Clinical trial NCT02369900
Conditions: Septic Shock Hypotension Tachycardia
Keywords: Esmolol Septic Shock Hypotension Tachycardia
Sponsor: Beth Israel Deaconess Medical Center
Start date: 2015-03-01; Completion date: 2019-12-31
Enrollment: 40 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The main purpose of this study is to determine the effects of controlling the heart rate of patients with septic shock using an intravenous medication called esmolol.

Detailed description:
Septic shock is a leading cause of death around the world, with a mortality that often ranges 30-50% but in some locations may be even higher. Despite advances in critical care medicine over the last several decades, few therapeutic interventions have demonstrated mortality benefit in this population besides antimicrobial medications, intravenous fluids, and controlling the source of the infection; multiple agents which at one time showed promise have ultimately failed to deliver meaningful clinical benefit. As such, there is an ongoing need to identify therapeutic interventions which can modify the course of disease for these patients.

Septic shock is traditionally characterized by a hyperdynamic hemodynamic profile with a high cardiac output (CO) and low systemic vascular resistance (SVR) in association with excessive catecholamine stimulation. Tachycardia is a common finding in septic shock as an early compensatory mechanism to increase cardiac output in the setting of low SVR. Often tachycardia persists beyond the initial stages of septic shock, and has been associated with restricted diastolic ventricular filling, increased oxygen requirements, and tachycardia-induced cardiomyopathy, as well as myocardial depression, immunosuppression, and direct myocyte toxicity via calcium overload. Generally, clinical practice has been to avoid trying to control the tachycardic response for fear of worsening cardiac output and causing cardiovascular collapse. However, a recent single center randomized trial of the intravenous beta-1 adrenoreceptor antagonist esmolol demonstrated that control of heart rate to a more 'normal' range was safe, well-tolerated, and appeared beneficial, with a 30% reduction in mortality found in this trial.

While an intriguing concept with results that appear promising, further investigation among an ICU cohort in the United States is necessary before the administration of beta-blockade therapy to a patient in septic shock should be implemented in routine clinical practice. We hypothesize that the provision of esmolol to patients in vasopressor-dependent septic shock with tachycardia will lower the heart rate, thereby improving diastolic filling time and improving cardiac output, resulting in a reduction in need for vasopressor support. To test our hypothesis, we are conducting a Phase II randomized trial to determine if esmolol decreases vasopressor requirements (primary endpoint) and alters the inflammatory cascade as well as oxygen consumption in patients with septic shock (secondary endpoints).

Arms: arm 1: Esmolol infusion for 24 hours. Esmolol will be titrated to a heart rate of 80 - 94 per minute, starting at 10mcg/kg/min and subsequently increasing every 20 minutes in increments of 10 mcg/kg/min (or slower at the discretion of the team) until target is achieved. The maximum allowed dose will be 300mcg/kg/min.

Patients, irrespective of treatment group, will be managed at the discretion of the clinical team. BIDMC has internal guidelines for the management of septic shock which reflect the most recent 2012 Surviving Sepsis Campaign guidelines and are incorporated into the care of patients with septic shock in the ICUs arm 2: Standard care (no esmolol). Patients, irrespective of treatment group, will be managed at the discretion of the clinical team. BIDMC has internal guidelines for the management of septic shock which reflect the most recent 2012 Surviving Sepsis Campaign guidelines and are incorporated into the care of patients with septic shock in the ICUs
Interventions: intervention 1: Esmolol intervention 2: Saline
Intervention descriptions: intervention 1: None intervention 2: None

Protocol documents:
ICF_002.pdf: 
Esmolol to Treat the Hemodynamic Effects of Septic Shock 
NCT02369900 
September 14, 2020 


[CCI] Committee on Clinical Investigations 
 
Page 1 of 11 
Informed Consent ± Part D 
CCI Form: 3-2013 
PI Revision Date: 09/10/2018    
 
 
 
INFORMED CONSENT FORM TO TAKE PART IN A RESEARCH STUDY 
 
SUBJECT’S NAME:        
TITLE OF RESEARCH PROTOCOL:  Esmolol to treat the hemodynamic effects of septic shock 
PRINCIPAL INVESTIGATOR:  Michael N Cocchi MD 
PROTOCOL NUMBER:  2014P-000415 
 
INTRODUCTION: 
¾ This is a research study; 
¾ Your participation is voluntary; 
¾ A research study includes only people who choose to take part; 
¾ You may or may not benefit from participating in the study.  However, your participation 
may help others in the future as a result of knowledge gained from the research; 
¾ You may leave the study at any time; 
¾ If you choose not to take part, or if you leave the study, your decision will in no way harm 
your relationship with any member of the research team or any other individuals at Beth 
Israel Deaconess Medical Center. 
 
Please read this consent form carefully and ask the investigators or study staff to explain any words or 
information that you do not clearly understand.  Once you read this consent form and understand what 
your participation in this study will involve, you will be asked to sign this form if you wish to take part.  
You will be given a signed copy of the form to keep for your records. 
 
DISCLOSURE OF SPECIAL INTERESTS OF BIDMC AND INVESTIGATORS 
 
This study is being conducted by Dr. Michael N Cocchi MD and is funded by The American Heart 
Association. The funding agency in this study (The American Heart Association) is paying Beth Israel 
Deaconess Medical Center and Dr. Cocchi to perform this research.  BIDMC or Dr. Cocchi have no 
additional interests in this research project. Dr. Michael Donnino, a co-investigator in the study, is a 
paid consultant to the AHA. 
 
WHOM TO CONTACT IF YOU HAVE QUESTIONS OR PROBLEMS 
 
If you have any questions, concerns or complaints about this research or experience any problems, 
you should contact Dr. Cocchi at [617] 754-2341.  
 
PURPOSE 
**FOR CCI USE ONLY** 
Approved by the Beth Israel Deaconess Medical Center Committee on 
Clinical Investigations:  
 
Consent Approval Date:   
9/14/2020 
 
 
 
Protocol Number:  
2014P-000415    
NCT02369900 / Z00.6
 
COMMITTEE ON CLINICAL INVESTIGATIONS 
APPROVAL EXPIRATION DATE 
 
09/13/2021


  [CCI] Committee on Clinical Investigations 
Page 2 of 11 
 
SUBJECT'S NAME: 
TITLE OF RESEARCH PROTOCOL: ESMOLOL TO TREAT THE HEMODYNAMIC 
EFFECTS OF SEPTIC SHOCK 
PRINCIPAL INVESTIGATOR'S NAME: MICHAEL N COCCHI MD 
PROTOCOL #: 2014P-000415 
 
Informed Consent ± Part D 
CCI Form: 3-2013 
PI Revision Date: 09/10/2018   
 
 
Septic shock is a condition where you develop low blood pressure and a fast heart rate due to a 
severe infection.  We often treat patients in septic shock with medications to raise the low blood 
pressure (called vasopressors).  We usually do not treat fast heart rates in patients with septic shock 
unless they are very fast.  Esmolol is a drug called a beta-blocker that is used to treat heart rhythm 
disorders, including fast heart rates. The main purpose of this study is to determine the effects of 
treating the fast heart rate in septic shock with esmolol.  
 
The drug involved in this study, esmolol, is FDA approved for other diseases and conditions where it is 
important to control heart rate, but it is currently unknown whether using esmolol in patients with septic 
shock will be useful, which is why we are conducting this trial.  There are previous studies which have 
indicated benefit to treating the heart rate during septic shock, but this needs to be studied further 
before esmolol could be routinely used for this purpose. 
 
As part of this study we will also obtain blood to run certain tests to compare the blood profile of 
patients who receive esmolol with the blood profile of patients who do not receive esmolol.  These lab 
tests include markers of inflammation and cell function.  
 
 
STUDY PARTICIPANTS 
You have been asked to be in the study because you have septic shock. Approximately 110 people 
will take part in this study at Beth Israel Deaconess Medical Center.   
 
DESCRIPTION OF STUDY DETAILS 
If you agree to be in this study, you will be asked to read and sign this consent form.  After you sign the 
consent form, the following things will happen: 
 
1. Screening Procedures:  Screening procedures are tests and procedures that will be done to 
determine if you are eligible to take part in the research study.  For this research study, the 
screening procedures include: A member of the study staff will review your medical chart and 
speak with you and your physician to determine if you are eligible to participate in the study. 
 
 
2. Randomization Procedures:   
You will be randomly assigned (like the flip of a coin) to receive either standard care for 
septic shock PLUS esmolol or standard care alone (no esmolol).  You have a 1 in 2 
chance of receiving esmolol.  You will not be able to choose the study group to which 
you will be assigned.  Standard care for septic shock is determined by your clinical 
team, in accordance with national guidelines and recommendations, and usually 
involves antibiotics to treat the infection, as well as medications to improve blood 
pressure; both groups will receive this standard care. 
 
 
COMMITTEE ON CLINICAL INVESTIGATIONS 
APPROVAL EXPIRATION DATE 
 
09/13/2021


  [CCI] Committee on Clinical Investigations 
Page 3 of 11 
 
SUBJECT'S NAME: 
TITLE OF RESEARCH PROTOCOL: ESMOLOL TO TREAT THE HEMODYNAMIC 
EFFECTS OF SEPTIC SHOCK 
PRINCIPAL INVESTIGATOR'S NAME: MICHAEL N COCCHI MD 
PROTOCOL #: 2014P-000415 
 
Informed Consent ± Part D 
CCI Form: 3-2013 
PI Revision Date: 09/10/2018   
 
 
 
3. Research Procedures:  If you qualify to take part in this research study, you will undergo 
these research procedures: Your treatment, irrespective of which group you are in, will be 
PaQaged b\ \RXU WeaP Rf cOiQiciaQV aQd baVed RQ BIDMC¶V iQWeUQaO gXideOiQeV fRU WUeaWiQg 
septic shock.  
 
All participants in this study (those receiving the study treatment and those receiving 
standard care) will undergo the following procedures: 
 
x Study Drug: Just after the first blood draw,  
           - If you are randomized to study drug, you will be given an intravenous (IV)  
               infusion of esmolol (weight-based and based on hospital guidelines). The  
               intravenous infusion will take place over approximately 24 hours, and may be  
               adjusted by your nurse to achieve a goal heart rate (80-94 beats per minute).  
 
                -If you are randomized to  standard of care, you will receive 100 mL of saline  
                 solution (lightly salted water). The saline solution is given to patients in order to  
                 keep the treatment of the two groups as similar as possible. The saline will also  
                 mark the beginning of the study in a manner similar to the patients receiving  
                 Esmolol. The initiation of the infusion will serve as the study start time for both  
                 groups. Having comparable time points in each of the groups is important in order  
                 to analyze differences in blood markers. 
 
x Blood Collection: Blood will be drawn at four (4) different times for patients in BOTH 
groups: at the start of the study (time 0) and at 6, 12 and 24 hours after you receive the 
study drug (or same time points if you are in the no esmolol group).  Each blood draw will 
be less than 3 tablespoons (approximately 40 mL).  The total amount of blood for the whole 
study will be 12 tablespoons (160 mL).  
- The blood will be sent to the BIDMC lab to analyze for lacate. The lactate tells 
us about the blood supply and oxygen to your major organs- for example the 
heart and kidneys. 
 - Remaining blood will be frozen and tested for inflammatory biomarkers- which 
are proteins in your blood that indicate or identify inflammation. 
- If you were not in this study, we would not be collecting your blood for this 
purpose.  
- The results of this testing will not be available to you, ICU staff, hospital or 
clinical study staff during the study and therefore will not impact your care 
 
x   Medical record review: We will also perform a more thorough review of your chart to see 
how you are doing while you are in the hospital. From your chart we will collect vital signs, 
laboratory results, radiological testing and other variables and record this information. We 
 
COMMITTEE ON CLINICAL INVESTIGATIONS 
APPROVAL EXPIRATION DATE 
 
09/13/2021


  [CCI] Committee on Clinical Investigations 
Page 4 of 11 
 
SUBJECT'S NAME: 
TITLE OF RESEARCH PROTOCOL: ESMOLOL TO TREAT THE HEMODYNAMIC 
EFFECTS OF SEPTIC SHOCK 
PRINCIPAL INVESTIGATOR'S NAME: MICHAEL N COCCHI MD 
PROTOCOL #: 2014P-000415 
 
Informed Consent ± Part D 
CCI Form: 3-2013 
PI Revision Date: 09/10/2018   
 
 
will collect information until you are discharged from the hospital. If you were not in this 
study we would not be reviewing your medical record. 
 
x Oxygen consumption measurements: If you have a breathing tube in place and are on 
the ventilator (respirator), you will be connected to the Compact Anesthesia Monitor for 
continuous measurements of oxygen consumption. The Compact Anesthesia Monitor will 
be attached to the ventilator tubing. Your ventilator settings will not be changed by our team 
and a respiratory therapist will be present to connect and disconnect the monitor from the 
ventilator tubing.   
 
x Cardiac output measurements:  You will be connected to a non-invasive cardiac output 
monitor for continuous measurements of your cardiac index (a measure of how well your 
heart squeezes).  Sensors will be attached to your chest wall which will provide these 
measurements. 
 
 
RISKS AND DISCOMFORTS 
As a result of your participation in this study, you are at risk for side effects listed in this section.  
You should discuss these with the investigator and with your regular doctor if you choose. 
 
Esmolol risk: 
More Common: Blood pressure decreased, nausea, infusion site reaction  
Less Common: Peripheral ischemia, dizziness, somnolence, confusion, headache, agitation,         
vomiting   
Rare: Abdominal discomfort, abnormal thinking, angioedema, anorexia, anxiety, bradycardia, 
bronchospasm, cardiac arrest, constipation, coronary arteriospasm, decompensated heart 
failure, depression, dyspepsia, flushing, heart block, hyperkalemia, lightheadedness, pallor, 
paresthesia, psoriasis, renal tubular acidosis, seizure, severe bradycardia/asystole, syncope, 
urinary retention, urticaria, xerostomia 
 
Blood Draw Risk:  
Blood will be drawn from a line that you already have in place, so no additional needle sticks will be 
required as part of this study. Every time a central venous or arterial line is accessed there is a very 
small risk of infection. Standard procedures will be followed to minimize this risk.  
 
LOSS OF CONFIDENTIALITY 
There is the potential for loss of confidentiality by participating in this study.  Every effort will be 
 
COMMITTEE ON CLINICAL INVESTIGATIONS 
APPROVAL EXPIRATION DATE 
 
09/13/2021


  [CCI] Committee on Clinical Investigations 
Page 5 of 11 
 
SUBJECT'S NAME: 
TITLE OF RESEARCH PROTOCOL: ESMOLOL TO TREAT THE HEMODYNAMIC 
EFFECTS OF SEPTIC SHOCK 
PRINCIPAL INVESTIGATOR'S NAME: MICHAEL N COCCHI MD 
PROTOCOL #: 2014P-000415 
 
Informed Consent ± Part D 
CCI Form: 3-2013 
PI Revision Date: 09/10/2018   
 
 
made to protect the confidentiality of your identifiable information.   
 
However, if your participation becomes known, it could create a problem or hardship for you 
depending upon the type of information disclosed.   
 
CONFIDENTIALITY 
Information learned from your participation in this study and from your medical record may be 
reviewed and photocopied by the Food and Drug Administration (FDA) and/or other federal and 
state regulatory agencies, and by the drug manufacturer, accreditation agencies, the Committee on 
Clinical Investigations, the Human Subjects Protection Office and others involved in research 
administration of the Beth Israel Deaconess Medical Center with protection of confidentiality so far 
as permitted by applicable law.  Information resulting from this study and from your medical record 
may be used for research purposes and may be published; however, you will not be identified by 
name in such publications. 
 
MEDICAL RECORD  
A copy of this consent form and information collected during this research may become part of your 
medical record, if the information is relevant to the care you receive at Beth Israel Deaconess 
Medical Center. Medical records are considered permanent records; therefore, information cannot 
be deleted from the record. Medical records are available to health care professionals at Beth Israel 
Deaconess Medical Center and may be reviewed by staff when carrying out their responsibilities, as 
well as by external parties such as health care insurers and others in certain circumstances. If you 
are not currently a patient at Beth Israel Deaconess Medical Center and do not have a medical 
record at Beth Israel Deaconess Medical Center, one may be created for you for your participation in 
this research. You may also be required to register as a patient of Beth Israel Deaconess Medical 
Center in order to participate in this research. 
 
POSSIBLE BENEFITS 
It is not possible to predict whether you will benefit directly from participation in this study.  However, 
your participation may help others in the future as a result of knowledge gained from the research. 
The investigators believe that esmolol will lower the heart rate, allowing the heart to fill with more 
blood and increasing the amount of blood being pumped by the heart to the rest of the body.  
 
 
OTHER AVAILABLE OPTIONS 
Taking part in this study is voluntary.  Instead of being in this study, you may choose not to 
participate. 
 
It is important to note that it is possible to get esmolol even if you do not take part in this study.   
Esmolol has not been approved by the FDA specifically for treatment of your condition. However it is 
approved by the FDA for other conditions and is already used in certain clinical scenarios in patients 
 
COMMITTEE ON CLINICAL INVESTIGATIONS 
APPROVAL EXPIRATION DATE 
 
09/13/2021


  [CCI] Committee on Clinical Investigations 
Page 6 of 11 
 
SUBJECT'S NAME: 
TITLE OF RESEARCH PROTOCOL: ESMOLOL TO TREAT THE HEMODYNAMIC 
EFFECTS OF SEPTIC SHOCK 
PRINCIPAL INVESTIGATOR'S NAME: MICHAEL N COCCHI MD 
PROTOCOL #: 2014P-000415 
 
Informed Consent ± Part D 
CCI Form: 3-2013 
PI Revision Date: 09/10/2018   
 
 
with septic shock.  
 
This research study is not meant to diagnose or treat medical problems. Participation in this 
research study does not take the place of routine physical examinations or visits to your regular 
doctor. 
 
IF YOU DECIDE NOT TO TAKE PART IN THE STUDY 
Participation in this study is voluntary.  You have the right to decide not to take part in this study.  If 
you choose to participate, you have the right to leave the study at any time. Your decision to not 
participate will not result in any penalties or loss of benefits to you. The investigators will tell you 
about new information that may affect your willingness to stay in this study.  
 
If you decide not to participate in the study or decide to leave the study early, your decision will not 
affect your relationship with the research team or any other individual at Beth Israel Deaconess 
Medical Center.   
 
 
INVESTIGATORS RIGHT TO STOP THE STUDY 
The investigators have the right to end your participation in this study if they determine that you no 
longer qualify to take part, or if it would be dangerous for you to continue, or if you do not follow 
study procedures as directed by the investigators.  Beth Israel Deaconess Medical Center or the 
funding source may stop the study at any time. 
 
COSTS AND/OR PAYMENTS TO YOU 
 
COSTS COVERED BY STUDY 
You will not be charged for the research drugs or any laboratory tests that are part of this research 
study.  However, you and your insurance company will be charged for other tests, procedures or 
medications of this study that are considered standard treatment for your medical condition.  
 
CO-PAYMENT/DEDUCTIBLE STATEMENT 
You will be responsible for any co-payments or deductibles that are standard for your insurance 
coverage.   
 
PAYMENTS TO YOU: 
You will not be paid for your participation in the study. 
 
COST OF RESEARCH RELATED INJURY: 
 
If you are injured as a direct result of your participation in this study you should contact the 
IQYeVWigaWRU aW Whe QXPbeU SURYided XQdeU Whe VecWiRQ ³WhRm WR CaOO if YRX HaYe QXeVWiRQV´ iQ WhiV 
 
COMMITTEE ON CLINICAL INVESTIGATIONS 
APPROVAL EXPIRATION DATE 
 
09/13/2021


  [CCI] Committee on Clinical Investigations 
Page 7 of 11 
 
SUBJECT'S NAME: 
TITLE OF RESEARCH PROTOCOL: ESMOLOL TO TREAT THE HEMODYNAMIC 
EFFECTS OF SEPTIC SHOCK 
PRINCIPAL INVESTIGATOR'S NAME: MICHAEL N COCCHI MD 
PROTOCOL #: 2014P-000415 
 
Informed Consent ± Part D 
CCI Form: 3-2013 
PI Revision Date: 09/10/2018   
 
 
form.  You will be offered the necessary care to treat your injury.  You or your insurance company 
will be billed for medical care and/or hospitalization related to this injury.  You will be responsible for 
all co-payments and deductibles required under your insurance.  BIDMC will consider 
reimbursement of injury related expenses not covered by your insurance on a case-by-case basis.  
At this time there is no plan to reimburse you for items such as lost wages or lost time from work.  
By signing this consent form you have not given up any legal rights. 
 
A description of this clinical trial will be available on 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. 
 
 
AUTHORIZATION FOR USE AND DISCLOSURE OF YOUR PROTECTED HEALTH 
INFORMATION 
As part of this study, we will be collecting, using and sharing with others information about you.  
Please review this section carefully as it contains information about the federal privacy rules and the 
use and disclosure of your information.   
 
 
PROTECTED HEALTH INFORMATION [PHI] 
By signing this informed consent document, you are allowing the investigators and other authorized 
personnel to use [internally at BIDMC] and disclose [to people and organizations outside the BIDMC 
workforce identified in this consent] health information about you.  This may include information 
about you that already exists (for example: your medical records and other sources of health 
information, demographic information, the results of any laboratory tests, as well as any new 
information generated as part of this study.  This is your Protected Health Information. 
 
PEOPLE/GROUPS AT BIDMC WHO WILL SHARE AND USE YOUR PROTECTED HEALTH INFORMATION 
Your Protected Health Information may be shared with and used by investigators listed on this 
consent form as well as the supporting research team [i.e. research assistants and coordinators, 
statisticians, data managers, laboratory personnel, pharmacy personnel, administrative assistants], 
and may also be shared and used by other health care providers at BIDMC who have treated you in 
the past and have information relevant to the research, or who provide services to you in connection 
with the research.  Your Protected Health Information may also be shared with the members and 
staff of the Committee on Clinical Investigations of Beth Israel Deaconess Medical Center, which is 
responsible for reviewing studies for the protection of the research subjects.  
 
PEOPLE/GROUPS OUTSIDE OF BIDMC WITH WHOM YOUR PROTECTED HEALTH INFORMATION WILL BE 
SHARED 
We will take care to maintain confidentiality and privacy about you and your Protected Health 
Information.  We may share your Protected Health Information with the following groups so that they 
 
COMMITTEE ON CLINICAL INVESTIGATIONS 
APPROVAL EXPIRATION DATE 
 
09/13/2021


  [CCI] Committee on Clinical Investigations 
Page 8 of 11 
 
SUBJECT'S NAME: 
TITLE OF RESEARCH PROTOCOL: ESMOLOL TO TREAT THE HEMODYNAMIC 
EFFECTS OF SEPTIC SHOCK 
PRINCIPAL INVESTIGATOR'S NAME: MICHAEL N COCCHI MD 
PROTOCOL #: 2014P-000415 
 
Informed Consent ± Part D 
CCI Form: 3-2013 
PI Revision Date: 09/10/2018   
 
 
may carry out their duties related to this study: 
 
x Any external health care providers who provide services to you in connection with this 
research 
x Laboratories not affiliated with BIDMC that are involved in conducting tests related to the 
research 
x Statisticians and other data monitors not affiliated with BIDMC 
x Centralized data collectors  
x Your health insurance company 
x The Food and Drug Administration [FDA], the Department of Health and Human Services 
[DHHS], the National Institute of Health [NIH], the Office for Human Research Protections 
[OHRP], and other federal and state agencies that may have jurisdiction over the research 
x Hospital and Clinical Research Accrediting Agencies 
x Data and Safety Monitoring boards that oversee this study (if applicable) 
 
Those who receive your Protected Health Information during the course of the research may not be 
required by the federal privacy regulations to protect it, and they may make further disclosures to 
others and use your information without being subject to penalties under those laws.   
 
 
WHY WE ARE USING AND SHARING YOUR PROTECTED HEALTH INFORMATION 
The main reason for using and sharing your Protected Health Information is to conduct and oversee 
the research as described in this Informed Consent Document.  There are many other reasons 
beyond the research for which BIDMC may use or disclose your Protected Health Information.  Not 
all of these reasons require your express written authorization.  For example, we will use and share 
your Protected Health Information to ensure that the research meets legal, institutional and 
accreditation requirements and to conduct public health activities.  The various ways in which 
BIDMC may use and disclose your protected health information without your authorization are 
explained in a document called the Notice of Privacy Practices.  If you have not received a copy of 
BIDMC¶V Notice of Privacy Practices, please ask us for one and review it before signing this form.  In 
addition to signing this document, you may also be asked to sign a BIDMC General Agreement form 
acknowledging that you have received the BIDMC Notice of Privacy Practices.   
 
NO EXPIRATION DATE – RIGHT TO WITHDRAW AUTHORIZATION 
Your authorization for the use and disclosure of your Protected Health Information in this Study shall 
never expire.  However, you may withdraw your authorization for the use and disclosure of your 
Protected Health Information at any time provided you notify the Principal Investigator in writing.  If 
you would like to take back your authorization so that your Protected Health Information can no 
longer be used in this study, please send a letter notifying the Principal Investigator of your 
withdrawal of your authorization to  
 
 
COMMITTEE ON CLINICAL INVESTIGATIONS 
APPROVAL EXPIRATION DATE 
 
09/13/2021


  [CCI] Committee on Clinical Investigations 
Page 9 of 11 
 
SUBJECT'S NAME: 
TITLE OF RESEARCH PROTOCOL: ESMOLOL TO TREAT THE HEMODYNAMIC 
EFFECTS OF SEPTIC SHOCK 
PRINCIPAL INVESTIGATOR'S NAME: MICHAEL N COCCHI MD 
PROTOCOL #: 2014P-000415 
 
Informed Consent ± Part D 
CCI Form: 3-2013 
PI Revision Date: 09/10/2018   
 
 
Dr. Michael N Cocchi 
1 Deaconess Rd., W/CC2, 
Boston, MA 02215 
 
Please be aware that the investigators in this study will not be required to destroy or retrieve any of 
your Protected Health Information that has already been used or disclosed before the Principal 
Investigator receives your letter, and they are permitted to continue to use and disclose your 
previously collected information as necessary to complete the research. 
 
REFUSAL TO SIGN 
Your clinical treatment may not be conditioned upon whether you sign the Authorization for 
Research. However, if you choose not to sign this informed consent document and authorization for 
the use and disclosure of your Protected Health Information, you will not be allowed to take part in 
the research study. 
 
RIGHT TO ACCESS AND COPY YOUR PHI 
If you wish to review or copy your Protected Health Information as it is made part of your medical 
record, you may do so after the completion or termination of the study by sending a letter to the 
Principal Investigator requesting a copy of your Protected Health Information.  You may not be 
allowed to inspect or copy your Protected Health Information until this study is completed or 
terminated. 
 
ADDITIONAL CONTACT FOR QUESTIONS OR CONCERNS 
You may contact the Human Subjects Protection Office at [617] 975-8500 in the event that you 
would like to obtain information or to offer input about the research study.   This office is 
iQdeSeQdeQW Rf Whe iQYeVWigaWRU RU iQYeVWigaWRU¶V UeVeaUch VWaff aQd caQ aOVR aVViVW ZiWh TXeVWiRQV 
relating to your rights as a participant in research, which may include questions, concerns or 
complaints about your participation in the study. 
 
 
 
ICF REVISION DATES:  
01/26/2015 first approved version 
07/30/2015: addition of co-investigators, addition of normal saline to control group 
09/21/2015: addition and removal of co-investigators 
01/11/2016: diVclRVXUe Rf DU. DRQQiQR¶V (cR-investigator) relationship with the funding entity. 
01/15/2016: change in telephone number for PI 
 
 
COMMITTEE ON CLINICAL INVESTIGATIONS 
APPROVAL EXPIRATION DATE 
 
09/13/2021


  [CCI] Committee on Clinical Investigations 
Page 10 of 11 
 
SUBJECT'S NAME: 
TITLE OF RESEARCH PROTOCOL: ESMOLOL TO TREAT THE HEMODYNAMIC 
EFFECTS OF SEPTIC SHOCK 
PRINCIPAL INVESTIGATOR'S NAME: MICHAEL N COCCHI MD 
PROTOCOL #: 2014P-000415 
 
Informed Consent ± Part D 
CCI Form: 3-2013 
PI Revision Date: 09/10/2018   
 
 
THE FOLLOWING PARAGRAPHS CONTAIN SOME STANDARD INFORMATION WHICH 
GENERALLY APPLIES TO INDIVIDUALS PARTICIPATING IN A RESEARCH STUDY. 
 
CONSENT FORM FOR CLINICAL RESEARCH 
 
I have read the previous page[s] of the consent form and the investigator has explained the details of the 
study.  I understand that I am free to ask additional questions. 
 
If I wish additional information regarding this research and my rights as a research subject, or if I believe I 
have been harmed by this study, I may contact the Human Subjects Protection Office (HSPO). 
 
I am aware that this is a research project and that unforeseen side effects may occur. 
 
I understand that the Beth Israel Deaconess Medical Center has no formal program for compensating 
patients for medical injuries arising from this research.  Medical treatment will be provided for injuries at the 
usual charge to me or to my insurer unless payment is otherwise provided for in this consent form. 
 
I understand that participation in this study is voluntary and I may refuse to participate or may discontinue 
participation at any time without penalty, loss of benefits, or prejudice to the quality of care which I will 
receive. 
 
I acknowledge that no guarantees have been made to me regarding the results of the treatment involved in 
this study, and I consent to participate in the study and have been given a copy of this form. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Subject or 
 
 
 
 
Date 
Legally Authorized Representative   
(Parent if the subject is a minor) 
 
 
 
 
 
 
 
 
 
 
 
Relationship of Legally Authorized Representative to Subject   
 
The subject has been given the opportunity to read this consent form and to ask questions before signing, and 
has been given a copy. 
 
___________________________________________________________ 
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COMMITTEE ON CLINICAL INVESTIGATIONS 
APPROVAL EXPIRATION DATE 
 
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  [CCI] Committee on Clinical Investigations 
Page 11 of 11 
 
SUBJECT'S NAME: 
TITLE OF RESEARCH PROTOCOL: ESMOLOL TO TREAT THE HEMODYNAMIC 
EFFECTS OF SEPTIC SHOCK 
PRINCIPAL INVESTIGATOR'S NAME: MICHAEL N COCCHI MD 
PROTOCOL #: 2014P-000415 
 
Informed Consent ± Part D 
CCI Form: 3-2013 
PI Revision Date: 09/10/2018   
 
 
THE FOLLOWING SECTIONS ARE NOT NEEDED FOR ALL STUDIES AND SHOULD BE 
UTILIZED AS INDICATED: 
 
If the subject is able to speak and understand English but is not able to read or write  
 
I was present dXUiQg Whe eQWiUe RUaO SUeVeQWaWiRQ Rf Whe iQfRUPed cRQVeQW aQd ZiWQeVVed Whe VXbjecW¶V agUeePeQW WR 
participate in the study. 
 
Signature of Witness:  
 
Printed Name of Witness:  
 
Date:   
 
 
If the subject is able to understand English but is not physically able to read or write or see 
 
I ZaV SUeVeQW dXUiQg Whe eQWiUe RUaO SUeVeQWaWiRQ Rf Whe iQfRUPed cRQVeQW aQd ZiWQeVVed Whe VXbjecW¶V agUeePeQW WR 
participate in the study. 
 
Signature of Witness:  
 
Printed Name of Witness:  
 
Date:   
 
 
 
If the subject is not English speaking and signed the translated Short Form in lieu of the English consent 
document. 
 
AV VRPeRQe ZhR XQdeUVWaQdV bRWh EQgOiVh aQd Whe OaQgXage VSRNeQ b\ Whe VXbjecW, I iQWeUSUeWed, iQ Whe VXbjecW¶V 
OaQgXage, Whe UeVeaUcheU¶V SUeVeQWaWiRQ Rf the English consent form.  The subject was given the opportunity to ask 
questions.  
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COMMITTEE ON CLINICAL INVESTIGATIONS 
APPROVAL EXPIRATION DATE 
 
09/13/2021

Prot_000.pdf: 
Esmolol to Treat the Hemodynamic Effects of Septic Shock  
NCT02369900  
 
January 1, 2015 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
B1. 
PURPOSE OF PROTOCOL 
 
We hypothesize that the provision of beta blockade to tachycardic patients in vasopressor-
dependent septic shock will lower the heart rate, thereby improving diastolic filling time and 
improving cardiac output, resulting in a reduction in need for vasopressor support.  To test our 
hypothesis, we propose a Phase II randomized trial to determine if esmolol decreases 
vasopressor requirements (primary endpoint) and alters the inflammatory cascade as well as 
oxygen consumption in patients with septic shock.  Given that the compelling finding of a 30% 
reduction in mortality was the result of a single center European study, we submit that a Phase 
II pilot study is needed in a U.S. critical care environment, to validate this concept, before 
a larger, multicenter U.S. trial could be justified.  If we find that esmolol does allow for more 
rapid decrease of vasopressor need over time, without evidence of harm, we will have the 
necessary and sufficient data upon which to design a larger Phase III investigation aimed at 
addressing clinical patient-related outcomes. 
 
Specific Aim #1: To determine if continuous infusion of esmolol improves the hemodynamic 
profile in septic shock by decreasing the need for vasopressor support.   
In order to achieve this Aim, we will perform a multi- center trial randomizing patients to receive 
a continuous infusion of esmolol compared to usual care (total of 104 patients) with the primary 
outcome of reduction in need for vasopressor support.  
Specific Aim #2: To characterize the effects of esmolol infusion on the pathophysiology of 
septic shock. 
Specific Aim #2a:  To characterize the effects of esmolol infusion on total body oxygen 
consumption (VO2) in patients with vasopressor-dependent septic shock.  
In the Morelli et al.6 study, there was significantly lower VO2 in the esmolol group vs the control 
group at every time point measured (p=0.001).  In that study, VO2 was measured indirectly via 
pulmonary artery catheter measurements; we aim to validate the finding of decreased oxygen 
consumption in patients receiving esmolol by directly measuring VO2 via the ventilator circuit in 
the subset of patients who are mechanically ventilated.  Our hypothesis is that esmolol infusion, 
in part by decreasing the workload of the cardiac myocytes, will decrease overall oxygen 
demand, leading to lower VO2 in septic shock. 
Specific Aim #2b:  To characterize the effects of esmolol on inflammatory markers in patients 
with vasopressor-dependent septic shock.  
 
In previous human and animal studies, esmolol has been associated with decreased 
inflammation as represented by attenuation of inflammatory cytokines and biomarkers.8-11  In 
this Aim, we will test the hypothesis that esmolol modifies the inflammatory response by 
measuring key biomarkers at 0, 6, 12, and 24 hours after enrollment. 
 
 
 
B2. 
SIGNIFICANCE AND BACKGROUND FOR THE STUDY 
Severe sepsis and septic shock are the cause of significant morbidity and mortality 
worldwide.  An estimated 751,000 cases (3.0 per 1,000 population) of severe sepsis 
occur in the U.S. each year, resulting in approximately 215,000 deaths.1 Septic 
shock is characterized by cardiovascular dysfunction (most typically systemic arterial 
hypotension), a hypermetabolic state, and lactic acidosis, potentially leading to death. In 
addition, the economic burden on the health care system for patients suffering from 
severe sepsis is striking.  Weycker et al. report that patients suffering from severe sepsis 
will require an average of $45,000 dollars of medical care cost on their index admission 


and up to $78,500 dollars in the first year post-diagnosis.12  These figures rival such 
entities as acute myocardial infarction, trauma, and stroke. 
 
Despite advances in critical care and increased awareness of the need for early 
identification and aggressive treatment of sepsis, morbidity and mortality for septic shock 
remains unacceptably high.  The downstream cardiovascular effects of septic shock, 
beyond the shock period itself, are not trivial: myocardial depression, tachycardia-
induced cardiomyopathy, and direct myocyte toxicity.2-5  Novel therapies for septic shock 
are continually being sought, with a long history of agents which have failed to improve 
outcomes for these patients, and in some cases, have actually conferred harm.13-18 
Currently, there is no adjunctive therapy for the treatment of septic shock that has 
adequately demonstrated an ability to reduce morbidity and mortality.  Furthermore, 
beyond the use of vasopressors and inotropes to support failing hemodynamics, 
there is currently no specific therapy targeted at the cardiovascular effects of 
septic shock.  Identification of a therapy which could improve outcomes for patients with 
septic shock, specifically related to cardiovascular dysfunction, would be a major 
advancement in a field plagued by a history of therapeutic failures.  While a recent single-
center European trial has shown promise for the use of beta blockade in septic shock, 
further evaluation is necessary before widespread application of this therapy could be 
safely and responsibly advocated.  However, there are reasonable existing data 
available to justify moving forward with this line of investigation, as outlined below.       
2.1a. Esmolol is associated with reductions in heart rates in patients with septic 
shock  Morelli et al.6 conducted an open-label randomized Phase II trial of esmolol for 
patients with septic shock who had a heart rate >95/min and received high dose 
norepinephrine to maintain a mean arterial pressure (MAP) >65mmHg.  The 
investigators randomly assigned 77 patients to esmolol and 77 to standard care, with a 
primary outcome of reduction of heart rate to 80-94/min for 96h. Secondary outcomes 
included organ dysfunction as well as mortality. They found that they were able to 
achieve heart rate control in all patients in the esmolol group without adverse effects. In 
what has received the most attention in the critical care community, 28 day mortality was 
49.4% in the esmolol group vs 80.5% in the control group (hazard ratio, 0.39; 95% CI, 
0.26 to 0.59; P < .001).  While these results appear promising, the study cohort may not 
represent a typical septic shock population in a United States ICU.  For example: 
1) The control group had a 28-day mortality of 80.5% and an overall in-hospital mortality 
of 90.9% which is much higher than typical mortality related to septic shock seen in the 
U.S. (generally 25-50% in most U.S. ICUs).19, 20 
2) All of these patients had pulmonary artery catheters (PACs) which are not routinely 
used in the care of septic shock patients in most ICUs   
3) The study patients were receiving what would be considered high doses of 
norepinephrine in most U.S. ICUs (the median dose of norepinephrine in the study was 
0.38 mcg/kg/min [0.21-0.87] in the esmolol group and 0.40 [0.18-0.71] in the control 
group) 
4) All study patients received hydrocortisone (300mg/day) which is not routine for all 
cases of septic shock in most U.S. ICUs 
5) Study patients who had a mixed venous oxygen saturation <65% or increasing arterial 
lactate concentration were treated with levosimendan, a non-adrenergic calcium 


sensitizer aimed at improving systemic oxygen delivery which is not used clinically in the 
United States   
For these reasons, it is essential to reproduce this trial in a critical care environment in 
the United States before larger scale trials could be advocated.  
2.1b. Use of esmolol in septic shock appears to be safe and well-tolerated 
Additionally, a group from the Czech Republic reported the results of a single center trial 
in which 10 septic shock patients were treated with esmolol infusion, demonstrating 
efficacy in terms of heart rate reduction as well as safety of this intervention (no change 
in norepinephrine infusion dosage, non-significant changes in stroke volume, oxygen 
delivery, VO2, or lactate).21 This study further contributes to the data that esmolol therapy 
can be safely administered in septic shock.  
2.1c. Esmolol may modulate the inflammatory response. Previous animal study and 
small human trials suggest that esmolol may modulate the immune response. In an 
animal model of septic shock, mice were injected with lipopolysaccharides (LPS) 
intraperitoneally, and then randomized to either esmolol infusion or normal saline 
infusion.  There was significantly higher survival at 120 hours in the esmolol group 
(34.9%) vs. the saline group (11.6%), p=0.01.  Additionally, the investigators found that 
there was increased gene expression in immunologic and apoptotic pathways which may 
have a role in the survival difference.9  Kim et al.8 performed a trial of esmolol infusion in 
patients undergoing laparoscopic gastrectomy; patients were randomized to one of three 
groups (saline, a clinical dose of esmolol, and a subclinical dose of esmolol).  They 
measured levels of IL-6, IL-4, IL-10, C-reactive protein (CRP), and found that post-
operative levels of IL-4 were decreased significantly in the clinical dose group compared 
to the saline group (2.14 vs 21.91 pg/mL, p=0.022), as well as lower CRP levels on post-
operative day 1 in the esmolol-treated groups in a dose-dependent manner.  
2.1d.  Beta-blocker improves survival of septic rats through preservation of gut 
barrier function. In this study, sepsis was induced via cecal ligation and perforation in 
19 rats, with 9 randomized to control treatment and 10 randomized to treatment with 
esmolol.  Investigators found that mean survival time in the esmolol group was 
significantly longer compared with the control group (69.5 +/- 26.8 vs. 28.6 +/- 11.0 h, 
p<0.01).  Furthermore, intraperitoneal fluid TNF-alpha levels were elevated in the control 
group but significantly depressed in the esmolol group (16.8 +/- 10.7 versus 5.4 +/- 7.1 
pg/mL, p<0.05), and the gut mucosal injury score was elevated (4.1 +/- 0.6 versus 2.8 
+/- 0.6, p<0.01) suggesting that the esmolol infusion may have modified gut barrier 
function in this animal model of intra-abdominal sepsis.10  
2.2 Significance 
2.2a. Overall significance of the current proposal: Given the sheer numbers of 
patients afflicted with septic shock each year, and the current mortality rates despite 
advances in early aggressive treatment and sophisticated critical care, new targets are 
needed in the armamentarium against this disease. With the ageing of the U.S. 
population, it is anticipated that the incidence of sepsis and septic shock will only 
increase1, adding to the urgency to identify an intervention to improve outcomes and 
reduce disease burden amongst survivors.  


2.2b. Innovation:  The current proposal is innovative in that it leverages an existing 
therapeutic agent for a new indication, building on existing data supporting the concept 
of beta-adrenergic antagonism in septic shock.  If the promising findings reported in the 
recent single center study from Italy6 could be confirmed in a pilot study in a septic shock 
cohort in a typical U.S. tertiary care medical center, the science of the resuscitation of 
septic shock could be considerably advanced.  Esmolol, which is already used in practice 
in other clinical scenarios in critical care, could easily be incorporated into the treatment 
of patients with septic shock, if the balance of evidence ultimately indicates benefit in this 
population.  In addition to evaluating the effects of esmolol on hemodynamics, our 
proposal is innovative in that we will also directly measure continuous VO2 in the subset 
of patients who are mechanically-ventilated in order to better understand how beta 
blockade therapy will affect overall oxygen consumption in a septic shock population, 
which to our knowledge has not been previously examined in this way.  
 
 


 
 
B3. 
DESCRIPTION OF RESEARCH PROTOCOL 
A. 
Study Design – Overview, Methods, Procedures 
 
Study Design: A Multi-center, open-label, randomized, phase II trial comparing esmolol 
to standard care (no esmolol) in septic shock patients with tachycardia.  
 
Screening: All patients admitted to the 
ICU will be identified through 
electronic patient records and 
screened for possible enrollment 
by trained research assistants. 
Our research group employs 
multiple 
full-time 
research 
assistants 
responsible 
for 
screening and enrollment. With 
this staffing structure, we are 
able to enroll patients 24 hours 
per day/7 days per week. 
Consent: If a patient meets all of the 
inclusion criteria and none of the 
exclusion criteria, a member of 
the research team will approach 
the patient for written informed 
consent. If the patient is unable 
to consent, a legally authorized 
surrogate may be approached 
per standard IRB procedures. 
Investigators will explain the 
study’s 
background 
and 
significance, potential risks and 
benefits, and study protocol. In 
the event that a physician Investigator or a surrogate is not physically present in 
the hospital to perform the consent process, a non-physician study staff (research 
assistant or research coordinator) will coordinate a conference (i.e. FaceTime or 
Skype video conferencing or telephone) for the physician investigator / surrogate 
to join in the consent discussion. If consent is obtained, a signed copy will be given 
to the patient and another copy placed in the medical record. The original signed 
informed consent will be kept in our locked research office (see specifics in 
Section B6 - Recruitment and Consent Procedures).  
Randomization:  The randomization will be done in a 1:1 ratio between treatment and 
control groups in varying blocks of two to six using SAS software. This main list 
of group assignment will be maintained in the hospital research pharmacy.  
Screening: Septic Shock 
(100% screening capacity) 
Consent, enrollment, and 
randomization within 6-12 hours 
of ICU admission 
(104 patients) 
Esmolol infusion 
(n=52) 
Standard care  
(n=52)  
Primary Outcome:  
Reduction in need for vasopressor support 
 
Secondary Outcome:  
a) Change in inflammatory biomarkers 
b) Change in VO2 (mechanically-ventilated patients) 


Study Arms: After randomization as described above, patients will be assigned to one 
of the following two arms: esmolol for 24 hours or standard care (no esmolol). 
1) Esmolol for 24 hours: Patients in this arm of the study will have Esmolol for 24 hours. 
 
2) “Usual Care”: Patients will receive 100 mL of normal saline over 5-10 minutes at the 
beginning of the study in addition to usual care. When patients are enrolled in a clinical 
trial there is a time period from consent to study drug administration that depends on 
the investigative team, the research pharmacy, and the available nursing staff. In 
order to guarantee that this time interval is similar between the two groups the 
control arm will receive a small bolus of saline at the beginning of the trial. This will 
ensure that “time zero” is similar between the two groups. 
 
 
Blinding: The study will not be blinded as an esmolol infusion must be actively titrated 
to effect by clinicians and it will noticeably decrease heart rate. 
 
Standard septic shock treatment: Patients, irrespective of treatment group, will be 
managed at the discretion of the clinical team.  BIDMC has internal guidelines for 
the management of septic shock which reflect the most recent 2012 Surviving 
Sepsis Campaign guidelines and are incorporated into the care of patients with 
septic shock in the ICUs.23  
 
Study medication preparation and administration: After consent and enrollment, a 
form will be faxed to the pharmacy confirming the consent, indicating the specific 
study, and supplying information on the location of the patient. An electronic order 
will be placed in the computer to initiate the study drug. Telephone contact will be 
made with the pharmacist to confirm receipt and execution of the study medication 
protocol. Enrolled patients will be randomized to either esmolol or standard care 
(see above). The study drug will then be sent to the ICU and will be administered 
to the patient by the treating nurse. Esmolol will be titrated to a heart rate of 80 - 
94 per minute, starting at 10mcg/kg/min and subsequently increasing every 20 
minutes in increments of 10 mcg/kg/min (or slower at the discretion of the team) 
until target is achieved. The maximum allowed dose will be 300mcg/kg/min. 
Esmolol will be continued for 24 hours. 
            If the patient is randomized to standard care, a one-time 100 mL saline placebo 
will be administered as a time stamp for the study protocol.  
  
 
Rationale for dosage regimen: The dosing regimen chosen for this study is similar to 
that described in the study by Morelli et al.6  In that study, the median esmolol 
dose was 100mg/hr (IQR 50-300), and they did not exceed a maximum of 
2000mg/hr.  At BIDMC, we administer esmolol via a weight-based protocol, and 
for an average 70kg patient, the mean dose would not be expected to exceed the 
maximum dose used in the Morelli et al. study, therefore helping to ensure safety.  
Since esmolol is titrated, we will have a titration protocol that will be utilized by the 


bedside nurse in the ICU to adjust the infusion based on target heart rate 
parameters.      
 
Safety considerations: In order to minimize the risk of causing a decrease in cardiac 
output and resultant worsening hypotension, we will only enroll patients after they 
have been adequately volume resuscitated such that preload is optimized.  
Furthermore, we will obtain a baseline measurement of CO/CI; study drug will 
only be administered if the CI >2.2 L/min/m2.  By using an ultra-short acting (t1/2 
approximately 9 minutes24) and titratable agent like esmolol, the infusion can be 
adjusted or even terminated without lingering effects of the medication if there are 
unintended hemodynamic effects such as hypotension or decrease in CI.  We will 
ensure nurse comfort and competency by having the dedicated ICU Clinical 
Nurse Specialists (CNS) oversee the implementation as it pertains to frontline ICU 
nurses.  We will also have a critical care pharmacist assist with the design of the 
titration protocol.   
 
Measurements: 
Hemodynamics: Heart rate and blood pressure will be measured hourly for all patients 
for the full study period. Cardiac index and stroke volume will be measured 
continuously with the use of the Non-invasive Cardiac Output Monitor (NICOM) 
(Cheetah Medical, Oregon, USA) which is a validated tool for hemodynamic 
measurements in the critically ill.25  
Vasopressors: Vasopressor doses will be recorded hourly for the full study period. 
Additional measurements: At baseline we will collect pertinent variables such as 
demographics and past medical history. At baseline, 6, 12 and 24 hours after, 
trained research assistants will collect information on laboratory values and 
interventions performed by the clinical team (including but not limited to fluid 
administration, procedures, pharmacological intervention etc.), ventilator settings, 
results of cultures, etc. Patients will be followed to hospital discharge and time on 
mechanical ventilation, length of ICU stay, length of hospital stay and mortality will 
be recorded. SOFA scores26 will be calculated at all time points.  In a subset of 
patients who are mechanically ventilated, we will also continuously measure 
oxygen consumption for these patients via continuous VO2 monitor connected to 
the ventilator circuit (see below for details). 
 
Research Blood draws: At each of the four time point approximately 40 mL of blood will 
be obtained by venipuncture, or from an existing venous or arterial catheter for a 
total of 160 mLs of blood: (40ml x 4 draws =160ml) 
1. Time zero (just before study drug administration) 
2. T=6 hrs (+/- 4 hrs) 
3. T=12 hrs (+/- 4 hrs) 
4. T=24 hrs (+/- 4 hrs) 
 
 
Data Collection: 


Cytokine and biomarker analysis: Blood will be processed, aliquoted and frozen at -80ºC 
for later cytokine and potential other biomarker analyses. Measurements will 
include but not necessarily be limited to Interleukin (IL)-1β, IL-6, IL-8, IL-10, 
metabolomic profile, CRP, procalcitonin, and IL-6, IL-4, IL-10, TNF alpha at serial 
time points (0, 6, 12, 24 hours) after study drug delivery.  The inflammatory 
cascade assays will be measured in the Center for Resuscitation Science 
Laboratory. 
 
Oxygen metabolism analysis: Research blood will be used in the isolation of peripheral 
blood mononuclear cells (PBMCs) from blood: Plasma will be separated by 
centrifugation at 800g for 15min at 4°C and saved without disturbing the buffy 
coat. Then plasma will be replaced with the same volume of phosphate buffered 
saline (PBS). The cell pellets will then be mixed by gently pipetting up and down 
several times to disperse the cells. Next, PBMCs will be isolated from the PBS 
substitute blood samples using density gradient, Ficoll-Paque premium (GE 
Healthcare Bio-Sciences Corp).  
 
The isolated PBMCs will be used in the cellular metabolism and mitochondrial function 
analysis. Using the XF24 Extracellular Flux Analyzer (Seahorse Bioscience) we 
will simultaneously measure the oxygen consumption rate (an indicator of 
mitochondrial respiration), and the extracellular acidification rate (an indicator of 
the lactate produced e.g. anaerobic metabolism). First, PBMCs will be re-
suspended in Dulbecco's modiﬁed Eagle's medium and seeded in a 24-well assay 
plate pre-coated with CellTak (BD Biosciences) and incubated at 37°C for 30 min 
to allow cells to attach to the bottom of the plate. Then the wells will be washed 
and 675uL of fresh XF assay buffer will be added to each well. The plate will be 
incubated at 37°C without Carbon Dioxide (CO2) for 1 hour prior to assay start.  
 
 
Lactate, ScVO2 measurements: Lactate and ScVO2 levels will be measured using whole 
blood collected in a standard blood gas syringe by the clinical nursing team with 
the assistance of our research staff at the bedside prior to drug delivery (baseline), 
and again at 0, 6, 12, 24 hours after enrollment. The sample will be sent to the 
hospital’s clinical lab for immediate analysis.  
 
 
VO2 measurements: The Compact Anesthesia Monitor by General Electric is a patient 
monitor with a built-in module for measuring spirometry and gas exchange. A 
respiratory therapist will be responsible for connecting/disconnecting the monitor.  
The gas exchange module measures the volume of inspired gas using a 
pneumotachograph, and the partial pressure of oxygen with inspiration and 
expiration using a rapid paramagnetic analyzer. Measurements are taken by a 
sensor placed in the ventilator tubing and connected to the gas analyzing 
module,27  providing continuous readings with each patient breath. All data are 
downloaded onto a laptop used solely for research purposes. The Compact 
Anesthesia Monitor has been FDA approved for the measurement of VO2 in 


mechanically ventilated patients. The technology has been validated against 
indirect calorimetry, and is perhaps even more accurate at higher FiO2.27, 28   
 
Outcome measures and data management:  
Primary endpoint: The primary endpoint will be improvement in the hemodynamic profile 
as measured by a decrease in the need for norepinephrine support. This will be 
defined as the difference in norepinephrine dose between groups at 6 hours after 
onset of study drug.     
Justification: The initial trial showed that esmolol not only decreases heart but also 
decreases vasopressor requirements in patients with septic shock. While the 
reduction in heart rate might be considered expected from a beta blocker, the 
reduction in vasopressor dosage is not. However, the reduction in vasopressor 
dosage would be a significant clinical advancement for the treatment of septic 
shock and therefore we chose this as the primary clinical endpoint for the trial. We 
chose the 6 hour time point as the primary endpoint since we anticipate the effect 
of esmolol will be apparent by that time (rapid onset and effect based on previous 
study) and that the variance between groups (based on our control preliminary 
data) is minimal at that time point allowing for adequate power to detect a 
difference. We also will have secondary endpoints evaluating other time points as 
well as change over time (below). 
Secondary endpoints:  
Additional hemodynamic endpoints: While the primary endpoint will be difference in 
norepinephrine dose at 6h, we will also measure the difference in vasopressor 
dose between groups at 12h and over time using mixed linear model (see data 
analysis).  We will also measure differences in heart rate at the 6 and 12h time 
points and over time (see data analysis). Other secondary hemodynamic 
endpoints will include time to shock reversal (cessation of all vasopressors for at 
least 12h) and change in lactate over time (0, 6, 12, 24 h). 
Oxygen consumption: Aim #2a endpoint will consist of difference in oxygen consumption 
over time between esmolol and control groups.  Based on findings in the Morelli 
et al. study, we anticipate a similar decrease in VO2 among those who receive 
esmolol.  While Morelli et al. measured VO2 via PA catheter, we will measure 
VO2 directly via the ventilator.  
Inflammatory endpoints: For Aim #2b, we will characterize the effects of esmolol infusion 
on the inflammatory cascade as measured by changes in select inflammatory 
biomarkers at time points 12 and 24 hours accounting for baseline measurements 
at time zero.  
Clinical endpoints: Recognizing that we lack power to detect differences in mortality, we 
will still collect in-hospital mortality anticipating that if the overall study is positive, 
we can use these data to help power a future Phase III trial.  In addition, we will 
measure the clinical endpoints of length of ICU stay, hospital length of stay, and 
organ dysfunction at 96 hours as defined with the SOFA score. 
Data acquisition and management: Dr. Cocchi and the Center for Resuscitation Science 
have extensive experience in data collection, data entry, database development, 
and data management for both large-scale observational trials and randomized 
clinical trials. The Center for Resuscitation Science currently manages over 20 


active databases with over 1 million data points from nearly 10 years of research. 
As such, we have honed an effective and reliable protocol for managing data as 
described below. 
Data Entry and Quality:  
Immediately following data collection, the paper data sheet will be entered directly into 
the electronic database REDCap (described below). Two trained research 
assistants will independently enter the data for primary and secondary endpoints 
to ensure transfer accuracy. Several measures are taken to assure data quality. 
They are as follows: 
1) Database access is restricted to team members trained in data entry for this study. 
2) The REDCap database is specifically designed to maintain data integrity by preventing 
unintentional changes or lost data. 
3) The principal investigator and/or his designee will perform random data spot-checks 
and audits. 
4) Designated database manager will be assigned to oversee the database and to 
maintain quality. 
 
Database: The database application we will use is REDCap. REDCap is a professional 
database endorsed by the National Institutes of Health (through the clinical and 
translational science award) that provides a secure, user-friendly database with 
capacity for easy statistical analysis. To ensure confidentiality, all entries will be 
identified by a patient identification number rather than a name or hospital medical 
record number. The REDCap data management system is fully HIPAA-compliant 
and includes a complete audit-trail for data entry validation. We will maintain an 
electronic and paper copy of the master list with identifiers. The computer list will 
be maintained on the hard-drive of two separate computers in password-
protected files. 
 
 
Information security: All hard copies of study data will be kept in a locked filing cabinet to 
which only the PI and co-investigators will have access.  All electronic data will be 
stored on the BIDMC secure server behind a firewall in a password protected 
database. We will also utilize the database application, REDCap. REDCap is a 
professional database endorsed by the National Institutes of Health (through the 
clinical and translational science award) that provides a secure, user-friendly 
database with capacity for easy statistical analysis. 
 
Safety Monitoring: 
In order to help ensure adequate protection of human subjects enrolled in this clinical 
study, we established an independent three-member panel with expertise in the 
areas of clinical trials, critical care and statistics. The Data Safety Monitoring 
Board (DSMB) will consist of: 1) Dr Peter Clardy MD (Pulmonary Critical Care at 
Mount Auburn Hospital and former MICU Director BIDMC, will serve as Chair of 
DSMB), 2) Dr. Marwa Sabe MD, MPH (Cardiovascular Disease and Advanced 
Heart Failure) and 3) Dr. Myles Boone MD (Anesthesia Critical Care).  
 


The DSMB will be charged with reviewing all serious adverse event reports and will also 
perform interim analysis of the data.  A statistician will prepare the data reports for 
review by the DSMB Committee.  Data will be reviewed for safety after the initial 
20 patients are enrolled and then every 40 patients thereafter; this schedule is 
subject to change depending on the recommendations of the DSMB.  Any 
adverse events will be reported in real-time.  The Chair of the DSMB can convene 
a meeting at more frequent interval if deemed necessary. 
 
The site PIs at each collaborating institution will be responsible for reporting all 
adverse events (AEs), serious adverse events (SAEs) as well as any other adverse 
events or issues felt to be related to the study protocol to the coordinating center , 
Beth Israel Deaconess Medical Center.  In addition to reporting all adverse events to 
the DSMB, all adverse events will be disseminated by BIDM to each participating 
institution’s IRB for review according to their policies and guidelines. 
 
 
 
 
 
 
POSSIBLE BENEFITS 
There may be no benefits to patients participating in this study. This is a randomized 
interventional trial. Although we do not know whether the active medication will provide 
benefit it is possible that patients enrolled in this investigation and receive the active 
medication will have improved lactate clearance and better clinical outcome. The 
knowledge gained from the proposed study may help similar patients in the future. 
 
 
 
 
B5. 
POSSIBLE RISKS AND ANALYSIS OF RISK/BENEFIT RATIO 
 
Risks to patients involve the following main areas:   
 
(1) Risk associated with hemodynamic effects of esmolol: Esmolol is an FDA-approved 
medication that is already utilized in clinical practice but in this trial will be applied 
for the purpose of controlling heart rate in septic shock, which is not standard clinical 
practice. We have created procedures to ensure that patients have been adequately 
volume resuscitated and will be well-monitored in a critical care setting before 
receiving this infusion.  All patients will have continuous monitoring of cardiac output 
during the study period.  
 
There are side effects associated with esmolol, which range from minor to serious: 


More common: Blood pressure decreased, nausea, infusion site reaction  
Less Common: Peripheral ischemia, dizziness, somnolence, confusion, headache, agitation, 
vomiting   
Rare: Abdominal discomfort, abnormal thinking, angioedema, anorexia, anxiety, 
bradycardia, bronchospasm, cardiac arrest, constipation, coronary arteriospasm, 
decompensated heart failure, depression, dyspepsia, flushing, heart block, hyperkalemia, 
lightheadedness, pallor, paresthesia, psoriasis, renal tubular acidosis, seizure, severe 
bradycardia/asystole, syncope, urinary retention, urticaria, xerostomia 
 
Esmolol is ultra-short acting and easily terminated if there are any untoward side effects like 
significant drop in cardiac output or hypotension.   The low risk of esmolol administration 
and the potential increased understanding of the role of the cardiovascular system in septic 
shock, as well as identification of a new therapeutic target, make the risk/benefit ratio of this 
study beneficial.   A three-physician panel along with a biostatistician will be convened a 
minimum of once a year to provide data safety and monitoring for the trial. Any adverse 
events will be reported in real-time. The Chair of the DSMB can convene a meeting at 
intervals more frequently if deemed necessary and all potential issues and concerns will be 
reported to both the Institutional Review Board (IRB) and the Chair of the DSMB in real-
time.  This study proposal will be reviewed by the IRB at BIDMC. All data will be kept 
confidential as detailed above.  
 
(2) Risk associated with blood draws: The majority of septic shock patients will have arterial 
and/or venous access at the time of the blood draws and phlebotomy will therefore not be 
necessary. There is a very small risk of infection associated with assessing venous or arterial 
lines. If patients do not have existing lines we will perform venipuncture the risks associated 
with venipuncture (for blood draws for biomarker analysis) include momentary pain during 
needle insertion and hematoma at the site of needle insertion. Infection, excess bleeding, 
clotting, and fainting also are possible, though unlikely. A qualified health care professional 
trained in accessing existing lines will do this thereby minimizing the already very low risk of 
infection. For those few patients requiring phlebotomy we will minimize the highly unlikely 
side effects of a blood draw by conforming with standard phlebotomy techniques including 
drawing blood while patients are supine, the site of the blood draw will be cleansed prior to 
the draw, and direct pressure will be held post-blood draw. All research assistants 
performing phlebotomy will have formalized training and oversight.    
 
(3) Risk associated with VO2 and cardiac index measurements: Connecting the GE monitor 
requires a brief disconnection (less than 5 seconds) of the ventilator tubing. This will always 
be done by a respiratory therapist, and we have had no adverse effects from this in any of our 
pilot studies using similar equipment. Once the monitor is connected it confers no risk or 
discomfort to the patient. The NICOM is connected with four adhesive sensors similar to 
electrocardiography (ECG) or telemetry leads. All ICU patients already have telemetry leads 


attached to the chest, so we do not think the addition of four sensors will add significantly to 
patient discomfort. 
 
(4) There is the risk of loss of confidentiality. However, none of the participant’s protected 
health information will be shared with any of the other sites.  In addition, all measures will 
be taken to ensure that no confidential information is released. All data will be kept on 
password protected computers behind the BIDMC firewall. The data safety and monitoring 
board (DSMB) will provide a multidisciplinary, independent review of the study design, 
ethical and scientific conduct of the study, monitor interim results and make 
recommendations with respect to continuation, modification, termination of study. Each 
individual is an experienced academician and together will provide clinical, research, and 
statistical expertise. The DSMB will meet at planned interim analyses for safety, at 
completion, and at any other needed interval. 
 
We do not anticipate any psychological risks of participating in the study. There will be no 
financial risks associated with study participation. 
 
      
 
B6. 
RECRUITMENT AND CONSENT PROCEDURES 
 
Recruitment 
Potential subjects will be evaluated for eligibility by the research team. Some of these patients 
may be critically ill and unable to provide informed consent. However, due to the severity of 
their illness, most of these patients will have family members or their health care proxy (HCP) 
in attendance.   If the patient is unable to consent for themselves, consent may be obtained 
from a legally authorized representative (LAR). 
 
Before the patient or surrogate is approached for consent, the case is reviewed by the study 
MD (PI or Co-investigator) to ensure that the patient is appropriate for inclusion in the trial. 
Additionally, the physician on the clinical team caring for the patient is contacted as well, to 
ensure that the clinical team authorizes approaching the patient/surrogate for consent.   
 
Consent 
Consent will be obtained by the Principal Investigator (Dr. Cocchi) or one of the physician co-
investigators prior to performing any procedures solely for the purpose of research. If the 
patient is eligible, the Principal Investigator (PI) or physician co-investigator will review the 
consent with the patient/proxy, making sure to discuss the potential risks and benefits as well 
as all steps that will be required for the patient to participate. The consenting Investigator will 
specify that participation in the trial is optional, and that the patient’s choice to participate or 
not participate in the study will not affect the care they receive. We rely on the independent 
assessment by the clinical team to determine the capacity of a subject to consent as this is 
routinely performed by clinicians who need consent for standard medical care and procedures. 
This methodology avoids bias from the research team and allows for expert clinician 
assessment of capacity.  If the clinical team has deemed or deems a patient not to have 
capacity to consent, we will approach the legally authorized surrogate. If the patient agrees to 


participate, he / she will sign and date (and a witness if applicable) the inform consent form. 
The name of the study investigator obtaining consent will be clearly documented, and this 
person will sign the informed consent document and provide the date of their signature and 
time. Signed copies of the consent form will be given to the participant/legally authorized 
representative (LAR), and the original consent document will be stored in the secure study 
file.  A copy of the consent form will also be placed in the subject’s medical record. 
 
At times, the surrogate may not be in the immediate Boston-area and is unable to come to 
BIDMC within the protocol mandated window for the initiation of study treatment. In such a 
circumstance, the study staff will send the informed consent document to the subject’s 
surrogate electronically (email, facsimile, etc.) and a licensed physician investigator, or a co-
investigator will conduct the consent discussion by video or telephone. Once the surrogate 
has had time to review the consent form, if he/she agrees to participation he/she will sign the 
consent and return the signed document to the investigator electronically (email, facsimile, 
etc.).  
 
All email correspondence will occur in accordance with BIDMC guidelines. Once the signed 
consent form has been received by the investigator, he/she will then sign, date, and time the 
form. No study procedures will occur before the consent form has been signed by both the 
surrogate and the investigator. The surrogate will be instructed to return the original signed 
consent form to BIDMC which will be kept in the subject’s research record with the 
electronically transmitted copy and a detailed note to file. 
 
In the rare event that a physician Investigator is not physically present in the hospital to perform 
the consent process (for example, overnight) and given the time-sensitive nature of this trial, 
a research assistant will coordinate a video conference (ie, FaceTime) between the physician 
investigator, the patient or LAR, and the research assistant; the physician investigator will 
perform the consent from a remote location.  The physician investigator will subsequently sign 
the paper copy; in the interim, the research assistant will sign the consent, in addition to the 
patient or LAR, and that signed copy will be included in the patient’s medical record and as 
well as be provided to the study subject.       
 
Once the patient is enrolled in the trial, the study MD enters a note in the patient’s medical 
record documenting the enrollment.  Only after the consent form is signed by both the 
family/HCP and the investigator, will study procedures take place. In obtaining and 
documenting informed consent, each investigator will comply with the applicable regulatory 
requirements and adhere to the ethical and Good Clinical Practice principles that have their 
origin in the Declaration of Helsinki. The consent must be the Institutional Review Board (IRB)-
approved version corresponding to the version of the protocol approved when the screening 
was initiated.  
 
 
Subject Protection 
There will be no undue influences on the potential study subjects to participate. No subjects 
will be vulnerable to coercion or undue influence. Patient information will be encrypted and 
stored on password protected computers, therefore minimizing the risk of their privacy being 
compromised. 
 
Dr. Cocchi will also periodically review the data to evaluate subjects’ safety and data integrity. 
The purpose is to determine whether study subjects are exposed to unreasonable risk 
because of study participation, and to monitor study progress and integrity. Dr. Cocchi will 


review and report all adverse events to the Committee on Clinical Investigation (CCI) 
according to the adverse event reporting policy of the CCI. 
 
All biological material will be stored in a locked refrigerator/freezer within a locked facility, 
which is under hospital security surveillance at all times.  All electronic records will be 
maintained on BIDMC IS compliant computers. 
  
 
B7. 
STUDY LOCATION 
  
Privacy  
In order to maintain privacy, the investigators will discuss the study and consent the subjects in 
a private area in-hospital. Standard clinical protocols regarding patient confidentiality will be 
followed during the course of the study.  The collection of sensitive information about subjects 
is limited to the amount necessary to achieve the aims of the research. 
 
Physical Setting 
The study will take place in the Emergency Department and ICUs at Beth Israel Deaconess 
Medical Center and Lahey Hospital & Medical Center in Burlington Massachussets. 
 
 
B8. 
DATA SECURITY 
 
All hard copies of study data will be kept in a locked filing cabinet to which only the PI and co-investigators will 
have access. 
 
All electronic data will be stored on the BIDMC secure server behind a firewall in a password-protected database. 
We will also utilize the database application, REDCap. REDCap is a professional database endorsed by the 
National Institutes of Health (through the clinical and translational science award) that provides a secure, user-
friendly database with capacity for easy statistical analysis. The program can support multiple research studies, 
is presently being used at dozens of major academic research centers to support numerous NIH and AHA funded 
projects and is available for free at our center. 
 
 
B9 
Multi-Site Studies 
 
Is the BIDMC the coordinating site?       
 Yes    
 No  
 
Is the BIDMC PI the lead investigator of the multi-site study?     
 Yes    
 No  
 
Coordinating Center (BIDMC) Responsibilities: The trial will be directed by the Principal Investigator, who 
will have responsibility for receiving and analyzing data for the trial, and will oversee all functions. We will 
provide the other institutions with documents to use and communicate procedures. 
 
As the coordinating center for this multicenter trial, Dr. Cocchi assumes full responsibility for 
ensuring all aspects of the study are conducted appropriately.  This will be achieved via the 
following mechanisms, under the direction of Dr. Cocchi: 
1. Coordinating center (the Center for Resuscitation Science – CRS) will receive a copy 
of the screening log from Lahey Hospital & Medical Center on a monthly basis  


2. At a minimum, quarterly conference calls will be held with Lahey Hospital & Medical 
Center site PI/research coordinator to discuss study progress 
3. Any questions or problems that arise during an enrollment will be addressed in real 
time through direct communication between Lahey Hospital & Medical Center staff 
and the CRS. The study PI will be available to Lahey Hospital & Medical Center site 
PI for consultation 24/7 via cell phone/email.  
4. CRS staff will track and report all serious adverse events and unanticipated problems 
5. CRS will provide periodic updates to affiliated investigators on participant enrollment, 
general study progress, and relevant scientific advances 
6. CRS staff will ensure that all relevant IRB correspondence (continuing review 
amendments) and study status changes are communicated to Lahey Hospital & 
Medical Center 
7. CRS staff will document receipt, shipment and storage of study specimens 
8. Data management: Study enrollment data will be entered into RedCap directly by 
Lahey Hospital & Medical Center research staff.  HPI (name, MRN, etc) will not be 
available to BIDMC staff.   In order to ensure strict data integrity, CRS staff will 
perform data checks in the REDCap database.  
9. The study PI will be personally notified within 24 hours of any serious adverse event 
and will receive a copy of the AE form submitted to Lahey Hospital & Medical Center 
IRB within a week of the event 
10. PI will be personally notified within 24 hours of a protocol deviation and will receive a 
copy of the deviation form submitted to the Lahey Hospital & Medical Center IRB.  
11. We will conduct an in-person site visit after every 20 enrollments or earlier on an as 
needed basis. During these site visits, we will assess research study progress and 
compliance with the IRB approved protocol and procedures. This will include review of 
source documents for key data elements.  
12. As part of our on-site visit, we will include a Lahey Hospital & Medical Center 
Research Pharmacy review to assess the following: documentation of secure drug 
storage; drug accountability from receipt of drug through all dispensing and ultimately 
destruction on drug accountability logs; documentation of performance of regular 
inventory verification; confirmation that orders for research medication are written only 
by authorized prescribers on the 1572 form or delegation of authority log; confirmation 
that study drug must has continuous temperature monitoring and recorded at least 
daily on temperature logs (minimum, maximum, current); verification of drug 
destruction per Lahey Hospital & Medical Center internal policy.  The BIDMC 
Research Pharmacy will be available to answer questions as they may arise from the 
Lahey Hospital & Medical Center Research Pharmacy.  
13.  A formal site monitoring report will be provided to Lahey Hospital & Medical Center 
and the CCI after each site visit. This report will include data on the number of charts 
reviewed, discuss any identified deficiencies and any corrective actions taken.  The 
Lahey Hospital & Medical Center site PI will then provide this report to their local IRB 
in accordance with local IRB reporting requirements.  
 
 
Database Management: The coordinating center (BIDMC) will be responsible for developing the online 
database (see section 4.4), including a shared database with common data definitions. All forms and data 
dictionary will be available online for all individuals who perform data entry. 


 
All sites will enter de-identified data into the electronic database. Data entry will be done via REDCap. 
Discrepancies or missing data points will be identified through a data review process by the coordinating center 
resulting in queries sent to the participating sites for resolution. Changes will be made in REDCap by each 
participating site. 
 
The coordinating center will oversee and instruct sites on specimen collection and separation. Sites will be 
provided with detailed instructions for laboratory processing. All sample types will be processed initially on site, 
separated by centrifugation if necessary, dispensed into aliquots if required, and kept frozen (preferable at -80°) 
until shipment to the Center for Resuscitation Lab .  
 
All de-identified research samples will be shipped by commercial courier on dry ice to the Center for 
Resuscitation Lab where a study staff will accept, unpack and place samples in the freezer.  
 
Laboratory analyses will be conducted at either the Center for Resuscitation or shipped off-site to a 3rd party 
vendor. Biological samples shipped to a 3rd party for analysis will occur through the Center for Resuscitation 
Lab. Study blood will only have the specimen ID # and will be devoid of any personal identifiers. 
 
 
 
B10 
Dissemination of Research Results 
 
We will aim to publish the results of this study in a pertinent peer-reviewed journal within 6 
months of completion of data collection. 
 
 
 
References: 
 
1. 
Angus DC, Linde-Zwirble WT, Lidicker J, Clermont G, Carcillo J, Pinsky MR. 
Epidemiology of severe sepsis in the united states: Analysis of incidence, outcome, and 
associated costs of care. Crit Care Med. 2001;29:1303-1310 
2. 
Rudiger A, Singer M. Mechanisms of sepsis-induced cardiac dysfunction. Crit 
Care Med. 2007;35:1599-1608 
3. 
Schmittinger CA, Dunser MW, Torgersen C, Luckner G, Lorenz I, Schmid S, 
Joannidis M, Moser P, Hasibeder WR, Halabi M, Steger CM. Histologic pathologies of 
the myocardium in septic shock: A prospective observational study. Shock. 
2013;39:329-335 
4. 
Romero-Bermejo FJ, Ruiz-Bailen M, Gil-Cebrian J, Huertos-Ranchal MJ. Sepsis-
induced cardiomyopathy. Current cardiology reviews. 2011;7:163-183 
5. 
Dunser MW, Hasibeder WR. Sympathetic overstimulation during critical illness: 
Adverse effects of adrenergic stress. J Intensive Care Med. 2009;24:293-316 
6. 
Morelli A, Ertmer C, Westphal M, Rehberg S, Kampmeier T, Ligges S, Orecchioni 
A, D'Egidio A, D'Ippoliti F, Raffone C, Venditti M, Guarracino F, Girardis M, Tritapepe L, 
Pietropaoli P, Mebazaa A, Singer M. Effect of heart rate control with esmolol on 
hemodynamic and clinical outcomes in patients with septic shock: A randomized clinical 
trial. JAMA. 2013;310:1683-1691 


7. 
Pinsky MR. Is there a role for beta-blockade in septic shock? JAMA. 
2013;310:1677-1678 
8. 
Kim Y, Hwang W, Cho ML, Her YM, Ahn S, Lee J. The effects of intraoperative 
esmolol administration on perioperative inflammatory responses in patients undergoing 
laparoscopic gastrectomy: A dose-response study. Surgical innovation. 2014 
9. 
Ibrahim-Zada I, Rhee P, Gomez CT, Weller J, Friese RS. Inhibition of sepsis-
induced inflammatory response by beta1-adrenergic antagonists. The journal of trauma 
and acute care surgery. 2014;76:320-327; discussion 327-328 
10. 
Mori K, Morisaki H, Yajima S, Suzuki T, Ishikawa A, Nakamura N, Innami Y, 
Takeda J. Beta-1 blocker improves survival of septic rats through preservation of gut 
barrier function. Intensive Care Med. 2011;37:1849-1856 
11. 
Schmitz D, Wilsenack K, Lendemanns S, Schedlowski M, Oberbeck R. Beta-
adrenergic blockade during systemic inflammation: Impact on cellular immune functions 
and survival in a murine model of sepsis. Resuscitation. 2007;72:286-294 
12. 
Weycker D, Akhras KS, Edelsberg J, Angus DC, Oster G. Long-term mortality 
and medical care charges in patients with severe sepsis. Crit Care Med. 2003;31:2316-
2323 
13. 
Marti-Carvajal AJ, Sola I, Gluud C, Lathyris D, Cardona AF. Human recombinant 
protein c for severe sepsis and septic shock in adult and paediatric patients. Cochrane 
Database Syst Rev. 2012;12:CD004388 
14. 
Schedel I, Dreikhausen U, Nentwig B, Hockenschnieder M, Rauthmann D, 
Balikcioglu S, Coldewey R, Deicher H. Treatment of gram-negative septic shock with an 
immunoglobulin preparation: A prospective, randomized clinical trial. Crit Care Med. 
1991;19:1104-1113 
15. 
Abraham E, Anzueto A, Gutierrez G, Tessler S, San Pedro G, Wunderink R, Dal 
Nogare A, Nasraway S, Berman S, Cooney R, Levy H, Baughman R, Rumbak M, Light 
RB, Poole L, Allred R, Constant J, Pennington J, Porter S. Double-blind randomised 
controlled trial of monoclonal antibody to human tumour necrosis factor in treatment of 
septic shock. Norasept ii study group. Lancet. 1998;351:929-933 
16. 
Abraham E, Wunderink R, Silverman H, Perl TM, Nasraway S, Levy H, Bone R, 
Wenzel RP, Balk R, Allred R, et al. Efficacy and safety of monoclonal antibody to 
human tumor necrosis factor alpha in patients with sepsis syndrome. A randomized, 
controlled, double-blind, multicenter clinical trial. Tnf-alpha mab sepsis study group. 
JAMA. 1995;273:934-941 
17. 
Deans KJ, Haley M, Natanson C, Eichacker PQ, Minneci PC. Novel therapies for 
sepsis: A review. J Trauma. 2005;58:867-874 
18. 
Eichacker PQ, Parent C, Kalil A, Esposito C, Cui X, Banks SM, Gerstenberger 
EP, Fitz Y, Danner RL, Natanson C. Risk and the efficacy of antiinflammatory agents: 
Retrospective and confirmatory studies of sepsis. Am J Respir Crit Care Med. 
2002;166:1197-1205 
19. 
Linde-Zwirble WT, Angus DC. Severe sepsis epidemiology: Sampling, selection, 
and society. Crit Care. 2004;8:222-226 
20. 
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;348:1546-1554 


21. 
Balik M, Rulisek J, Leden P, Zakharchenko M, Otahal M, Bartakova H, Korinek J. 
Concomitant use of beta-1 adrenoreceptor blocker and norepinephrine in patients with 
septic shock. Wiener klinische Wochenschrift. 2012;124:552-556 
22. 
Fink MP. Bench-to-bedside review: Cytopathic hypoxia. Crit Care. 2002;6:491-
499 
23. 
Dellinger RP, Levy MM, Rhodes A, Annane D, Gerlach H, Opal SM, Sevransky 
JE, Sprung CL, Douglas IS, Jaeschke R, Osborn TM, Nunnally ME, Townsend SR, 
Reinhart K, Kleinpell RM, Angus DC, Deutschman CS, Machado FR, Rubenfeld GD, 
Webb SA, Beale RJ, Vincent JL, Moreno R, Surviving Sepsis Campaign Guidelines 
Committee including the Pediatric S. Surviving sepsis campaign: International 
guidelines for management of severe sepsis and septic shock: 2012. Crit Care Med. 
2013;41:580-637 
24. 
Wiest D. Esmolol. A review of its therapeutic efficacy and pharmacokinetic 
characteristics. Clinical pharmacokinetics. 1995;28:190-202 
25. 
Squara P, Denjean D, Estagnasie P, Brusset A, Dib JC, Dubois C. Noninvasive 
cardiac output monitoring (nicom): A clinical validation. Intensive Care Med. 
2007;33:1191-1194 
26. 
Vincent JL, Moreno R, Takala J, Willatts S, De Mendonca A, Bruining H, Reinhart 
CK, Suter PM, Thijs LG. The sofa (sepsis-related organ failure assessment) score to 
describe organ dysfunction/failure. On behalf of the working group on sepsis-related 
problems of the european society of intensive care medicine. Intensive Care Med. 
1996;22:707-710 
27. 
Donaldson L, Dodds S, Walsh TS. Clinical evaluation of a continuous oxygen 
consumption monitor in mechanically ventilated patients. Anaesthesia. 2003;58:455-460 
28. 
McLellan S, Walsh T, Burdess A, Lee A. Comparison between the datex-ohmeda 
m-covx metabolic monitor and the deltatrac ii in mechanically ventilated patients. 
Intensive Care Med. 2002;28:870-876 
 
 


 (CCI) Committee on Clinical Investigations 
Page 1 of 62 
                                                                                                                                                                                                                       Amendment Form  
                                                                                                                                                                                              CCI Form Revised: 3-2013 
 
AMENDMENT FORM 
STUDY INFORMATION 
TITLE OF PROTOCOL: Esmolol to treat the hemodynamic effects of septic shock 
CCI PROTOCOL # : 2014P-000415 
PRINCIPAL INVESTIGATOR: Michael Cocchi MD 
E-MAIL ADDRESS: mcocchi@bidmc.harvard.edu 
STUDY COORDINATOR¶S NAME: ELINITA ROSSETO 
P.I.¶S TELEPHONE : 617-754-2388 
P.I.¶S  PAGER #:  38983 
FAX # :617-754-2350 
 
 
AMENDMENT DETAILS 
Indicate which components(s) or element(s) of your protocol are being changed.  Check all applicable items. 
  Principal Investigator 
 Study Type (e.g. Phase) 
 Co-Investigators/Study Staff (include Part Q if adding new 
staff) 
 Recruitment, Publicity Materials and/or procedures 
 Study Title 
 Consent Procedures 
 Sponsor 
 Duration of Subject Participation 
 Application (CCI or sponsor protocol) Content/Version 
 Patient Materials (e.g. diaries) 
 Consent Form 
 Questionnaires, or Investigator Brochure 
 Local Site Enrollment # of Subjects 
 Remuneration 
 Total Enrollment # of Subjects (Multi-Center Trials) 
 Research Related Use of Medical Records (Part O) 
 Types of Subjects 
 Use of Specimens 
 Source of Subjects 
 Research Related Use of Discarded Material (Part N) 
 Other (specify): Part E 
  *Study Status Change (i.e., CTE, hold, suspension) 
 
*This refers to changes prior to Continuing Review  
Industry Sponsored Protocols only:  
Sponsor Amendment/Version #:        
Revised Protocol Issue Date:        
 
 
AMENDMENT ATTACHMENTS 
Indicate study documents that have been modified as a result of this amendment and are appended to this application. 
 Revised Protocol (New Version) (1 clean, 1 highlighted) 
 New or Revised Advertisement (1 clean, 1 highlighted) 
 Revised Consent Form (1 clean, 1 highlighted) 
 Revised Research Participant Materials or  Questionnaires  
     (1 clean, 1 highlighted) 
 Other (specify): Part E 
 
 
AMENDMENT DESCRIPTION 
A detailed description of the amendment, in your own words, MUST be provided below.  The PI may provide a summary of a lengthy 
sponsor amendment in an attached cover letter or memo, however this should not simply be a copy of the sponsors amendment 
and/or letter.  Either list the current item followed by the new item, or attach a redlined version of the changed document.  If the 
consent form is revised, attach one copy of the consent form in which the changes (including additions and deletions) are clearly 
highlighted, and one clean copy of the consent form. 
1. Addition of detail in Part E. 
  PI Memo/Cover Letter Describing Changes is attached 
  Sponsor Letter Describing Changes is Attached 
 
 


 (CCI) Committee on Clinical Investigations 
Page 2 of 62 
                                                                                                                                                                                                                       Amendment Form  
                                                                                                                                                                                              CCI Form Revised: 3-2013 
 
Impact on Budget/Funding 
Does this amendment affect the current budget for 
the study? 
 
 No 
 
 Yes, if yes, explain       
 
and contact:  
- 
Clinical Trials Office for Industry Funded Studies 
- 
Office of Sponsored Programs for Other Funding 
Sources 
 
 
 
Does this amendment affect the current funding for 
the study? 
 
  No 
 
  Yes, if yes, explain       
 
 and contact: 
- 
Clinical Trials Office for Industry Funded Studies 
- 
Office of Sponsored Programs for Other Funding 
Sources 
 
 
 
AMENDMENT RATIONALE 
The reason or justification for the changes must be discussed as well as how the change might affect the risk/benefit ratio.  Please 
also address how or if a change in the risk/benefit ratio impacts the informed consent form, and if the change necessitates a change in 
the consent form.  The rationale may be provided here or in an attached cover letter or memo.   
1. These changes were made to clarify operational details in drug preparation and dispensing.  
 
This change does not affect the risk benefit ratio.  This change does not necessitate a change in the consent form.  
  PI Memo/Cover letter Describing Rationale is Attached 
  Sponsor Letter Describing Rationale is Attached 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Principal Investigator  
 
 
 
 
Date 
 
 
Print Name  
 
Michael Cocchi MD 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 (CCI) Committee on Clinical Investigations 
Page 3 of 62 
                                                                                                                                                                                                                       Amendment Form  
                                                                                                                                                                                              CCI Form Revised: 3-2013 
 
AMENDMENT FORM 
STUDY INFORMATION 
TITLE OF PROTOCOL: Esmolol to treat the hemodynamic effects of septic shock 
CCI PROTOCOL # : 2014P-000415 
PRINCIPAL INVESTIGATOR: Michael Cocchi MD 
E-MAIL ADDRESS: mcocchi@bidmc.harvard.edu 
STUDY COORDINATOR¶S NAME: ELINITA ROSSETO 
P.I.¶S TELEPHONE : 617-754-2388 
P.I.¶S  PAGER #:  38983 
FAX # :617-754-2350 
 
AMENDMENT DETAILS 
Indicate which components(s) or element(s) of your protocol are being changed.  Check all applicable items. 
  Principal Investigator 
 Study Type (e.g. Phase) 
 Co-Investigators/Study Staff (include Part Q if adding new 
staff) 
 Recruitment, Publicity Materials and/or procedures 
 Study Title 
 Consent Procedures 
 Sponsor 
 Duration of Subject Participation 
 Application (CCI or sponsor protocol) Content/Version 
 Patient Materials (e.g. diaries) 
 Consent Form 
 Questionnaires, or Investigator Brochure 
 Local Site Enrollment # of Subjects 
 Remuneration 
 Total Enrollment # of Subjects (Multi-Center Trials) 
 Research Related Use of Medical Records (Part O) 
 Types of Subjects 
 Use of Specimens 
 Source of Subjects 
 Research Related Use of Discarded Material (Part N) 
 Other (specify): Change in inclusion/exclusion criteria 
  *Study Status Change (i.e., CTE, hold, suspension) 
 
*This refers to changes prior to Continuing Review  
Industry Sponsored Protocols only:  
Sponsor Amendment/Version #:        
Revised Protocol Issue Date:        
 
AMENDMENT ATTACHMENTS 
Indicate study documents that have been modified as a result of this amendment and are appended to this application. 
 Revised Protocol (New Version) (1 clean, 1 highlighted) 
 New or Revised Advertisement (1 clean, 1 highlighted) 
 Revised Consent Form (1 clean, 1 highlighted) 
 Revised Research Participant Materials or  Questionnaires  
     (1 clean, 1 highlighted) 
 Other (specify): Part A, HIPAA, Part Q 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 (CCI) Committee on Clinical Investigations 
Page 4 of 62 
                                                                                                                                                                                                                       Amendment Form  
                                                                                                                                                                                              CCI Form Revised: 3-2013 
 
AMENDMENT DESCRIPTION 
A detailed description of the amendment, in your own words, MUST be provided below.  The PI may provide a summary of a lengthy 
sponsor amendment in an attached cover letter or memo, however this should not simply be a copy of the sponsors amendment 
and/or letter.  Either list the current item followed by the new item, or attach a redlined version of the changed document.  If the 
consent form is revised, attach one copy of the consent form in which the changes (including additions and deletions) are clearly 
highlighted, and one clean copy of the consent form. 
1. Addition of Gabriel Verzino as co-investigator. 
2. 15 cc RI e[LVWLQJ bORRd WRWaOV WR DU. SKaSLUR¶V ³MaUNeUV´ 2005P-000116 at 0 or 6 hours and 24 hour time points (no 
additional volume will be taken). 
3. Add a placebo of 100 mL normal saline for patients randomized to standard care.  
4. IQcOXVLRQ cULWeULa #3 UePRYaO RI  ³aQd a ceQWUaO YeQRXV SUeVVXUe´. 
5. IQcOXVLRQ cULWeULa #5 UePRYaO RI ³ICU´ aQd WKe OaWeU OLPLW RI 24 KRXUV. 
6. E[cOXVLRQ cULWeULa #5 cKaQJe ³DR QRW UeVXVcLWaWe (DNR)¶ WR ³CRPIRUW PeaVXUe RQO\ (CMO)´.  
7. E[cOXVLRQ cULWeULa #6 UePRYaO RI ³dRSaPLQe, SKeQ\OeSKULQe´. 
8. Exclusion criteria #7 addition of ³that would preclude administration of a beta blocker medication; this would be 
determined by the clinical team caring for the patient so as to not create a conflict of interest.  For example, a 
patient may have a history of COPD but is already on a beta blocker medication as an outpatient; that patient 
should not be excluded for consideration of enrollment in this trial.´  
  PI Memo/Cover Letter Describing Changes is attached 
  Sponsor Letter Describing Changes is Attached 
 
 
Impact on Budget/Funding 
Does this amendment affect the current budget for 
the study? 
 
 No 
 
 Yes, if yes, explain       
 
and contact:  
- 
Clinical Trials Office for Industry Funded Studies 
- 
Office of Sponsored Programs for Other Funding 
Sources 
 
 
 
Does this amendment affect the current funding for 
the study? 
 
  No 
 
  Yes, if yes, explain       
 
 and contact: 
- 
Clinical Trials Office for Industry Funded Studies 
- 
Office of Sponsored Programs for Other Funding 
Sources 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 (CCI) Committee on Clinical Investigations 
Page 5 of 62 
                                                                                                                                                                                                                       Amendment Form  
                                                                                                                                                                                              CCI Form Revised: 3-2013 
 
 
AMENDMENT RATIONALE 
The reason or justification for the changes must be discussed as well as how the change might affect the risk/benefit ratio.  Please 
also address how or if a change in the risk/benefit ratio impacts the informed consent form, and if the change necessitates a change in 
the consent form.  The rationale may be provided here or in an attached cover letter or memo.   
1. Gabriel Verzino is being added as co-investigator to increase productivity and enrollment.  
2. For collaboration, we will provide blood sample at two time points to Dr ShaSLUR¶V bLRPaUNeUV VWXd\. TKLV ZLOO be 
deducted from the amount already being collected in the Esmolol study; no additional volume will be taken. 
3. This will serve as a time stamp for the study start for those patients not receiving esmolol. 
4. The reason for the removal of this criterion is that the standard of care around sepsis has changed and clinicians 
are not routinely checking CVP measurements. For consistency, we would use the more consistent clinical 
parameters already in place, which are a minimum fluid administration of 30mL/kg and the measurement of 
cardiac function via the NICOM. This should not result in any increased risk to the patient since most clinicians are 
already not using CVP to guide resuscitation; this amendment will reflect current clinical practice.  
5. EOLPLQaWLRQ RI ³ICU´ aV VRPe SaWLeQWV Pa\ bRaUd LQ WKe ED IRU SURORQJed SeULRdV RI WLPe. EOLPLQaWLRQ RI WKe OaWeU 
limit of 24 hours as it is not necessary, for example if a patient was in the ICU for another reason and on day 3 
developed septic shock it would be okay to enroll this patient.  
6. A patient with a DNR order is acceptable to enroll in the study. We would not enroll a DNI patient as this is a more 
significant limitation on aggressive resuscitation, nor would be enroll a patient who is comfort measures only 
(CMO). 
7. RePRYaO RI ³dRSaPLQe, SKeQ\OeSKULQe¶ aV e[cOXVLRQV aV VRPe SaWLeQWV Pa\ be RQ WKeVe YaVRSUeVVRUV, aOWKRXJK 
the most common vasopressor used in septic shock is norepinephrine. This should not result in any increased risk 
to the patient. 
8. The purpose of this exclusion was to avoid giving a beta blocker to a patient who is at high risk for respiratory 
distress, however many patients with asthma or COPD routinely receive beta blocker medications without side 
effects.  For example, a patient may have a history of COPD but is already on a beta blocker medication as an 
outpatient; that patient should not be excluded for consideration of enrollment in this trial.  Therefore, we would 
like to add the language that ³that would preclude administration of a beta blocker medication; this would be 
determined by the clinical team caring for the patient so as to not cUeaWe a cRQIOLcW RI LQWeUeVW.¶ TKLV VKRXOd QRW 
represent an increased risk to the patient as the clinical team would also be potentially administering this class of 
medication if clinically-indicated.  If there were an unexpected reaction to the study drug, as with any patient 
enrolled in this study, they are being continuously monitored in a critical care setting and would be treated 
immediately, and the drug would be discontinued.  
 
 
  PI Memo/Cover letter Describing Rationale is Attached 
  Sponsor Letter Describing Rationale is Attached 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Principal Investigator  
 
 
 
 
Date 
 
 
Print Name  
Michael Cocchi 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 (CCI) Committee on Clinical Investigations 
Page 6 of 62 
                                                                                                                                                                                                                       Amendment Form  
                                                                                                                                                                                              CCI Form Revised: 3-2013 
 
 
AMENDMENT FORM 
STUDY INFORMATION 
TITLE OF PROTOCOL: Esmolol to treat the hemodynamic effects of septic shock 
CCI PROTOCOL # : 2014P-000415 
PRINCIPAL INVESTIGATOR: Michael Cocchi MD 
E-MAIL ADDRESS: mcocchi@bidmc.harvard.edu 
STUDY COORDINATOR¶S NAME: ELINITA ROSSETO 
P.I.¶S TELEPHONE : 617-754-2388 
P.I.¶S  PAGER #:  38983 
FAX # :617-754-2350 
 
AMENDMENT DETAILS 
Indicate which components(s) or element(s) of your protocol are being changed.  Check all applicable items. 
  Principal Investigator 
 Study Type (e.g. Phase) 
 Co-Investigators/Study Staff (include Part Q if adding new 
staff) 
 Recruitment, Publicity Materials and/or procedures 
 Study Title 
 Consent Procedures 
 Sponsor 
 Duration of Subject Participation 
 Application (CCI or sponsor protocol) Content/Version 
 Patient Materials (e.g. diaries) 
 Consent Form 
 Questionnaires, or Investigator Brochure 
 Local Site Enrollment # of Subjects 
 Remuneration 
 Total Enrollment # of Subjects (Multi-Center Trials) 
 Research Related Use of Medical Records (Part O) 
 Types of Subjects 
 Use of Specimens 
 Source of Subjects 
 Research Related Use of Discarded Material (Part N) 
 Other (specify): Change in inclusion/exclusion criteria 
  *Study Status Change (i.e., CTE, hold, suspension) 
 
*This refers to changes prior to Continuing Review  
Industry Sponsored Protocols only:  
Sponsor Amendment/Version #:        
Revised Protocol Issue Date:        
 
AMENDMENT ATTACHMENTS 
Indicate study documents that have been modified as a result of this amendment and are appended to this application. 
 Revised Protocol (New Version) (1 clean, 1 highlighted) 
 New or Revised Advertisement (1 clean, 1 highlighted) 
 Revised Consent Form (1 clean, 1 highlighted) 
 Revised Research Participant Materials or  Questionnaires  
     (1 clean, 1 highlighted) 
 Other (specify):  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 (CCI) Committee on Clinical Investigations 
Page 7 of 62 
                                                                                                                                                                                                                       Amendment Form  
                                                                                                                                                                                              CCI Form Revised: 3-2013 
 
AMENDMENT DESCRIPTION 
A detailed description of the amendment, in your own words, MUST be provided below.  The PI may provide a summary of a lengthy 
sponsor amendment in an attached cover letter or memo, however this should not simply be a copy of the sponsors amendment 
and/or letter.  Either list the current item followed by the new item, or attach a redlined version of the changed document.  If the 
consent form is revised, attach one copy of the consent form in which the changes (including additions and deletions) are clearly 
highlighted, and one clean copy of the consent form. 
1. IQcOXVLRQ cULWeULa #3 UePRYaO RI  ³aQd a ceQWUaO YeQRXV SUeVVXUe´. 
2. Inclusion criteria #5 removal of ³ICU´ aQd WKe OaWeU OLPLW RI 24 KRXUV. 
3. E[cOXVLRQ cULWeULa #5 cKaQJe ³DR QRW UeVXVcLWaWe (DNR)¶ WR ³CRPIRUW PeaVXUe RQO\ (CMO)´.  
4. E[cOXVLRQ cULWeULa #6 UePRYaO RI ³dRSaPLQe, SKeQ\OeSKULQe´. 
5. Exclusion criteria #7 addition of ³that would preclude administration of a beta blocker medication; this would be 
determined by the clinical team caring for the patient so as to not create a conflict of interest.  For example, a 
patient may have a history of COPD but is already on a beta blocker medication as an outpatient; that patient 
should not be excluded for consideration of enrollment in this trial.´  
  PI Memo/Cover Letter Describing Changes is attached 
  Sponsor Letter Describing Changes is Attached 
 
 
Impact on Budget/Funding 
Does this amendment affect the current budget for 
the study? 
 
 No 
 
 Yes, if yes, explain       
 
and contact:  
- 
Clinical Trials Office for Industry Funded Studies 
- 
Office of Sponsored Programs for Other Funding 
Sources 
 
 
 
Does this amendment affect the current funding for 
the study? 
 
  No 
 
  Yes, if yes, explain       
 
 and contact: 
- 
Clinical Trials Office for Industry Funded Studies 
- 
Office of Sponsored Programs for Other Funding 
Sources 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 (CCI) Committee on Clinical Investigations 
Page 8 of 62 
                                                                                                                                                                                                                       Amendment Form  
                                                                                                                                                                                              CCI Form Revised: 3-2013 
 
AMENDMENT RATIONALE 
The reason or justification for the changes must be discussed as well as how the change might affect the risk/benefit ratio.  Please 
also address how or if a change in the risk/benefit ratio impacts the informed consent form, and if the change necessitates a change in 
the consent form.  The rationale may be provided here or in an attached cover letter or memo.   
1. The reason for the removal of this criterion is that the standard of care around sepsis has changed and clinicians 
are not routinely checking CVP measurements. For consistency, we would use the more consistent clinical 
parameters already in place, which are a minimum fluid administration of 30mL/kg and the measurement of 
cardiac function via the NICOM. This should not result in any increased risk to the patient since most clinicians are 
already not using CVP to guide resuscitation; this amendment will reflect current clinical practice.  
2. EOLPLQaWLRQ RI ³ICU´ as some patients may board in the ED for prolonged periods of time. Elimination of the later 
limit of 24 hours as it is not necessary, for example if a patient was in the ICU for another reason and on day 3 
developed septic shock it would be okay to enroll this patient.  
3. A patient with a DNR order is acceptable to enroll in the study. We would not enroll a DNI patient as this is a more 
significant limitation on aggressive resuscitation, nor would be enroll a patient who is comfort measures only 
(CMO). 
4. RemoYaO RI ³dRSaPLQe, SKeQ\OeSKULQe¶ aV e[cOXVLRQV aV VRPe SaWLeQWV Pa\ be RQ WKeVe YaVRSUeVVRUV, aOWKRXJK 
the most common vasopressor used in septic shock is norepinephrine. This should not result in any increased risk 
to the patient. 
5. The purpose of this exclusion was to avoid giving a beta blocker to a patient who is at high risk for respiratory 
distress, however many patients with asthma or COPD routinely receive beta blocker medications without side 
effects.  For example, a patient may have a history of COPD but is already on a beta blocker medication as an 
outpatient; that patient should not be excluded for consideration of enrollment in this trial.  Therefore, we would 
like to add the language that ³that would preclude administration of a beta blocker medication; this would be 
determined by the clinical team caring for the patient so as to not cUeaWe a cRQIOLcW RI LQWeUeVW.¶ TKLV VKRXOd QRW 
represent an increased risk to the patient as the clinical team would also be potentially administering this class of 
medication if clinically-indicated.  If there were an unexpected reaction to the study drug, as with any patient 
enrolled in this study, they are being continuously monitored in a critical care setting and would be treated 
immediately, and the drug would be discontinued.  
 
These changes do not affect the risk/benefit ratio. These changes do not necessitate a revised written informed consent 
form. 
 
  PI Memo/Cover letter Describing Rationale is Attached 
  Sponsor Letter Describing Rationale is Attached 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Principal Investigator  
 
 
 
 
Date 
 
 
Print Name  
Michael Cocchi 
MD 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 (CCI) Committee on Clinical Investigations 
Page 9 of 62 
                                                                                                                                                                                                                       Amendment Form  
                                                                                                                                                                                              CCI Form Revised: 3-2013 
 
AMENDMENT FORM 
STUDY INFORMATION 
TITLE OF PROTOCOL: Esmolol to treat the hemodynamic effects of septic shock 
CCI PROTOCOL # : 2014P-000415 
PRINCIPAL INVESTIGATOR: Michael Cocchi MD 
E-MAIL ADDRESS: mcocchi@bidmc.harvard.edu 
STUDY COORDINATOR¶S NAME: ELINITA ROSSETO 
P.I.¶S TELEPHONE : 617-754-2388 
P.I.¶S  PAGER #:  38983 
FAX # :617-754-2350 
 
AMENDMENT DETAILS 
Indicate which components(s) or element(s) of your protocol are being changed.  Check all applicable items. 
  Principal Investigator 
 Study Type (e.g. Phase) 
 Co-Investigators/Study Staff (include Part Q if adding new 
staff) 
 Recruitment, Publicity Materials and/or procedures 
 Study Title 
 Consent Procedures 
 Sponsor 
 Duration of Subject Participation 
 Application (CCI or sponsor protocol) Content/Version 
 Patient Materials (e.g. diaries) 
 Consent Form 
 Questionnaires, or Investigator Brochure 
 Local Site Enrollment # of Subjects 
 Remuneration 
 Total Enrollment # of Subjects (Multi-Center Trials) 
 Research Related Use of Medical Records (Part O) 
 Types of Subjects 
 Use of Specimens 
 Source of Subjects 
 Research Related Use of Discarded Material (Part N) 
 Other (specify):  
  *Study Status Change (i.e., CTE, hold, suspension) 
 
*This refers to changes prior to Continuing Review  
Industry Sponsored Protocols only:  
Sponsor Amendment/Version #:        
Revised Protocol Issue Date:        
 
AMENDMENT ATTACHMENTS 
Indicate study documents that have been modified as a result of this amendment and are appended to this application. 
 Revised Protocol (New Version) (1 clean, 1 highlighted) 
 New or Revised Advertisement (1 clean, 1 highlighted) 
 Revised Consent Form (1 clean, 1 highlighted) 
 Revised Research Participant Materials or  Questionnaires  
     (1 clean, 1 highlighted) 
 Other (specify):  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 (CCI) Committee on Clinical Investigations 
Page 10 of 62 
                                                                                                                                                                                                                       Amendment Form  
                                                                                                                                                                                              CCI Form Revised: 3-2013 
 
AMENDMENT DESCRIPTION 
A detailed description of the amendment, in your own words, MUST be provided below.  The PI may provide a summary of a lengthy 
sponsor amendment in an attached cover letter or memo, however this should not simply be a copy of the sponsors amendment 
and/or letter.  Either list the current item followed by the new item, or attach a redlined version of the changed document.  If the 
consent form is revised, attach one copy of the consent form in which the changes (including additions and deletions) are clearly 
highlighted, and one clean copy of the consent form. 
1. Addition of a placebo of 100 mL normal saline for patients randomized to standard care.  
2. Addition of Gabriel Verzino and Alexander Wulff as co-investigators. 
3. Removal of Michael Michalcyzk as co-investigator. 
 
  PI Memo/Cover Letter Describing Changes is attached 
  Sponsor Letter Describing Changes is Attached 
 
 
Impact on Budget/Funding 
Does this amendment affect the current budget for 
the study? 
 
 No 
 
 Yes, if yes, explain       
 
and contact:  
- 
Clinical Trials Office for Industry Funded Studies 
- 
Office of Sponsored Programs for Other Funding 
Sources 
 
 
 
Does this amendment affect the current funding for 
the study? 
 
  No 
 
  Yes, if yes, explain       
 
 and contact: 
- 
Clinical Trials Office for Industry Funded Studies 
- 
Office of Sponsored Programs for Other Funding 
Sources 
 
 
AMENDMENT RATIONALE 
The reason or justification for the changes must be discussed as well as how the change might affect the risk/benefit ratio.  Please 
also address how or if a change in the risk/benefit ratio impacts the informed consent form, and if the change necessitates a change in 
the consent form.  The rationale may be provided here or in an attached cover letter or memo.   
 
1. In order to clearly mark the start time of the study for patients who are randomized to standard care, a 100 mL 
saline placebo will be administered as a one-time time stamp. This will be provided by the Research Pharmacy 
and administered by the bedside nurse. 
2. Gabriel and Alexander are being added as co-investigators to increase enrollment capacity and productivity. 
3. Michael Michalcyzk is being removed as co-investigator as he is no longer with the insitition. 
 
 
These changes do not affect the risk/benefit ratio. These changes do necessitate a revised written informed consent form. 
 
  PI Memo/Cover letter Describing Rationale is Attached 
  Sponsor Letter Describing Rationale is Attached 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Principal Investigator  
 
 
 
 
Date 
 
 
Print Name  
Michael Cocchi 
MD 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 (CCI) Committee on Clinical Investigations 
Page 11 of 62 
                                                                                                                                                                                                                       Amendment Form  
                                                                                                                                                                                              CCI Form Revised: 3-2013 
 
 
AMENDMENT FORM 
STUDY INFORMATION 
TITLE OF PROTOCOL: Esmolol to treat the hemodynamic effects of septic shock 
CCI PROTOCOL # : 2014P-000415 
PRINCIPAL INVESTIGATOR: Michael Cocchi MD 
STUDY COORDINATOR: Elinita Rosseto 
STUDY COORDINATOR EMAIL ADDRESS: EROSSETO@BIDMC.HARVARD.EDU 
 
AMENDMENT DETAILS 
Indicate which components(s) or element(s) of your protocol are being changed.  Check all applicable items. 
  Principal Investigator 
 Change and/or New Recruitment or Publicity Materials 
 
 DSMB Reports/Monitoring Reports/Safety Reports 
 Recruitment, Publicity Materials and/or procedures 
 Revised and/or New Consent Form 
 Consent Procedures 
 Change and/or Addition of Study Procedures 
 Duration of Subject Participation 
 Local Site Enrollment # of Subjects 
 Revised and/or New Study Documents or Subject Materials 
(e.g. diaries, questionnaires) 
 Total Enrollment # of Subjects (Multi-Center Trials) 
 Investigator Brochure, Date/Version: 
 Change in subject selection or subject population 
 Change in Remuneration 
 Change of Sponsor/Funding 
 Research Related Use of Medical Records  
  Study Status Change (i.e., CTE, hold, re-open to enrollment) 
 Use of Specimens 
 
 Industry Sponsored Protocols only:  
Sponsor Amendment/Version #:        
 Research Related Use of Discarded Material 
 Change related to pharmacy or study drug administration 
 
  Revised Sponsor Protocol,  Issue Date/Version:        
 Addition/Removal of Co-Investigator or Research Staff Member 
 
For amendments limited to only the addition or removal of research staff in addition to this form the following is 
required:  
x 
Research Staffing Form (1 clean, 1 highlighted) 
x 
Revised Part E if amendment involves change in Authorized Prescribers for study medication 
x 
Part Q and CITI training documentation for any non-BIDMC research staff member.   
 
AMENDMENT ATTACHMENTS: 
 Revised Sponsor Protocol (New Version) (1 clean, 1 highlighted) 
 New or Revised Advertisement (1 clean, 1 highlighted) 
 Revised Part A (1 clean, 1 highlighted) 
 Revised Part B (1 clean, 1 highlighted) 
 Revised Consent Form (1 clean, 1 highlighted) 
 Revised Research Participant Materials or  Questionnaires  
     (1 clean, 1 highlighted) 
 Revised Research Staffing Form (1 Clean, I highlighted: ) 
 Part Q(s) for addition of any non-BIDMC personnel  
 Revised/New Part E (Obtain pharmacy signature and detail change below) 
 Other Revised Part/Form Document  (1 Clean, I highlighted: ) 
     Specify:       
 
 
 
AMENDMENT DESCRIPTION- REQUIRED FOR ALL SUBMISSIONS 


 (CCI) Committee on Clinical Investigations 
Page 12 of 62 
                                                                                                                                                                                                                       Amendment Form  
                                                                                                                                                                                              CCI Form Revised: 3-2013 
 
A detailed description of the amendment, in your own words, MUST be provided below.  The PI may provide a summary of a lengthy 
sponsor amendment in an attached cover letter or memo, however this should not simply be a copy of the sponsors amendment 
and/or letter.  Either list the current item followed by the new item, or attach a redlined version of the changed document.  If the 
consent form is revised, attach one copy of the consent form in which the changes (including additions and deletions) are clearly 
highlighted, and one clean copy of the consent form. 
1. Removal of two study staff. 
2. Addition of one study staff. 
  PI Memo/Cover Letter Describing Changes is attached 
  Sponsor Letter Describing Changes is Attached 
 
 
Impact on Budget/Funding 
Does this amendment affect the current budget for the 
study? 
 
 No 
 
 Yes, if yes, explain       
 
and contact:  
- 
Clinical Trials Office for Industry Funded Studies 
- 
Office of Sponsored Programs for Other Funding 
Sources 
 
 
 
Does this amendment affect the current funding for the 
study? 
 
  No 
 
  Yes, if yes, explain       
 
 and contact: 
- 
Clinical Trials Office for Industry Funded Studies 
- 
Office of Sponsored Programs for Other Funding 
Sources 
 
 
AMENDMENT RATIONALE- REQUIRED FOR ALL SUBMISSIONS 
The reason or justification for the changes must be discussed as well as how the change might affect the risk/benefit ratio.  Please 
also address how or if a change in the risk/benefit ratio impacts the informed consent form, and if the change necessitates a change in 
the consent form.  The rationale may be provided here or in an attached cover letter or memo.   
1. Mary MacDonald and Mathias Holmberg are being removed as they are no longer involved with the protocol. 
2. Mathias Karlsson Is being added as consenting co-investigator to increase productivity.   
 
These changes do not affect the risk/benefit ratio. This study is approved with written, informed consent. 
  PI Memo /Cover letter Describing Rationale is Attached 
  Sponsor Letter Describing Rationale is Attached 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Principal Investigator  
 
 
 
 
Date 
 
 
Print Name  
 
Michael Cocchi MD 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 (CCI) Committee on Clinical Investigations 
Page 13 of 62 
                                                                                                                                                                                                                       Amendment Form  
                                                                                                                                                                                              CCI Form Revised: 3-2013 
 
AMENDMENT FORM 
STUDY INFORMATION 
TITLE OF PROTOCOL: Esmolol to treat the hemodynamic effects of septic shock 
CCI PROTOCOL # : 2014P-000415 
PRINCIPAL INVESTIGATOR: Michael Cocchi MD 
STUDY COORDINATOR: Elinita Rosseto 
STUDY COORDINATOR EMAIL ADDRESS: EROSSETO@BIDMC.HARVARD.EDU 
 
AMENDMENT DETAILS 
Indicate which components(s) or element(s) of your protocol are being changed.  Check all applicable items. 
  Principal Investigator 
 Change and/or New Recruitment or Publicity Materials 
 
 DSMB Reports/Monitoring Reports/Safety Reports 
 Recruitment, Publicity Materials and/or procedures 
 Revised and/or New Consent Form 
 Consent Procedures 
 Change and/or Addition of Study Procedures 
 Duration of Subject Participation 
 Local Site Enrollment # of Subjects 
 Revised and/or New Study Documents or Subject Materials 
(e.g. diaries, questionnaires) 
 Total Enrollment # of Subjects (Multi-Center Trials) 
 Investigator Brochure, Date/Version: 
 Change in subject selection or subject population 
 Change in Remuneration 
 Change of Sponsor/Funding 
 Research Related Use of Medical Records  
  Study Status Change (i.e., CTE, hold, re-open to enrollment) 
 Use of Specimens 
 
 Industry Sponsored Protocols only:  
Sponsor Amendment/Version #:        
 Research Related Use of Discarded Material 
 Change related to pharmacy or study drug administration 
 
  Revised Sponsor Protocol,  Issue Date/Version:        
 Addition/Removal of Co-Investigator or Research Staff Member 
 
For amendments limited to only the addition or removal of research staff in addition to this form the following is 
required:  
x 
Research Staffing Form (1 clean, 1 highlighted) 
x 
Revised Part E if amendment involves change in Authorized Prescribers for study medication 
x 
Part Q and CITI training documentation for any non-BIDMC research staff member.   
 
AMENDMENT ATTACHMENTS: 
 Revised Sponsor Protocol (New Version) (1 clean, 1 highlighted) 
 New or Revised Advertisement (1 clean, 1 highlighted) 
 Revised Part A (1 clean, 1 highlighted) 
 Revised Part B (1 clean, 1 highlighted) 
 Revised Consent Form (1 clean, 1 highlighted) 
 Revised Research Participant Materials or  Questionnaires  
     (1 clean, 1 highlighted) 
 Revised Research Staffing Form (1 Clean, I highlighted: ) 
 Part Q(s) for addition of any non-BIDMC personnel  
 Revised/New Part E (Obtain pharmacy signature and detail change below) 
 Other Revised Part/Form Document  (1 Clean, I highlighted: ) 
     Specify:       
 
 
 
AMENDMENT DESCRIPTION- REQUIRED FOR ALL SUBMISSIONS 


 (CCI) Committee on Clinical Investigations 
Page 14 of 62 
                                                                                                                                                                                                                       Amendment Form  
                                                                                                                                                                                              CCI Form Revised: 3-2013 
 
A detailed description of the amendment, in your own words, MUST be provided below.  The PI may provide a summary of a lengthy 
sponsor amendment in an attached cover letter or memo, however this should not simply be a copy of the sponsors amendment 
and/or letter.  Either list the current item followed by the new item, or attach a redlined version of the changed document.  If the 
consent form is revised, attach one copy of the consent form in which the changes (including additions and deletions) are clearly 
highlighted, and one clean copy of the consent form. 
1. Addition and removal of study staff members 
2. Addition of alternate number for subjects to call besides the PI on the ICF, WHOM TO CONTACT IF YOU 
HAVE QUESTIONS OR PROBLEMS. 
. 
 
  PI Memo/Cover Letter Describing Changes is attached 
  Sponsor Letter Describing Changes is Attached 
 
 
Impact on Budget/Funding 
Does this amendment affect the current budget for the 
study? 
 
 No 
 
 Yes, if yes, explain       
 
and contact:  
- 
Clinical Trials Office for Industry Funded Studies 
- 
Office of Sponsored Programs for Other Funding 
Sources 
 
 
 
Does this amendment affect the current funding for the 
study? 
 
  No 
 
  Yes, if yes, explain       
 
 and contact: 
- 
Clinical Trials Office for Industry Funded Studies 
- 
Office of Sponsored Programs for Other Funding 
Sources 
 
 
AMENDMENT RATIONALE- REQUIRED FOR ALL SUBMISSIONS 
The reason or justification for the changes must be discussed as well as how the change might affect the risk/benefit ratio.  Please 
also address how or if a change in the risk/benefit ratio impacts the informed consent form, and if the change necessitates a change in 
the consent form.  The rationale may be provided here or in an attached cover letter or memo.   
 
1. 
Removal of Gabriel Verzino as he is no longer with the institution. Addition of 2 consenting co-investigators: Sarah 
Ganley John Paul Couce. 
2. 
We are changing the contact number to a telephone number where subjects can easily reach someone and have their 
questions answered. 
. 
 
These changes do not affect the risk/benefit ratio. This study DOES necessitate a change in the written, informed consent form. 
  PI Memo /Cover letter Describing Rationale is Attached 
  Sponsor Letter Describing Rationale is Attached 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Principal Investigator  
 
 
 
 
Date 
 
 
Print Name  
 
Michael Cocchi MD 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 (CCI) Committee on Clinical Investigations 
Page 15 of 62 
                                                                                                                                                                                                                       Amendment Form  
                                                                                                                                                                                              CCI Form Revised: 3-2013 
 
 
AMENDMENT FORM 
STUDY INFORMATION 
TITLE OF PROTOCOL: Esmolol to treat the hemodynamic effects of septic shock 
CCI PROTOCOL # : 2014P-000415 
PRINCIPAL INVESTIGATOR: Michael Cocchi MD 
STUDY COORDINATOR: Elinita Rosseto 
STUDY COORDINATOR EMAIL ADDRESS: EROSSETO@BIDMC.HARVARD.EDU 
 
AMENDMENT DETAILS 
Indicate which components(s) or element(s) of your protocol are being changed.  Check all applicable items. 
  Principal Investigator 
 Change and/or New Recruitment or Publicity Materials 
 
 DSMB Reports/Monitoring Reports/Safety Reports 
 Recruitment, Publicity Materials and/or procedures 
 Revised and/or New Consent Form 
 Consent Procedures 
 Change and/or Addition of Study Procedures 
 Duration of Subject Participation 
 Local Site Enrollment # of Subjects 
 Revised and/or New Study Documents or Subject Materials 
(e.g. diaries, questionnaires) 
 Total Enrollment # of Subjects (Multi-Center Trials) 
 Investigator Brochure, Date/Version: 
 Change in subject selection or subject population 
 Change in Remuneration 
 Change of Sponsor/Funding 
 Research Related Use of Medical Records  
  Study Status Change (i.e., CTE, hold, re-open to enrollment) 
 Use of Specimens 
 
 Industry Sponsored Protocols only:  
Sponsor Amendment/Version #:        
 Research Related Use of Discarded Material 
 Change related to pharmacy or study drug administration 
 
  Revised Sponsor Protocol,  Issue Date/Version:        
 Addition/Removal of Co-Investigator or Research Staff Member 
 
For amendments limited to only the addition or removal of research staff in addition to this form the following is 
required:  
x 
Research Staffing Form (1 clean, 1 highlighted) 
x 
Revised Part E if amendment involves change in Authorized Prescribers for study medication 
x 
Part Q and CITI training documentation for any non-BIDMC research staff member.   
 
AMENDMENT ATTACHMENTS: 
 Revised Sponsor Protocol (New Version) (1 clean, 1 highlighted) 
 New or Revised Advertisement (1 clean, 1 highlighted) 
 Revised Part A (1 clean, 1 highlighted) 
 Revised Part B (1 clean, 1 highlighted) 
 Revised Consent Form (1 clean, 1 highlighted) 
 Revised Research Participant Materials or  Questionnaires  
     (1 clean, 1 highlighted) 
 Revised Research Staffing Form (1 Clean, I highlighted: ) 
 Part Q(s) for addition of any non-BIDMC personnel  
 Revised/New Part E (Obtain pharmacy signature and detail change below) 
 Other Revised Part/Form Document  (1 Clean, I highlighted: ) 
     Specify: Part E to add Ari Moskowitz MD as an authorized prescriber.  
 
 
 
AMENDMENT DESCRIPTION- REQUIRED FOR ALL SUBMISSIONS 


 (CCI) Committee on Clinical Investigations 
Page 16 of 62 
                                                                                                                                                                                                                       Amendment Form  
                                                                                                                                                                                              CCI Form Revised: 3-2013 
 
A detailed description of the amendment, in your own words, MUST be provided below.  The PI may provide a summary of a lengthy 
sponsor amendment in an attached cover letter or memo, however this should not simply be a copy of the sponsors amendment 
and/or letter.  Either list the current item followed by the new item, or attach a redlined version of the changed document.  If the 
consent form is revised, attach one copy of the consent form in which the changes (including additions and deletions) are clearly 
highlighted, and one clean copy of the consent form. 
3. Addition of study staff member. 
. 
 
  PI Memo/Cover Letter Describing Changes is attached 
  Sponsor Letter Describing Changes is Attached 
 
 
Impact on Budget/Funding 
Does this amendment affect the current budget for the 
study? 
 
 No 
 
 Yes, if yes, explain       
 
and contact:  
- 
Clinical Trials Office for Industry Funded Studies 
- 
Office of Sponsored Programs for Other Funding 
Sources 
 
 
 
Does this amendment affect the current funding for the 
study? 
 
  No 
 
  Yes, if yes, explain       
 
 and contact: 
- 
Clinical Trials Office for Industry Funded Studies 
- 
Office of Sponsored Programs for Other Funding 
Sources 
 
 
AMENDMENT RATIONALE- REQUIRED FOR ALL SUBMISSIONS 
The reason or justification for the changes must be discussed as well as how the change might affect the risk/benefit ratio.  Please 
also address how or if a change in the risk/benefit ratio impacts the informed consent form, and if the change necessitates a change in 
the consent form.  The rationale may be provided here or in an attached cover letter or memo.   
 
Ari Moskowitz is being added as a co-investigator and an authorized prescriber. 
 
These changes do not affect the risk/benefit ratio. This study DOES necessitate a change in the written, informed consent form. 
  PI Memo /Cover letter Describing Rationale is Attached 
  Sponsor Letter Describing Rationale is Attached 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Principal Investigator  
 
 
 
 
Date 
 
 
Print Name  
 
Michael Cocchi MD 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 (CCI) Committee on Clinical Investigations 
Page 17 of 62 
                                                                                                                                                                                                                       Amendment Form  
                                                                                                                                                                                              CCI Form Revised: 3-2013 
 
AMENDMENT FORM 
STUDY INFORMATION 
TITLE OF PROTOCOL: Esmolol to treat the hemodynamic effects of septic shock 
CCI PROTOCOL # : 2014P-000415 
PRINCIPAL INVESTIGATOR: Michael Cocchi MD 
STUDY COORDINATOR: Elinita Rosseto 
STUDY COORDINATOR EMAIL ADDRESS: EROSSETO@BIDMC.HARVARD.EDU 
 
AMENDMENT DETAILS 
Indicate which components(s) or element(s) of your protocol are being changed.  Check all applicable items. 
  Principal Investigator 
 Change and/or New Recruitment or Publicity Materials 
 
 DSMB Reports/Monitoring Reports/Safety Reports 
 Recruitment, Publicity Materials and/or procedures 
 Revised and/or New Consent Form 
 Consent Procedures 
 Change and/or Addition of Study Procedures 
 Duration of Subject Participation 
 Local Site Enrollment # of Subjects 
 Revised and/or New Study Documents or Subject Materials 
(e.g. diaries, questionnaires) 
 Total Enrollment # of Subjects (Multi-Center Trials) 
 Investigator Brochure, Date/Version: 
 Change in subject selection or subject population 
 Change in Remuneration 
 Change of Sponsor/Funding 
 Research Related Use of Medical Records  
  Study Status Change (i.e., CTE, hold, re-open to enrollment) 
 Use of Specimens 
 
 Industry Sponsored Protocols only:  
Sponsor Amendment/Version #:        
 Research Related Use of Discarded Material 
 Change related to pharmacy or study drug administration 
 
  Revised Sponsor Protocol,  Issue Date/Version:        
 Addition/Removal of Co-Investigator or Research Staff Member 
 
For amendments limited to only the addition or removal of research staff in addition to this form the following is 
required:  
x 
Research Staffing Form (1 clean, 1 highlighted) 
x 
Revised Part E if amendment involves change in Authorized Prescribers for study medication 
x 
Part Q and CITI training documentation for any non-BIDMC research staff member.   
 
AMENDMENT ATTACHMENTS: 
 Revised Sponsor Protocol (New Version) (1 clean, 1 highlighted) 
 New or Revised Advertisement (1 clean, 1 highlighted) 
 Revised Part A (1 clean, 1 highlighted) 
 Revised Part B (1 clean, 1 highlighted) 
 Revised Consent Form (1 clean, 1 highlighted) 
 Revised Research Participant Materials or  Questionnaires  
     (1 clean, 1 highlighted) 
 Revised Research Staffing Form (1 Clean, I highlighted: ) 
 Part Q(s) for addition of any non-BIDMC personnel  
 Revised/New Part E (Obtain pharmacy signature and detail change below) 
 Other Revised Part/Form Document  (1 Clean, I highlighted: ) 
     Specify:  
 
 
AMENDMENT DESCRIPTION- REQUIRED FOR ALL SUBMISSIONS 


 (CCI) Committee on Clinical Investigations 
Page 18 of 62 
                                                                                                                                                                                                                       Amendment Form  
                                                                                                                                                                                              CCI Form Revised: 3-2013 
 
A detailed description of the amendment, in your own words, MUST be provided below.  The PI may provide a summary of a lengthy 
sponsor amendment in an attached cover letter or memo, however this should not simply be a copy of the sponsors amendment 
and/or letter.  Either list the current item followed by the new item, or attach a redlined version of the changed document.  If the 
consent form is revised, attach one copy of the consent form in which the changes (including additions and deletions) are clearly 
highlighted, and one clean copy of the consent form. 
. 
1. One additional site is being added 
  PI Memo/Cover Letter Describing Changes is attached 
  Sponsor Letter Describing Changes is Attached 
 
 
Impact on Budget/Funding 
Does this amendment affect the current budget for the 
study? 
 
 No 
 
 Yes, if yes, explain       
 
and contact:  
- 
Clinical Trials Office for Industry Funded Studies 
- 
Office of Sponsored Programs for Other Funding 
Sources 
 
 
 
Does this amendment affect the current funding for the 
study? 
 
  No 
 
  Yes, if yes, explain       
 
 and contact: 
- 
Clinical Trials Office for Industry Funded Studies 
- 
Office of Sponsored Programs for Other Funding 
Sources 
 
 
AMENDMENT RATIONALE- REQUIRED FOR ALL SUBMISSIONS 
The reason or justification for the changes must be discussed as well as how the change might affect the risk/benefit ratio.  Please 
also address how or if a change in the risk/benefit ratio impacts the informed consent form, and if the change necessitates a change in 
the consent form.  The rationale may be provided here or in an attached cover letter or memo.   
 
1. Henry Ford Hospital in Detroit Michigan is being added to increase the enrollment speed. We will not be 
increasing the global number of enrollment. 
 
These changes do not affect the risk/benefit ratio. This study DOES NOT necessitate a change in the written, informed consent form. 
 
  PI Memo /Cover letter Describing Rationale is Attached 
  Sponsor Letter Describing Rationale is Attached 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Principal Investigator  
 
 
 
 
Date 
 
 
Print Name  
 
Michael Cocchi MD 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 (CCI) Committee on Clinical Investigations 
Page 19 of 62 
                                                                                                                                                                                                                       Amendment Form  
                                                                                                                                                                                              CCI Form Revised: 3-2013 
 
AMENDMENT FORM 
STUDY INFORMATION 
TITLE OF PROTOCOL: Esmolol to treat the hemodynamic effects of septic shock 
CCI PROTOCOL # : 2014P-000415 
PRINCIPAL INVESTIGATOR: Michael Cocchi MD 
STUDY COORDINATOR: Elinita Rosseto 
STUDY COORDINATOR EMAIL ADDRESS: EROSSETO@BIDMC.HARVARD.EDU 
 
AMENDMENT DETAILS 
Indicate which components(s) or element(s) of your protocol are being changed.  Check all applicable items. 
  Principal Investigator 
 Change and/or New Recruitment or Publicity Materials 
 
 DSMB Reports/Monitoring Reports/Safety Reports 
 Recruitment, Publicity Materials and/or procedures 
 Revised and/or New Consent Form 
 Consent Procedures 
 Change and/or Addition of Study Procedures 
 Duration of Subject Participation 
 Local Site Enrollment # of Subjects 
 Revised and/or New Study Documents or Subject Materials 
(e.g. diaries, questionnaires) 
 Total Enrollment # of Subjects (Multi-Center Trials) 
 Investigator Brochure, Date/Version: 
 Change in subject selection or subject population 
 Change in Remuneration 
 Change of Sponsor/Funding 
 Research Related Use of Medical Records  
  Study Status Change (i.e., CTE, hold, re-open to enrollment) 
 Use of Specimens 
 
 Industry Sponsored Protocols only:  
Sponsor Amendment/Version #:        
 Research Related Use of Discarded Material 
 Change related to pharmacy or study drug administration 
 
  Revised Sponsor Protocol,  Issue Date/Version:        
 Addition/Removal of Co-Investigator or Research Staff Member 
 
For amendments limited to only the addition or removal of research staff in addition to this form the following is 
required:  
x 
Research Staffing Form (1 clean, 1 highlighted) 
x 
Revised Part E if amendment involves change in Authorized Prescribers for study medication 
x 
Part Q and CITI training documentation for any non-BIDMC research staff member.   
 
AMENDMENT ATTACHMENTS: 
 Revised Sponsor Protocol (New Version) (1 clean, 1 highlighted) 
 New or Revised Advertisement (1 clean, 1 highlighted) 
 Revised Part A (1 clean, 1 highlighted) 
 Revised Part B (1 clean, 1 highlighted) 
 Revised Consent Form (1 clean, 1 highlighted) 
 Revised Research Participant Materials or  Questionnaires  
     (1 clean, 1 highlighted) 
 Revised Research Staffing Form (1 Clean, I highlighted: ) 
 Part Q(s) for addition of any non-BIDMC personnel  
 Revised/New Part E (Obtain pharmacy signature and detail change below) 
 Other Revised Part/Form Document  (1 Clean, I highlighted: ) 
     Specify:  
 
 
AMENDMENT DESCRIPTION- REQUIRED FOR ALL SUBMISSIONS 


 (CCI) Committee on Clinical Investigations 
Page 20 of 62 
                                                                                                                                                                                                                       Amendment Form  
                                                                                                                                                                                              CCI Form Revised: 3-2013 
 
A detailed description of the amendment, in your own words, MUST be provided below.  The PI may provide a summary of a lengthy 
sponsor amendment in an attached cover letter or memo, however this should not simply be a copy of the sponsors amendment 
and/or letter.  Either list the current item followed by the new item, or attach a redlined version of the changed document.  If the 
consent form is revised, attach one copy of the consent form in which the changes (including additions and deletions) are clearly 
highlighted, and one clean copy of the consent form. 
. 
Update study staff. 
  PI Memo/Cover Letter Describing Changes is attached 
  Sponsor Letter Describing Changes is Attached 
 
 
Impact on Budget/Funding 
Does this amendment affect the current budget for the 
study? 
 
 No 
 
 Yes, if yes, explain       
 
and contact:  
- 
Clinical Trials Office for Industry Funded Studies 
- 
Office of Sponsored Programs for Other Funding 
Sources 
 
 
 
Does this amendment affect the current funding for the 
study? 
 
  No 
 
  Yes, if yes, explain       
 
 and contact: 
- 
Clinical Trials Office for Industry Funded Studies 
- 
Office of Sponsored Programs for Other Funding 
Sources 
 
 
AMENDMENT RATIONALE- REQUIRED FOR ALL SUBMISSIONS 
The reason or justification for the changes must be discussed as well as how the change might affect the risk/benefit ratio.  Please 
also address how or if a change in the risk/benefit ratio impacts the informed consent form, and if the change necessitates a change in 
the consent form.  The rationale may be provided here or in an attached cover letter or memo.   
 
1.  Removal of Josie Scheunemann, Julia Balkema, Chris Sulmonte and Alex Wulff as they are no longer with the 
institution. 
2.  Addition of Varun Konanki as co-investigator to increase enrollment capacity. 
 
These changes do not affect the risk/benefit ratio. This study DOES NOT necessitate a change in the written, informed consent form. 
 
  PI Memo /Cover letter Describing Rationale is Attached 
  Sponsor Letter Describing Rationale is Attached 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Principal Investigator  
 
 
 
 
Date 
 
 
Print Name  
 
Michael Cocchi MD 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 (CCI) Committee on Clinical Investigations 
Page 21 of 62 
                                                                                                                                                                                                                       Amendment Form  
                                                                                                                                                                                              CCI Form Revised: 3-2013 
 
 
AMENDMENT FORM 
STUDY INFORMATION 
TITLE OF PROTOCOL: Esmolol to treat the hemodynamic effects of septic shock 
CCI PROTOCOL # : 2014P-000415 
PRINCIPAL INVESTIGATOR: Michael Cocchi MD 
STUDY COORDINATOR: Elinita Rosseto 
STUDY COORDINATOR EMAIL ADDRESS: EROSSETO@BIDMC.HARVARD.EDU 
 
AMENDMENT DETAILS 
Indicate which components(s) or element(s) of your protocol are being changed.  Check all applicable items. 
  Principal Investigator 
 Change and/or New Recruitment or Publicity Materials 
 
 DSMB Reports/Monitoring Reports/Safety Reports 
 Recruitment, Publicity Materials and/or procedures 
 Revised and/or New Consent Form 
 Consent Procedures 
 Change and/or Addition of Study Procedures 
 Duration of Subject Participation 
 Local Site Enrollment # of Subjects 
 Revised and/or New Study Documents or Subject Materials 
(e.g. diaries, questionnaires) 
 Total Enrollment # of Subjects (Multi-Center Trials) 
 Investigator Brochure, Date/Version: 
 Change in subject selection or subject population 
 Change in Remuneration 
 Change of Sponsor/Funding 
 Research Related Use of Medical Records  
  Study Status Change (i.e., CTE, hold, re-open to enrollment) 
 Use of Specimens 
 
 Industry Sponsored Protocols only:  
Sponsor Amendment/Version #:        
 Research Related Use of Discarded Material 
 Change related to pharmacy or study drug administration 
 
  Revised Sponsor Protocol,  Issue Date/Version:        
 Addition/Removal of Co-Investigator or Research Staff Member 
 
For amendments limited to only the addition or removal of research staff in addition to this form the following is 
required:  
x 
Research Staffing Form (1 clean, 1 highlighted) 
x 
Revised Part E if amendment involves change in Authorized Prescribers for study medication 
x 
Part Q and CITI training documentation for any non-BIDMC research staff member.   
 
AMENDMENT ATTACHMENTS: 
 Revised Sponsor Protocol (New Version) (1 clean, 1 highlighted) 
 New or Revised Advertisement (1 clean, 1 highlighted) 
 Revised Part A (1 clean, 1 highlighted) 
 Revised Part B (1 clean, 1 highlighted) 
 Revised Consent Form (1 clean, 1 highlighted) 
 Revised Research Participant Materials or  Questionnaires  
     (1 clean, 1 highlighted) 
 Revised Research Staffing Form (1 Clean, I highlighted: ) 
 Part Q(s) for addition of any non-BIDMC personnel  
 Revised/New Part E (Obtain pharmacy signature and detail change below) 
 Other Revised Part/Form Document  (1 Clean, I highlighted: ) 
     Specify:  
 
 
AMENDMENT DESCRIPTION- REQUIRED FOR ALL SUBMISSIONS 


 (CCI) Committee on Clinical Investigations 
Page 22 of 62 
                                                                                                                                                                                                                       Amendment Form  
                                                                                                                                                                                              CCI Form Revised: 3-2013 
 
A detailed description of the amendment, in your own words, MUST be provided below.  The PI may provide a summary of a lengthy 
sponsor amendment in an attached cover letter or memo, however this should not simply be a copy of the sponsors amendment 
and/or letter.  Either list the current item followed by the new item, or attach a redlined version of the changed document.  If the 
consent form is revised, attach one copy of the consent form in which the changes (including additions and deletions) are clearly 
highlighted, and one clean copy of the consent form. 
. 
Update study staff. 
  PI Memo/Cover Letter Describing Changes is attached 
  Sponsor Letter Describing Changes is Attached 
 
 
Impact on Budget/Funding 
Does this amendment affect the current budget for the 
study? 
 
 No 
 
 Yes, if yes, explain       
 
and contact:  
- 
Clinical Trials Office for Industry Funded Studies 
- 
Office of Sponsored Programs for Other Funding 
Sources 
 
 
 
Does this amendment affect the current funding for the 
study? 
 
  No 
 
  Yes, if yes, explain       
 
 and contact: 
- 
Clinical Trials Office for Industry Funded Studies 
- 
Office of Sponsored Programs for Other Funding 
Sources 
 
 
AMENDMENT RATIONALE- REQUIRED FOR ALL SUBMISSIONS 
The reason or justification for the changes must be discussed as well as how the change might affect the risk/benefit ratio.  Please 
also address how or if a change in the risk/benefit ratio impacts the informed consent form, and if the change necessitates a change in 
the consent form.  The rationale may be provided here or in an attached cover letter or memo.   
 
Addition of Anne Grossestreur Mathias Holmberg Michael McNaughton Jocelyn Portmann Nikola Stankovic 
Amy Ube and Jocelyn Portmann as co-investigators to increase enrollment capacity and assist with the 
protocol. 
Removal of John Paul Couce and Mathias Karlsson as they are no longer with the institution. 
 
These changes do not affect the risk/benefit ratio. This study DOES NOT necessitate a change in the written, informed consent form. 
 
  PI Memo /Cover letter Describing Rationale is Attached 
  Sponsor Letter Describing Rationale is Attached 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Principal Investigator  
 
 
 
 
Date 
 
 
Print Name  
 
Michael Cocchi MD 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 (CCI) Committee on Clinical Investigations 
Page 23 of 62 
                                                                                                                                                                                                                       Amendment Form  
                                                                                                                                                                                              CCI Form Revised: 3-2013 
 
 
AMENDMENT FORM 
STUDY INFORMATION 
TITLE OF PROTOCOL: Esmolol to treat the hemodynamic effects of septic shock 
CCI PROTOCOL # : 2014P-000415 
PRINCIPAL INVESTIGATOR: Michael Cocchi MD 
STUDY COORDINATOR: Elinita Rosseto 
STUDY COORDINATOR EMAIL ADDRESS: EROSSETO@BIDMC.HARVARD.EDU 
 
AMENDMENT DETAILS 
Indicate which components(s) or element(s) of your protocol are being changed.  Check all applicable items. 
  Principal Investigator 
 Change and/or New Recruitment or Publicity Materials 
 
 DSMB Reports/Monitoring Reports/Safety Reports - 
membership 
 Recruitment, Publicity Materials and/or procedures 
 Revised and/or New Consent Form 
 Consent Procedures 
 Change and/or Addition of Study Procedures 
 Duration of Subject Participation 
 Local Site Enrollment # of Subjects 
 Revised and/or New Study Documents or Subject Materials 
(e.g. diaries, questionnaires) 
 Total Enrollment # of Subjects (Multi-Center Trials) 
 Investigator Brochure, Date/Version: 
 Change in subject selection or subject population 
 Change in Remuneration 
 Change of Sponsor/Funding 
 Research Related Use of Medical Records  
  Study Status Change (i.e., CTE, hold, re-open to enrollment) 
 Use of Specimens 
 
 Industry Sponsored Protocols only:  
Sponsor Amendment/Version #:        
 Research Related Use of Discarded Material 
 Change related to pharmacy or study drug administration 
 
  Revised Sponsor Protocol,  Issue Date/Version:        
 Addition/Removal of Co-Investigator or Research Staff Member 
 
For amendments limited to only the addition or removal of research staff in addition to this form the following is 
required:  
x 
Research Staffing Form (1 clean, 1 highlighted) 
x 
Revised Part E if amendment involves change in Authorized Prescribers for study medication 
x 
Part Q and CITI training documentation for any non-BIDMC research staff member.   
 
AMENDMENT ATTACHMENTS: 
 Revised Sponsor Protocol (New Version) (1 clean, 1 highlighted) 
 New or Revised Advertisement (1 clean, 1 highlighted) 
 Revised Part A (1 clean, 1 highlighted) 
 Revised Part B (1 clean, 1 highlighted) 
 Revised Consent Form (1 clean, 1 highlighted) 
 Revised Research Participant Materials or  Questionnaires  
     (1 clean, 1 highlighted) 
 Revised Research Staffing Form (1 Clean, I highlighted: ) 
 Part Q(s) for addition of any non-BIDMC personnel  
 Revised/New Part E (Obtain pharmacy signature and detail change below) 
 Other Revised Part/Form Document  (1 Clean, I highlighted: ) 
     Specify: Part P- Data Safety Monitoring Plan 
 
 
AMENDMENT DESCRIPTION- REQUIRED FOR ALL SUBMISSIONS 


 (CCI) Committee on Clinical Investigations 
Page 24 of 62 
                                                                                                                                                                                                                       Amendment Form  
                                                                                                                                                                                              CCI Form Revised: 3-2013 
 
A detailed description of the amendment, in your own words, MUST be provided below.  The PI may provide a summary of a lengthy 
sponsor amendment in an attached cover letter or memo, however this should not simply be a copy of the sponsors amendment 
and/or letter.  Either list the current item followed by the new item, or attach a redlined version of the changed document.  If the 
consent form is revised, attach one copy of the consent form in which the changes (including additions and deletions) are clearly 
highlighted, and one clean copy of the consent form. 
. 
Update DSMB member list. 
  PI Memo/Cover Letter Describing Changes is attached 
  Sponsor Letter Describing Changes is Attached 
 
 
Impact on Budget/Funding 
Does this amendment affect the current budget for the 
study? 
 
 No 
 
 Yes, if yes, explain       
 
and contact:  
- 
Clinical Trials Office for Industry Funded Studies 
- 
Office of Sponsored Programs for Other Funding 
Sources 
 
 
 
Does this amendment affect the current funding for the 
study? 
 
  No 
 
  Yes, if yes, explain       
 
 and contact: 
- 
Clinical Trials Office for Industry Funded Studies 
- 
Office of Sponsored Programs for Other Funding 
Sources 
 
 
AMENDMENT RATIONALE- REQUIRED FOR ALL SUBMISSIONS 
The reason or justification for the changes must be discussed as well as how the change might affect the risk/benefit ratio.  Please 
also address how or if a change in the risk/benefit ratio impacts the informed consent form, and if the change necessitates a change in 
the consent form.  The rationale may be provided here or in an attached cover letter or memo.   
 
The DSMB is being modified due to prior members being unable to participate. Todd Sarge has been replaced by Dustin 
Boone (same division); Robb Kociol has been replaced by Marwa Sabe (same division).  Due to difficulties with 
scheduling, we had to schedule the first DSMB meeting for Thursday December 15th/ 
 
These changes do not affect the risk/benefit ratio. This study DOES NOT necessitate a change in the written, informed consent form. 
 
  PI Memo /Cover letter Describing Rationale is Attached 
  Sponsor Letter Describing Rationale is Attached 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Principal Investigator  
 
 
 
 
Date 
 
 
Print Name  
 
Michael Cocchi MD 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 (CCI) Committee on Clinical Investigations 
Page 25 of 62 
                                                                                                                                                                                                                       Amendment Form  
                                                                                                                                                                                              CCI Form Revised: 3-2013 
 
AMENDMENT FORM 
STUDY INFORMATION 
TITLE OF PROTOCOL: Esmolol to treat the hemodynamic effects of septic shock 
CCI PROTOCOL # : 2014P-000415 
PRINCIPAL INVESTIGATOR: Michael Cocchi MD 
STUDY COORDINATOR: Elinita Rosseto 
STUDY COORDINATOR EMAIL ADDRESS: EROSSETO@BIDMC.HARVARD.EDU 
 
AMENDMENT DETAILS 
Indicate which components(s) or element(s) of your protocol are being changed.  Check all applicable items. 
  Principal Investigator 
 Change and/or New Recruitment or Publicity Materials 
 
 DSMB Reports/Monitoring Reports/Safety Reports - 
 Recruitment, Publicity Materials and/or procedures 
 Revised and/or New Consent Form 
 Consent Procedures 
 Change and/or Addition of Study Procedures 
 Duration of Subject Participation 
 Local Site Enrollment # of Subjects 
 Revised and/or New Study Documents or Subject Materials 
(e.g. diaries, questionnaires) 
 Total Enrollment # of Subjects (Multi-Center Trials) 
 Investigator Brochure, Date/Version: 
 Change in subject selection or subject population 
 Change in Remuneration 
 Change of Sponsor/Funding 
 Research Related Use of Medical Records  
  Study Status Change (i.e., CTE, hold, re-open to enrollment) 
 Use of Specimens 
 
 Industry Sponsored Protocols only:  
Sponsor Amendment/Version #:        
 Research Related Use of Discarded Material 
 Change related to pharmacy or study drug administration 
 
  Revised Sponsor Protocol,  Issue Date/Version:        
 Addition/Removal of Co-Investigator or Research Staff Member 
 
For amendments limited to only the addition or removal of research staff in addition to this form the following is 
required:  
x 
Research Staffing Form (1 clean, 1 highlighted) 
x 
Revised Part E if amendment involves change in Authorized Prescribers for study medication 
x 
Part Q and CITI training documentation for any non-BIDMC research staff member.   
 
AMENDMENT ATTACHMENTS: 
 Revised Sponsor Protocol (New Version) (1 clean, 1 highlighted) 
 New or Revised Advertisement (1 clean, 1 highlighted) 
 Revised Part A (1 clean, 1 highlighted) 
 Revised Part B (1 clean, 1 highlighted) 
 Revised Consent Form (1 clean, 1 highlighted) 
 Revised Research Participant Materials or  Questionnaires  
     (1 clean, 1 highlighted) 
 Revised Research Staffing Form (1 Clean, I highlighted: ) 
 Part Q(s) for addition of any non-BIDMC personnel  
 Revised/New Part E (Obtain pharmacy signature and detail change below) 
 Other Revised Part/Form Document  (1 Clean, I highlighted: ) 
     Specify: DSMB letter dated 12/18/2016 
 
 
AMENDMENT DESCRIPTION- REQUIRED FOR ALL SUBMISSIONS 


 (CCI) Committee on Clinical Investigations 
Page 26 of 62 
                                                                                                                                                                                                                       Amendment Form  
                                                                                                                                                                                              CCI Form Revised: 3-2013 
 
A detailed description of the amendment, in your own words, MUST be provided below.  The PI may provide a summary of a lengthy 
sponsor amendment in an attached cover letter or memo, however this should not simply be a copy of the sponsors amendment 
and/or letter.  Either list the current item followed by the new item, or attach a redlined version of the changed document.  If the 
consent form is revised, attach one copy of the consent form in which the changes (including additions and deletions) are clearly 
highlighted, and one clean copy of the consent form. 
. 
The DSMB met on 12/15/2016 
  PI Memo/Cover Letter Describing Changes is attached 
  Sponsor Letter Describing Changes is Attached 
 
 
Impact on Budget/Funding 
Does this amendment affect the current budget for the 
study? 
 
 No 
 
 Yes, if yes, explain       
 
and contact:  
- 
Clinical Trials Office for Industry Funded Studies 
- 
Office of Sponsored Programs for Other Funding 
Sources 
 
 
 
Does this amendment affect the current funding for the 
study? 
 
  No 
 
  Yes, if yes, explain       
 
 and contact: 
- 
Clinical Trials Office for Industry Funded Studies 
- 
Office of Sponsored Programs for Other Funding 
Sources 
 
 
AMENDMENT RATIONALE- REQUIRED FOR ALL SUBMISSIONS 
The reason or justification for the changes must be discussed as well as how the change might affect the risk/benefit ratio.  Please 
also address how or if a change in the risk/benefit ratio impacts the informed consent form, and if the change necessitates a change in 
the consent form.  The rationale may be provided here or in an attached cover letter or memo.   
 
The DSMB for the study met on 12/15/2016. There were no safety concerns and the board approved the study to 
continue. 
 
Assessment of risk/benefit ratio:  These changes do not alter the risk/benefit ratio of the study. These changes DO NOT 
necessitate a change in the consent form.   
 
 
  PI Memo /Cover letter Describing Rationale is Attached 
  Sponsor Letter Describing Rationale is Attached 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Principal Investigator  
 
 
 
 
Date 
 
 
Print Name  
 
Michael Cocchi MD 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 (CCI) Committee on Clinical Investigations 
Page 27 of 62 
                                                                                                                                                                                                                       Amendment Form  
                                                                                                                                                                                              CCI Form Revised: 3-2013 
 
AMENDMENT FORM 
STUDY INFORMATION 
TITLE OF PROTOCOL: Esmolol to treat the hemodynamic effects of septic shock 
CCI PROTOCOL # : 2014P-000415 
PRINCIPAL INVESTIGATOR: Michael Cocchi MD 
STUDY COORDINATOR: Elinita Rosseto 
STUDY COORDINATOR EMAIL ADDRESS: EROSSETO@BIDMC.HARVARD.EDU 
 
AMENDMENT DETAILS 
Indicate which components(s) or element(s) of your protocol are being changed.  Check all applicable items. 
  Principal Investigator 
 Change and/or New Recruitment or Publicity Materials 
 
 DSMB Reports/Monitoring Reports/Safety Reports 
 Recruitment, Publicity Materials and/or procedures 
 Revised and/or New Consent Form 
 Consent Procedures 
 Change and/or Addition of Study Procedures 
 Duration of Subject Participation 
 Local Site Enrollment # of Subjects 
 Revised and/or New Study Documents or Subject Materials 
(e.g. diaries, questionnaires) 
 Total Enrollment # of Subjects (Multi-Center Trials) 
 Investigator Brochure, Date/Version: 
 Change in subject selection or subject population 
 Change in Remuneration 
 Change of Sponsor/Funding 
 Research Related Use of Medical Records  
  Study Status Change (i.e., CTE, hold, re-open to enrollment) 
 Use of Specimens 
 
 Industry Sponsored Protocols only:  
Sponsor Amendment/Version #:        
 Research Related Use of Discarded Material 
 Change related to pharmacy or study drug administration 
 
  Revised Sponsor Protocol,  Issue Date/Version:        
 Addition/Removal of Co-Investigator or Research Staff Member 
 
For amendments limited to only the addition or removal of research staff in addition to this form the following is 
required:  
x 
Research Staffing Form (1 clean, 1 highlighted) 
x 
Revised Part E if amendment involves change in Authorized Prescribers for study medication 
x 
Part Q and CITI training documentation for any non-BIDMC research staff member.   
 
AMENDMENT ATTACHMENTS: 
 Revised Sponsor Protocol (New Version) (1 clean, 1 highlighted) 
 New or Revised Advertisement (1 clean, 1 highlighted) 
 Revised Part A (1 clean, 1 highlighted) 
 Revised Part B (1 clean, 1 highlighted) 
 Revised Consent Form (1 clean, 1 highlighted) 
 Revised Research Participant Materials or  Questionnaires  
     (1 clean, 1 highlighted) 
 Revised Research Staffing Form (1 Clean, I highlighted: ) 
 Part Q(s) for addition of any non-BIDMC personnel  
 Revised/New Part E (Obtain pharmacy signature and detail change below) 
 Other Revised Part/Form Document  (1 Clean, I highlighted: ) 
     Specify:  
 
 
AMENDMENT DESCRIPTION- REQUIRED FOR ALL SUBMISSIONS 


 (CCI) Committee on Clinical Investigations 
Page 28 of 62 
                                                                                                                                                                                                                       Amendment Form  
                                                                                                                                                                                              CCI Form Revised: 3-2013 
 
A detailed description of the amendment, in your own words, MUST be provided below.  The PI may provide a summary of a lengthy 
sponsor amendment in an attached cover letter or memo, however this should not simply be a copy of the sponsors amendment 
and/or letter.  Either list the current item followed by the new item, or attach a redlined version of the changed document.  If the 
consent form is revised, attach one copy of the consent form in which the changes (including additions and deletions) are clearly 
highlighted, and one clean copy of the consent form. 
. 
Update study staff. 
 
  PI Memo/Cover Letter Describing Changes is attached 
  Sponsor Letter Describing Changes is Attached 
 
 
Impact on Budget/Funding 
Does this amendment affect the current budget for the 
study? 
 
 No 
 
 Yes, if yes, explain       
 
and contact:  
- 
Clinical Trials Office for Industry Funded Studies 
- 
Office of Sponsored Programs for Other Funding 
Sources 
 
 
 
Does this amendment affect the current funding for the 
study? 
 
  No 
 
  Yes, if yes, explain       
 
 and contact: 
- 
Clinical Trials Office for Industry Funded Studies 
- 
Office of Sponsored Programs for Other Funding 
Sources 
 
 
AMENDMENT RATIONALE- REQUIRED FOR ALL SUBMISSIONS 
The reason or justification for the changes must be discussed as well as how the change might affect the risk/benefit ratio.  Please 
also address how or if a change in the risk/benefit ratio impacts the informed consent form, and if the change necessitates a change in 
the consent form.  The rationale may be provided here or in an attached cover letter or memo.   
 
Addition of Marcel Casasola and Derek Guanaga as co-investigator to increase enrollment capacity and assist with the 
protocol. 
 
These changes do not affect the risk/benefit ratio. This study DOES NOT necessitate a change in the written, informed consent form. 
 
  PI Memo /Cover letter Describing Rationale is Attached 
  Sponsor Letter Describing Rationale is Attached 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Principal Investigator  
 
 
 
 
Date 
 
 
Print Name  
Michael Cocchi MD 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 (CCI) Committee on Clinical Investigations 
Page 29 of 62 
                                                                                                                                                                                                                       Amendment Form  
                                                                                                                                                                                              CCI Form Revised: 3-2013 
 
AMENDMENT FORM 
STUDY INFORMATION 
TITLE OF PROTOCOL: Esmolol to treat the hemodynamic effects of septic shock 
CCI PROTOCOL # : 2014P-000415 
PRINCIPAL INVESTIGATOR: Michael Cocchi MD 
STUDY COORDINATOR: Elinita Rosseto 
STUDY COORDINATOR EMAIL ADDRESS: EROSSETO@BIDMC.HARVARD.EDU 
 
AMENDMENT DETAILS 
Indicate which components(s) or element(s) of your protocol are being changed.  Check all applicable items. 
  Principal Investigator 
 Change and/or New Recruitment or Publicity Materials 
 
 DSMB Reports/Monitoring Reports/Safety Reports 
 Recruitment, Publicity Materials and/or procedures 
 Revised and/or New Consent Form 
 Consent Procedures 
 Change and/or Addition of Study Procedures 
 Duration of Subject Participation 
 Local Site Enrollment # of Subjects 
 Revised and/or New Study Documents or Subject Materials 
(e.g. diaries, questionnaires) 
 Total Enrollment # of Subjects (Multi-Center Trials) 
 Investigator Brochure, Date/Version: 
 Change in subject selection or subject population 
 Change in Remuneration 
 Change of Sponsor/Funding 
 Research Related Use of Medical Records  
  Study Status Change (i.e., CTE, hold, re-open to enrollment) 
 Use of Specimens 
 
 Industry Sponsored Protocols only:  
Sponsor Amendment/Version #:        
 Research Related Use of Discarded Material 
 Change related to pharmacy or study drug administration 
 
  Revised Sponsor Protocol,  Issue Date/Version:        
 Addition/Removal of Co-Investigator or Research Staff Member 
 
For amendments limited to only the addition or removal of research staff in addition to this form the following is 
required:  
x 
Research Staffing Form (1 clean, 1 highlighted) 
x 
Revised Part E if amendment involves change in Authorized Prescribers for study medication 
x 
Part Q and CITI training documentation for any non-BIDMC research staff member.   
 
AMENDMENT ATTACHMENTS: 
 Revised Sponsor Protocol (New Version) (1 clean, 1 highlighted) 
 New or Revised Advertisement (1 clean, 1 highlighted) 
 Revised Part A (1 clean, 1 highlighted) 
 Revised Part B (1 clean, 1 highlighted) 
 Revised Consent Form (1 clean, 1 highlighted) 
 Revised Research Participant Materials or  Questionnaires  
     (1 clean, 1 highlighted) 
 Revised Research Staffing Form (1 Clean, I highlighted: ) 
 Part Q(s) for addition of any non-BIDMC personnel  
 Revised/New Part E (Obtain pharmacy signature and detail change below) 
 Other Revised Part/Form Document  (1 Clean, I highlighted: ) 
     Specify:  
 
 
AMENDMENT DESCRIPTION- REQUIRED FOR ALL SUBMISSIONS 


 (CCI) Committee on Clinical Investigations 
Page 30 of 62 
                                                                                                                                                                                                                       Amendment Form  
                                                                                                                                                                                              CCI Form Revised: 3-2013 
 
A detailed description of the amendment, in your own words, MUST be provided below.  The PI may provide a summary of a lengthy 
sponsor amendment in an attached cover letter or memo, however this should not simply be a copy of the sponsors amendment 
and/or letter.  Either list the current item followed by the new item, or attach a redlined version of the changed document.  If the 
consent form is revised, attach one copy of the consent form in which the changes (including additions and deletions) are clearly 
highlighted, and one clean copy of the consent form. 
. 
Update study staff. 
Update in IRB correspondence status for Derek Guanaga. 
 
  PI Memo/Cover Letter Describing Changes is attached 
  Sponsor Letter Describing Changes is Attached 
 
 
Impact on Budget/Funding 
Does this amendment affect the current budget for the 
study? 
 
 No 
 
 Yes, if yes, explain       
 
and contact:  
- 
Clinical Trials Office for Industry Funded Studies 
- 
Office of Sponsored Programs for Other Funding 
Sources 
 
 
 
Does this amendment affect the current funding for the 
study? 
 
  No 
 
  Yes, if yes, explain       
 
 and contact: 
- 
Clinical Trials Office for Industry Funded Studies 
- 
Office of Sponsored Programs for Other Funding 
Sources 
 
 
AMENDMENT RATIONALE- REQUIRED FOR ALL SUBMISSIONS 
The reason or justification for the changes must be discussed as well as how the change might affect the risk/benefit ratio.  Please 
also address how or if a change in the risk/benefit ratio impacts the informed consent form, and if the change necessitates a change in 
the consent form.  The rationale may be provided here or in an attached cover letter or memo.   
 
Addition of Deanna Lee and Eric Mubang as Research Students to increase enrollment capacity and assist with the 
protocol. 
Derek Guanaga is to receive IRB communications to better assist with the protocol. 
 
These changes do not affect the risk/benefit ratio. This study DOES NOT necessitate a change in the written, informed consent form. 
 
  PI Memo /Cover letter Describing Rationale is Attached 
  Sponsor Letter Describing Rationale is Attached 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Principal Investigator  
 
 
 
 
Date 
 
 
Print Name  
Michael Cocchi MD 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 (CCI) Committee on Clinical Investigations 
Page 31 of 62 
                                                                                                                                                                                                                       Amendment Form  
                                                                                                                                                                                              CCI Form Revised: 3-2013 
 
AMENDMENT FORM 
STUDY INFORMATION 
TITLE OF PROTOCOL: Esmolol to treat the hemodynamic effects of septic shock 
CCI PROTOCOL # : 2014P-000415 
PRINCIPAL INVESTIGATOR: Michael Cocchi MD 
STUDY COORDINATOR: Elinita Rosseto 
STUDY COORDINATOR EMAIL ADDRESS: EROSSETO@BIDMC.HARVARD.EDU 
 
AMENDMENT DETAILS 
Indicate which components(s) or element(s) of your protocol are being changed.  Check all applicable items. 
  Principal Investigator 
 Change and/or New Recruitment or Publicity Materials 
 
 DSMB Reports/Monitoring Reports/Safety Reports 
 Recruitment, Publicity Materials and/or procedures 
 Revised and/or New Consent Form 
 Consent Procedures 
 Change and/or Addition of Study Procedures 
 Duration of Subject Participation 
 Local Site Enrollment # of Subjects 
 Revised and/or New Study Documents or Subject Materials 
(e.g. diaries, questionnaires) 
 Total Enrollment # of Subjects (Multi-Center Trials) 
 Investigator Brochure, Date/Version: 
 Change in subject selection or subject population 
 Change in Remuneration 
 Change of Sponsor/Funding 
 Research Related Use of Medical Records  
  Study Status Change (i.e., CTE, hold, re-open to enrollment) 
 Use of Specimens 
 
 Industry Sponsored Protocols only:  
Sponsor Amendment/Version #:        
 Research Related Use of Discarded Material 
 Change related to pharmacy or study drug administration 
 
  Revised Sponsor Protocol,  Issue Date/Version:        
 Addition/Removal of Co-Investigator or Research Staff Member 
 
For amendments limited to only the addition or removal of research staff in addition to this form the following is 
required:  
x 
Research Staffing Form (1 clean, 1 highlighted) 
x 
Revised Part E if amendment involves change in Authorized Prescribers for study medication 
x 
Part Q and CITI training documentation for any non-BIDMC research staff member.   
 
AMENDMENT ATTACHMENTS: 
 Revised Sponsor Protocol (New Version) (1 clean, 1 highlighted) 
 New or Revised Advertisement (1 clean, 1 highlighted) 
 Revised Part A (1 clean, 1 highlighted) 
 Revised Part B (1 clean, 1 highlighted) 
 Revised Consent Form (1 clean, 1 highlighted) 
 Revised Research Participant Materials or  Questionnaires  
     (1 clean, 1 highlighted) 
 Revised Research Staffing Form (1 Clean, I highlighted: ) 
 Part Q(s) for addition of any non-BIDMC personnel  
 Revised/New Part E (Obtain pharmacy signature and detail change below) 
 Other Revised Part/Form Document  (1 Clean, I highlighted: ) 
     Specify:  
 
 
AMENDMENT DESCRIPTION- REQUIRED FOR ALL SUBMISSIONS 


 (CCI) Committee on Clinical Investigations 
Page 32 of 62 
                                                                                                                                                                                                                       Amendment Form  
                                                                                                                                                                                              CCI Form Revised: 3-2013 
 
A detailed description of the amendment, in your own words, MUST be provided below.  The PI may provide a summary of a lengthy 
sponsor amendment in an attached cover letter or memo, however this should not simply be a copy of the sponsors amendment 
and/or letter.  Either list the current item followed by the new item, or attach a redlined version of the changed document.  If the 
consent form is revised, attach one copy of the consent form in which the changes (including additions and deletions) are clearly 
highlighted, and one clean copy of the consent form. 
. 
Update study staff. 
 
  PI Memo/Cover Letter Describing Changes is attached 
  Sponsor Letter Describing Changes is Attached 
 
 
Impact on Budget/Funding 
Does this amendment affect the current budget for the 
study? 
 
 No 
 
 Yes, if yes, explain       
 
and contact:  
- 
Clinical Trials Office for Industry Funded Studies 
- 
Office of Sponsored Programs for Other Funding 
Sources 
 
 
 
Does this amendment affect the current funding for the 
study? 
 
  No 
 
  Yes, if yes, explain       
 
 and contact: 
- 
Clinical Trials Office for Industry Funded Studies 
- 
Office of Sponsored Programs for Other Funding 
Sources 
 
 
AMENDMENT RATIONALE- REQUIRED FOR ALL SUBMISSIONS 
The reason or justification for the changes must be discussed as well as how the change might affect the risk/benefit ratio.  Please 
also address how or if a change in the risk/benefit ratio impacts the informed consent form, and if the change necessitates a change in 
the consent form.  The rationale may be provided here or in an attached cover letter or memo.   
 
Update study staff: Removal of Sarah Ganley and Nikola Stankovic as they are no longer with the institution. Addition of 
Jacob Boise as co-investigator, Prachi Patel and Sierra Hagerty as Research Students to increase enrollment capacity 
and assist with the protocol. 
 
These changes do not affect the risk/benefit ratio. This study DOES NOT necessitate a change in the written, informed consent form. 
 
  PI Memo /Cover letter Describing Rationale is Attached 
  Sponsor Letter Describing Rationale is Attached 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Principal Investigator  
 
 
 
 
Date 
 
 
 
Michael Cocchi MD 
 
 
 
 
Print Name 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 (CCI) Committee on Clinical Investigations 
Page 33 of 62 
                                                                                                                                                                                                                       Amendment Form  
                                                                                                                                                                                              CCI Form Revised: 3-2013 
 
AMENDMENT FORM 
STUDY INFORMATION 
TITLE OF PROTOCOL: Esmolol to treat the hemodynamic effects of septic shock 
CCI PROTOCOL # : 2014P-000415 
PRINCIPAL INVESTIGATOR: Michael Cocchi MD 
STUDY COORDINATOR: Elinita Rosseto 
STUDY COORDINATOR EMAIL ADDRESS: EROSSETO@BIDMC.HARVARD.EDU 
 
AMENDMENT DETAILS 
Indicate which components(s) or element(s) of your protocol are being changed.  Check all applicable items. 
  Principal Investigator 
 Change and/or New Recruitment or Publicity Materials 
 
 DSMB Reports/Monitoring Reports/Safety Reports 
 Recruitment, Publicity Materials and/or procedures 
 Revised and/or New Consent Form 
 Consent Procedures 
 Change and/or Addition of Study Procedures 
 Duration of Subject Participation 
 Local Site Enrollment # of Subjects 
 Revised and/or New Study Documents or Subject Materials 
(e.g. diaries, questionnaires) 
 Total Enrollment # of Subjects (Multi-Center Trials) 
 Investigator Brochure, Date/Version: 
 Change in subject selection or subject population 
 Change in Remuneration 
 Change of Sponsor/Funding 
 Research Related Use of Medical Records  
  Study Status Change (i.e., CTE, hold, re-open to enrollment) 
 Use of Specimens 
 
 Industry Sponsored Protocols only:  
Sponsor Amendment/Version #:        
 Research Related Use of Discarded Material 
 Change related to pharmacy or study drug administration 
 
  Revised Sponsor Protocol,  Issue Date/Version:        
 Addition/Removal of Co-Investigator or Research Staff Member 
 
For amendments limited to only the addition or removal of research staff in addition to this form the following is 
required:  
x 
Research Staffing Form (1 clean, 1 highlighted) 
x 
Revised Part E if amendment involves change in Authorized Prescribers for study medication 
x 
Part Q and CITI training documentation for any non-BIDMC research staff member.   
 
AMENDMENT ATTACHMENTS: 
 Revised Sponsor Protocol (New Version) (1 clean, 1 highlighted) 
 New or Revised Advertisement (1 clean, 1 highlighted) 
 Revised Part A (1 clean, 1 highlighted) 
 Revised Part B (1 clean, 1 highlighted) 
 Revised Consent Form (1 clean, 1 highlighted) 
 Revised Research Participant Materials or  Questionnaires  
     (1 clean, 1 highlighted) 
 Revised Research Staffing Form (1 Clean, I highlighted: ) 
 Part Q(s) for addition of any non-BIDMC personnel  
 Revised/New Part E (Obtain pharmacy signature and detail change below) 
 Other Revised Part/Form Document  (1 Clean, I highlighted: ) 
     Specify:  
 
 
AMENDMENT DESCRIPTION- REQUIRED FOR ALL SUBMISSIONS 


 (CCI) Committee on Clinical Investigations 
Page 34 of 62 
                                                                                                                                                                                                                       Amendment Form  
                                                                                                                                                                                              CCI Form Revised: 3-2013 
 
A detailed description of the amendment, in your own words, MUST be provided below.  The PI may provide a summary of a lengthy 
sponsor amendment in an attached cover letter or memo, however this should not simply be a copy of the sponsors amendment 
and/or letter.  Either list the current item followed by the new item, or attach a redlined version of the changed document.  If the 
consent form is revised, attach one copy of the consent form in which the changes (including additions and deletions) are clearly 
highlighted, and one clean copy of the consent form. 
. 
Administering the informed consent by telephone and email/fax: In the event that a patient does not have the 
capacity to consent and the surrogate is unable to come to BIDMC, we plan to contact the LAR over the phone 
following and send the informed cRQVeQW dRcXPeQW WR WKe VXbMecW¶V VXUURJaWe eOecWURQLcaOO\ (ePaLO, IacVLPLOe, eWc.) 
and a licensed physician investigator will conduct the consent discussion by video or telephone. Once the 
surrogate has had time to review the consent form, if he/she agrees to participation he/she will sign the consent 
and return the signed document to the investigator electronically (email, facsimile, etc.). All email correspondence 
will occur in accordance with BIDMC guidelines. Once the signed consent form has been received by the 
investigator, he/she will then sign, date, and time the form. No study procedures will occur before the consent form 
has been signed by both the surrogate and the investigator. The surrogate will be instructed to return the original 
signed conseQW IRUP WR BIDMC ZKLcK ZLOO be NeSW LQ WKe VXbMecW¶V UeVeaUcK UecRUd ZLWK WKe eOecWURQLcaOO\ 
transmitted copy and a detailed note to file. 
 
As a result, Part B (Page 5 and Page 15) is updated 
 
  PI Memo/Cover Letter Describing Changes is attached 
  Sponsor Letter Describing Changes is Attached 
 
Impact on Budget/Funding 
Does this amendment affect the current budget for the 
study? 
 
 No 
 
 Yes, if yes, explain       
 
and contact:  
- 
Clinical Trials Office for Industry Funded Studies 
- 
Office of Sponsored Programs for Other Funding 
Sources 
Does this amendment affect the current funding for the 
study? 
 
  No 
 
  Yes, if yes, explain       
 
 and contact: 
- 
Clinical Trials Office for Industry Funded Studies 
- 
Office of Sponsored Programs for Other Funding 
Sources 
 
AMENDMENT RATIONALE- REQUIRED FOR ALL SUBMISSIONS 
The reason or justification for the changes must be discussed as well as how the change might affect the risk/benefit ratio.  Please 
also address how or if a change in the risk/benefit ratio impacts the informed consent form, and if the change necessitates a change in 
the consent form.  The rationale may be provided here or in an attached cover letter or memo.   
 
Administering the informed consent by telephone and email/fax: Consenting over phone and email/fax will allow us to 
increase our enrollment capacity for those patients who get excluded for falling out of the protocol mandated window for 
the initiation of study treatment but are otherwise eligible to participate. No study procedures will occur before the consent 
form has been signed by both the surrogate and the investigator (as described above and in Part B). The surrogate will be 
LQVWUXcWed WR UeWXUQ WKe RULJLQaO VLJQed cRQVeQW IRUP WR BIDMC ZKLcK ZLOO be NeSW LQ WKe VXbMecW¶V UeVeaUcK UecRUd ZLWK WKe 
electronically transmitted copy and a detailed note to file.  
 
These changes do not affect the risk/benefit ratio. This study DOES NOT necessitate a change in the written, informed 
consent form. 
 
  PI Memo /Cover letter Describing Rationale is Attached 
  Sponsor Letter Describing Rationale is Attached 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Principal Investigator  
 
 
 
 
Date 
 
 
 
Michael Cocchi MD 
 
 
 
 
Print Name 
 
 


 (CCI) Committee on Clinical Investigations 
Page 35 of 62 
                                                                                                                                                                                                                       Amendment Form  
                                                                                                                                                                                              CCI Form Revised: 3-2013 
 
AMENDMENT FORM 
STUDY INFORMATION 
TITLE OF PROTOCOL: Esmolol to treat the hemodynamic effects of septic shock 
CCI PROTOCOL # : 2014P-000415 
PRINCIPAL INVESTIGATOR: Michael Cocchi MD 
STUDY COORDINATOR: Elinita Rosseto 
STUDY COORDINATOR EMAIL ADDRESS: EROSSETO@BIDMC.HARVARD.EDU 
 
AMENDMENT DETAILS 
Indicate which components(s) or element(s) of your protocol are being changed.  Check all applicable items. 
  Principal Investigator 
 Change and/or New Recruitment or Publicity Materials 
 
 DSMB Reports/Monitoring Reports/Safety Reports 
 Recruitment, Publicity Materials and/or procedures 
 Revised and/or New Consent Form 
 Consent Procedures 
 Change and/or Addition of Study Procedures 
 Duration of Subject Participation 
 Local Site Enrollment # of Subjects 
 Revised and/or New Study Documents or Subject Materials 
(e.g. diaries, questionnaires) 
 Total Enrollment # of Subjects (Multi-Center Trials) 
 Investigator Brochure, Date/Version: 
 Change in subject selection or subject population 
 Change in Remuneration 
 Change of Sponsor/Funding 
 Research Related Use of Medical Records  
  Study Status Change (i.e., CTE, hold, re-open to enrollment) 
 Use of Specimens 
 
 Industry Sponsored Protocols only:  
Sponsor Amendment/Version #:        
 Research Related Use of Discarded Material 
 Change related to pharmacy or study drug administration 
 
  Revised Sponsor Protocol,  Issue Date/Version:        
 Addition/Removal of Co-Investigator or Research Staff Member 
 
For amendments limited to only the addition or removal of research staff in addition to this form the following is 
required:  
x 
Research Staffing Form (1 clean, 1 highlighted) 
x 
Revised Part E if amendment involves change in Authorized Prescribers for study medication 
x 
Part Q and CITI training documentation for any non-BIDMC research staff member.   
 
AMENDMENT ATTACHMENTS: 
 Revised Sponsor Protocol (New Version) (1 clean, 1 highlighted) 
 New or Revised Advertisement (1 clean, 1 highlighted) 
 Revised Part A (1 clean, 1 highlighted) 
 Revised Part B (1 clean, 1 highlighted) 
 Revised Consent Form (1 clean, 1 highlighted) 
 Revised Research Participant Materials or  Questionnaires  
     (1 clean, 1 highlighted) 
 Revised Research Staffing Form (1 Clean, I highlighted: ) 
 Part Q(s) for addition of any non-BIDMC personnel  
 Revised/New Part E (Obtain pharmacy signature and detail change below) 
 Other Revised Part/Form Document  (1 Clean, I highlighted: ) 
     Specify:  
 
 
AMENDMENT DESCRIPTION- REQUIRED FOR ALL SUBMISSIONS 


 (CCI) Committee on Clinical Investigations 
Page 36 of 62 
                                                                                                                                                                                                                       Amendment Form  
                                                                                                                                                                                              CCI Form Revised: 3-2013 
 
A detailed description of the amendment, in your own words, MUST be provided below.  The PI may provide a summary of a lengthy 
sponsor amendment in an attached cover letter or memo, however this should not simply be a copy of the sponsors amendment 
and/or letter.  Either list the current item followed by the new item, or attach a redlined version of the changed document.  If the 
consent form is revised, attach one copy of the consent form in which the changes (including additions and deletions) are clearly 
highlighted, and one clean copy of the consent form. 
. 
Update study staff. 
 
  PI Memo/Cover Letter Describing Changes is attached 
  Sponsor Letter Describing Changes is Attached 
 
 
Impact on Budget/Funding 
Does this amendment affect the current budget for the 
study? 
 
 No 
 
 Yes, if yes, explain       
 
and contact:  
- 
Clinical Trials Office for Industry Funded Studies 
- 
Office of Sponsored Programs for Other Funding 
Sources 
 
 
 
Does this amendment affect the current funding for the 
study? 
 
  No 
 
  Yes, if yes, explain       
 
 and contact: 
- 
Clinical Trials Office for Industry Funded Studies 
- 
Office of Sponsored Programs for Other Funding 
Sources 
 
 
AMENDMENT RATIONALE- REQUIRED FOR ALL SUBMISSIONS 
The reason or justification for the changes must be discussed as well as how the change might affect the risk/benefit ratio.  Please 
also address how or if a change in the risk/benefit ratio impacts the informed consent form, and if the change necessitates a change in 
the consent form.  The rationale may be provided here or in an attached cover letter or memo.   
 
Update study staff: Removal of Eric Mubang as he is no longer with the institution. Addition of Lise Witten as co-
investigator to increase enrollment capacity and assist with the protocol. 
 
These changes do not affect the risk/benefit ratio. This study DOES NOT necessitate a change in the written, informed consent form. 
 
  PI Memo /Cover letter Describing Rationale is Attached 
  Sponsor Letter Describing Rationale is Attached 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Principal Investigator  
 
 
 
 
Date 
 
 
 
Michael Cocchi MD 
 
 
 
 
Print Name 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 (CCI) Committee on Clinical Investigations 
Page 37 of 62 
                                                                                                                                                                                                                       Amendment Form  
                                                                                                                                                                                              CCI Form Revised: 3-2013 
 
AMENDMENT FORM 
STUDY INFORMATION 
TITLE OF PROTOCOL: Esmolol to treat the hemodynamic effects of septic shock 
CCI PROTOCOL # : 2014P-000415 
PRINCIPAL INVESTIGATOR: Michael Cocchi MD 
STUDY COORDINATOR: Elinita Rosseto 
STUDY COORDINATOR EMAIL ADDRESS: EROSSETO@BIDMC.HARVARD.EDU 
 
AMENDMENT DETAILS 
Indicate which components(s) or element(s) of your protocol are being changed.  Check all applicable items. 
  Principal Investigator 
 Change and/or New Recruitment or Publicity Materials 
 
 DSMB Reports/Monitoring Reports/Safety Reports 
 Recruitment, Publicity Materials and/or procedures 
 Revised and/or New Consent Form 
 Consent Procedures 
 Change and/or Addition of Study Procedures 
 Duration of Subject Participation 
 Local Site Enrollment # of Subjects 
 Revised and/or New Study Documents or Subject Materials 
(e.g. diaries, questionnaires) 
 Total Enrollment # of Subjects (Multi-Center Trials) 
 Investigator Brochure, Date/Version: 
 Change in subject selection or subject population 
 Change in Remuneration 
 Change of Sponsor/Funding 
 Research Related Use of Medical Records  
  Study Status Change (i.e., CTE, hold, re-open to enrollment) 
 Use of Specimens 
 
 Industry Sponsored Protocols only:  
Sponsor Amendment/Version #:        
 Research Related Use of Discarded Material 
 Change related to pharmacy or study drug administration 
 
  Revised Sponsor Protocol,  Issue Date/Version:        
 Addition/Removal of Co-Investigator or Research Staff Member 
 
For amendments limited to only the addition or removal of research staff in addition to this form the following is 
required:  
x 
Research Staffing Form (1 clean, 1 highlighted) 
x 
Revised Part E if amendment involves change in Authorized Prescribers for study medication 
x 
Part Q and CITI training documentation for any non-BIDMC research staff member.   
 
AMENDMENT ATTACHMENTS: 
 Revised Sponsor Protocol (New Version) (1 clean, 1 highlighted) 
 New or Revised Advertisement (1 clean, 1 highlighted) 
 Revised Part A (1 clean, 1 highlighted) 
 Revised Part B (1 clean, 1 highlighted) 
 Revised Consent Form (1 clean, 1 highlighted) 
 Revised Research Participant Materials or  Questionnaires  
     (1 clean, 1 highlighted) 
 Revised Research Staffing Form (1 Clean, I highlighted: ) 
 Part Q(s) for addition of any non-BIDMC personnel  
 Revised/New Part E (Obtain pharmacy signature and detail change below) 
 Other Revised Part/Form Document  (1 Clean, I highlighted: ) 
     Specify:  
 
 
AMENDMENT DESCRIPTION- REQUIRED FOR ALL SUBMISSIONS 


 (CCI) Committee on Clinical Investigations 
Page 38 of 62 
                                                                                                                                                                                                                       Amendment Form  
                                                                                                                                                                                              CCI Form Revised: 3-2013 
 
A detailed description of the amendment, in your own words, MUST be provided below.  The PI may provide a summary of a lengthy 
sponsor amendment in an attached cover letter or memo, however this should not simply be a copy of the sponsors amendment 
and/or letter.  Either list the current item followed by the new item, or attach a redlined version of the changed document.  If the 
consent form is revised, attach one copy of the consent form in which the changes (including additions and deletions) are clearly 
highlighted, and one clean copy of the consent form. 
 
Change in participating study sites: One study site (Henry Ford Hospital) is being removed and one additional 
study site (Lahey Hospital & Medical Center) is been added. 
 
  PI Memo/Cover Letter Describing Changes is attached 
  Sponsor Letter Describing Changes is Attached 
 
 
Impact on Budget/Funding 
Does this amendment affect the current budget for the 
study? 
 
 No 
 
 Yes, if yes, explain       
 
and contact:  
- 
Clinical Trials Office for Industry Funded Studies 
- 
Office of Sponsored Programs for Other Funding 
Sources 
 
 
 
Does this amendment affect the current funding for the 
study? 
 
  No 
 
  Yes, if yes, explain       
 
 and contact: 
- 
Clinical Trials Office for Industry Funded Studies 
- 
Office of Sponsored Programs for Other Funding 
Sources 
 
 
AMENDMENT RATIONALE- REQUIRED FOR ALL SUBMISSIONS 
The reason or justification for the changes must be discussed as well as how the change might affect the risk/benefit ratio.  Please 
also address how or if a change in the risk/benefit ratio impacts the informed consent form, and if the change necessitates a change in 
the consent form.  The rationale may be provided here or in an attached cover letter or memo.   
 
Change in participating study sites: Henry Ford Hospital in Detroit Michigan will no longer participate as a 
study site for our study. Lahey Hospital & Medical Center being added to increase the enrollment speed. We 
will not be increasing the global number of enrollment. 
 
These changes do not affect the risk/benefit ratio. This study DOES NOT necessitate a change in the written, informed consent form. 
 
  PI Memo /Cover letter Describing Rationale is Attached 
  Sponsor Letter Describing Rationale is Attached 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Principal Investigator  
 
 
 
 
Date 
 
 
 
Michael Cocchi MD 
 
 
 
 
Print Name 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 (CCI) Committee on Clinical Investigations 
Page 39 of 62 
                                                                                                                                                                                                                       Amendment Form  
                                                                                                                                                                                              CCI Form Revised: 3-2013 
 
AMENDMENT FORM 
STUDY INFORMATION 
TITLE OF PROTOCOL: Esmolol to treat the hemodynamic effects of septic shock 
CCI PROTOCOL # : 2014P-000415 
PRINCIPAL INVESTIGATOR: Michael Cocchi MD 
STUDY COORDINATOR: Elinita Rosseto 
STUDY COORDINATOR EMAIL ADDRESS: EROSSETO@BIDMC.HARVARD.EDU 
 
AMENDMENT DETAILS 
Indicate which components(s) or element(s) of your protocol are being changed.  Check all applicable items. 
  Principal Investigator 
 Change and/or New Recruitment or Publicity Materials 
 
 DSMB Reports/Monitoring Reports/Safety Reports 
 Recruitment, Publicity Materials and/or procedures 
 Revised and/or New Consent Form 
 Consent Procedures 
 Change and/or Addition of Study Procedures 
 Duration of Subject Participation 
 Local Site Enrollment # of Subjects 
 Revised and/or New Study Documents or Subject Materials 
(e.g. diaries, questionnaires) 
 Total Enrollment # of Subjects (Multi-Center Trials) 
 Investigator Brochure, Date/Version: 
 Change in subject selection or subject population 
 Change in Remuneration 
 Change of Sponsor/Funding 
 Research Related Use of Medical Records  
  Study Status Change (i.e., CTE, hold, re-open to enrollment) 
 Use of Specimens 
 
 Industry Sponsored Protocols only:  
Sponsor Amendment/Version #:        
 Research Related Use of Discarded Material 
 Change related to pharmacy or study drug administration 
 
  Revised Sponsor Protocol,  Issue Date/Version:        
 Addition/Removal of Co-Investigator or Research Staff Member 
 
For amendments limited to only the addition or removal of research staff in addition to this form the following is 
required:  
x 
Research Staffing Form (1 clean, 1 highlighted) 
x 
Revised Part E if amendment involves change in Authorized Prescribers for study medication 
x 
Part Q and CITI training documentation for any non-BIDMC research staff member.   
 
AMENDMENT ATTACHMENTS: 
 Revised Sponsor Protocol (New Version) (1 clean, 1 highlighted) 
 New or Revised Advertisement (1 clean, 1 highlighted) 
 Revised Part A (1 clean, 1 highlighted) 
 Revised Part B (1 clean, 1 highlighted) 
 Revised Consent Form (1 clean, 1 highlighted) 
 Revised Research Participant Materials or  Questionnaires  
     (1 clean, 1 highlighted) 
 Revised Research Staffing Form (1 Clean, I highlighted: ) 
 Part Q(s) for addition of any non-BIDMC personnel  
 Revised/New Part E (Obtain pharmacy signature and detail change below) 
 Other Revised Part/Form Document  (1 Clean, I highlighted: ) 
     Specify:  
 
 
 
 
 


 (CCI) Committee on Clinical Investigations 
Page 40 of 62 
                                                                                                                                                                                                                       Amendment Form  
                                                                                                                                                                                              CCI Form Revised: 3-2013 
 
AMENDMENT DESCRIPTION- REQUIRED FOR ALL SUBMISSIONS 
A detailed description of the amendment, in your own words, MUST be provided below.  The PI may provide a summary of a lengthy 
sponsor amendment in an attached cover letter or memo, however this should not simply be a copy of the sponsors amendment 
and/or letter.  Either list the current item followed by the new item, or attach a redlined version of the changed document.  If the 
consent form is revised, attach one copy of the consent form in which the changes (including additions and deletions) are clearly 
highlighted, and one clean copy of the consent form. 
. 
Update study staff. 
 
  PI Memo/Cover Letter Describing Changes is attached 
  Sponsor Letter Describing Changes is Attached 
 
 
Impact on Budget/Funding 
Does this amendment affect the current budget for the 
study? 
 
 No 
 
 Yes, if yes, explain       
 
and contact:  
- 
Clinical Trials Office for Industry Funded Studies 
- 
Office of Sponsored Programs for Other Funding 
Sources 
 
 
 
Does this amendment affect the current funding for the 
study? 
 
  No 
 
  Yes, if yes, explain       
 
 and contact: 
- 
Clinical Trials Office for Industry Funded Studies 
- 
Office of Sponsored Programs for Other Funding 
Sources 
 
 
AMENDMENT RATIONALE- REQUIRED FOR ALL SUBMISSIONS 
The reason or justification for the changes must be discussed as well as how the change might affect the risk/benefit ratio.  Please 
also address how or if a change in the risk/benefit ratio impacts the informed consent form, and if the change necessitates a change in 
the consent form.  The rationale may be provided here or in an attached cover letter or memo.   
 
Update study staff: Addition of Thomas Leith as co-investigator to increase enrollment capacity and assist with the 
protocol. 
 
These changes do not affect the risk/benefit ratio. This study DOES NOT necessitate a change in the written, informed 
consent form. 
 
  PI Memo /Cover letter Describing Rationale is Attached 
  Sponsor Letter Describing Rationale is Attached 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Principal Investigator  
 
 
 
 
Date 
 
 
 
Michael Cocchi MD 
 
 
 
 
Print Name 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 (CCI) Committee on Clinical Investigations 
Page 41 of 62 
                                                                                                                                                                                                                       Amendment Form  
                                                                                                                                                                                              CCI Form Revised: 3-2013 
 
 
AMENDMENT FORM 
STUDY INFORMATION 
TITLE OF PROTOCOL: Esmolol to treat the hemodynamic effects of septic shock 
CCI PROTOCOL # : 2014P-000415 
PRINCIPAL INVESTIGATOR: Michael Cocchi MD 
STUDY COORDINATOR: Elinita Rosseto 
STUDY COORDINATOR EMAIL ADDRESS: EROSSETO@BIDMC.HARVARD.EDU 
 
AMENDMENT DETAILS 
Indicate which components(s) or element(s) of your protocol are being changed.  Check all applicable items. 
  Principal Investigator 
 Change and/or New Recruitment or Publicity Materials 
 
 DSMB Reports/Monitoring Reports/Safety Reports 
 Recruitment, Publicity Materials and/or procedures 
 Revised and/or New Consent Form 
 Consent Procedures 
 Change and/or Addition of Study Procedures 
 Duration of Subject Participation 
 Local Site Enrollment # of Subjects 
 Revised and/or New Study Documents or Subject Materials 
(e.g. diaries, questionnaires) 
 Total Enrollment # of Subjects (Multi-Center Trials) 
 Investigator Brochure, Date/Version: 
 Change in subject selection or subject population 
 Change in Remuneration 
 Change of Sponsor/Funding 
 Research Related Use of Medical Records  
  Study Status Change (i.e., CTE, hold, re-open to enrollment) 
 Use of Specimens 
 
 Industry Sponsored Protocols only:  
Sponsor Amendment/Version #:        
 Research Related Use of Discarded Material 
 Change related to pharmacy or study drug administration 
 
  Revised Sponsor Protocol,  Issue Date/Version:        
 Addition/Removal of Co-Investigator or Research Staff Member 
 
For amendments limited to only the addition or removal of research staff in addition to this form the following is 
required:  
x 
Research Staffing Form (1 clean, 1 highlighted) 
x 
Revised Part E if amendment involves change in Authorized Prescribers for study medication 
x 
Part Q and CITI training documentation for any non-BIDMC research staff member.   
 
AMENDMENT ATTACHMENTS: 
 Revised Sponsor Protocol (New Version) (1 clean, 1 highlighted) 
 New or Revised Advertisement (1 clean, 1 highlighted) 
 Revised Part A (1 clean, 1 highlighted) 
 Revised Part B (1 clean, 1 highlighted) 
 Revised Consent Form (1 clean, 1 highlighted) 
 Revised Research Participant Materials or  Questionnaires  
     (1 clean, 1 highlighted) 
 Revised Research Staffing Form (1 Clean, I highlighted: ) 
 Part Q(s) for addition of any non-BIDMC personnel  
 Revised/New Part E (Obtain pharmacy signature and detail change below) 
 Other Revised Part/Form Document  (1 Clean, I highlighted: ) 
     Specify:  
 
 
 
 
 


 (CCI) Committee on Clinical Investigations 
Page 42 of 62 
                                                                                                                                                                                                                       Amendment Form  
                                                                                                                                                                                              CCI Form Revised: 3-2013 
 
AMENDMENT DESCRIPTION- REQUIRED FOR ALL SUBMISSIONS 
A detailed description of the amendment, in your own words, MUST be provided below.  The PI may provide a summary of a lengthy 
sponsor amendment in an attached cover letter or memo, however this should not simply be a copy of the sponsors amendment 
and/or letter.  Either list the current item followed by the new item, or attach a redlined version of the changed document.  If the 
consent form is revised, attach one copy of the consent form in which the changes (including additions and deletions) are clearly 
highlighted, and one clean copy of the consent form. 
. 
Update study staff. 
 
  PI Memo/Cover Letter Describing Changes is attached 
  Sponsor Letter Describing Changes is Attached 
 
 
Impact on Budget/Funding 
Does this amendment affect the current budget for the 
study? 
 
 No 
 
 Yes, if yes, explain       
 
and contact:  
- 
Clinical Trials Office for Industry Funded Studies 
- 
Office of Sponsored Programs for Other Funding 
Sources 
 
 
 
Does this amendment affect the current funding for the 
study? 
 
  No 
 
  Yes, if yes, explain       
 
 and contact: 
- 
Clinical Trials Office for Industry Funded Studies 
- 
Office of Sponsored Programs for Other Funding 
Sources 
 
 
AMENDMENT RATIONALE- REQUIRED FOR ALL SUBMISSIONS 
The reason or justification for the changes must be discussed as well as how the change might affect the risk/benefit ratio.  Please 
also address how or if a change in the risk/benefit ratio impacts the informed consent form, and if the change necessitates a change in 
the consent form.  The rationale may be provided here or in an attached cover letter or memo.   
 
Update study staff: Addition of Anthony Mahoney-Pacheco as research student to increase enrollment capacity and 
assist with the protocol. 
 
These changes do not affect the risk/benefit ratio. This study DOES NOT necessitate a change in the written, informed 
consent form. 
 
  PI Memo /Cover letter Describing Rationale is Attached 
  Sponsor Letter Describing Rationale is Attached 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Principal Investigator  
 
 
 
 
Date 
 
 
 
Michael Cocchi MD 
 
 
 
 
Print Name 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 (CCI) Committee on Clinical Investigations 
Page 43 of 62 
                                                                                                                                                                                                                       Amendment Form  
                                                                                                                                                                                              CCI Form Revised: 3-2013 
 
AMENDMENT FORM 
STUDY INFORMATION 
TITLE OF PROTOCOL: Esmolol to treat the hemodynamic effects of septic shock 
CCI PROTOCOL # : 2014P-000415 
PRINCIPAL INVESTIGATOR: Michael Cocchi MD 
STUDY COORDINATOR: Elinita Rosseto 
STUDY COORDINATOR EMAIL ADDRESS: EROSSETO@BIDMC.HARVARD.EDU 
 
AMENDMENT DETAILS 
Indicate which components(s) or element(s) of your protocol are being changed.  Check all applicable items. 
  Principal Investigator 
 Change and/or New Recruitment or Publicity Materials 
 
 DSMB Reports/Monitoring Reports/Safety Reports 
 Recruitment, Publicity Materials and/or procedures 
 Revised and/or New Consent Form 
 Consent Procedures 
 Change and/or Addition of Study Procedures 
 Duration of Subject Participation 
 Local Site Enrollment # of Subjects 
 Revised and/or New Study Documents or Subject Materials 
(e.g. diaries, questionnaires) 
 Total Enrollment # of Subjects (Multi-Center Trials) 
 Investigator Brochure, Date/Version: 
 Change in subject selection or subject population 
 Change in Remuneration 
 Change of Sponsor/Funding 
 Research Related Use of Medical Records  
  Study Status Change (i.e., CTE, hold, re-open to enrollment) 
 Use of Specimens 
 
 Industry Sponsored Protocols only:  
Sponsor Amendment/Version #:        
 Research Related Use of Discarded Material 
 Change related to pharmacy or study drug administration 
 
  Revised Sponsor Protocol,  Issue Date/Version:        
 Addition/Removal of Co-Investigator or Research Staff Member 
 
For amendments limited to only the addition or removal of research staff in addition to this form the following is 
required:  
x 
Research Staffing Form (1 clean, 1 highlighted) 
x 
Revised Part E if amendment involves change in Authorized Prescribers for study medication 
x 
Part Q and CITI training documentation for any non-BIDMC research staff member.   
 
AMENDMENT ATTACHMENTS: 
 Revised Sponsor Protocol (New Version) (1 clean, 1 highlighted) 
 New or Revised Advertisement (1 clean, 1 highlighted) 
 Revised Part A (1 clean, 1 highlighted) 
 Revised Part B (1 clean, 1 highlighted) 
 Revised Consent Form (1 clean, 1 highlighted) 
 Revised Research Participant Materials or  Questionnaires  
     (1 clean, 1 highlighted) 
 Revised Research Staffing Form (1 Clean, I highlighted: ) 
 Part Q(s) for addition of any non-BIDMC personnel  
 Revised/New Part E (Obtain pharmacy signature and detail change below) 
 Other Revised Part/Form Document  (1 Clean, I highlighted: ) 
     Specify:  
 
 
 
 
 


 (CCI) Committee on Clinical Investigations 
Page 44 of 62 
                                                                                                                                                                                                                       Amendment Form  
                                                                                                                                                                                              CCI Form Revised: 3-2013 
 
AMENDMENT DESCRIPTION- REQUIRED FOR ALL SUBMISSIONS 
A detailed description of the amendment, in your own words, MUST be provided below.  The PI may provide a summary of a lengthy 
sponsor amendment in an attached cover letter or memo, however this should not simply be a copy of the sponsors amendment 
and/or letter.  Either list the current item followed by the new item, or attach a redlined version of the changed document.  If the 
consent form is revised, attach one copy of the consent form in which the changes (including additions and deletions) are clearly 
highlighted, and one clean copy of the consent form. 
. 
Update study staff. 
 
  PI Memo/Cover Letter Describing Changes is attached 
  Sponsor Letter Describing Changes is Attached 
 
 
Impact on Budget/Funding 
Does this amendment affect the current budget for the 
study? 
 
 No 
 
 Yes, if yes, explain       
 
and contact:  
- 
Clinical Trials Office for Industry Funded Studies 
- 
Office of Sponsored Programs for Other Funding 
Sources 
 
 
 
Does this amendment affect the current funding for the 
study? 
 
  No 
 
  Yes, if yes, explain       
 
 and contact: 
- 
Clinical Trials Office for Industry Funded Studies 
- 
Office of Sponsored Programs for Other Funding 
Sources 
 
 
AMENDMENT RATIONALE- REQUIRED FOR ALL SUBMISSIONS 
The reason or justification for the changes must be discussed as well as how the change might affect the risk/benefit ratio.  Please 
also address how or if a change in the risk/benefit ratio impacts the informed consent form, and if the change necessitates a change in 
the consent form.  The rationale may be provided here or in an attached cover letter or memo.   
 
Update study staff: DeaQQa Lee UROe¶V LQ WKe VWXd\ LV cKaQJed WR CR-Investigator to assist with the protocol. 
 
These changes do not affect the risk/benefit ratio. This study DOES NOT necessitate a change in the written, informed 
consent form. 
 
  PI Memo /Cover letter Describing Rationale is Attached 
  Sponsor Letter Describing Rationale is Attached 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Principal Investigator  
 
 
 
 
Date 
 
 
 
Michael Cocchi MD 
 
 
 
 
Print Name 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 (CCI) Committee on Clinical Investigations 
Page 45 of 62 
                                                                                                                                                                                                                       Amendment Form  
                                                                                                                                                                                              CCI Form Revised: 3-2013 
 
AMENDMENT FORM 
STUDY INFORMATION 
TITLE OF PROTOCOL: Esmolol to treat the hemodynamic effects of septic shock 
CCI PROTOCOL # : 2014P-000415 
PRINCIPAL INVESTIGATOR: Michael Cocchi MD 
STUDY COORDINATOR: Elinita Rosseto 
STUDY COORDINATOR EMAIL ADDRESS: EROSSETO@BIDMC.HARVARD.EDU 
 
AMENDMENT DETAILS 
Indicate which components(s) or element(s) of your protocol are being changed.  Check all applicable items. 
  Principal Investigator 
 Change and/or New Recruitment or Publicity Materials 
 
 DSMB Reports/Monitoring Reports/Safety Reports 
 Recruitment, Publicity Materials and/or procedures 
 Revised and/or New Consent Form 
 Consent Procedures 
 Change and/or Addition of Study Procedures 
 Duration of Subject Participation 
 Local Site Enrollment # of Subjects 
 Revised and/or New Study Documents or Subject Materials 
(e.g. diaries, questionnaires) 
 Total Enrollment # of Subjects (Multi-Center Trials) 
 Investigator Brochure, Date/Version: 
 Change in subject selection or subject population 
 Change in Remuneration 
 Change of Sponsor/Funding 
 Research Related Use of Medical Records  
  Study Status Change (i.e., CTE, hold, re-open to enrollment) 
 Use of Specimens 
 
 Industry Sponsored Protocols only:  
Sponsor Amendment/Version #:        
 Research Related Use of Discarded Material 
 Change related to pharmacy or study drug administration 
 
  Revised Sponsor Protocol,  Issue Date/Version:        
 Addition/Removal of Co-Investigator or Research Staff Member 
 
For amendments limited to only the addition or removal of research staff in addition to this form the following is 
required:  
x 
Research Staffing Form (1 clean, 1 highlighted) 
x 
Revised Part E if amendment involves change in Authorized Prescribers for study medication 
x 
Part Q and CITI training documentation for any non-BIDMC research staff member.   
 
AMENDMENT ATTACHMENTS: 
 Revised Sponsor Protocol (New Version) (1 clean, 1 highlighted) 
 New or Revised Advertisement (1 clean, 1 highlighted) 
 Revised Part A (1 clean, 1 highlighted) 
 Revised Part B (1 clean, 1 highlighted) 
 Revised Consent Form (1 clean, 1 highlighted) 
 Revised Research Participant Materials or  Questionnaires  
     (1 clean, 1 highlighted) 
 Revised Research Staffing Form (1 Clean, I highlighted: ) 
 Part Q(s) for addition of any non-BIDMC personnel  
 Revised/New Part E (Obtain pharmacy signature and detail change below) 
 Other Revised Part/Form Document  (1 Clean, I highlighted: ) 
     Specify:  
 
 
 
 
 


 (CCI) Committee on Clinical Investigations 
Page 46 of 62 
                                                                                                                                                                                                                       Amendment Form  
                                                                                                                                                                                              CCI Form Revised: 3-2013 
 
AMENDMENT DESCRIPTION- REQUIRED FOR ALL SUBMISSIONS 
A detailed description of the amendment, in your own words, MUST be provided below.  The PI may provide a summary of a lengthy 
sponsor amendment in an attached cover letter or memo, however this should not simply be a copy of the sponsors amendment 
and/or letter.  Either list the current item followed by the new item, or attach a redlined version of the changed document.  If the 
consent form is revised, attach one copy of the consent form in which the changes (including additions and deletions) are clearly 
highlighted, and one clean copy of the consent form. 
. 
Update study staff. 
 
  PI Memo/Cover Letter Describing Changes is attached 
  Sponsor Letter Describing Changes is Attached 
 
 
Impact on Budget/Funding 
Does this amendment affect the current budget for the 
study? 
 
 No 
 
 Yes, if yes, explain       
 
and contact:  
- 
Clinical Trials Office for Industry Funded Studies 
- 
Office of Sponsored Programs for Other Funding 
Sources 
 
 
 
Does this amendment affect the current funding for the 
study? 
 
  No 
 
  Yes, if yes, explain       
 
 and contact: 
- 
Clinical Trials Office for Industry Funded Studies 
- 
Office of Sponsored Programs for Other Funding 
Sources 
 
 
AMENDMENT RATIONALE- REQUIRED FOR ALL SUBMISSIONS 
The reason or justification for the changes must be discussed as well as how the change might affect the risk/benefit ratio.  Please 
also address how or if a change in the risk/benefit ratio impacts the informed consent form, and if the change necessitates a change in 
the consent form.  The rationale may be provided here or in an attached cover letter or memo.   
 
Update study staff: Addition of Tuyen Yankama as co-investigator to assist with the protocol. Removal of Michael 
McNaughton as he is no longer with the institution. 
 
These changes do not affect the risk/benefit ratio. This study DOES NOT necessitate a change in the written, informed 
consent form. 
  PI Memo /Cover letter Describing Rationale is Attached 
  Sponsor Letter Describing Rationale is Attached 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Principal Investigator  
 
 
 
 
Date 
 
 
 
Michael Cocchi MD 
 
 
 
 
Print Name 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 (CCI) Committee on Clinical Investigations 
Page 47 of 62 
                                                                                                                                                                                                                       Amendment Form  
                                                                                                                                                                                              CCI Form Revised: 3-2013 
 
AMENDMENT FORM 
STUDY INFORMATION 
TITLE OF PROTOCOL: Esmolol to treat the hemodynamic effects of septic shock 
CCI PROTOCOL # : 2014P-000415 
PRINCIPAL INVESTIGATOR: Michael Cocchi MD 
STUDY COORDINATOR: Elinita Rosseto 
STUDY COORDINATOR EMAIL ADDRESS: EROSSETO@BIDMC.HARVARD.EDU 
 
AMENDMENT DETAILS 
Indicate which components(s) or element(s) of your protocol are being changed.  Check all applicable items. 
  Principal Investigator 
 Change and/or New Recruitment or Publicity Materials 
 
 DSMB Reports/Monitoring Reports/Safety Reports 
 Recruitment, Publicity Materials and/or procedures 
 Revised and/or New Consent Form 
 Consent Procedures 
 Change and/or Addition of Study Procedures 
 Duration of Subject Participation 
 Local Site Enrollment # of Subjects 
 Revised and/or New Study Documents or Subject Materials 
(e.g. diaries, questionnaires) 
 Total Enrollment # of Subjects (Multi-Center Trials) 
 Investigator Brochure, Date/Version: 
 Change in subject selection or subject population 
 Change in Remuneration 
 Change of Sponsor/Funding 
 Research Related Use of Medical Records  
  Study Status Change (i.e., CTE, hold, re-open to enrollment) 
 Use of Specimens 
 
 Industry Sponsored Protocols only:  
Sponsor Amendment/Version #:        
 Research Related Use of Discarded Material 
 Change related to pharmacy or study drug administration 
 
  Revised Sponsor Protocol,  Issue Date/Version:        
 Addition/Removal of Co-Investigator or Research Staff Member 
 
For amendments limited to only the addition or removal of research staff in addition to this form the following is 
required:  
x 
Research Staffing Form (1 clean, 1 highlighted) 
x 
Revised Part E if amendment involves change in Authorized Prescribers for study medication 
x 
Part Q and CITI training documentation for any non-BIDMC research staff member.   
 
AMENDMENT ATTACHMENTS: 
 Revised Sponsor Protocol (New Version) (1 clean, 1 highlighted) 
 New or Revised Advertisement (1 clean, 1 highlighted) 
 Revised Part A (1 clean, 1 highlighted) 
 Revised Part B (1 clean, 1 highlighted) 
 Revised Consent Form (1 clean, 1 highlighted) 
 Revised Research Participant Materials or  Questionnaires  
     (1 clean, 1 highlighted) 
 Revised Research Staffing Form (1 Clean, I highlighted: ) 
 Part Q(s) for addition of any non-BIDMC personnel  
 Revised/New Part E (Obtain pharmacy signature and detail change below) 
 Other Revised Part/Form Document  (1 Clean, I highlighted: ) 
     Specify: Lahey Clinic, Inc. Institutional Review Board approval letter. (dated 04/03/2018) 
 
 
 
 
 


 (CCI) Committee on Clinical Investigations 
Page 48 of 62 
                                                                                                                                                                                                                       Amendment Form  
                                                                                                                                                                                              CCI Form Revised: 3-2013 
 
 
AMENDMENT DESCRIPTION- REQUIRED FOR ALL SUBMISSIONS 
A detailed description of the amendment, in your own words, MUST be provided below.  The PI may provide a summary of a lengthy 
sponsor amendment in an attached cover letter or memo, however this should not simply be a copy of the sponsors amendment 
and/or letter.  Either list the current item followed by the new item, or attach a redlined version of the changed document.  If the 
consent form is revised, attach one copy of the consent form in which the changes (including additions and deletions) are clearly 
highlighted, and one clean copy of the consent form. 
. 
Participating study site – Local IRB approval granted to Lahey Hospital & Medical Center study site: The 
CCI approved the addition of Lahey Hospital & Medical Center as a study site on 11/28/2017. Local IRB approval 
has been obtained at Lahey Hospital & Medical Center; we are submitting a copy of the Lahey Clinic, Inc. 
Institutional Review Board approval letter. 
 
  PI Memo/Cover Letter Describing Changes is attached 
  Sponsor Letter Describing Changes is Attached 
 
 
Impact on Budget/Funding 
Does this amendment affect the current budget for the 
study? 
 
 No 
 
 Yes, if yes, explain       
 
and contact:  
- 
Clinical Trials Office for Industry Funded Studies 
- 
Office of Sponsored Programs for Other Funding 
Sources 
 
 
 
Does this amendment affect the current funding for the 
study? 
 
  No 
 
  Yes, if yes, explain       
 
 and contact: 
- 
Clinical Trials Office for Industry Funded Studies 
- 
Office of Sponsored Programs for Other Funding 
Sources 
 
 
AMENDMENT RATIONALE- REQUIRED FOR ALL SUBMISSIONS 
The reason or justification for the changes must be discussed as well as how the change might affect the risk/benefit ratio.  Please 
also address how or if a change in the risk/benefit ratio impacts the informed consent form, and if the change necessitates a change in 
the consent form.  The rationale may be provided here or in an attached cover letter or memo.   
 
Participating study site – Local IRB approval granted to Lahey Hospital & Medical Center study site: The 
CCI approved the addition of Lahey Hospital & Medical Center as a study site on 11/28/2017. Local IRB approval 
has been obtained at Lahey Hospital & Medical Center; we are submitting a copy of the Lahey Clinic, Inc. 
Institutional Review Board approval letter. 
 
This update does not affect the risk/benefit ratio. This study DOES NOT necessitate a change in the written, informed consent form. 
 
  PI Memo /Cover letter Describing Rationale is Attached 
  Sponsor Letter Describing Rationale is Attached 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Principal Investigator  
 
 
 
 
Date 
 
 
 
Michael Cocchi MD 
 
 
 
 
Print Name 
 
 
 
 
 
 
 
 
 


 (CCI) Committee on Clinical Investigations 
Page 49 of 62 
                                                                                                                                                                                                                       Amendment Form  
                                                                                                                                                                                              CCI Form Revised: 3-2013 
 
AMENDMENT FORM 
STUDY INFORMATION 
TITLE OF PROTOCOL: Esmolol to treat the hemodynamic effects of septic shock 
CCI PROTOCOL # : 2014P-000415 
PRINCIPAL INVESTIGATOR: Michael Cocchi MD 
STUDY COORDINATOR: Elinita Rosseto 
STUDY COORDINATOR EMAIL ADDRESS: EROSSETO@BIDMC.HARVARD.EDU 
 
AMENDMENT DETAILS 
Indicate which components(s) or element(s) of your protocol are being changed.  Check all applicable items. 
  Principal Investigator 
 Change and/or New Recruitment or Publicity Materials 
 
 DSMB Reports/Monitoring Reports/Safety Reports 
 Recruitment, Publicity Materials and/or procedures 
 Revised and/or New Consent Form 
 Consent Procedures 
 Change and/or Addition of Study Procedures 
 Duration of Subject Participation 
 Local Site Enrollment # of Subjects 
 Revised and/or New Study Documents or Subject Materials 
(e.g. diaries, questionnaires) 
 Total Enrollment # of Subjects (Multi-Center Trials) 
 Investigator Brochure, Date/Version: 
 Change in subject selection or subject population 
 Change in Remuneration 
 Change of Sponsor/Funding 
 Research Related Use of Medical Records  
  Study Status Change (i.e., CTE, hold, re-open to enrollment) 
 Use of Specimens 
 
 Industry Sponsored Protocols only:  
Sponsor Amendment/Version #:        
 Research Related Use of Discarded Material 
 Change related to pharmacy or study drug administration 
 
  Revised Sponsor Protocol,  Issue Date/Version:        
 Addition/Removal of Co-Investigator or Research Staff Member 
 
For amendments limited to only the addition or removal of research staff in addition to this form the following is 
required:  
x 
Research Staffing Form (1 clean, 1 highlighted) 
x 
Revised Part E if amendment involves change in Authorized Prescribers for study medication 
x 
Part Q and CITI training documentation for any non-BIDMC research staff member.   
 
AMENDMENT ATTACHMENTS: 
 Revised Sponsor Protocol (New Version) (1 clean, 1 highlighted) 
 New or Revised Advertisement (1 clean, 1 highlighted) 
 Revised Part A (1 clean, 1 highlighted) 
 Revised Part B (1 clean, 1 highlighted) 
 Revised Consent Form (1 clean, 1 highlighted) 
 Revised Research Participant Materials or  Questionnaires  
     (1 clean, 1 highlighted) 
 Revised Research Staffing Form (1 Clean, I highlighted: ) 
 Part Q(s) for addition of any non-BIDMC personnel  
 Revised/New Part E (Obtain pharmacy signature and detail change below) 
 Other Revised Part/Form Document  (1 Clean, I highlighted: ) 
     Specify:  
 
 
 
 
 


 (CCI) Committee on Clinical Investigations 
Page 50 of 62 
                                                                                                                                                                                                                       Amendment Form  
                                                                                                                                                                                              CCI Form Revised: 3-2013 
 
AMENDMENT DESCRIPTION- REQUIRED FOR ALL SUBMISSIONS 
A detailed description of the amendment, in your own words, MUST be provided below.  The PI may provide a summary of a lengthy 
sponsor amendment in an attached cover letter or memo, however this should not simply be a copy of the sponsors amendment 
and/or letter.  Either list the current item followed by the new item, or attach a redlined version of the changed document.  If the 
consent form is revised, attach one copy of the consent form in which the changes (including additions and deletions) are clearly 
highlighted, and one clean copy of the consent form. 
. 
Update study staff. 
 
  PI Memo/Cover Letter Describing Changes is attached 
  Sponsor Letter Describing Changes is Attached 
 
 
Impact on Budget/Funding 
Does this amendment affect the current budget for the 
study? 
 
 No 
 
 Yes, if yes, explain       
 
and contact:  
- 
Clinical Trials Office for Industry Funded Studies 
- 
Office of Sponsored Programs for Other Funding 
Sources 
 
 
 
Does this amendment affect the current funding for the 
study? 
 
  No 
 
  Yes, if yes, explain       
 
 and contact: 
- 
Clinical Trials Office for Industry Funded Studies 
- 
Office of Sponsored Programs for Other Funding 
Sources 
 
 
AMENDMENT RATIONALE- REQUIRED FOR ALL SUBMISSIONS 
The reason or justification for the changes must be discussed as well as how the change might affect the risk/benefit ratio.  Please 
also address how or if a change in the risk/benefit ratio impacts the informed consent form, and if the change necessitates a change in 
the consent form.  The rationale may be provided here or in an attached cover letter or memo.   
 
Update study staff: Addition of Shamsher Ali as coordinator to assist with the protocol. Removal of Amy Uber and Sierra 
Hagerty as they are no longer with the institution. 
 
These changes do not affect the risk/benefit ratio. This study DOES NOT necessitate a change in the written, informed 
consent form. 
  PI Memo /Cover letter Describing Rationale is Attached 
  Sponsor Letter Describing Rationale is Attached 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Principal Investigator  
 
 
 
 
Date 
 
 
 
Michael Cocchi MD 
 
 
 
 
Print Name 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 (CCI) Committee on Clinical Investigations 
Page 51 of 62 
                                                                                                                                                                                                                       Amendment Form  
                                                                                                                                                                                              CCI Form Revised: 3-2013 
 
 
AMENDMENT FORM 
STUDY INFORMATION 
TITLE OF PROTOCOL: Esmolol to treat the hemodynamic effects of septic shock 
CCI PROTOCOL # : 2014P-000415 
PRINCIPAL INVESTIGATOR: Michael Cocchi MD 
STUDY COORDINATOR: Elinita Rosseto 
STUDY COORDINATOR EMAIL ADDRESS: EROSSETO@BIDMC.HARVARD.EDU 
 
AMENDMENT DETAILS 
Indicate which components(s) or element(s) of your protocol are being changed.  Check all applicable items. 
  Principal Investigator 
 Change and/or New Recruitment or Publicity Materials 
 
 DSMB Reports/Monitoring Reports/Safety Reports 
 Recruitment, Publicity Materials and/or procedures 
 Revised and/or New Consent Form 
 Consent Procedures 
 Change and/or Addition of Study Procedures 
 Duration of Subject Participation 
 Local Site Enrollment # of Subjects 
 Revised and/or New Study Documents or Subject Materials 
(e.g. diaries, questionnaires) 
 Total Enrollment # of Subjects (Multi-Center Trials) 
 Investigator Brochure, Date/Version: 
 Change in subject selection or subject population 
 Change in Remuneration 
 Change of Sponsor/Funding 
 Research Related Use of Medical Records  
  Study Status Change (i.e., CTE, hold, re-open to enrollment) 
 Use of Specimens 
 
 Industry Sponsored Protocols only:  
Sponsor Amendment/Version #:        
 Research Related Use of Discarded Material 
 Change related to pharmacy or study drug administration 
 
  Revised Sponsor Protocol,  Issue Date/Version:        
 Addition/Removal of Co-Investigator or Research Staff Member 
 
For amendments limited to only the addition or removal of research staff in addition to this form the following is 
required:  
x 
Research Staffing Form (1 clean, 1 highlighted) 
x 
Revised Part E if amendment involves change in Authorized Prescribers for study medication 
x 
Part Q and CITI training documentation for any non-BIDMC research staff member.   
 
AMENDMENT ATTACHMENTS: 
 Revised Sponsor Protocol (New Version) (1 clean, 1 highlighted) 
 New or Revised Advertisement (1 clean, 1 highlighted) 
 Revised Part A (1 clean, 1 highlighted) 
 Revised Part B (1 clean, 1 highlighted) 
 Revised Consent Form (1 clean, 1 highlighted) 
 Revised Research Participant Materials or  Questionnaires  
     (1 clean, 1 highlighted) 
 Revised Research Staffing Form (1 Clean, I highlighted: ) 
 Part Q(s) for addition of any non-BIDMC personnel  
 Revised/New Part E (Obtain pharmacy signature and detail change below) 
 Other Revised Part/Form Document  (1 Clean, I highlighted: ) 
     Specify:  
 
 
 
 
 


 (CCI) Committee on Clinical Investigations 
Page 52 of 62 
                                                                                                                                                                                                                       Amendment Form  
                                                                                                                                                                                              CCI Form Revised: 3-2013 
 
AMENDMENT DESCRIPTION- REQUIRED FOR ALL SUBMISSIONS 
A detailed description of the amendment, in your own words, MUST be provided below.  The PI may provide a summary of a lengthy 
sponsor amendment in an attached cover letter or memo, however this should not simply be a copy of the sponsors amendment 
and/or letter.  Either list the current item followed by the new item, or attach a redlined version of the changed document.  If the 
consent form is revised, attach one copy of the consent form in which the changes (including additions and deletions) are clearly 
highlighted, and one clean copy of the consent form. 
. 
Update study staff: Addition of Ying loo as co-investigator, Shivani Mehta and Evans Jabari as research students as to 
assist with the protocol. 
 
  PI Memo/Cover Letter Describing Changes is attached 
  Sponsor Letter Describing Changes is Attached 
 
 
Impact on Budget/Funding 
Does this amendment affect the current budget for the 
study? 
 
 No 
 
 Yes, if yes, explain       
 
and contact:  
- 
Clinical Trials Office for Industry Funded Studies 
- 
Office of Sponsored Programs for Other Funding 
Sources 
 
 
 
Does this amendment affect the current funding for the 
study? 
 
  No 
 
  Yes, if yes, explain       
 
 and contact: 
- 
Clinical Trials Office for Industry Funded Studies 
- 
Office of Sponsored Programs for Other Funding 
Sources 
 
 
AMENDMENT RATIONALE- REQUIRED FOR ALL SUBMISSIONS 
The reason or justification for the changes must be discussed as well as how the change might affect the risk/benefit ratio.  Please 
also address how or if a change in the risk/benefit ratio impacts the informed consent form, and if the change necessitates a change in 
the consent form.  The rationale may be provided here or in an attached cover letter or memo.   
 
Update study staff: Addition of Ying loo as co-investigator, Shivani Mehta and Evans Jabari as research students as to 
assist with the protocol.  
 
These changes do not affect the risk/benefit ratio. This study DOES NOT necessitate a change in the written, informed 
consent form. 
  PI Memo /Cover letter Describing Rationale is Attached 
  Sponsor Letter Describing Rationale is Attached 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Principal Investigator  
 
 
 
 
Date 
 
 
 
Michael Cocchi MD 
 
 
 
 
Print Name 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 (CCI) Committee on Clinical Investigations 
Page 53 of 62 
                                                                                                                                                                                                                       Amendment Form  
                                                                                                                                                                                              CCI Form Revised: 3-2013 
 
AMENDMENT FORM 
STUDY INFORMATION 
TITLE OF PROTOCOL: Esmolol to treat the hemodynamic effects of septic shock 
CCI PROTOCOL # : 2014P-000415 
PRINCIPAL INVESTIGATOR: Michael Cocchi MD 
STUDY COORDINATOR: Shamsher Ali 
STUDY COORDINATOR EMAIL ADDRESS: SALI11@BIDMC.HARVARD.EDU  
 
AMENDMENT DETAILS 
Indicate which components(s) or element(s) of your protocol are being changed.  Check all applicable items. 
  Principal Investigator 
 Change and/or New Recruitment or Publicity Materials 
 
 DSMB Reports/Monitoring Reports/Safety Reports 
 Recruitment, Publicity Materials and/or procedures 
 Revised and/or New Consent Form 
 Consent Procedures 
 Change and/or Addition of Study Procedures 
 Duration of Subject Participation 
 Local Site Enrollment # of Subjects 
 Revised and/or New Study Documents or Subject Materials 
(e.g. diaries, questionnaires) 
 Total Enrollment # of Subjects (Multi-Center Trials) 
 Investigator Brochure, Date/Version: 
 Change in subject selection or subject population 
 Change in Remuneration 
 Change of Sponsor/Funding 
 Research Related Use of Medical Records  
  Study Status Change (i.e., CTE, hold, re-open to enrollment) 
 Use of Specimens 
 
 Industry Sponsored Protocols only:  
Sponsor Amendment/Version #:        
 Research Related Use of Discarded Material 
 Change related to pharmacy or study drug administration 
 
  Revised Sponsor Protocol,  Issue Date/Version:        
 Addition/Removal of Co-Investigator or Research Staff Member 
 
For amendments limited to only the addition or removal of research staff in addition to this form the following is 
required:  
x 
Research Staffing Form (1 clean, 1 highlighted) 
x 
Revised Part E if amendment involves change in Authorized Prescribers for study medication 
x 
Part Q and CITI training documentation for any non-BIDMC research staff member.   
 
AMENDMENT ATTACHMENTS: 
 Revised Sponsor Protocol (New Version) (1 clean, 1 highlighted) 
 New or Revised Advertisement (1 clean, 1 highlighted) 
 Revised Part A (1 clean, 1 highlighted) 
 Revised Part B (1 clean, 1 highlighted) 
 Revised Consent Form (1 clean, 1 highlighted) 
 Revised Research Participant Materials or  Questionnaires  
     (1 clean, 1 highlighted) 
 Revised Research Staffing Form (1 Clean, I highlighted: ) 
 Part Q(s) for addition of any non-BIDMC personnel  
 Revised/New Part E (Obtain pharmacy signature and detail change below) 
 Other Revised Part/Form Document  (1 Clean, I highlighted: ) 
     Specify:  
 
 
 
 
 


 (CCI) Committee on Clinical Investigations 
Page 54 of 62 
                                                                                                                                                                                                                       Amendment Form  
                                                                                                                                                                                              CCI Form Revised: 3-2013 
 
AMENDMENT DESCRIPTION- REQUIRED FOR ALL SUBMISSIONS 
A detailed description of the amendment, in your own words, MUST be provided below.  The PI may provide a summary of a lengthy 
sponsor amendment in an attached cover letter or memo, however this should not simply be a copy of the sponsors amendment 
and/or letter.  Either list the current item followed by the new item, or attach a redlined version of the changed document.  If the 
consent form is revised, attach one copy of the consent form in which the changes (including additions and deletions) are clearly 
highlighted, and one clean copy of the consent form. 
. 
x 
Addition/Removal of Co-Investigator or Research Staff Member: We are adding Amanda Frias-Howard as Administrator 
and changing the role of Shivani Mehta to co-investigator to assist with the protocol. We are removing Francesca as 
Administrator. We are removing Anthony Mahoney-Pacheco, Jabari Evans, Varun Konanki, Thomas Leith. They are no 
longer with the institution.   
x 
Requested Modifications: Moved Lars Andersen from active staff to outside collaborator. He will work with de-identified data 
for analysis as needed.  Adding Emma Hershey as co-investigator to assist with the study. 
Part Q included. 
 
 
  PI Memo/Cover Letter Describing Changes is attached 
  Sponsor Letter Describing Changes is Attached 
 
 
Impact on Budget/Funding 
Does this amendment affect the current budget for the 
study? 
 
 No 
 
 Yes, if yes, explain       
 
and contact:  
- 
Clinical Trials Office for Industry Funded Studies 
- 
Office of Sponsored Programs for Other Funding 
Sources 
 
 
 
Does this amendment affect the current funding for the 
study? 
 
  No 
 
  Yes, if yes, explain       
 
 and contact: 
- 
Clinical Trials Office for Industry Funded Studies 
- 
Office of Sponsored Programs for Other Funding 
Sources 
 
 
AMENDMENT RATIONALE- REQUIRED FOR ALL SUBMISSIONS 
The reason or justification for the changes must be discussed as well as how the change might affect the risk/benefit ratio.  Please 
also address how or if a change in the risk/benefit ratio impacts the informed consent form, and if the change necessitates a change in 
the consent form.  The rationale may be provided here or in an attached cover letter or memo.   
x 
Addition/Removal of Co-Investigator or Research Staff Member: We are adding Amanda Frias-Howard as Administrator 
and changing the role of Shivani Mehta to co-investigator to assist with the protocol. We are removing Francesca as 
Administrator. We are removing Anthony Mahoney-Pacheco, Jabari Evans, Varun Konanki, Thomas Leith. They are no 
longer with the institution.   
x 
Requested Modifications: Moved Lars Andersen from active staff to outside collaborator. He will work with de-identified data 
for analysis as needed.  Adding Emma Hershey as co-investigator to assist with the study. 
Part Q included. 
 
This change does not affect the risk/benefit ratio. This study DOES NOT necessitate a change in the written, informed 
consent form. 
  PI Memo /Cover letter Describing Rationale is Attached 
  Sponsor Letter Describing Rationale is Attached 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Principal Investigator  
 
 
 
 
Date 
 
 
 
Michael Cocchi MD 
 
 
 
 
Print Name 
 
 
 


 (CCI) Committee on Clinical Investigations 
Page 55 of 62 
                                                                                                                                                                                                                       Amendment Form  
                                                                                                                                                                                              CCI Form Revised: 3-2013 
 
 
 
AMENDMENT FORM 
STUDY INFORMATION 
TITLE OF PROTOCOL: Esmolol to treat the hemodynamic effects of septic shock 
CCI PROTOCOL # : 2014P-000415 
PRINCIPAL INVESTIGATOR: Michael Cocchi MD 
STUDY COORDINATOR: Deanna Lee 
STUDY COORDINATOR EMAIL ADDRESS: DLEE19@BIDMC.HARVARD.EDU  
 
AMENDMENT DETAILS 
Indicate which components(s) or element(s) of your protocol are being changed.  Check all applicable items. 
  Principal Investigator 
 Change and/or New Recruitment or Publicity Materials 
 
 DSMB Reports/Monitoring Reports/Safety Reports 
 Recruitment, Publicity Materials and/or procedures 
 Revised and/or New Consent Form 
 Consent Procedures 
 Change and/or Addition of Study Procedures 
 Duration of Subject Participation 
 Local Site Enrollment # of Subjects 
 Revised and/or New Study Documents or Subject Materials 
(e.g. diaries, questionnaires) 
 Total Enrollment # of Subjects (Multi-Center Trials) 
 Investigator Brochure, Date/Version: 
 Change in subject selection or subject population 
 Change in Remuneration 
 Change of Sponsor/Funding 
 Research Related Use of Medical Records  
  Study Status Change (i.e., CTE, hold, re-open to enrollment) 
 Use of Specimens 
 
 Industry Sponsored Protocols only:  
Sponsor Amendment/Version #:        
 Research Related Use of Discarded Material 
 Change related to pharmacy or study drug administration 
 
  Revised Sponsor Protocol,  Issue Date/Version:        
 Addition/Removal of Co-Investigator or Research Staff Member 
 
For amendments limited to only the addition or removal of research staff in addition to this form the following is 
required:  
x 
Research Staffing Form (1 clean, 1 highlighted) 
x 
Revised Part E if amendment involves change in Authorized Prescribers for study medication 
x 
Part Q and CITI training documentation for any non-BIDMC research staff member.   
 
AMENDMENT ATTACHMENTS: 
 Revised Sponsor Protocol (New Version) (1 clean, 1 highlighted) 
 New or Revised Advertisement (1 clean, 1 highlighted) 
 Revised Part A (1 clean, 1 highlighted) 
 Revised Part B (1 clean, 1 highlighted) 
 Revised Consent Form (1 clean, 1 highlighted) 
 Revised Research Participant Materials or  Questionnaires  
     (1 clean, 1 highlighted) 
 Revised Research Staffing Form (1 Clean, I highlighted: ) 
 Part Q(s) for addition of any non-BIDMC personnel  
 Revised/New Part E (Obtain pharmacy signature and detail change below) 
 Other Revised Part/Form Document  (1 Clean, I highlighted: ) 
     Specify:  
 
 
 
 


 (CCI) Committee on Clinical Investigations 
Page 56 of 62 
                                                                                                                                                                                                                       Amendment Form  
                                                                                                                                                                                              CCI Form Revised: 3-2013 
 
 
AMENDMENT DESCRIPTION- REQUIRED FOR ALL SUBMISSIONS 
A detailed description of the amendment, in your own words, MUST be provided below.  The PI may provide a summary of a lengthy 
sponsor amendment in an attached cover letter or memo, however this should not simply be a copy of the sponsors amendment 
and/or letter.  Either list the current item followed by the new item, or attach a redlined version of the changed document.  If the 
consent form is revised, attach one copy of the consent form in which the changes (including additions and deletions) are clearly 
highlighted, and one clean copy of the consent form. 
. 
x 
Addition/Removal of Co-Investigator or Research Staff Member: We are adding Amanda Frias-Howard as Administrator 
and changing the role of Shivani Mehta to co-investigator to assist with the protocol. We are removing Francesca as 
Administrator. We are removing Anthony Mahoney-Pacheco, Jabari Evans, Varun Konanki, Thomas Leith. They are no 
longer with the institution.   
x 
Requested Modifications: Moved Lars Andersen from active staff to outside collaborator. He will work with de-identified data 
for analysis as needed.  Adding Emma Hershey as co-investigator to assist with the study. 
Part Q included. 
 
 
  PI Memo/Cover Letter Describing Changes is attached 
  Sponsor Letter Describing Changes is Attached 
 
 
Impact on Budget/Funding 
Does this amendment affect the current budget for the 
study? 
 
 No 
 
 Yes, if yes, explain       
 
and contact:  
- 
Clinical Trials Office for Industry Funded Studies 
- 
Office of Sponsored Programs for Other Funding 
Sources 
 
 
 
Does this amendment affect the current funding for the 
study? 
 
  No 
 
  Yes, if yes, explain       
 
 and contact: 
- 
Clinical Trials Office for Industry Funded Studies 
- 
Office of Sponsored Programs for Other Funding 
Sources 
 
 
AMENDMENT RATIONALE- REQUIRED FOR ALL SUBMISSIONS 
The reason or justification for the changes must be discussed as well as how the change might affect the risk/benefit ratio.  Please 
also address how or if a change in the risk/benefit ratio impacts the informed consent form, and if the change necessitates a change in 
the consent form.  The rationale may be provided here or in an attached cover letter or memo.   
 
x 
Addition/Removal of Co-Investigator or Research Staff Member: We are removing Shamsher Ali, Marcel Casasola, and 
Lise Witten as they are no longer with the institution.  
 
This change does not affect the risk/benefit ratio. This study does not necessitate a change in the written, informed consent 
form. 
  PI Memo /Cover letter Describing Rationale is Attached 
  Sponsor Letter Describing Rationale is Attached 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Principal Investigator  
 
 
 
 
Date 
 
 
 
Michael Cocchi MD 
 
 
 
 
Print Name 
 
 
 
 
 
 


 (CCI) Committee on Clinical Investigations 
Page 57 of 62 
                                                                                                                                                                                                                       Amendment Form  
                                                                                                                                                                                              CCI Form Revised: 3-2013 
 
AMENDMENT FORM 
STUDY INFORMATION 
TITLE OF PROTOCOL: Esmolol to treat the hemodynamic effects of septic shock 
CCI PROTOCOL # : 2014P-000415 
PRINCIPAL INVESTIGATOR: Michael Cocchi MD 
STUDY COORDINATOR: Deanna Lee 
STUDY COORDINATOR EMAIL ADDRESS: DLEE19@BIDMC.HARVARD.EDU  
 
AMENDMENT DETAILS 
Indicate which components(s) or element(s) of your protocol are being changed.  Check all applicable items. 
  Principal Investigator 
 Change and/or New Recruitment or Publicity Materials 
 
 DSMB Reports/Monitoring Reports/Safety Reports 
 Recruitment, Publicity Materials and/or procedures 
 Revised and/or New Consent Form 
 Consent Procedures 
 Change and/or Addition of Study Procedures 
 Duration of Subject Participation 
 Local Site Enrollment # of Subjects 
 Revised and/or New Study Documents or Subject Materials 
(e.g. diaries, questionnaires) 
 Total Enrollment # of Subjects (Multi-Center Trials) 
 Investigator Brochure, Date/Version: 
 Change in subject selection or subject population 
 Change in Remuneration 
 Change of Sponsor/Funding 
 Research Related Use of Medical Records  
  Study Status Change (i.e., CTE, hold, re-open to enrollment) 
 Use of Specimens 
 
 Industry Sponsored Protocols only:  
Sponsor Amendment/Version #:        
 Research Related Use of Discarded Material 
 Change related to pharmacy or study drug administration 
 
  Revised Sponsor Protocol,  Issue Date/Version:        
 Addition/Removal of Co-Investigator or Research Staff Member 
 
For amendments limited to only the addition or removal of research staff in addition to this form the following is 
required:  
x 
Research Staffing Form (1 clean, 1 highlighted) 
x 
Revised Part E if amendment involves change in Authorized Prescribers for study medication 
x 
Part Q and CITI training documentation for any non-BIDMC research staff member.   
 
AMENDMENT ATTACHMENTS: 
 Revised Sponsor Protocol (New Version) (1 clean, 1 highlighted) 
 New or Revised Advertisement (1 clean, 1 highlighted) 
 Revised Part A (1 clean, 1 highlighted) 
 Revised Part B (1 clean, 1 highlighted) 
 Revised Consent Form (1 clean, 1 highlighted) 
 Revised Research Participant Materials or  Questionnaires  
     (1 clean, 1 highlighted) 
 Revised Research Staffing Form (1 Clean, I highlighted: ) 
 Part Q(s) for addition of any non-BIDMC personnel  
 Revised/New Part E (Obtain pharmacy signature and detail change below) 
 Other Revised Part/Form Document  (1 Clean, I highlighted: ) 
     Specify:  
 
 
 
 
 


 (CCI) Committee on Clinical Investigations 
Page 58 of 62 
                                                                                                                                                                                                                       Amendment Form  
                                                                                                                                                                                              CCI Form Revised: 3-2013 
 
AMENDMENT DESCRIPTION- REQUIRED FOR ALL SUBMISSIONS 
A detailed description of the amendment, in your own words, MUST be provided below.  The PI may provide a summary of a lengthy 
sponsor amendment in an attached cover letter or memo, however this should not simply be a copy of the sponsors amendment 
and/or letter.  Either list the current item followed by the new item, or attach a redlined version of the changed document.  If the 
consent form is revised, attach one copy of the consent form in which the changes (including additions and deletions) are clearly 
highlighted, and one clean copy of the consent form. 
. 
x 
Addition/Removal of Co-Investigator or Research Staff Member: We are adding Lakshman Balaji to the study protocol to 
assist with data monitoring. 
 
 
  PI Memo/Cover Letter Describing Changes is attached 
  Sponsor Letter Describing Changes is Attached 
 
 
Impact on Budget/Funding 
Does this amendment affect the current budget for the 
study? 
 
 No 
 
 Yes, if yes, explain       
 
and contact:  
- 
Clinical Trials Office for Industry Funded Studies 
- 
Office of Sponsored Programs for Other Funding 
Sources 
 
 
 
Does this amendment affect the current funding for the 
study? 
 
  No 
 
  Yes, if yes, explain       
 
 and contact: 
- 
Clinical Trials Office for Industry Funded Studies 
- 
Office of Sponsored Programs for Other Funding 
Sources 
 
 
AMENDMENT RATIONALE- REQUIRED FOR ALL SUBMISSIONS 
The reason or justification for the changes must be discussed as well as how the change might affect the risk/benefit ratio.  Please 
also address how or if a change in the risk/benefit ratio impacts the informed consent form, and if the change necessitates a change in 
the consent form.  The rationale may be provided here or in an attached cover letter or memo.   
 
x 
Addition/Removal of Co-Investigator or Research Staff Member: We are adding Lakshman Balaji to the study protocol to 
assist with data monitoring. 
 
This change does not affect the risk/benefit ratio. This study does not necessitate a change in the written, informed consent 
form. 
  PI Memo /Cover letter Describing Rationale is Attached 
  Sponsor Letter Describing Rationale is Attached 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Principal Investigator  
 
 
 
 
Date 
 
 
 
Michael Cocchi MD 
 
 
 
 
Print Name 
 
 
 
 
 
 
 
 
 
 
 
 


 (CCI) Committee on Clinical Investigations 
Page 59 of 62 
                                                                                                                                                                                                                       Amendment Form  
                                                                                                                                                                                              CCI Form Revised: 3-2013 
 
AMENDMENT FORM 
STUDY INFORMATION 
TITLE OF PROTOCOL: Esmolol to treat the hemodynamic effects of septic shock 
CCI PROTOCOL # : 2014P-000415 
PRINCIPAL INVESTIGATOR: Michael Cocchi MD 
STUDY COORDINATOR: AMANDA FRIAS-HOWARD 
STUDY COORDINATOR EMAIL ADDRESS: AFHOWARD@BIDMC.HARVARD.EDU  
 
AMENDMENT DETAILS 
Indicate which components(s) or element(s) of your protocol are being changed.  Check all applicable items. 
  Principal Investigator 
 Change and/or New Recruitment or Publicity Materials 
 
 DSMB Reports/Monitoring Reports/Safety Reports 
 Recruitment, Publicity Materials and/or procedures 
 Revised and/or New Consent Form 
 Consent Procedures 
 Change and/or Addition of Study Procedures 
 Duration of Subject Participation 
 Local Site Enrollment # of Subjects 
 Revised and/or New Study Documents or Subject Materials 
(e.g. diaries, questionnaires) 
 Total Enrollment # of Subjects (Multi-Center Trials) 
 Investigator Brochure, Date/Version: 
 Change in subject selection or subject population 
 Change in Remuneration 
 Change of Sponsor/Funding 
 Research Related Use of Medical Records  
  Study Status Change (i.e., CTE, hold, re-open to enrollment) 
 Use of Specimens 
 
 Industry Sponsored Protocols only:  
Sponsor Amendment/Version #:        
 Research Related Use of Discarded Material 
 Change related to pharmacy or study drug administration 
 
  Revised Sponsor Protocol,  Issue Date/Version:        
 Addition/Removal of Co-Investigator or Research Staff Member 
 
For amendments limited to only the addition or removal of research staff in addition to this form the following is 
required:  
x 
Research Staffing Form (1 clean, 1 highlighted) 
x 
Revised Part E if amendment involves change in Authorized Prescribers for study medication 
x 
Part Q and CITI training documentation for any non-BIDMC research staff member.   
 
AMENDMENT ATTACHMENTS: 
 Revised Sponsor Protocol (New Version) (1 clean, 1 highlighted) 
 New or Revised Advertisement (1 clean, 1 highlighted) 
 Revised Part A (1 clean, 1 highlighted) 
 Revised Part B (1 clean, 1 highlighted) 
 Revised Consent Form (1 clean, 1 highlighted) 
 Revised Research Participant Materials or  Questionnaires  
     (1 clean, 1 highlighted) 
 Revised Research Staffing Form (1 Clean, I highlighted: ) 
 Part Q(s) for addition of any non-BIDMC personnel  
 Revised/New Part E (Obtain pharmacy signature and detail change below) 
 Other Revised Part/Form Document  (1 Clean, I highlighted: ) 
     Specify:  
 
 
 
 
 


 (CCI) Committee on Clinical Investigations 
Page 60 of 62 
                                                                                                                                                                                                                       Amendment Form  
                                                                                                                                                                                              CCI Form Revised: 3-2013 
 
AMENDMENT DESCRIPTION- REQUIRED FOR ALL SUBMISSIONS 
A detailed description of the amendment, in your own words, MUST be provided below.  The PI may provide a summary of a lengthy 
sponsor amendment in an attached cover letter or memo, however this should not simply be a copy of the sponsors amendment 
and/or letter.  Either list the current item followed by the new item, or attach a redlined version of the changed document.  If the 
consent form is revised, attach one copy of the consent form in which the changes (including additions and deletions) are clearly 
highlighted, and one clean copy of the consent form. 
. 
Addition/Removal of Co-Investigator or Research Staff Member: We are adding removing Emma Hershey, Mathias Holmberg, 
Jocelyn Portmann, Deanna Lee, Ying, Loo, Lethu Ntshinga, Garrett Thompson, Lara Roessler as they are  no longer with the 
group or working on this protocol. 
 
  PI Memo/Cover Letter Describing Changes is attached 
  Sponsor Letter Describing Changes is Attached 
 
 
Impact on Budget/Funding 
Does this amendment affect the current budget for the 
study? 
 
 No 
 
 Yes, if yes, explain       
 
and contact:  
- 
Clinical Trials Office for Industry Funded Studies 
- 
Office of Sponsored Programs for Other Funding 
Sources 
 
 
 
Does this amendment affect the current funding for the 
study? 
 
  No 
 
  Yes, if yes, explain       
 
 and contact: 
- 
Clinical Trials Office for Industry Funded Studies 
- 
Office of Sponsored Programs for Other Funding 
Sources 
 
 
AMENDMENT RATIONALE- REQUIRED FOR ALL SUBMISSIONS 
The reason or justification for the changes must be discussed as well as how the change might affect the risk/benefit ratio.  Please 
also address how or if a change in the risk/benefit ratio impacts the informed consent form, and if the change necessitates a change in 
the consent form.  The rationale may be provided here or in an attached cover letter or memo.   
 
Addition/Removal of Co-Investigator or Research Staff Member: We are adding removing Emma Hershey, Mathias Holmberg, 
Jocelyn Portmann, Deanna Lee, Ying, Loo, Lethu  Ntshinga, Garrett Thompson, Lara Roessler as they are  no longer with the 
group or working on this protocol. 
 
This change does not affect the risk/benefit ratio. This study does not necessitate a change in the written, informed consent 
form. 
  PI Memo /Cover letter Describing Rationale is Attached 
  Sponsor Letter Describing Rationale is Attached 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Principal Investigator  
 
 
 
 
Date 
 
 
 
Michael Cocchi MD 
 
 
 
 
Print Name 
 
 
 
 
 
 
 
 
 
 
 


 (CCI) Committee on Clinical Investigations 
Page 61 of 62 
                                                                                                                                                                                                                       Amendment Form  
                                                                                                                                                                                              CCI Form Revised: 3-2013 
 
AMENDMENT FORM 
STUDY INFORMATION 
TITLE OF PROTOCOL: Esmolol to treat the hemodynamic effects of septic shock 
CCI PROTOCOL # : 2014P-000415 
PRINCIPAL INVESTIGATOR: Michael Cocchi MD 
STUDY COORDINATOR: NATIA PERADZE 
STUDY COORDINATOR EMAIL ADDRESS: NPERADZE@BIDMC.HARVARD.EDU  
 
AMENDMENT DETAILS 
Indicate which components(s) or element(s) of your protocol are being changed.  Check all applicable items. 
  Principal Investigator 
 Change and/or New Recruitment or Publicity Materials 
 
 DSMB Reports/Monitoring Reports/Safety Reports 
 Recruitment, Publicity Materials and/or procedures 
 Revised and/or New Consent Form 
 Consent Procedures 
 Change and/or Addition of Study Procedures 
 Duration of Subject Participation 
 Local Site Enrollment # of Subjects 
 Revised and/or New Study Documents or Subject Materials 
(e.g. diaries, questionnaires) 
 Total Enrollment # of Subjects (Multi-Center Trials) 
 Investigator Brochure, Date/Version: 
 Change in subject selection or subject population 
 Change in Remuneration 
 Change of Sponsor/Funding 
 Research Related Use of Medical Records  
  Study Status Change (i.e., CTE, hold, re-open to enrollment) 
 Use of Specimens 
 
 Industry Sponsored Protocols only:  
Sponsor Amendment/Version #:        
 Research Related Use of Discarded Material 
 Change related to pharmacy or study drug administration 
 
  Revised Sponsor Protocol,  Issue Date/Version:        
 Addition/Removal of Co-Investigator or Research Staff Member 
 
For amendments limited to only the addition or removal of research staff in addition to this form the following is 
required:  
x 
Research Staffing Form (1 clean, 1 highlighted) 
x 
Revised Part E if amendment involves change in Authorized Prescribers for study medication 
x 
Part Q and CITI training documentation for any non-BIDMC research staff member.   
 
AMENDMENT ATTACHMENTS: 
 Revised Sponsor Protocol (New Version) (1 clean, 1 highlighted) 
 New or Revised Advertisement (1 clean, 1 highlighted) 
 Revised Part A (1 clean, 1 highlighted) 
 Revised Part B (1 clean, 1 highlighted) 
 Revised Consent Form (1 clean, 1 highlighted) 
 Revised Research Participant Materials or  Questionnaires  
     (1 clean, 1 highlighted) 
 Revised Research Staffing Form (1 Clean, I highlighted: ) 
 Part Q(s) for addition of any non-BIDMC personnel  
 Revised/New Part E (Obtain pharmacy signature and detail change below) 
 Other Revised Part/Form Document  (1 Clean, I highlighted: ) 
     Specify:  
 
 
 
 
 


 (CCI) Committee on Clinical Investigations 
Page 62 of 62 
                                                                                                                                                                                                                       Amendment Form  
                                                                                                                                                                                              CCI Form Revised: 3-2013 
 
AMENDMENT DESCRIPTION- REQUIRED FOR ALL SUBMISSIONS 
A detailed description of the amendment, in your own words, MUST be provided below.  The PI may provide a summary of a lengthy 
sponsor amendment in an attached cover letter or memo, however this should not simply be a copy of the sponsors amendment 
and/or letter.  Either list the current item followed by the new item, or attach a redlined version of the changed document.  If the 
consent form is revised, attach one copy of the consent form in which the changes (including additions and deletions) are clearly 
highlighted, and one clean copy of the consent form. 
. 
Study staff update.  
 
  PI Memo/Cover Letter Describing Changes is attached 
  Sponsor Letter Describing Changes is Attached 
 
 
Impact on Budget/Funding 
Does this amendment affect the current budget for the 
study? 
 
 No 
 
 Yes, if yes, explain       
 
and contact:  
- 
Clinical Trials Office for Industry Funded Studies 
- 
Office of Sponsored Programs for Other Funding 
Sources 
 
 
 
Does this amendment affect the current funding for the 
study? 
 
  No 
 
  Yes, if yes, explain       
 
 and contact: 
- 
Clinical Trials Office for Industry Funded Studies 
- 
Office of Sponsored Programs for Other Funding 
Sources 
 
 
AMENDMENT RATIONALE- REQUIRED FOR ALL SUBMISSIONS 
The reason or justification for the changes must be discussed as well as how the change might affect the risk/benefit ratio.  Please 
also address how or if a change in the risk/benefit ratio impacts the informed consent form, and if the change necessitates a change in 
the consent form.  The rationale may be provided here or in an attached cover letter or memo.   
 
Study staff update:  
We are removing Amanda Frias-Howard as she is no longer working on this protocol.  
We are removing Ting Sun as she is no longer part of BIDMC.  
We are adding correspondence to Natia Peradze as she will be working on this protocol and communicating with the IRB.  
 
This change does not affect the risk/benefit ratio. This study does not necessitate a change in the written, informed consent 
form. 
  PI Memo /Cover letter Describing Rationale is Attached 
  Sponsor Letter Describing Rationale is Attached 
 
 
Michael Cocchi, MD 
 
 
 
 
 
 
 
 
 
05/12/2021 
 
 
 
Signature of Principal Investigator  
 
 
 
 
Date 
 
 
 
Michael Cocchi MD 
 
 
 
 
Print Name 
 
 

SAP_001.pdf: 
Esmolol to Treat the Hemodynamic Effects of Septic Shock 
 
NCT02369900 
 
December 3, 2020 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
Statistical Analyses  
 
Preliminary observational data on a cohort of septic shock patients indicated a mean 
norepinephrine equivalent dose was 0.15 ± 0.09 mcg/kg/min at the 6 hour time point. We 
anticipated a 33% reduction in mean norepinephrine dose to 0.10 ± 0.09 mcg/kg/min after 6 
hours of continuous treatment with esmolol. Based on these estimates, for a two-sample t-test 
with a power of 80% and a type I error of 0.05, we estimated that a total of 104 patients would 
be required to show a statistically significant difference between treatment and control groups.   
 
Descriptive statistics are provided for baseline and outcome variables.  Continuous variables are 
presented as means with standard deviations or medians with interquartile ranges (IQR), based 
on the distribution of the data. Categorical variables are presented as counts with percentages. 
In univariate analysis, continuous variables were analyzed using a Student’s t-test if normally 
distributed and a Wilcoxon ranked sum test if non-normal. Categorical variables were analyzed 
using a Fisher’s exact test. 
 
The association between continuous infusion of esmolol and need for vasopressor support was 
assessed by comparing the median 6 hour norepinephrine equivalent dose (NED) between 
groups using a Wilcoxon rank-sum test. No patients expired prior to 6 hours after enrollment. To 
analyze the difference in vasopressor dose between groups at 12 hours and over time, we 
compared NED (recorded hourly for 12 hours) over time between groups using linear mixed 
effect models accounting for repeated measures and adjusting for pre-intervention NED. The 
appropriate variance-covariance structure was selected based on Akaike information criterion. 
Using this model, we tested whether NED was different at 12 hours and for differences in the 
overall trend over time. A similar analysis was used to assess the difference in heart rate between 
groups over the first 12 hours and lactate between groups over the first 24 hours; however, in 
the heart rate analysis, we tested for mean differences at 6 hours, 12 hours and for differences 
in the overall trend over time, and in the lactate analysis, we used a log-transformed lactate value 
to test for mean differences at 12 and 24 hours and for differences in the overall trend over time. 
We compared the median number of shock free days, defined as cessation of all vasopressors 
during the first 7 days, between the two groups.   
 
To characterize the effects of esmolol infusion on VO2, we limited the analysis to patients who 
were mechanically ventilated during the study period. The VO2 values were cleaned based on a 
custom algorithm that eliminated points that met any of the following four criteria: 1) VO2 value 
corresponding to a Fraction of Inspired Oxygen (FiO2) value above 61%. 2) VO2 value within 10 
minutes of a 10-unit change in FiO2 . 3) VO2 value above 800 mL/kg/min or below 80 mL/kg/min 
that is not sustained for at least 30 consecutive minutes. 4) VO2 value that is 15% higher or lower 
than the average of the VO2 values 5 minutes before and after the point in question.  
 
To analyze the difference in oxygen consumption between groups at 12 hours, 24 hours and over 
time for patients who were on mechanical ventilation at enrollment, we compared VO2 
measurements (standardized by bodyweight in kilograms) over time (recorded every minute 


from the time of study drug administration over a period of at least 24 hours) between groups 
using mixed linear model accounting for repeated measures (n = 15). We did not adjust for pre-
intervention VO2 measurements. Using this model, we tested for mean differences at 12 hours, 
24 hours and for differences in the overall trend over time. The appropriate variance-covariance 
structure was selected based on Akaike information criterion.  Additionally, a figure was created 
by first computing the mean of all the VO2 observations for a patient by timepoint, and then 
computing the mean of the means for each timepoint by treatment group. 
 
To characterize effects of esmolol on inflammatory markers in patients with vasopressor-
dependent septic shock, we compared log-transformed values of biomarkers at 12 and 24 hours 
and over time between groups using mixed linear model accounting for repeated measures and 
adjusting for pre-intervention biomarkers. The appropriate variance-covariance structure was 
selected based on Akaike information criterion. 
 
In-hospital mortality was compared between groups using the Fisher’s Exact test. Baseline 
covariates appeared to be balanced, so we did not adjust for any additional covariates. Length of 
hospital and ICU stay was compared between groups using a Wilcoxon ranked sum test and 
stratified based on hospital survival. To characterize effects of esmolol on SOFA score over the 
first 24 hours, we compared SOFA at 6, 12, and 24 hours and over time between groups using a 
mixed linear model accounting for repeated measures and adjusting for pre-intervention SOFA. 
 
 All analyses were conducted using Stata 14.2 (College Station, TX) and a p-value of <0.05 was 
considered significant.