DMID QMP documents are available on the DMID Clinical Research 
Operations Management and Support (CROMS) website to help guide sites.   
 
 
DMID Quality Management Plan – Standard Operation Procedure 
 
Quality Management Plan, version-controlled, template 
 
Chart Review Tool, template 
 
Regulatory File Review Tool, template 
 
Quality Management Summary Report, template 
 
Quality Management Plan Fact Sheet. 


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13.2    Investigator Obligations 
 
The investigator(s) will ensure that this study is conducted in full conformity with the 
principles of the Belmont Report: Ethical Principles and Guidelines for the Protection of 
Human Subjects of Research of the National Commission for the Protection of Human 
Subjects of Biomedical and Behavioral Research (April 18, 1979) and codified in 45 CFR 
46 and/or ICH E6; 62 Federal Register 25691 (1997). The PI/Institution will hold a 
current FWA issued by OHRP for federally funded research. 
13.2.1 
Documentation 
The investigator must provide the following to Duke University Medical Center prior to 
the start of the study: 
• 
A fully executed contract and agreement between the investigator and the Duke 
University Medical Center. 
• 
The Investigator’s Statement page of this protocol signed and dated by the 
investigator, and all subsequent amended protocol versions. 
• 
Copy of the completed Site Staff Delegation & Signature Log 
• 
Copy of training on all approved protocol versions for all study staff listed on the Site 
Staff Delegation & Signature Log 
• 
Curriculum vitae for the site PI and all sub-investigators including a copy of  their 
medical license  
• 
A copy of the original IRB approval letter for conducting the study protocol. Renewals 
must be submitted at yearly intervals, if the study is ongoing. All subsequent 
modifications must be submitted and approved by the IRB, as described in Section 
18.2.  
• 
Copy of the IRB/EC-approved ICF. 
• 
FDA IRB registration confirmation (IORG number). 
• 
A copy of the HIPAA authorization form (US only, may be included in site specific 
ICF). 
• 
DHHS Federalwide Assurance Number or roster of IRB membership. 
• 
Laboratory certifications and normal ranges. 
• 
Copies of Financial Disclosures for the site PI and all sub-investigators. 
• 
Copy of Human Subject Protection training completion certificate for all study staff 
listed on the Site Staff Delegation & Signature Log. 
• 
Copy of NIH Computer Security Awareness Training completion certificate for all 
study staff responsible for eCRF data entry. 
• 
Copy of InForm training for all study staff responsible for eCRF entry. 


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13.2.2 
Performance 
The investigator must demonstrate reasonable efforts to consent qualified patients for 
the study. 
13.2.3 
  Use of Investigational Materials 
The study medication is an approved drug for this indication and will be supplied from 
the hospital pharmacy. 
 
13.2.4 
Electronic Case Report Forms 
All data relating to the study will be entered into eCRFs to be provided by Duke Medical 
Center. Data will be entered from the patient’s medical records and other source 
documentation such as lab reports into the eCRF. Source documentation will be 
maintained at the site. The investigator is responsible for the data entered into the 
eCRF, and for verifying that all data entries in the eCRFs are accurate and correct. 


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14 
ETHICS/PROTECTION OF HUMAN SUBJECTS 
14.1 Ethical Standard 
The investigator will ensure that this study is conducted in full conformity with the 
principles set forth in the Declaration of Helsinki, The Belmont Report: Ethical Principles 
and Guidelines for the Protection of Human Subjects of Research of the US National 
Commission for the Protection of Human Subjects of Biomedical and Behavioral 
Research (April 18, 1979) and codified in 45 CFR Part 46 and/or the ICH E6; 62 Federal 
Regulations 25691 (1997).  
 
The Investigator must ensure that patients or their legally acceptable representatives are 
clearly and fully informed about the purpose, potential risks and other critical issues 
regarding clinical trials in which they volunteer to participate.  An investigator shall 
provide the patient or representative sufficient opportunity to consider whether or not to 
participate in the study and minimize any coercion of the patient to participate.  The 
consent form must include all elements required by CFR 21 Part 50.25, 45 CFR 46, and 
the local IRB. 
14.2 Institutional Review Board/Ethics Committee 
Before initiating this study, the protocol, site-specific ICFs, HIPAA forms, recruitment 
materials, and other relevant information will be reviewed by a properly constituted 
IRB/EC at each participating clinical site. A copy of the signed and dated IRB/EC 
approval at each clinical site will be retrieved prior to site activation and archived at the 
DCRI. Any amendments to the protocol, other than simple administrative and 
typographical changes, must be approved by each IRB/EC before they are implemented. 
The sites will seek annual renewals of their IRB approvals in accordance with local 
procedures. 
This study will be carried out in full compliance with FDA guidelines for Good Clinical 
Practices (GCPs). Approval by the IRB prior to the start of the study will be the 
responsibility of the investigator. A copy of the approval letter must be supplied to Duke 
Medical Center along with a roster of IRB members or DHHS General Assurance 
Number. During the course of the study, the investigator shall make timely and accurate 
reports to the IRB on the progress of the study, at intervals not exceeding one year (or 
as appropriate), and notify the IRB of SAEs or other significant safety findings. 
 


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14.2.1 
Amendments to the Protocol 
Any amendment to this protocol will be provided to the investigator in writing by Duke 
Medical Center. No protocol amendment may be implemented (with the exceptions 
noted below) before it has been approved by the Institutional Review Board (IRB) and 
the signature page, signed by the investigator, has been received by Duke Medical 
Center. Where the protocol is amended to eliminate or reduce the risk to the patient, the 
amendment may be implemented before IRB review and approval. However, the IRB 
must be informed in writing of such an amendment and approval obtained within 
reasonable time limits. Deviating from the protocol is permitted only if absolutely 
necessary for the safety or clinical management of the patient, and must be immediately 
reported to the Duke Clinical Research Institute. 
14.3 Informed Consent Process 
The informed consent must contain all of the elements of informed consent; the HIPAA 
authorization must contain all of the core elements and mandatory statements as 
defined in the code of federal regulations. Signed copies of the informed consent and 
HIPAA authorization forms will be given to the subject or LAR and the signed originals of 
both documents will be placed in the investigator’s study files.  
Informed consent is a process that is initiated prior to the individual’s agreeing to 
participate in the study and continuing throughout the individual’s study participation. 
Extensive discussion of risks and possible benefits of this treatment will be provided to 
the subjects and their families. Consent forms describing in detail the study 
interventions/products, study procedures, and risks are given to the subject and written 
documentation.  Informed consent and HIPAA authorization is required prior to starting 
any study-specific procedures. HIPAA language may be part of the Informed Consent 
document or in a separate document. Consent and HIPAA forms will be IRB-approved 
and the subject will be asked to read and review the document(s). Upon reviewing the 
document, the Investigator will explain the research study to the subject and answer any 
questions that may arise. The subject (or LAR) will indicate their consent by signing the 
informed consent document prior to any procedures being done specifically for the 
study. The subject (or LAR) should have the opportunity to discuss the study with their 
surrogates or think about it prior to agreeing to participate. If the patient is unable to 
provide written informed consent, then verbal assent must be obtained if required by 
applicable regional regulations e.g. for the mentally impaired, and written consent 
obtained from the LAR in accordance with the appropriate State Laws, where applicable. 
The subject may withdraw consent at any time throughout the course of the trial. Signed 
copies of the Informed Consent and HIPAA authorization form will be placed in the 
investigator’s study files. A copy of the informed consent document will be given to the 
subject (or LAR) for their records. The rights and welfare of the subject or LAR will be 
protected by emphasizing to them that the quality of their medical care will not be 
adversely affected if they decline to participate in this study.   


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DCRI and/or DMID will provide the Investigator, in writing, any new information that 
bears significantly on the subject’s risk to participate in this study.  This new information 
will be communicated by the Investigator to subjects who consent to participate in the 
trial in accordance with IRB requirements.  The informed consent document will be 
updated and subjects will be reconsented, if necessary. 
Site staff may employ IRB-approved recruitment efforts prior to the subject consenting; 
however, before any protocol-specific procedures are performed to determine protocol 
eligibility, an informed consent form must be signed.  Subjects or their LAR will be given 
a copy of all consent forms that they sign. 
By signing the informed consent form, the subject agrees to complete all evaluations 
required by the trial, unless the subject withdraws voluntarily or is terminated from the 
trial for any reason, and adverse events will be followed as described in Section 9.4 of 
this protocol. 
 
Required elements of the Informed consent per Code of Federal Regulations, Title 21, 
Volume 1, Part 50, Subpart B, revised April 1, 2009, follow:  
1. A statement that the study involves research, an explanation of the purposes 
of the research and the expected duration of the subject's participation, a 
description of the procedures to be followed, and identification of any 
procedures which are experimental. 
2. A description of any reasonably foreseeable risks or discomforts to the 
subject. 
3. A description of any benefits to the subject or to others which may 
reasonably be expected from the research. 
4. A disclosure of appropriate alternative procedures or courses of treatment, if 
any, that might be advantageous to the subject. 
5. A statement describing the extent, if any, to which confidentiality of records 
identifying the subject will be maintained and that notes the possibility that 
the Food and Drug Administration may inspect the records. 
6. For research involving more than minimal risk, an explanation as to whether 
any compensation and an explanation as to whether any medical treatments 
are available if injury occurs and, if so, what they consist of, or where further 
information may be obtained. 
7. An explanation of whom to contact for answers to pertinent questions about 
the research and research subjects' rights, and whom to contact in the event 
of a research-related injury to the subject. 
8. A statement that participation is voluntary, that refusal to participate will 
involve no penalty or loss of benefits to which the subject is otherwise 
entitled, and that the subject may discontinue participation at any time 
without penalty or loss of benefits to which the subject is otherwise entitled. 
 
When appropriate, one or more of the following elements of information shall also be 
provided to each subject: 


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1. A statement that the particular treatment or procedure may involve 
risks to the subject (or to the embryo or fetus, if the subject is or may 
become pregnant) which are currently unforeseeable. 
2. Anticipated circumstances under which the subject's participation may 
be terminated by the investigator without regard to the subject's 
consent. 
3. Any additional costs to the subject that may result from participation in 
the research. 
4. The consequences of a subject's decision to withdraw from the 
research and procedures for orderly termination of participation by the 
subject. 
5. A statement that significant new findings developed during the course 
of the research which may relate to the subject's willingness to 
continue participation will be provided to the subject. 
6. The approximate number of subjects involved in the study. 
 
The informed consent requirements in these regulations are not intended to preempt any 
applicable Federal, State, or local laws which require additional information to be 
disclosed for informed consent to be legally effective.  Nothing in these regulations is 
intended to limit the authority of a physician to provide emergency medical care to the 
extent the physician is permitted to do so under applicable Federal, State, or local law. 
 
Informed Consent/Assent Process (in Case of a Minor) 
As patients must be 18 years or older to enroll in the study (inclusion criterion no.1); 
informed consent/assent process for minors is not applicable. 
14.4 Exclusion of Women, Minorities, and Children (Special 
Populations) 
Children under the age of 18 years will not be enrolled in this study, because the 
investigational intervention is a treatment algorithm based on adult-dosing guidelines for 
vancomycin (or acceptable vancomycin substitutes), and the comparison will be SOC 
based on treatment of adult patients . 
14.5 Patient Confidentiality 
All patient records will be identified only by code number. Patients’ names are not to be 
transmitted to Duke Medical Center. The investigator will keep a Master Patient List, on 
which the identification number and full name, address, and telephone number of each 
patient is kept. 


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Patient confidentiality is strictly held in trust by the participating investigators, their staff, 
and the sponsor(s) and their agents. This confidentiality is extended to cover testing of 
biological samples and genotyping of bacteria isolates in addition to the clinical 
information relating to participating patients. 
The study protocol, documentation, data, and all other information generated will be held 
in strict confidence. No information concerning the study or the data will be released to 
any third party with the exception of the NIAID. 
The study monitor or other authorized representatives of the sponsor, the NIAID and 
DMID may inspect all documents and records required to be maintained by the 
investigator, including but not limited to, medical records (office, clinic, or hospital) and 
pharmacy records for the patients in this study. The clinical study site will permit access 
to such records. 
14.6 Study Discontinuation 
Duke University Medical Center and the NIAID reserve the right to terminate the study in 
its entirety or at a specific site, at any time.    
14.7 Future Use of Stored Specimens 
Isolates will be stored for future testing, including bacterial genetic testing of patient 
samples, with patient’s (or LAR’s) informed consent.  This is optional and patients may 
be enrolled in the study but “opt out” of future testing of stored specimens.  Specimens 
will be labeled only with patient numbers, sample numbers, date of collection and name 
of isolate.  No personal information such as initials, date of birth, etc, will be recorded on 
the specimen or shipping form.   
 


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15 
DATA HANDLING AND RECORD KEEPING 
The investigator is responsible for the integrity and accuracy of the data.  The 
investigator must ensure completeness, legibility, and timeliness of the data reported. In 
addition, the PI must review and sign off electronically to verify data accuracy. All source 
documents should be completed in a neat, legible manner to ensure accurate 
interpretation of data. Black ink is required to ensure clarity of reproduced copies. When 
making changes or corrections, cross out the original entry with a single line, and initial 
and date the change. DO NOT ERASE, OVERWRITE, OR USE CORRECTION FLUID 
OR TAPE ON THE ORIGINAL SOURCE DOCUMENTS. 
15.1 Data Management Responsibilities 
DCRI will submit a Data Management Plan to DMID for review.  The plan must meet 
both DCRI and DMID expectations.  The plan will be finalized by key staff at DMID and 
DCRI.  
Data collection is the responsibility of the clinical trial staff at the site under the 
supervision of the site investigator. During the study, the investigator must maintain 
complete and accurate documentation for the study. 
Investigators are responsible for reviewing and signing off on all data entered into the 
EDC system by study staff.  
15.2 Data Capture Methods 
Qualified study staff at each site will perform primary data collection from source-
document reviews. DCRI will perform clinical monitoring, including review of eCRFs with 
verification to the source documentation.  
This study will use web-based electronic CRFs (eCRFs) developed through a validated, 
ERES-compliant platform (21 CFR Part 11). Prior to initiation of the trial, each site will be 
contacted as to computer availability, hardware specifications, and internet connectivity, 
to evaluate the capacity of the site to use this type of data collection system. The 
investigator's site staff who will be entering data, will receive training on the system; after 
which, each person will be issued a unique user identification and password. 
For security reasons, and in compliance with regulatory guidelines, it is imperative that 
only the person who owns the user identification and password access the system using 
their own unique access codes. Access codes are non-transferable. Site personnel who 
have not undergone training may not use the system and will not be issued user 
identification and password until appropriate training is completed. 


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15.3 Types of Data 
All data relating to the study will be entered into the eCRFs. Data will be entered from 
the patient’s medical records into the eCRF. Patient’s medical records will be maintained 
at the site and considered the source documents for this clinical trial. The investigator is 
responsible for the data recorded on the eCRF, and for verifying that all data entries in 
the eCRFs are accurate and correct. 
15.4 Timing/Reports 
Data will be collected on an ongoing basis and the CRA and the site management team 
will review the eCRFs on a continuous basis throughout the trial. The CRA will monitor 
each site approximately 4 times per year.  This schedule may be altered depending on 
enrollment and site need.  The electronic data will be reviewed by the site management 
team prior to the visits and between visits. There will be several safety data reviews after 
125, 250, and 350 patients have enrolled in the study.   
Safety and efficacy data with written summaries will be generated and sent to DMID for 
the final study report.   
15.5 Study Records Retention 
It is recommended that investigators retain all records and documents (including 
electronic data capture materials) pertaining to the conduct of the study for at least 6 
years after submission of the final study report in the event follow up is necessary to help 
determine any potential hazards to patients who took part in these studies. The 
investigator agrees to obtain DMID agreement prior to disposal, moving, or transferring 
of any study-related records. Additionally, if the investigator retires, relocates, or for 
other reasons withdraws from the responsibility of the study, then another investigator 
must be assigned if the study is still active. Any new investigator must be approved by 
DMID and DCRI. 
Data generated by the methods described in the protocol will be recorded in the patient’s 
medical records and/or study progress notes. Data may be transcribed legibly on case 
report forms supplied for each patient or directly inputted into an electronic system or 
any combination thereof. The investigator and DCRI will mutually agree upon the 
storage format for the retention of electronic data. 
The investigator will agree to provide access to the office, clinic, and/or hospital records 
of all patients entered in this study. Access inspection of these records may be required 
by the DCRI, DMID, and/or their representative(s) at the time of each monitoring visit. In 
addition, all records may be subject to inspection by other health authorities. The 
investigator shall make accurate and adequate written progress reports to the IRB/IEC at 
appropriate intervals, not exceeding one year. The investigator shall make an accurate 


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and adequate final report to the IRB/IEC within three months after completion or 
termination of the study.  
15.6 Protocol Deviations 
A protocol deviation is defined as an event where the investigator or site personnel did 
not conduct the study according to the protocol.   
Investigators are required to obtain prior approval from the Clinical Medical Monitor 
before initiating deviations from the protocol, except where necessary to protect the life 
or physical well-being of a patient in an emergency. Prior approval is generally not 
expected in situations where unforeseen circumstances are beyond the investigator’s 
control, (e.g., patient was not reached for a follow-up telephone call or clinic visit, sample 
lost by laboratory, etc.); however, the event is still considered a deviation. 
Deviations will be reported to DCRI within 3 business days by Investigator, Study 
Coordinator, or Monitors knowledge of deviation, whichever occurs first, regardless of 
whether medically justifiable, preapproved by the Clinical Medical Monitor, or taken to 
protect the patient in an emergency.  DCRI will batch report deviations to DMID once per 
week. 
The IRB/EC will be informed of all protocol changes by the investigator in accordance 
with applicable regulations and the IRB/EC’s established procedures. No deviations of 
any type from the protocol will be made without complying with all the IRB/EC’s 
established procedures. 
Investigators will maintain documentation of the dates and reasons for each deviation 
from the protocol. 
15.7  Patient Privacy 
The Executive Committee affirms the patient’s right to protection against invasion of 
privacy. Only a patient identification number will identify patient data retrieved by the 
Executive Committee. However, in compliance with US federal and/or local regulations, 
the Executive Committee requires the investigator to permit the Executive Committee’s 
representatives and, when necessary, representatives of the NIAID to review and/or 
copy any medical records relevant to the study. By law, the NIAID are required to 
maintain confidentiality. 
The Executive Committee will ensure that the use and disclosure of protected health 
information obtained during a research study complies with the HIPAA Privacy Rule. The 
Rule provides US federal protection for the privacy of protected health information by 
implementing standards to protect and guard against the misuse of individually 
identifiable health information of patients participating in Clinical Trials. “Authorization” is 
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a covered entity for the use or disclosure of an individual’s protected health information. 
A valid authorization must meet the implementation specifications under the HIPAA 
Privacy Rule. Authorization may be combined in the Informed Consent document 
(approved by the IRB/EC) or it may be a separate document (approved by the IRB/EC or 
designated privacy board [PB]), or provided by the investigator or Executive Committee 
(without IRB/EC or PB approval). It is the responsibility of the investigator and institution 
to obtain such waiver/authorization in writing from the appropriate individual. 
 


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16 
PUBLICATION POLICY 
A Publication Policy will be developed by the Executive Committee to ensure all 
publications meet DMID goals. The study sponsor, DMID has designated the DCRI PI to 
serve as the "Responsible Party" and register, update and report basic results of the trial 
to the “clinicaltrials.gov”, which is sponsored by the National Library of Medicine, The 
trial will be registered prior to enrollment.    
Members of the Executive Committee (e.g., the principal investigators from each site as 
well as the study principal investigator and co-investigator) and/or the CEC committee 
will be primarily responsible for creation, review, and submission of publications and 
presentations relating to the major aspects of the study and approved ancillary analyses 
within a timely fashion after completion of the study.  
The manuscript containing the overall study results as well as future manuscripts 
containing analyses of trial data will be distributed to the NIH according to present 
guidelines/requirements. Submitted publications will conform to international standards 
for biomedical manuscripts, including those regarding authorship. The final analysis and 
manuscript will take approximately six months to complete. 
 
 


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17 
LITERATURE REFERENCES 
 
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2 Taubes G.  The bacteria fight back.  Science. 2008;321(5887):356-361 
 
3 Kirst HA, Thompson DG, Nicas TI, Historical yearly usage of vancomycin.  Antimicrob. Agents 
Chemother.  1998;42(5):1303-1304 
 
4 Tenover FC, Biddle JW, Lancaster MV.  Increasing resistance to vancomycin and other 
glycopeptides in Staphylococcus aureus.  Emerging Infect. Dis. 2001;7(2):327-332 
 
5 Staphylococcus aureus resistant to vancomycin-United States; 2002.  MMWR Morb. Mortal. 
Wkly. Rep. 2002;51(26):565-567 
 
6 Vancomycin-resistant Staphylococcus aureus-Pennsylvania, 2002.  MMWR Morb. Mortal. Wkly. 
Rep. 2002;51(40):902 
 
7 Vancomycin-resistant Staphylococcus aureus-New York, 2004, MMWR Morb Mortal. Wkly. Rep. 
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8 Jones RN.  Microbiological features of vancomycin in the 21st century:  minimum inhibitory 
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outcomes or detect resistant strains.  Clin. Infect. Dis. 2006;42 Suppl 1:S13-24 
 
9 Aubert G, Passot S, Lucht F, Dorche G. Selection of vancomycin- and teicoplanin-resistant 
Staphyloccoccus haemolyticus during teicoplanin treatment of S. epidermidis infection. J. 
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10 Veach LA, Pfaller MA, Barrett M, Koontz FP, Wenzel RP. Vancomycin resistance in 
Staphylococcus haemolyticus causing colonization and bloodstream infection. J. Clin. Microbiol.  
1990;28(9):2064-2068 
 
11 Sanyal D, Johnson AP, George RC, Cookson BD, Williams AJ. Peritonitis due to vancomycin-
resistant Staphylococcus epidermidis.  Lancet.  1991;337(8732):54 
 
12 Krcmery V, Trupl J, Drgona L, et al.  Nosocomial bacteremia due to vancomycin-resistant 
Staphylococcus epidermidis in four patients with cancer, neutropenia, and previous treatment 
with vancomycin. Eur. J. Clin. Microbiol. Infect. Dis.  1996; 15(3):259-261 
 
13 Dunne WM, Qureshi H, Pervez H. Nafziger DA.  Staphylococcus epidermidis with intermediate 
resistance to vancomycin; elusive phenotype or laboratory artifact?  Clin. Infect. Dis. 
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14 Martin GS, Mannino DM, Eaton S, Moss M. The epidemiology of sepsis in the United States 
from 1979 through 2000. N. Engl. J. Med. 2003;348(16):1546-1554 
 
15 Wisplinghoff H, Bischoff T, Tallent SM, et al.  Nosocomial bloodstream infections in US 
hospitals; analysis of 24,179 cases from a prospective nationwide surveillance study.  Clin. Infect. 
Dis. 2004;39(3):309-317 
 
16 Skinner D, Keefer C,. Significance of bacteremia caused by Staphylococcus aureus. Arch. 
Intern. Med.  1941;68:851-875 
 
17 Fowler VG, Sanders LL, Kong LK, et al.  Infective endocarditis due to Staphylococcus aureus:  
59 prospectively identified cases with follow-up.  Clin. Infect.Dis. 1999;28(1):106-114 
 
18 Fowler VG, Olsen MK, Corey GR, et al.  Clinical identifiers of complicated Staphylococcus 
aureus bacteremia.   Arch. Intern. Med. 2003;163(17): 2066-2072 
 
19 Crowley AL, Peterson GE, Benjamin DK, et al.  Venous thrombosis in patients with short- and 
long-term central venous catheter-associated Staphylococcus aureus bacteremia.  Crit. Care 
Med. 2008;36(2):385-390 
 
20 Mermel LA, Farr BM, Sherertz RJ, et al.  Guidelines for the management of intravascular 
catheter-related infections.  Clin. Infect. Dis.  2001;32(9):1249-1272 
 
21 Mermel LA, Allon M, Bouza E, et al.  Clinical practice guidelines for the diagnosis and 
management of intravascular catheter-related infections:  2009 Update by the Infectious Diseases 
Society of America.  Clin. Infect. Dis.  2009;49(1):1-45 
 
22 Bekeris L, Tworek J, Walsh M, Valenstein P.  Trends in blood culture contamination:  a College 
of Americian Pathologists Q-Tracks study of 356 institutions.  Arch Pathol Lab Med. 
2005;129:1222-1225 
 
23 Hall K, Lyman J.  Updated Review of Blood Culture Contamination.  Clin Micro 
Rev.2006;19(4):788-802 
 
24 American Thoracic Society; Infectious Diseases Society of America.  Guidelines for the 
management of adults with hospital-acquired, ventilator-associated, and health care associated 
pneumonia.  Am. J. Respir. Crit. Care Med 2005;171:388-416 
 
25 Fowler VG, Boucher HW, Corey GR, et al.  Daptomycin versus standard therapy for bacteremia 
and endocarditis caused by Staphylococcus aureus.  N. Engl. J. Med. 2006;355(7):653-665 
 
26 Rupp ME, Holley HP, Lutz J, et al.  Phase II, randomized multicenter, double-blind, placebo-
controlled trial of a polyclonal anti-Staphylococcus aureus capsular polysaccharide immune 
globulin in treatment of Staphylococcus aureus bacteremia.  Antimicrob. Agents. Chemother. 
2007;51(12):4249-4254 
 
27 Food & Drug Administration.  Briefing Document for Anti-Infective Drugs Advisory committee 
Meeting, October 14, 2004.  Available at: [Accessed December 4, 2009]. 
 
 


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Version 5.0 
 
05 November 2014 
 
 
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28 Raad I, Darouiche R, Vazquez J, et al.  Efficacy and safety of weekly dalbavancin therapy for 
catheter–related bloodstream infection caused by gram-positive pathogens.  Clin. Infect. Dis. 
2005;40(3):374-380 
 
29 Fowler J, Sanders LL, Sexton DJ, et al.  Outcome of Staphylococcus aureus Bacteremia 
According to Compliance with Recommendations of Infectious Diseases Specialists:  Experience 
with 244 Patients.  Clinical Infectious Diseases.  1998;27(3):478-486 
 
30 Rosen AB, Fowler VG, Corey GR, et al.  Cost-effectiveness of transesophageal 
echocardiography to determine the duration of therapy for intravascular catheter-associated 
Staphylococcus aureus bacteremia.  Ann. Intern. Med. 1999;130(10):810-820 
 
31 Weems JJ, Steinberg JP, Filler S, et al.  Phase II, randomized, double-blind, multicenter study 
comparing the safety and pharmacokinetics of tefibazumab to placebo for treatment of 
Staphylococcus aureus bacteremia.  Antimicrob. Agents Chemother. 2006;50(8):2751-2755. 
 
32 Friedman ND, Kaye KS, Stout JE, et al.  Health care-associated bloodstream infections in 
adults:  a reason to change the accepted definition of community-acquired infections.  Ann Intern. 
Med. 2002;137(10):791-797. 
 
33 Rybak MJ, Lomaestro BM, Rotscahfer JC, et al.  Vancomycin therapeutic guidelines:  a 
summary of consensus recommendations from the Infectious Diseases Society of America, the 
American Society of Health-System Pharmacists, and the Society of Infectious Diseases 
Pharmacists.  Clin. Infect. Dis. 2009;49(3):325-327. 
 
34 Lodise TP, McKinnon PS, Swiderski L, Rybak, MJ.  Outcomes analysis of delayed antibiotic 
treatment for hospital-acquired Staphylococcus aureus bacteremia.  Clin. Infect. Dis 
2003;36(11):1418-1423 
 
35 Etienne J, Renaud F, Bes M, et al.  Instability of characteristics amongst coagulase-negative 
staphylococci causing endocarditis.  J. Med. Microbiol.  1990;32(2):115-122 
 
36 Fowler VG, Kong LK, Corey GR, et al.  Recurrent Staphylococcus aureus bacteremia: pulsed-
field gel electrophoresis findings in 29 patients. J. Infect. Dis. 1999;179(5):1157-1161 
 
37 Fowler VG, Sakoulas G, McIntyre LM, et al.  Persistent bacteremia due to methicillin-resistant 
Staphylococcus aureus infection is associated with agr dysfunction and low-level in vitro 
resistance to thrombin-induced platelet microbicidal protein.  J. Infect. Dis. 2004;190(6):1140-
1149  
 
38 Fowler VG, Nelson CL, McIntyre LM, et al.  Potential associations between hematogenous 
complications and bacterial genotype in Staphylococcus aureus infection. J. Infect. Dis. 
2007;196(5):738-747 
 
39 cqmp 
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40 Lodise TP, Graves J, Evans A, et al.  Relationship between vancomycin MIC and failure among 
patients with methicillin-resistant Staphylococcus aureus bacteremia treated with vancomycin. 
Antmicrob. Agents Chemother. 2008;52(9):3315-3320 
 
41 Sanfillippo A, Picard M, Newell J, Echocardiographic assessment of patients with infectious 
endocarditis: predication of risk for complications. J. Am. Coll. Cardiol. 1991;18(5):1191-1199 
 
42 Chow S, Liu J.  Design and Analysis of Clinical Trials, 2nd ed. New York, New York:  John Wiley 
& Sons; 2004. 
 
43 Chow S, Shao J, Wang H.  Sample Size Calculations in Clinical Research. 2nd ed. New York, 
New York:  Chapman & Hall/CRC Press, Taylor & Francis;2008. 
 
44 Jenkins TC, Price CS, Sabel AL, et al.  Impact of routine infectious diseases service 
consultation on the evaluation, management and outcomes of Staphylococcus aureus 
bacteremia..  Clin. Infect. Dis. 2008;46:1000-1008 
 
 

SAP_000.pdf: 
 
1. TITLE PAGE                                                                          
 
 
 
 
 
 
 
Statistical Analysis Plan   
 
 
 
 
DMID Protocol Number: 09-0080 Version 4 
 
 
 
 
 
 
 
 
 
Date of Analysis Plan 
December 12, 2013 
 
                                                                                                           
 
 
   
A Multi-Center, Randomized, Open-Label, Comparative Study to Assess the Safety and 
Efficacy of a Treatment Algorithm to Reduce the Use of Vancomycin in Adult Patients with  
Blood Stream Infections due to Staphylococci 


STATISTICAL ANALYSIS PLAN 
  
 
 
 
 
2 
1. 
TITLE PAGE ............................................................................................................................................... 1 
2. 
LIST OF TABLES/FIGURE/LISTINGS ................................................................................................... 3 
3. 
LIST OF ABBREVIATIONS ..................................................................................................................... 3 
4. 
INTRODUCTION ........................................................................................................................................ 4 
4.1 
STUDY DESIGN ..................................................................................................................................... 4 
4.2 
SAMPLE SIZE AND POWER ................................................................................................................... 6 
4.3 
RANDOMIZATION ................................................................................................................................... 7 
5. 
OBJECTIVES ............................................................................................................................................. 7 
5.1 
PRIMARY ............................................................................................................................................... 7 
5.2 
SECONDARY .......................................................................................................................................... 7 
6. 
SAFETY AND EFFICACY ENDPOINTS ................................................................................................ 7 
6.1 
PRIMARY ENDPOINTS ........................................................................................................................... 7 
6.2 
SECONDARY ENDPOINT ........................................................................................................................ 9 
6.3 
ENDPOINTS FOR SENSITIVITY ANALYSES ............................................................................................. 9 
6.4 
ENDPOINTS FOR EXPLORATORY ANALYSES ...................................................................................... 10 
7. 
STUDY POPULATION ............................................................................................................................ 10 
8. 
HALTING RULES .................................................................................................................................... 11 
9. 
STATISTICAL METHODS...................................................................................................................... 11 
9.1 
GENERAL ANALYSIS CONVENTIONS/RULES ....................................................................................... 11 
9.2 
BASELINE COMPARABILITY ................................................................................................................. 12 
9.3 
HANDLING OF MISSING DATA ............................................................................................................. 12 
9.4 
HANDLING OF DUPLICATE LAB AND EKG DATA ................................................................................. 13 
9.5 
PATIENT DISPOSITION, DISCONTINUATION AND BASELINE DATA ...................................................... 13 
9.5.1 
Patient Disposition, Discontinuation ..................................................................................... 13 
9.5.2 
Demographics and Baseline Characteristics ....................................................................... 13 
9.6 
CONCOMITANT MEDICATIONS............................................................................................................. 13 
9.7 
STATISTICAL ANALYSES...................................................................................................................... 14 
9.7.1 
Primary Analyses ..................................................................................................................... 14 
9.7.2 
Secondary Efficacy Analysis .................................................................................................. 14 
9.7.3 
Sensitivity Analyses ................................................................................................................. 15 
9.7.4 
Exploratory Analyses .............................................................................................................. 15 
9.8 
SAFETY ANALYSES ............................................................................................................................. 17 
9.8.1 
Adverse Events ........................................................................................................................ 17 
9.8.2 
Laboratory Data ....................................................................................................................... 17 
9.8.3 
Vital Signs ................................................................................................................................. 18 
10. 
MONTHLY SAFETY REPORT ........................................................................................................... 18 
11. 
REFERENCES ...................................................................................................................................... 18 
12. 
REVISION HISTORY ........................................................................................................................... 18 
 
  


STATISTICAL ANALYSIS PLAN 
  
 
 
 
 
3 
2. 
 LIST OF TABLES/FIGURE/LISTINGS 
Table 1: Mode of treatment administration—Days of Vancomycin Use--------------------5 
Table 2: Protocol-approved Vancomycin Alternatives by Clinical Setting-----------------5 
Table 3: Definitions of Primary Endpoint Outcomes ------------------------------------------8 
Table 4: Summary of Efficacy Endpoints-------------------------------------------------------16 
Table 5: Summary of Halting Rules--------------------------------------------------------------21 
Figure 1: Schematic of Study Design------------------------------------------------------------20 
Listing 1-1: List of subjects having SAEs, Persisting and/or relapsing infections  
                    and simple or uncomplicated bacteremia------------------------------------------21 
Listing 1-2: List of dead subjects—ITT population (unique) ---------------------------------21 
 
3. LIST OF ABBREVIATIONS 
 
Abbreviation 
Term 
ABT 
AE 
Algorithm 
Alpha 
ANOVA 
CEC 
CMH test 
CoNS 
DCRI 
DSMB 
Algorithm-Based Treatment 
Adverse Event 
Algorithm Based Therapy 
Statistical Significance Level 
Analysis of Variance 
Clinical Event Committee  
Cochran-Mantel-Haenszel Test 
Coagulase Negative Staphylococcus 
Duke Clinical Research Institute 
Data and Safety Monitoring Board 
eCRF 
EKG 
Electronic Case Report Form 
Electrocardiogram 
ITT 
Intent-to-treat 
IVRS 
Interactive Voice Randomization  System 
MedDRA 
MIC 
Medical Dictionary for Regulatory Activities 
Minimum Inhibitory Concentrations 
PENSPP 
PPE 
 
SAE 
SOC 
TOC 
Potentially Effective Non-study AntibioticPer protocol Population 
Per Protocol Population after excluding the patients with complicated 
staphylococcal infection 
Serious Adverse Event/Serious Adverse Experience 
Standard of Care 
Test of Cure 
___________________________________________________________________ 


STATISTICAL ANALYSIS PLAN 
  
 
 
 
 
4 
4. INTRODUCTION 
 
The algorithm-based treatment study with staphylococcal blood stream infection evaluates 
the safety and efficacy of a treatment algorithm to reduce the use of vancomycin in adult 
patients with blood stream infections due to staphylococci. This statistical analysis plan was 
developed based on the information contained in the study protocol DMID 09-0080. Tables, 
Figures and Listings of DSMB and final study reports are displayed in separate documents. 
The purpose of this analysis plan is to provide a detailed description of the planned statistical 
analysis of the safety and efficacy endpoints presented for monthly safety monitoring, 
DSMB, and final study reports.  
4.1 Study Design 
This is a phase 2, multi-center, randomized, open-label comparative study to assess the safety 
and efficacy of a treatment algorithm to reduce the use of vancomycin in adult patients with 
blood stream infections due to staphylococci. It is a multicenter trial conducted in 16 sites- 15 
sites in the United States (US) and 1 site in Spain. The study will last about six years. The 
total enrollment is of approximately 500 patients at least 18 years of age who have a blood 
stream infection with staphylococci (see details in Sample size and Power section). 
Randomization will be 1:1 Algorithm vs SOC in permuted randomized blocks by site using 
an interactive voice randomization system (IVRS). As the primary safety and efficacy 
endpoint, cure rate will be recorded at Final Test of Cure (TOC) evaluation following last 
dose of antibiotic, which will be evaluated at 28 ± 4 days for CoNS infections and at 42 
± 4 days for S. aureus infections by telephone call or clinic visit. Early TOC, by telephone 
call or clinic visit, will be recorded between [10, 24] days for CoNS and [17, 31] days for 
S.aureus infections. If patient terminates study early for any reason, TOC assessment should 
be performed at the time of termination. 
 
Safety analysis will include analysis of all AEs leading to study drug withdrawal and all 
SAEs recorded on case report form, and the incidence rates of change from vancomycin or a 
protocol-approved study antibiotic to another protocol-approved study antibiotic due to AE 
associated with study drug. In order to demonstrate that algorithm-based treatment of patients 
with blood stream infection can decrease antimicrobial usage when compared to current 
SOC, duration of treatments will be compared as our secondary efficacy endpoint. 


STATISTICAL ANALYSIS PLAN 
  
 
 
 
 
5 
 
Table 1 Mode of treatment administration—Days of Vancomycin Use 
Days of 
treatment-- 
Vancomycin* 
Identified Organism 
S. aureus[1] 
CoNS[2] 
uncomplicated complicated 
simple 
uncomp
licated 
complicated 
Algorithm 
14(±2) 
28-42(±2) 
1-3(+1) [3] 
; 
0-
Randomizati
on(+1) [4] 
5(±1) 
7-28(±2) 
SOC 
14-28(±2) 
28-42(±2) 
4(±1) 
10(±1) 
7-28(±2) 
*: See Table 2  for Vancomycin alternatives by clinical setting. 
S. aureus[1]: Final TOC(early TOC) at 42 ± 4(17-31) days following last dose of antibiotic. 
CoNS[2] : Final TOC(early TOC)  at 28 ± 4 (10-24) days following last dose of antibiotic. 
[3] : Based on protocol prior v4; [4] : Based on protocol v4. 
 
 
Table 2:  Vancomycin Alternatives by Clinical Setting* 
Antibiotic 
Dosing 
Comments 
Vancomycin alternative antibiotics for methicillin susceptible staphylococci  
US - Nafcillin, Oxacillin 
Spain – Cloxacillin 
 
 
 
 
 
 
 
2 gm q 4h IV, or 
equivalent dosing 
through continuous 
infusion, in 
algorithm 
arm(dosing per 
SOC in SOC arm) 
 
Preferred agents for MSSA and 
susceptible CoNS.  If penicillin-
allergic or intolerant, may use 
vancomycin instead 
 
Penicillin 
4 million units q4h 
IV or equivalent 
dosing through 
continuous 
infusion, in 
algorithm arm 
(dosing per SOC in 
SOC arm) 
 
Cefazolin 
1.5 gm q 6h IV or 
equivalent, e.g. 2 
gm q 8h IV**, 
renally dose-
adjusted per 
In the US, may use for S. aureus only, 
per FDA indication.  In Spain, may 
use for any methicillin-susceptible 


STATISTICAL ANALYSIS PLAN 
  
 
 
 
 
6 
package insert 
staphylococci 
Vancomycin alternative antibiotics for methicillin resistant staphylococci  
US - Daptomycin***  
Spain – Cubicin 
6 mg/kg IV q 24h 
in algorithm 
arm(dosing per 
SOC in SOC arm) 
 
Use only if unable to give 
vancomycin due to allergy, 
intolerance, elevated 
vancomycin MIC, or AE/SAE 
*any antibiotic may be utilized in SOC patients in order to follow standard clinical practice 
**recommended dose per package insert is 1-1.5 g q 6h IV, which is equivalent to the 2 gm q 8h IV 
recommended by current guidelines, and less than the 12 g/day maximum dose allowed per package insert 
***FDA-Approved for S. aureus bacteremia and right-sided endocarditis, including infections caused by 
methicillin resistant S. aureus.  
 
 
 
In addition to the investigator evaluation of clinical outcomes, a Clinical Event 
Committee (CEC) will adjudicate the following events for at least 50 patients or 
~ 12 patients per year for the 4 years of study enrollment:  1) establishing the presence 
and significance of PENS antibiotics; 2) evaluating patient outcome in a randomly 
selected cohort of study patients; and 3) adjudicate death for attribution.  We will use 
the adjudicated outcomes if they are available.  
4.2 Sample Size and Power 
Sample size calculation (N=500) will be performed based on primary efficacy endpoint, 
which is the cure rate at final TOC. We assume that both treatments have an equal cure rate 
of 75%. Under a non-inferiority margin of 15% and a consideration of 28% drop out rate, 
with approximately 250 subjects per treatment, the study will have at least 90% power for 
establishing non-inferiority at a significance level of 5% (2-sided). See reference [1] chapter 
4 for details about sample size calculation for testing non-inferiority.In order to validate these 
assumptions, and to confirm the appropriate target number of patients, a blinded sample size 
re-estimation will be performed after 250 patients have been enrolled and completed the final 
TOC visit, and also after 350 patients have been enrolled and completed the final TOC visit.  
The sample size re-estimation will be reviewed by the DSMB and the DSMB will provide 
recommendations. The Executive Committee will determine an appropriate course of action. 
If the sample size re-estimation performed at 350 patients enrolled confirms that at least 80% 
power can be achieved by enrolling 400 patients as indicated in Table 3 in the protocol, the 
total patient target will be reduced to 400 enrolled patients. 
 


STATISTICAL ANALYSIS PLAN 
  
 
 
 
 
7 
Patients who discontinue after beginning treatment will not be replaced; Patients who 
discontinue after randomization and before starting treatment will be replaced. 
 
 
 
 
4.3 Randomization 
 
Approximately 500 subjects will be randomized to one of two treatment arms (Algorithm and 
SOC) using an interactive voice randomization system (IVRS). Randomization will be 1:1 
Algorithm vs SOC in permuted randomized blocks by site. The randomization code will be 
generated by statistician(s) at DCRI. 
 
5. OBJECTIVES  
5.1 Primary   
 
The primary object of this trial is to (1) demonstrate that the clinical efficacy of algorithm-
based treatment of patients with staphylococcal blood stream infection is noninferior to 
current standard of care (SOC); (2) evaluate the safety of algorithm-based treatment as an 
alternative to current SOC. 
 
5.2 Secondary 
 
The secondary object of this trial is to demonstrate that algorithm-based treatment of patients 
with staphylococcal blood stream infection can decrease antimicrobial usage when compared 
to current SOC. 
 
6. SAFETY AND EFFICACY ENDPOINTS 
6.1   Primary Endpoints 
 
The primary efficacy endpoint is the cure rate of subjects who were classified as either 
“Success” (see Protocol sections 3.2.3.1 and  3.2.3.8), “Failure” (see Protocol section 
3.2.3.1), or “Non-Evaluable” (see Protocol section 3.2.3.1) at final TOC.  


STATISTICAL ANALYSIS PLAN 
  
 
 
 
 
8 
Table 3: Definitions of Primary Endpoint Outcomes 
Non-Evaluable [Protocol 3.2.3.1] 
Failure [Protocol 3.2.3.1] 
Meet the following Criteria: Failure 
for Administrative Reasons (e.g., 
patient withdraws consent for study 
participation; patient discontinues 
medical treatment against medical 
advice; patient withdrawn from the 
study; patient lost to follow-up) in 
patients who do not fail for other 
reasons. 
 
 Patients will be classified as “Failure” at or 
before final TOC if they meet any of the 
following Criteria*: 
a.   Were judged “Failure” at early or final TOC 
by the Site PI or designated SI 
b. Treatment was changed due to Unsatisfactory 
Clinical Response defined as failure to resolve 
clinical manifestations of infection (e.g. fever, 
elevated WBC count). 
c. Had persisting or relapsing infection (Section 
3.2.3.2 and Section 3.2.3.3,   respectively). 
d. Identification of a New Complicated 
Staphylococcal Infection (Section 3.2.3.5) not 
known to be present at either randomization or 
after completion of study treatment for their 
baseline clinical classification of bacteremia.  
These patients will be retained in their original 
group and counted as treatment failures.  
e. Died prior to early or final TOC evaluation. 
 
* if patients fail prior to the  final TOC visit, final 
TOC assessments can be conducted at the time of 
failure and the patient can be classified as 
completing the study at that time. 
 
 
Success: Meet all of the following criteria defined by site PI or SI at final TOC, and 
exhibited none of the criteria of “Failure” or “Non- Evaluable” outcomes [Protocol 
3.2.3.1/ 3.2.3.8] 
 
Si
mp
le 
Co
NS
[2] 
Uncomplicat
ed CoNS[2] 
Complicated 
CoNS[2] 
Uncomplic
ated S. 
aureus[1] 
Complicated S. 
aureus [1] 
negative follow-
up blood culture 
 
√ 
 
        √ 
 
        √ 
 
        √ 
 
        √ 
Clinical resolution 
of signs and 
symptoms  
 
 
√ 
 
 
        √ 
 
 
        √ 
 
 
        √ 
 
 
        √ 


STATISTICAL ANALYSIS PLAN 
  
 
 
 
 
9 
Exhibit none of 
the criteria for 
“Failure” or 
“Non-Evaluable” 
outcomes 
     
 
√ 
 
 
        √ 
 
 
        √ 
 
 
        √ 
 
        √ 
and no 
additional sites 
of Complicated 
Staphylococcal 
Infection, up to 
the respective 
TOC 
Population 
restriction: 
 
 
Population 
comes from 
Simple or/and  
uncomplicated 
CoNS 
 
Population 
comes from 
Uncomplicated 
S. aureus  
S. aureus[1]: Final TOC(early TOC) at 42 ± 4(17-31) days following last dose of antibiotic. 
CoNS[2] : Final TOC(early TOC)  at 28 ± 4 (10-24) days following last dose of antibiotic. 
 
 
Safety analysis will also include analysis of all AEs leading to study drug withdrawal and all 
SAEs recorded on case report form, and the incidence rates of change from vancomycin or a 
protocol-approved study antibiotic to another protocol-approved study antibiotic due to AE 
associated with study drug. 
 
6.2   Secondary Endpoint 
 
The secondary endpoint (see Protocol 3.2.1) is antibiotic days in support of the secondary 
objective for the Per protocol population after excluding the patients with a complicated 
staphylococcal infection after randomization but prior to the completion of study treatment 
for their baseline clinical classification of bacteremia (i.e., on PPE population).  
 
 
 
6.3 Endpoints for Sensitivity Analyses 
 
For assessment of the primary efficacy endpoint, missing values at final TOC assessment will 
be counted as missing, or imputed by early TOC for the sensitivity analysis.   
 
 


STATISTICAL ANALYSIS PLAN 
  
 
 
 
 
10 
6.4 Endpoints for Exploratory Analyses 
 
The exploratory outcome measures include:  
(a) Cure rate, the days of antibiotic, and days to discontinuation (using survival analysis 
methods) for the following diagnostics subgroups in the ITT and PP populations, 
respectively: 
1.  Cohort of CoNS 
2.  Sub-cohort of simple CoNS 
3.  Sub-cohort of Uncomplicated CoNS  
4. Cohort of S. aureus Bacteremia 
5. Sub-Cohort within uncomplicated S. aureus Bacteremia; 
(b) Vancomycin MIC values to investigate potential associations to clinical outcomes (e.g., 
cure rates, duration of bacteremia on treatment, and incidence of development of new 
complicated staphylococcal infection).  
 
The above cohorts recorded in INFORM, that were evaluated by site PIs, will also be 
compared by the derived cohort (defined in protocol Table 1). 
 
7. STUDY POPULATION  
 
● Intent-To-Treat (ITT) Population: All patients who are randomized in the study.   
 ●Per Protocol Population (PP):  Patients from ITT population meeting any of the following 
criteria will be EXCLUDED from PP analysis: 
a) Received a PENS antibiotic 
b) Did not undergo removal of intravascular catheter suspected to be infected. Note that 
patients with simple CoNS bacteremia may retain the catheter; all other patients 
should have their catheter(s) removed 
c) Had blood stream infection with a vancomycin-resistant staphylococcus; or a 
staphylococcus resistant to protocol-identified alternative drugs if these were used 
d) Discontinued study medication prematurely for reasons other than clinical failure  
e) Did not undergo final TOC assessment 
f) Did not comply with all Patient Inclusion Criteria as listed in 5.1. 
g) Violated any Patient Exclusion Criteria as listed in 5.2. 
h) Died within 3 days of randomization 
i) Were classified as non-evaluable 


STATISTICAL ANALYSIS PLAN 
  
 
 
 
 
11 
●Per Protocol Population after excluding the patients with  complicated staphylococcal 
infection (PPE): Patients from PP population who did not have a complicated staphylococcal 
infection. 
● MITT Population: Subjects in ITT population and who either completed the study, or 
discontinued the study.  This population is used for DSMB only if ITT and MITT are 
different. 
 
 
8. 
HALTING RULES 
The Data and Safety Monitoring Board (DSMB) will define halting rules in their charter. The 
DSMB will consider stopping the trial if one or more of the following conditions occur: 
 
1. In the patients with simple or uncomplicated bacteremia, there is evidence that the 
incidence of SAEs in the algorithm group is >= 20% higher than the standard of care group 
(SOC) and is not by chance alone (defined as P-value <0.05). 
 
2. In patients with simple or uncomplicated infections, the incidence of persisting and/or 
relapsing infections is >= 20% higher in the algorithm group than the SOC group and is not 
by chance alone (defined as P-value <0.05). See protocol sections 3.2.3.2 and 3.2.3.3 for 
definitions of persisting and relapsing infection. 
 
3. In all randomized patients, there is >= 20% difference in the death rate between the SOC 
and algorithm group and is not by chance alone (defined as P-value <0.05). 
 
To assure adequate data is available, halting rule analysis will be performed prior to DSMB 
meetings after 125, 250 and 350 patients have enrolled and completed the Test of Cure visit. 
The DSMB will evaluate the halting rule results during regularly scheduled DSMB meetings 
and will decide if the trial may proceed or should be stopped during each meeting. 
 
9. STATISTICAL METHODS 
9.1   General Analysis Conventions/Rules 
 
● Continuous variables: Descriptive statistics for continuous variables will be displayed as 
the number of observations, mean, standard deviation, median, minimum, and maximum 
within the subjects with non-missing values. Efficacy data will be tabulated to count 3 
categories:  total number of subjects, success responders, number of subjects who had non-
missing assessments.   
 


STATISTICAL ANALYSIS PLAN 
  
 
 
 
 
12 
● Discrete variables: Categorical variables will be provided with the counts and percentages 
in each category, within the subjects with non-missing values.  
 
● Level of statistical significance: Unless specified otherwise, any tests of hypotheses are 
two-sided and the nominal level of significance will be 5%; and p-values will be obtained 
based on two-sided tests. No intra-block correlation will be assumed in statistical analysis of 
the collected data. 
● Computer software: SAS statistical analysis software version 9.2 (or newer version), (SAS 
Institute, Cary, NC), will be used for statistical analyses on a UNIX operating system at 
DCRI.  
9.2 Baseline Comparability 
 
Patient disposition in terms of the number and percent of patients enrolled by site will be 
tabulated. The number of patients randomized, number completing the study, and reasons for 
discontinuation, reasons for exclusion from the PP population will be summarized by 
treatment group within each cohort. Patient demographics and baseline characteristics such 
as age, weight, route of acquisition of infection (nosocomial, health-care associated and 
community-acquired), and comorbid condition(s) will be tabulated and compared across 
treatment groups within each cohort. All comparisons will be performed by use of the 
Cochran-Mantel-Haenszel (CMH) test for categorical variables and two-way analysis of 
variance (ANOVA) for continuous variables. If statistically significant differences in 
demographic or patient characteristics (potential confounding risk factors) of the enrolled 
patients between treatments are detected, they will be used as the covariates adjusted in a 
logistic regression model (SAS LOGISTIC procedure) model for the primary endpoint. The 
odds ratios for ABT versus SOC together with the two-side 95% confidence intervals and 
corresponding p-values will be summarized. Similarly, if statistically significant differences 
for the parameters among the sites are detected, analysis of covariance (ANCOVA) will be 
performed to compare the days of antibiotic use between treatments with the confounding 
factor of site and the above parameters that have significant differences among sites.  
 
 
 
9.3 Handling of Missing Data 
 
Missing efficacy data will be handled as follows: subjects who had infection and missing 
values in efficacy variable at final TOC will be considered as treatment failure for the 
primary analyses. If a subject was randomized without infection, the efficacy variable will be 
missing, and will not be included in efficacy analysis. 
 
For assessment of the primary endpoint, missing values will be counted as missing, and 
imputed by early TOC for the sensitivity analysis. 
 


STATISTICAL ANALYSIS PLAN 
  
 
 
 
 
13 
 
9.4 Handling of Duplicate Lab and EKG Data 
Handling of duplicate lab and ECG records from 2 samples drawn at the same date is shown 
as follows: 
If one of the duplicate records can be identified as the unscheduled one from source 
document, only the scheduled record will be included in the analyses. 
If duplicate records are collected all for the scheduled visit for some reason, worst case 
scenario will be applied in the analyses.  
All records will be included in the listings. 
  
9.5 Patient Disposition, Discontinuation and Baseline Data 
9.5.1   Patient Disposition, Discontinuation 
Number of subjects randomized, treated, completing the study and reasons for 
discontinuation will be summarized by treatment group. 
 
 
9.5.2   Demographics and Baseline Characteristics 
In order to assess the baseline comparability of the treatment groups, relevant data on the 
following demographic and baseline characteristics will be tabulated by treatment and overall 
for the ITT and per protocol population.  
 
Demographics and Baseline Characteristics: Age (years), Race, Ethnicity, Weight, BMI, 
route of acquisition of infection (nosocomial, health-care associated and community-
acquired) and comorbid condition(s). 
     
9.6 Concomitant Medications 
 
Empiric treatment for Gram-negative pathogens is allowable; these agents will not be 
counted when calculating antibiotic days unless: 1) susceptibility testing of the bloodstream 
staphylococcal isolate reveals that the staphylococcus is susceptible to the antibiotic, and 2) 
the patient is not receiving other protocol approved antistaphylococcal treatment (e.g., 
methicillin-susceptible staphylococcal bloodstream isolate from a patient receiving empiric 
beta-lactam therapy for gram-negative infection).  
 
A Medical Coder will code concomitant medications using a current version of the 
WHODRL dictionary. The number and percent of patients taking concomitant medications 
will be tabulated by treatment group.  


STATISTICAL ANALYSIS PLAN 
  
 
 
 
 
14 
9.7 Statistical Analyses 
9.7.1   Primary Analyses 
 
The primary efficacy analysis is to compare cure rate between algorithm-based treatment and 
SOC treatment.  
 
Point estimates and the corresponding two-sided 95% confidence intervals for the difference 
of cure rate in each treatment will be calculated. The large sample z-test for comparing the 
two proportions will be performed to test the inferiority with the pre-specified non-inferiority 
margin. The CMH test and ANOVA or ANCOVA will also be performed to compare the 
difference of the intrinsic differences in the clinical experiences and practices at each site, 
characteristics of enrolled patients(including route of acquisition of infection), and variations 
in administering antibiotic dosing schemas as appropriate.  If there is statistically significant 
difference for the above parameters among the sites detected, the logistic regression model 
with the confounding factor(s), which had significant difference among sites, will be used to 
comparing the cure rate between treatments. The odds ratios of cure rate of algorithm-based 
treatment versus SOC therapy together with the 95% confidence intervals, corresponding p-
value will be summarized. 
Because safety will also be assessed as a primary endpoint in this trial, safety will be 
evaluated by comparing all SAEs in the algorithm-based treatment and SOC treatment.   
 
9.7.2   Secondary Efficacy Analysis 
 
The secondary analysis is to compare the days of antibiotic use between the algorithm-based 
treatment and SOC treatment for the PPE population, which includes subjects having simple 
CoNS, or uncomplicated CoNS, or uncomplicated S. aureus.  For DSMB, compliance with 
study antibiotic days per protocol will be evaluated and compared by treatment. 
 
Patients in the simple or uncomplicated cohort who develop new complicated staphylococcal 
infection after the completion of study treatment for their baseline clinical classification of 
bacteremia will be remained in their original group and counted as failure.  They will be 
included in the PP analyses as treatment failures and their antibiotic days for their original 
grouping (e.g., the clinical group to which they had been assigned before being defined as 
having complicated infection) will be included in the Secondary analysis. 
 
Patients in the simple or uncomplicated cohort who develop complicated staphylococcal 
infection after randomization but prior to the completion of effective treatment for their 
baseline clinical classification of bacteremia should remain in the PP analysis. Cure will be 
determined at their TOC visits.  These patients will be regrouped in the complicated 
bacteremia population of the algorithm. 
 


STATISTICAL ANALYSIS PLAN 
  
 
 
 
 
15 
Point estimates and the corresponding two-sided 95% confidence intervals for the difference 
in the days of antibiotic use between the algorithm-based treatment and SOC will be 
calculated. ANCOVA will be performed to compare the days of antibiotic use between 
treatments after adjusting the organism and type of infections, and any significant  
confounding factor(s).  
 
Extent of exposure to study medication will be presented in terms of treatment duration and 
mean daily dose. A summary table will be provided for dose compliance. 
 
9.7.3   Sensitivity Analyses 
 
 
Sensitivity analysis with respect to missing data imputation will be performed. More 
specifically, for the first step, we will construct the primary estimates and corresponding two-
sided 95% confidence intervals denoted as (L, U) of cure rate by imputing method specified 
in Section 11.3.6; for the second step, we will construct the secondary estimates and 
corresponding two-sided 95% confidence intervals of cure rate without imputing the missing 
values, that is, treating missing as missing. If the secondary estimates drop in the 
corresponding (L, U), or their confidence intervals do overlay with the primary ones, then we 
can conclude that our primary analysis is robust. Otherwise, our conclusion based on the 
primary analysis will have limitations.  
9.7.4   Exploratory Analyses 
 
The exploratory analyses include comparisons of the treatment effects for the endpoints cure 
rate and the days of antibiotic for the following diagnostics subgroups in the ITT and PP 
populations, respectively: 
1.  Cohort of CoNS 
2.  Sub-cohort of simple CoNS 
3.  Sub-cohort of Uncomplicated CoNS  
4. Cohort of S. aureus Bacteremia 
5. Sub-Cohort within uncomplicated S. aureus Bacteremia 
 
 
 
 
 
 
 
 
 
 


STATISTICAL ANALYSIS PLAN 
  
 
 
 
 
16 
Table 4 Summary of Endpoints  
Comparison 
Endpoint 
Population/Analysis 
ABT vs SOC* 
 
Cure rate at TOC  
 
 
 
Event rate of SAE 
Event rate of AEs 
leading to study drug  
withdrawal 
 
Antibiotic days 
ITT/ Primary 1  
PPE/ Secondary 1 
ITT/ Sensitivity2 
 
ITT/ Primary   
PPE/ Exploratory 
 
 
 
PPE/ Secondary 
 CoNS:  ABT vs SOC 
                     
Cure rate at TOC  
ITT/ Exploratory 1 
PPE/ Exploratory 1 
S. aureus:  ABT vs SOC         Same as above 
    Same as above 
CoNS-simple:  ABT vs 
SOC                
    Same as above 
    Same as above 
CoNS-uncomplicated:  
ABT vs SOC                 
    Same as above 
    Same as above 
S. aureus –  
uncomplicated:  ABT vs 
SOC           
    Same as above 
    Same as above 
 CoNS:  ABT vs SOC         Antibiotic days 
 ITT, PPE/Exploratory  
S. aureus:  ABT vs SOC         Same as above 
    Same as above 
CoNS-simple:  ABT vs 
SOC             
    Same as above 
    Same as above 
CoNS-uncomplicated:  
ABT vs SOC           
    Same as above 
    Same as above 
S. aureus –  
uncomplicated:  ABT vs 
SOC          
    Same as above 
    Same as above 
ABT vs SOC 
●associations between 
vancomycin MIC 
values and clinical 
outcomes 
●incidence of changing  
study medication due to 
AE 
●Days to  
discontinuation since 
the first dose 
 
 
 
ITT/ Exploratory 
PPE/ Exploratory 
 
 
 
1    Missing at final TOC will be considered as treatment failure 
2    Missing at final TOC will be considered as missing, and imputed by early TOC 
*:  perform the similar analysis after  adjusting for the confounding factor of site and demographics and baseline characteristics , if they are 
significant by treatments. 
 


STATISTICAL ANALYSIS PLAN 
  
 
 
 
 
17 
In addition, potential associations between vancomycin MIC values and clinical outcomes 
(e.g., cure rates, duration of bacteremia on treatment, and incidence of development of new 
complicated staphylococcal infection) will be assessed as part of exploratory efficacy 
analyses.  
 
9.8 Safety Analyses  
 
The safety analyses will be performed within the ITT population. All AEs leading to study 
drug withdrawal and all SAEs will be collected and tabulated. The incidence rates of change 
vancomycin or a protocol-approved study antibiotic to another protocol-approved study 
antibiotic due to AE associated with study drug will also be tabulated by each treatment 
group. Separate tabulations will list events according to seriousness, maximum severity, and 
worst possible association with study drug.  Other safety parameters, such as laboratory data, 
will also be listed and summarized. 
 
 
9.8.1 Adverse Events 
The number of subjects who have or report at least one adverse event (AE) during the study 
will be tabulated for each treatment group. The number of AEs reported by subject will be 
summarized for each treatment group. Subject frequency counts and percentages by 
MedDRA current version 14.0 and update version lock will be presented by maximum 
severity for each treatment group.  
 
 
9.8.2 Laboratory Data 
Summary statistics (n, mean, standard deviation, median, minimum, and maximum) for 
baseline values, actual values, changes from baseline, and percentage changes from baseline 
will be presented as appropriate by last visit, worst values (either minimum or maximum)  
among post-baseline visits, and treatment group for the following 16 tests-- hemoglobin, 
hematocrit, WBC, Platelet, Alkaline phosphatase, ALT (SGPT),  AST (SGOT), Total 
bilirubin, BUN, Creatinine, Calcium, Glucose, Potassium, Sodium.  
 
Echocardiography will be performed on all algorithm subjects with a baseline blood culture 
positive for S. aureus . The TEE is preferred over the TTE. The echocardiogram will be 
interpreted by both the site’s echocardiographer and an experienced echocardiographer at the 
DCRI Echocardiography Core Laboratory.  A comparison between the site and central 
echocardiogram readings will be performed.  If there are discrepancies, then only the site 
interpretation will be reported on the eCRF and used for clinical decision-making at the study 
site.  Patient outcome at final TOC for those patients randomly selected for CEC adjudication 
of outcome will also be assessed by the CEC using the interpretation of the 


STATISTICAL ANALYSIS PLAN 
  
 
 
 
 
18 
Echocardiography Core Laboratory to ensure that no bias is introduced by the fact that the 
onsite clinicians interpreting the echocardiogram know the clinical condition of the patient. 
 
9.8.3 Vital Signs 
Summary statistics (n, mean, standard deviation, median, minimum and maximum) for 
baseline values, actual values, changes from baseline, and percentage changes from baseline 
will be presented as appropriate by treatment group for vital signs data, including systolic 
blood pressure, diastolic blood pressure, heart rate, and temperature.  
 
10. MONTHLY SAFETY REPORT 
The DSMB charter requests the DCRI to monitor the following event rates on a monthly 
basis: 
  
1. In the patients with simple or uncomplicated bacteremia, compare the incidence of serious 
adverse events (SAEs) between the algorithm and standard of care arm 
2. In patients with simple or uncomplicated infections, compare the incidence of persisting 
and/or relapsing infections between the algorithm and standard of care arm 
3. In all randomized patients, compare the death rate between the algorithm and standard of 
care arms 
  
DCRI will also calculate the Fisher’s exact test comparing incidence rates between the two 
treatment groups, and send an e-mail alerting the study medical monitor if the test is 
significant at the 0.01 level. Table and listings shells are shown in Table 5, and listing 1-1 
and listing 1-2, respectively.  
 
  
The medical monitor will inform the DSMB chair, who will determine whether an unplanned 
DSMB meeting(s) should be convened to study and review the event(s) in more detail. 
  
 
11. REFERENCES 
 
[1]. Chow, S., Shao, J., and Wang, H. (2007). Sample Size Calculations in Clinical Research. 
Second Edition, Chapman and Hall/CRC Press, Taylor & Francis, New York, NY, Chapter 4.  
- For sample size calculation for testing non-inferiority.  
 
12. REVISION HISTORY 
 


STATISTICAL ANALYSIS PLAN 
  
 
 
 
 
19 
Date 
Version / Summary of Change 
September 
13, 
2012 
2nd draft, based on Protocol version 3.0 on August 26, 2011 
April 20, 2011 
1st draft  
July 5, 2011 
Adding imputation for TOC using early TOC for sensitivity 
analysis (section 9.3 2nd paragraph, Table 4) 
August 4, 2011 
Add the frequency of changing study drug into safety analysis, 
CEC description under section study design, add reasons for 
exclusion from PP population under baseline comparability 
section; add Days to discontinuation since the first dose in the 
exploratory analysis 
Nov 19, 2012 
Changed based on protocol amendment version 3.1_12 
March 1, 2013 
Changed based on protocol amendment version 3.1_26 
December 
12, 
2013 
Changed based on protocol amendment version 4.0_11 July 13 
2013 
 


STATISTICAL ANALYSIS PLAN 
  
 
 
 
 
20 
Figure 1: Schematic of Study Design  
 
 
 
* Complicated infection is one of the protocol exclusions however, it is not reason to withdraw patient when 
diagnosed following randomization.  
 
 
 
 
 
 
Blood Culture Results
Positive  for 
S. Aureus or  CoNS  
Coagulase Negative
Staphylococcus
S.aureus 
Bacteremia 
Uncomplicated Complicated
Simple
Complicated
Uncomplicated
Standard of Care
Algorithm Based 
Treatment
Randomized
Coagulase Negative
Staphylococcus
S. aureus 
Bacteremia
Uncomplicated Complicated
Simple
Complicated
Uncomplicated 


STATISTICAL ANALYSIS PLAN 
  
 
 
 
 
21 
Table 5: Summary of Halting Rules 
 
                                                                                ABT                SOC                          P value@ 
ITT population                                                           N=                   N=  
_____________________________________      ___________    ___________   _________  
Number of subjects with simple or                         N1/N (%)        N2/N (%)                   --- 
            Uncomplicated bacteremia             
   SAEs*                                                              N3/N1 (%) N4     N5/N2(%)  N6       
   Persisting and/or relapsing infections                N7/N1 (%) N8     N9/N2(%)  N10     
 
Death—ITT population                                        N11/N (%)           N12/N(%) 
___________________________________________________________________________ 
@: using Fisher’s exact test 
* Entry format: Number of subjects/Number of Eligible subjects (%) # of events 
 Generated based on data downloaded on DDMMMYYYY 
 
 
 
 
 
 
 
Listing 1-1: List of subjects having SAEs, Persisting and/or relapsing infections and simple 
or uncomplicated bacteremia 
--Number of Subjects   
              
Treatment     Cohort     Having SAE                  Having Persisting and/or relapsing infections               
_________    ______   _______________         _____________________________________ 
 
__________________________________________________________________________ 
Generated based on data downloaded on DDMMMYYYY 
 
 
 
 
Listing 1-2: List of dead subjects—ITT population (unique) 
 
Treatment   Cohort  Subject#      Age/gender/race      Days since dose Day 1#           Events leading up to death 
________  ______ ________ ______________ ____________________  _____________________ 
 
_____________________________________________________________________________________ 
#:flag for the death related to study treatment 
Generated based on data downloaded on DDMMMYYYY