Cardiogenic Shock Intravascular Cooling Trial (CHILL-SHOCK)
Phase: NA
Conditions: Cardiogenic Shock
Sponsor: University of Chicago

Version:  26Mar2018 
 
Page 1 of 23 
INVESTIGATIONAL PLAN 
 
Study Title: Cardiogenic SHock Intravascular CooLing TriaL (CHILL-SHOCK) 
 
Principal Investigator: 
Jonathan D. Paul, MD 
 
Co-Investigators: 
Rohan J. Kalathiya, MD 
Nir Uriel, MD 
Nitasha Sarswat, MD 
Sirtaz Adatya, MD 
Sandeep Nathan, MD 
Atman P. Shah, MD 
John E. A. Blair, MD 
Roberto M. Lang, MD 
Roderick Tung, MD 
Hemal M. Nayak, MD 
Gaurav A. Upadhyay, MD 
Michael Timothy Broman, MD, PhD 
Janet Friant, APN 
Margaret Lee, MPH 
 
 
Sponsor:  Investigator initiated with support from ZOLL Circulation, Inc. 
 
 
Intervention:  Therapeutic hypothermia using FDA approved ZOLL Intravascular Temperature 
Management (IVTM™) system to achieve core temperature of 32-34 for 24 hours in patients 
who present with cardiogenic shock.  
 
 
Manufacturer of Intervention:  ZOLL (Chelmsford, MA)  

Version:  26Mar2018 
 
Page 2 of 23 
 
Background 
Cardiogenic shock complicates 2-8% of all myocardial infarctions in hospitalized patients and 
despite advances in revascularization and mechanical support, the mortality rate in these patients 
can be as high as 50% during the index hospitalization.1 Cardiogenic shock from alternative 
causes such as advanced heart failure, acute myopericarditis, stress-induced cardiomyopathy, and 
acute valvular regurgitation are also associated with significant morbidity and mortality. 
Hypothermia, as defined by 32-34° Celsius, has been proposed as a potential adjunctive therapy 
in patients with cardiogenic shock. The role of mild hypothermia has been well established in out 
of hospital cardiac arrests due to ventricular tachycardia or ventricular fibrilation for improved 
neurological outcome.2 In fact, the American Heart Association (AHA) guidelines recommend 
therapeutic hypothermia (Class I recommendation) with targeted temperature of 32°C to 34°C 
for 12 to 24 hours in patients who suffer out-of-hospital cardiac arrest due to ventricular 
fibrillation (VF).3 AHA also recommends induced hypothermia for patients after in hospital 
cardiac arrest due to any initial rhythm or after out-of-hospital cardiac arrest due to pulseless 
electric activity or asystole. This is a Class IIb recommendation, compared to Class I for out-of-
hospital VF arrest. 
 
The proposed mechanism of improved neurological outcomes with therapeutic hypothermia 
(TH) likely involves changes in cerebral metabolism.4-6 In addition to neuroprotective effects, 
hypothermia may improve cardiac performance. Several animal and small human trials have 
tried to understand the effect of hypothermia on hemodynamics in patients with cardiogenic 
shock. 7-11 These have showed improved cardiac performance with TH with improved 
contractility, cardiac output, and reduction in the inflammatory response that accompanies shock.  
A small trial published in 2012 by Schmidt-Schweda et. al prospectively enrolled 14 patients that 
were cooled to 33°C and studied their hemodynamics. Interestingly, patients experienced a 
statistically significant drop in heart rate, but with increased stroke volume, higher mean arterial 
blood pressure (MAP), and higher cardiac Power index (CPI).10 All these indices have been 
associated with improved outcomes in cardiogenic shock.13 Most importantly, the Schmidt-
Schweda trial established that hypothermia is safe in patients with cardiogenic shock with no 
severe adverse events experienced in their cohort. There were no complications associated with 
insertion or removal of cooling catheters and anti-shivering measures were effective even in non-
ventilated patients (5 out of 14 patients were breathing spontaneously during therapeutic 
hypothermia (TH)). While there was a decline in platelets with TH, this did not lead to an 
increase in bleeding. Another study from authors at the Cleveland Clinic retrospectively 
evaluated the hemodynamic effects of TH on 14 consecutive patients with cardiogenic shock 
who underwent therapeutic hypothermia.9 The patients who underwent TH had higher cardiac 
index, lower SVR, and lower vasopressor requirements.9 Importantly, TH was deemed safe, and 
given the positive effects on hemodynamic parameters, the authors proposed that prospective 
trials are needed to potentially expand the role of TH outside of cardiac arrest. 
 

Version:  26Mar2018 
 
Page 3 of 23 
Patients with cardiogenic shock, regardless of the underlying etiology, present with hypotension, 
shortness of breath, altered mental status, signs of volume overload (elevated jugular venous 
pressure, pulmonary rales, lower extremity edema), and evidence of end-organ hypoperfusion. 
These patients are typically admitted to the Coronary Care Unit (CCU) for aggressive treatment 
to reverse the course of the disease. Standard of care therapy for these patients involves initiation 
of ionotropes and/or vasopressors along with diuretics. Often, mechanical circulatory support (i.e 
Intra-arterial balloon pump or temporary left-ventricular assist devices) and invasive 
hemodymamic monitoring (i.e. placement of a pulmonary artery catheter) is necessary. 
 
The results of the small trials mentioned above are encouraging, but larger randomized trials are 
necessary to establish the role of TH in patients with cardiogenic shock.  We propose a first-ever 
randomized clinical trial to prospectively study the effects of TH in patients with cardiogenic 
shock. In addition to assessing the safety of TH in this patient population, hemodynamic 
parameters, echocardiographic assessment of cardiac function during hypothermia, as well 
electrocardiographic changes with hypothermia will be studied. The echocardiographic changes 
during TH have never been previously reported. Studying TH in patients with cardiogenic shock 
is important, as therapies for this highly morbid condition have remained largely unchanged for 
many years. Given the high mortality associated with cardiogenic shock despite advances in 
medical and mechanical support, the clinical implications of results from this trial may be large. 
 
Objective 
The purpose of the study is to prospectively randomize patients with cardiogenic shock to 
standard therapy plus therapeutic hypothermia or standard medical therapy alone in order to 
assess the safety of TH in patients with cardiogenic shock. This study will also help understand 
the physiologic effects of TH in cardiogenic shock. This will be a pilot study to establish the 
safety of TH and to assess tolerability of TH in this patient population. 
 
Methods 
A. Patient Population: 
All patients meeting criteria for cardiogenic shock (defined as systolic blood pressure <90mmHg 
for at least 30 minutes, Cardiac Index < 2.2 L/min/m2, pulmonary capillary wedge pressure 
(PCWP) ≥ 15mmHg, need for vasopressors, or need for mechanical support to keep systolic 
blood pressure ≥ 90mmHg) admitted to the University of Chicago Coronary Care Unit (CCU) 
will be randomized to standard medical therapy or to therapeutic hypothermia (32-34°) for 24 
hours plus medical therapy in a non-blinded manner with 1:1 randomization using computer-
generated random numbers (simple randomization).  The cardiogenic shock may be a result of 
acute coronary syndromes (STEMI, NSTEMI, or UA), ischemic or non-ischemic 
cardiomyopathy, myocarditis, hypertrophic cardiomyopathy, stress-induced cardiomyopathy, 
peripartum cardiomyopathy, or cardiogenic shock in a patient with HF with preserved EF. 
Patients less than 18 years of age or greater than 89 years of age will be excluded. Patients with 

Version:  26Mar2018 
 
Page 4 of 23 
baseline heart rate less than 60 beats per minute, baseline temperatures less than 35°C, recent 
cardiotomy, history of cardiac transplantation, or those who are pregnant will be excluded. 
 
All patients between the ages of 18 and 89 who meet the criteria for cardiogenic shock in the 
CCU will be screened. Inclusion and exclusion criteria are listed below. 
 
Inclusion Criteria:  
1) Cardiogenic shock 
a) Systolic blood pressure <90mmHg for at least 30 minutes 
b) Cardiac Index < 2.2 L/min/m2 
c) Pulmonary capillary wedge pressure (PCWP) ≥ 15mmHg 
d) Need for central venous access, vasopressors, inotropes and/or mechanical 
circulatory support (i.e. intra-aortic balloon pump, Impella, ECMO) to maintain 
systolic blood pressure ≥ 90mmHg 
2) Etiology of shock 
a) Acute coronary syndromes (STEMI, NSTEMI, or UA) 
b) Ischemic or non-ischemic cardiomyopathy 
c) Myocarditis 
d) Hypertrophic cardiomyopathy 
e) Stress-induced cardiomyopathy 
f) Peripartum cardiomyopathy 
g) Cardiogenic shock in a patient with HF with preserved EF 
3) Age  18 years AND  89 years 
4) Admission to the University of Chicago CCU 
 
Exclusion Criteria: 
1) Baseline heart rate < 60 beats per minute 
2) Baseline temperatures < 35°C 
3) Recent cardiotomy 
4) History of cardiac transplantation 
5) Current pregnancy 
6) Contraindication to 9.3 French femoral venous access for placement of intravascular 
cooling catheter 
7) Hospice designation (either currently in hospice or previously enrolled within the past 
30 days) 
 
B. Data Collected: 
The data elements of interest include, but are not limited to the following: 
1. Patient information 
a. Name 

Version:  26Mar2018 
 
Page 5 of 23 
b. Date of birth 
c. Medical record number 
d. Phone number 
e. Primary diagnosis 
f. Relevant social and family history 
g. Previous medical history such as clinic notes, current medications, results of all 
tests, procedures and laboratory assessments. 
h. Medications 
i. Weight and height  
2. Transthoracic echocardiogram (TTE) 
3. Hemodynamics via pulmonary artery catheter 
a. RA pressures 
b. RV pressures 
c. PA pressures 
d. Pulmonary capillary wedge pressure (PCWP) 
e. Fick cardiac output and cardiac index 
f. Systemic vascular resistance (SVR) 
g. Pulmonary vascular resistance (PVR) 
h. Cardiac power and cardiac power index 
i. Mixed venous saturation (MVO2) 
4. Metabolic parameters 
a. Serum lactate level 
b. Basic metabolic panel - Renal function and serum electrolytes  
c. Hepatic function 
d. Coagulation parameters 
e. Complete blood count (CBC) 
f. Arterial blood gas (ABG) 
5. Physiologic parameters and vital signs  
a. Urine output  
b. Blood pressure 
c. Heart rate 
d. Bladder or esophageal temperature 
e. Respiratory rate 
6. Electrocardiogram 
7. Vasoactive medication requirements 
a. Cumulative inotrope (i.e. milrinone, dobutamine) and vasopressor (i.e. 
norepinephrine, phenylephrine, dopamine, vasopressin) doses 
8. Blood samples for future research 
a. Stored without identifying information for future research, which may include 
genetic testing 

Version:  26Mar2018 
 
Page 6 of 23 
b. May be shared with outside collaborators for research purposes, with identifiers 
removed 
 
C. Timing of Data Collection: 
Baseline parameters (prior to initiation of cooling): 
1. TTE 
2. Hemodynamics 
3. Metabolic parameters 
4. Physiologic parameters and vital signs (including temperature) 
5. Electrocardiogram 
6. Blood sample for future research 
 
Parameters collected during cooling protocol (18-24 hours after onset of cooling, prior to 
rewarming): 
1.  Hemodynamics 
2. Metabolic parameters 
3. Physiologic parameters and vital signs (body temperature measurements every 1-2 
hours, as per the CCU policy) 
4. Electrocardiogram 
5. TTE 
6. Cumulative inotrope and vasopressor dosing (at the end of 24 hours of intervention) 
7. Blood sample for future research 
 
Parameters collected after rewarming (48-96 hours after completion of cooling protocol): 
1. Hemodynamics  
2. Metabolic parameters 
3. Physiologic parameters and vital signs 
4. Electrocardiogram 
5. TTE 
6. Blood sample for future research 
 
Endpoints 
Primary safety endpoints: 
1. Arrhythmia requiring medical therapy or therapy with temporary pacemaker 
2. Bleeding requiring transfusions as a direct result of the cooling catheter insertion or 
secondary to resulting coagulopathy 
3. Clinically important bloodstream infection, as confirmed with 2 positive blood 
cultures, or suspected sepsis in the absence of positive blood cultures with a 
sequential organ failure assessment (SOFA) score >2 
4. Hypokalemia with potassium levels below 3.0mEq/L, not secondary to other 
identifiable causes 

Version:  26Mar2018 
 
Page 7 of 23 
Secondary endpoints: 
1. Hemodynamic changes during intervention period – Cardiac output/Cardiac Index, 
PCWP, SVR, mixed venous oxygen saturation (MVO2), cardiac power index 
2. Cumulative vasopressor and inotrope dose requirements (i.e. number of vasoactive 
and/or inotropic drugs used) 
3. Echocardiographic % change in ejection fraction at 18-24 hours (from baseline)  
4. In-hospital all-cause mortality  
 
Procedures 
Patients admitted to the Coronary Care unit (CCU) at the University of Chicago will be screened 
by the study investigators and the cardiology fellow on the CCU rotation. Patients meeting the 
inclusion criteria, as defined previously, will be identified and randomized after informed 
consent within 12 hours of presentation. Patients will be randomized to either TH plus standard 
medical care or to standard medical care alone. A pulmonary artery (PA) catheter will be placed 
at the bedside or in the Cardiac Cath lab if difficult anatomy is anticipated. As mentioned earlier, 
placement of a PA catheter is part of the standard of care for management of cardiogenic shock. 
Currently, patients who are admitted to the University of Chicago CCU with cardiogenic shock 
routinely undergo placement of PA catheter by the cardiology fellow in the CCU or in the 
cardiac cath lab. Data from the PA catheter is vital in initiating vasopressors/inotropes, assessing 
the response to the therapies, and possible need for escalation of therapy (i.e. mechanical 
support). In this study, patients in each arm will undergo PA catheter placement. 
 
Cooling will then be initiated and maintained using FDA approved ZOLL (Chelmsford, MA) 
Intravascular Temperature Management (IVTM™) system with the ZOLL Quattro cooling 
catheter. The ZOLL IVTM along with the Quattro cooling catheter are currently FDA approved 
for use in cardiac surgery patients to achieve and maintain normothermia during surgery and in 
recovery and to induce, maintain, and reverse mild hypothermia in neurosurgery patients during  
surgery and in recovery [11]. The IVTM is not currently FDA approved to achieve therapeutic 
hypothermia in cardiogenic shock. The use of the cooling catheter and the temperature 
management system will be off-label for this study.  Notably, although not FDA approved for 
this purpose, current AHA practice guidelines recommend therapeutic hypothermia with a goal 
temperature of 32°C to 34°C for 12 to 24 hours in patients successfully resuscitated after cardiac 
arrest as a Class I recommendation if the arrest is from VT/VF and as Class IIb recommendation 
for CA from other nonshockable rhythms. The European Resuscitation Council guidelines for 
resuscitation recommend therapeutic hypothermia for all comatose survivors of CA regardless of 
initial rhythm 
 
The ZOLL 9.3 French Quattro® catheter is inserted into the central venous system via the 
femoral approach by personnel certified to insert central venous catheters. Placement of the 
ZOLL catheter is identical to central venous line insertion, such as triple lumen insertion for 

Version:  26Mar2018 
 
Page 8 of 23 
administration of medications or a dialysis catheter for temporary dialysis. After successful 
insertion of the cooling catheter, it will be connected to the Thermogard XP® thermal regulation 
system. The Quattro® catheter functions as both a central venous triple lumen catheter as well as 
a cooling catheter. Cooling is achieved by circulating normal saline in a closed system through 
the catheter. The flow and temperature (range 4°C to 42°C) of the circulating saline serves as the 
heat exchange mechanism and is controlled by the external Thermoguard® thermal regulation 
system. The temperature is measured and adjustments are made by the thermal regulation system 
to automatically maintain target temperature.  The target temperature is achieved within 2-3 
hours of initiation of TH. Rewarming is accomplished using the same balloon catheter system 
and heat exchange occurs without infusion of any saline or fluids into the patient. In clinical 
trials, intravenous catheter based cooling system has been shown to achieve target temperature 
faster and maintain target temperature with more precision.12,14,15 
 
Medical therapy in both intervention and non-intervention groups will be based on the current 
recommendations for management of cardiogenic shock. This includes inotropic therapy (i.e. 
dobutamine or milrinone) for cardiac support, vasopressor therapy (i.e. norepinephrine, 
dopamine, phenylephrine, epinephrine) to achieve target blood pressure (mean arterial blood 
pressure ≥ 60 mmHg), diuretics for volume removal, and mechanical circulatory support as 
clinically indicated. All patients included in this study will have pulmonary artery (PA) catheters 
inserted within 12 hours of randomization via either the internal jugular or femoral venous 
approach to monitor real-time hemodynamics. The clinicians in the CCU will use the data from 
PA catheters (cardiac output, mixed venous saturation, systemic vascular resistance, etc.) to 
guide therapy for both the intervention and non-intervention groups. The primary investigator of 
this study (Dr. Paul) will have no role in the clinical management of the patients. 
 
Laboratory, echocardiographic, and hemodynamic parameters will be obtained for patients prior 
to randomization, near the end of 24 hour cooling therapy, and after 48-96 hours post-
randomization. Core temperature will be measured via either thermal tip at the end of a 
transurethral urinary catheter or endotracheal temperature probe in intubated patients. 
Rewarming will be accomplished at 0.3°C per hour until temperature reaches 37°C. 
 
Target Enrollment and Study Duration 
In this initial pilot study, we anticipate enrolling 20 patients to the study, 10 randomized to 
standard medical therapy and 10 patients randomized to standard medical therapy and 24 hours 
of TH. We anticipate completing enrollment within 6 months. 
 
Statistical Methods 
The three-dichotomous primary endpoints will be analyzed using a two-sample independent 
proportion test or a Fisher’s exact test with a Bonferroni method continuity correction for 
multiple endpoints.  Furthermore, numerical secondary endpoints will be presented as either 

Version:  26Mar2018 
 
Page 9 of 23 
mean ± standard deviation or median (interquartile range) based upon the distribution of the data.  
In addition, all numerical secondary endpoints will be assessed using two independent t tests or 
Mann-Whitney U test for comparisons.  Categorical variables will be tested with chi-square tests 
of association or Fisher’s exact tests.  Differences will be considered significant using an alpha 
value of 0.05 for a two-sided test.  Analyses will be performed using STATA MP Version 14 
(College Station, TX). 
 
Potential risks and benefits to subjects 
A. Benefits: 
There is mounting evidence that TH has positive effects on cardiac function. Multiple studies 
have suggested that TH may offer particular benefit in cardiogenic shock. In this prospective 
trial, the patients will be randomized to TH or standard medical care using simple randomization. 
With TH, we expect increased cardiac output, increased contractility, lower SVR, and higher 
cardiac power index which will lead to improved hemodynamics and potentially decreasing 
pressor requirements.  
 
B. Risks: 
Anticipated adverse events that could possibly occur during the study include, but are not limited 
to: 
1. Risks associated with TH 
a. Shivering 
b. Arrhythmia 
c. Coagulopathy with or without clinically significant bleeding 
d. Hyperglycemia 
e. Hypothermia 
f. Electrolyte abnormalities 
g. Infections 
2. Risks associated with cooling catheter insertion 
a. Bleeding 
b. Infection 
c. Vascular injury 
 
Mitigating Risks associated with TH: 
Shivering is the most common risk associated with TH. Shivering is a normal physiological 
response to cooling as it allows the body to expend energy and generate heat. This leads to 
increasing metabolic demands and subsequent oxygen consumption. Various strategies can be 
used to combat shivering and have these have been well described in the literature. In patients 
that are intubated, the most common means of combating shivering is a combination of 
benzodiazepines, opioid analgesics, and/or neuromuscular blockade.16 In awake patients, 
combination of meperedine and warming of skin with air-warming products such a ‘Bair Hugger 

Version:  26Mar2018 
 
Page 10 of 23 
blanket’ (3M, St. Paul, MN) hugger’ are utilized.17  Meperedine is the most beneficial agent to 
prevent shivering and previous studies have demonstrated significant lowering of the shivering 
threshold with meperidine.17,18 Given that intravascular cooling therapy is common in multiple 
ICU settings, including the cardiac care unit (CCU), protocols are already in place for the 
management of shivering, with an institutional-approved anti-shivering protocol often used in 
patients undergoing TH.18 In the event of persistent shivering despite therapy with intravenous 
sedatives, anesthetics (i.e. propofol or meperidine) and/or paralytic agents in intubated patients, 
the TH protocol will be stopped and patients will be rewarmed to normothermia. 
 
Therapeutic hypothermia may potentially increase the risk of arrhythmias and will be evaluated 
in this trial. Bradycardia is expected with TH. In the previously published studies, the reduction 
in heart rate is not significant enough to cause hemodynamic compromise.9,17,19 However, if a 
patient is noted to be persistently bradycardic, with signs or symptoms requiring temporary 
pacemaker insertion, the TH protocol will be stopped.  Bradycardia requiring temporary pacing 
will be considered an adverse event of cooling if the patient did not have underlying conduction 
system disease (i.e. first or second degree AV block) prior to cooling, In such cases, patients will 
be rewarmed to normothermia per the rewarming protocol currently in place for intravascular 
cooling of critically ill patients. 
 
In addition to bradycardia, ventricular arrhythmias are potential adverse effects of TH. While 
ventricular arrhythmias have veen reported with TH, data from trials suggests that there is no 
demonstrable increase in risk of ventricular arrhythmias in patients undergoing therapeutic 
hypoethermia.24,25 Importantly, patients in cardiogenic shock have a high risk of developing 
ventricular arrhythmias either due to ischemia or underlying myocardial scaring. All ventricular 
arrhythmia epidsodes requiring intervention will be recorded. If arrhythmia is deemed to be as a 
result of hypothermia and alternative explanations have been exhausted, the patient will be 
rewarmed to normothermia per the rewarming protocol. 
 
Another risk associated with TH is mild coagulopathy. Temperatures below 33C have been 
associated with mild platelet dysfunction in vitro. However, the risk of bleeding with mild TH 
(32-34C) is minimal and none of the trials of TH in cardiac arrest or stroke have demonstrated 
increased risk of bleeding.20,21 TH has also been used safely in patients with ischemic stroke who 
are treated with tPA.22 Based on the currently published data, the risk of bleeding with TH is 
minimal. Bleeding adverse events will be classified using the GUSTO bleeding criteria.26 In 
patients who develop moderate bleeding deemed to be a direct result of TH, initial conservative 
measures of simple transfusions will be implemented. However, if bleeding does not respond to 
these conservative measures or progresses to severe bleeding, the TH protocol will be stopped 
and patients will be safely rewarmed. 
 

Version:  26Mar2018 
 
Page 11 of 23 
Hyperglycemia is common during TH as lower temperatures decrease insulin secretion and 
increase insulin resistance. Many patients with heart failure and cardiogenic shock have 
concominant diabetes and glucose control can often be difficult to achieve in these critically ill 
patients. Clinically significant hyperglycemia will be defined as glucose level exceeding 
200mg/d requiring continuous insulin infusion in patients without a diagnosis of diabetes 
mellitus. Hyperglycemia in patients with diagnosis of diabetes mellitus, or hyperglycemia as a 
result of other identifiable causes (i.e. administration of steroids, adrenal derangements) will not 
be considered as a result of TH. In patients who develop hyperglycemia requiring continuous 
insuling infusion as a direct result of TH, the patient will be treated expectantly and 
hyperglycemia will be recorded as an adverse event. During TH period, blood glucose will be 
measured at least hourly during TH, especially in patients receiving intravenous insulin, and 
during rewarming, when glucose levels can fall. 
 
Hypothermia will lower serum potassium levels, primarily by promoting inward cellular 
potassium flux, although hypothermia also induces a mild diuresis with concurrent electrolyte 
wasting. Serum electrolytes will be measured at regular intervals (every 4–6 hours). Potassium 
will be repleted to maintain levels above 3.5 mEq/L. Rewarming reverses the potassium flux and 
increases serum levels, so repletion will be held 4 hours before rewarming begins. Clinically 
significant hyperkalemia is unusual in patients with preserved renal function. In patients with 
hypokalemia not due to other identifiable causes (diuretic administration, adrenal derangements, 
etc.), potassium supplements will be administered as per standard of care.  Hypokalemia with 
potassium levels below 3.0mEq/L not secondary to other identifiable causes in patients 
undergoing TH will be considered an adverse event. 
 
The target temperature of 32-34C will be achieved using the intravascular cooling catheters. 
The body temperature will be recorded every 1-2 hours as per the CCU policy in the TH group 
(as well as the control group). The time spent in the therapeutic window will be recorded and 
reported. Any deviations outside of the range, specifically <32C lasting >5 minutes will be 
reported as an adverse event. 
 
Mitigating Risks associated with cooling catheter insertion: 
The risks associated with insertion of a cooling catheter are the same as insertion of any central 
lumen catheter. These include, but are not limited to, bleeding, infection, and vascular injury. 
Previously published studies have quoted risk of localized hematomas at 4.7% and risk of 
vascular injury (most frequently due to inadvertent arterial puncture) at <1%.23 Incidence of line-
associated blood stream infection has been reported as 80-189 episodes per 100,000 patient 
years.23 
 
Insertion of a central venous catheter is standard of care in patients in cardiogenic shock to allow 
for administration of inotropes/vasopressors. The ZOLL Quattro catheters include three standard 

Version:  26Mar2018 
 
Page 12 of 23 
central venous catheter infusion lumens to allow for administration of these vasoactive 
medications. Therefore, patients randomized to TH arm will not need an additional central 
venous line. Rather, insertion of a cooling catheter will serve the purpose of initiation and 
maintenance of TH while also allowing for administration of drugs via the infusion lumens. The 
risk associated with cooling catheter insertion is not expected to be higher than insertion of a 
standard central venous line. 
 
C. Monitoring of Safety: 
During the intervention period, participants will be monitored by physicians, nurses, and 
technicians in accordance with standard medical care.  This includes 24-hour monitored 
telemetry, with measurement of heart rate, blood pressure, oxygen saturation, and respiratory 
rate.  Real-time hemodynamic monitoring will be measured using pulmonary artery catheters. 
Blood glucose and electrolyte measurements will be performed as per protocol for patients 
undergoing therapeutic hypothermia, and correction of abnormalities will be performed by the 
treating team.  Shivering will be monitored by the treating nurse, per ICU protocol, and will be 
reported to the treating team.  TH will not influence the clinician’s medical decisions – any 
medical or mechanical intervention necessary based on clinical status will be allowed. 
 
D. Data Safety Monitoring Board: 
Adverse events will be reviewed by the Data Safety Monitoring Board as described below.  The 
study will be halted upon the discovery of unanticipated adverse device events that present a 
significant or unreasonable risk to subjects enrolled in the study. 
 
The DSMB will meet (in person or via telephone conference) a minimum of 3 times:  
• after treatment of the first 4 subjects (2 in the TH arm and 2 in the control arm) 
• after treatment of the first 10 subjects (5 in the TH arm and 5 in the control arm) 
• at the conclusion of the study 
 
In addition, the DSMB may convene additional meetings if necessary to ensure the ongoing 
monitoring and safety of the subjects treated with therapeutic hypothermia (TH).  A copy of the 
DSMB charter is located in Appendix 2. 
 
We will collect all treatment emergent and serious unsolicited adverse events during the index 
hospitalization.  A treatment emergent adverse event is any untoward medical occurrence 
associated with the use of therapeutic hypothermia, whether or not considered related.  The 
DSMB will be informed of expected adverse events, such as shivering, bleeding, and 
bradycardia, that result in termination of the protocol. Additionally, any unexpected adverse 
events while undergoing TH will be reported to the DSMB, whether deemed related to TH or 
not.  All adverse event details will be provided to the DSMB prior to the meeting with ample 
time allowed for analysis.  This will include details of the individual adverse events as well as 
the PI’s analysis related to causality, severity and frequency.  The DSMB will be responsible for 

Version:  26Mar2018 
 
Page 13 of 23 
confirmation of the PI’s assessment of all adverse events and final adjudication of all adverse 
events. 
 
The DSMB will include the following individuals who have agreed to serve on it: 
Dr. Gabe Sayer (University of Chicago Medicine – Section of Cardiology) 
Dr. Mardi Gomberg-Maitland (Inova Health System – Section of Cardiology) 
Dr. Gene Kim (University of Chicago Medicine – Section of Cardiology) 
 
Payment to Subjects 
Participants will not receive monetary compensation for their participation in this study.  The 
cost of the TH catheters, thermal regulation system and associated monitoring will be part of the 
study costs and patients will not be charged for these services. 
 
Informed Consent 
Informed consent for the study will be obtained from the patient if possible, or the medical 
decision maker in the event that the patient is incapable of making informed decisions. Due to 
the nature of the study, we expect that the patient’s clinical status will preclude consent directly 
from the patient. We anticipate that a majority of the consents will be obtained from family and 
medical decision makers. Once the referring physician has given approval and solicited a 
patient’s or decision maker’s interest, a co-investigator will approach and discuss the possibility 
of participating in this research protocol. The co-investigator will discuss the background and 
significance of the study, the inclusion and exclusion requirements, and why they are suitable for 
participation. The study will be summarized for the subject. They will also be informed that they 
may withdraw at any time during the study without influencing their medical care. The potential 
participant, including decision maker, will be given the opportunity to ask questions. 
 
Confidentiality 
A study file containing all study related information will be kept by the primary investigator in a 
file cabinet within a locked office or on an encrypted electronic file.  Each subject enrolled will 
have their own file including: study ID number, physician’s consent, clinical data as described in 
Methods, the original signed consent form, proof of eligibility, and any other forms or 
information.  
 
Protection of Special Populations 
Patients younger than 18 years or older than 89 years will be excluded. Additional exclusions 
will be made as described in Methods. No group of patients will bear disproportionate risk or 
burden.  This includes all eligible Medicare and Medicaid beneficiaries and will not discriminate 
any patient on the basis of gender, age, disability, and racial or ethnic background.  As such, we 
believe that the results obtained from this study will be generalizable to the Medicare and 
Medicaid beneficiary population within our specifically stated inclusion/exclusion criteria.

Version:  26Mar2018 
 
Page 14 of 23 
 
References 
1. Babaev A, Frederick PD, Pasta DJ, Every N, Sichrovsky T, Hochman JS; NRMI 
Investigators. Trends in management and outcomes of patients with acute myocardial 
infarction complicated by cardiogenic shock. JAMA. 2005 Jul 27;294(4):448-54.  
2. Bernard SA, Gray TW, Buist MD, Jones BM, Silvester W, Gutteridge G, Smith K. Treatment 
of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia. N Engl J 
Med. 2002 Feb 21;346(8):557-63.  
3. Peberdy MA, Callaway CW, Neumar RW, Geocadin RG, Zimmerman JL, Donnino M, 
Gabrielli A, Silvers SM, Zaritsky AL, Merchant R, Vanden Hoek TL, Kronick SL. Part 9: 
post-cardiac arrest care: 2010 American Heart Association guidelines for cardiopulmonary 
resuscitation and emergency cardiovascular care. Circulation. 2010;122():S768–S786 
4. Hägerdal M, Harp J, Nilsson L, Siesjöu BK. THE EFFECT OF INDUCED 
HYPOTHERMIA UPON OXYGEN CONSUMPTION IN THE RAT BRAIN. Journal of 
Neurochemistry. 1975;24(2):311-6. 
5. Erecinska M, Thoresen M, Silver IA. Effects of Hypothermia on Energy Metabolism in 
Mammalian Central Nervous System. J Cereb Blood Flow Metab. 2003;23(5):513-30. 
6. Yenari MA, Han HS. Neuroprotective mechanisms of hypothermia in brain ischaemia. Nat 
Rev Neurosci. 2012 Feb 22;13(4):267-78.  
7. Götberg M, van der Pals J, Olivecrona GK, Götberg M, Koul S, Erlinge D. Mild hypothermia 
reduces acute mortality and improves hemodynamic outcome in a cardiogenic shock pig 
model. Resuscitation. 2010 Sep;81(9):1190-6.  
8. Dae MW, Gao DW, Sessler DI, Chair K, Stillson CA. Effect of endovascular cooling on 
myocardial temperature, infarct size, and cardiac output in human-sized pigs. Am J Physiol 
Heart Circ Physiol. 2002 May;282(5):H1584-91.  
9. Stegman B, Aggarwal B, Senapati A, Shao M, Menon V. Serial hemodynamic measurements 
in post-cardiac arrest cardiogenic shock treated with therapeutic hypothermia. Eur Heart J 
Acute Cardiovasc Care. 2015 Jun;4(3):263-9.  
10. Schmidt-Schweda S, Ohler A, Post H, Pieske B. Moderate hypothermia for severe 
cardiogenic shock (COOL Shock Study I &amp; II). Resuscitation. 2013 Mar;84(3):319-25.  
11. http://www.zoll.com/medical-products/product-manuals/?pid=12583 
12. Zobel C, Adler C, Kranz A, Seck C, Pfister R, Hellmich M, Kochanek M, Reuter H. Mild 
therapeutic hypothermia in cardiogenic shock syndrome. Crit Care Med. 2012 
Jun;40(6):1715-23.  
13. Fincke R, Hochman JS, Lowe AM, Menon V, Slater JN, Webb JG, LeJemtel TH, Cotter G; 
SHOCK Investigators. Cardiac power is the strongest hemodynamic correlate of mortality in 
cardiogenic shock: a report from the SHOCK trial registry. J Am Coll Cardiol. 2004 Jul 
21;44(2):340-8.  
14. Heard KJ, Peberdy MA, Sayre MR, Sanders A, Geocadin RG, Dixon SR, Larabee TM, Hiller 
K, Fiorello A, Paradis NA, O'Neil BJ. A randomized controlled trial comparing the Arctic 

Version:  26Mar2018 
 
Page 15 of 23 
Sun to standard cooling for induction of hypothermia after cardiac arrest. Resuscitation. 2010 
Jan;81(1):9-14. doi: 10.1016/j.resuscitation.2009.09.015. Epub 2009 Oct 24.  
15. Hoedemaekers CW, Ezzahti M, Gerritsen A, van der Hoeven JG. Comparison of cooling 
methods to induce and maintain normo- and hypothermia in intensive care unit patients: a 
prospective intervention study. Critical Care. 2007;11(4):R91. 
16. Bernard SA, Gray TW, Buist MD, et al. Treatment of comatose survivors of out-of-hospital 
cardiac arrest with induced hypothermia. N Engl J Med 2002;346:557– 63. 
17. Delhaye C, Mahmoudi M, Waksman R. Hypothermia therapy: neurological and cardiac 
benefits. J Am Coll Cardiol. 2012 Jan 17;59(3):197-210.  
18. Choi HA, Ko SB, Presciutti M, Fernandez L, Carpenter AM, Lesch C, Gilmore E, Malhotra 
R, Mayer SA, Lee K, Claassen J, Schmidt JM, Badjatia N. Prevention of shivering during 
therapeutic temperature modulation: the Columbia anti-shivering protocol.Neurocrit Care. 
2011 Jun;14(3):389-94. 
19. Polderman KH, Herold I. Therapeutic hypothermia and controlled normothermia in the 
intensive care unit: practical considerations, side effects, and cooling methods. Crit Care Med 
2009;37:1101–20. 
20. Polderman KH. Mechanisms of action, physiological effects, and complications of 
hypothermia. Crit Care Med. 2009 Jul;37(7 Suppl):S186-202.  
21. Polderman KH. Hypothermia and coagulation. Crit Care. 2012; 16(Suppl 2): A20. 
22. Hemmen TM, Raman R, Guluma KZ, Meyer BC, Gomes JA, Cruz-Flores S, Wijman CA, 
Rapp KS, Grotta JC, Lyden PD. Intravenous thrombolysis plus hypothermia for acute 
treatment of ischemic stroke (ICTuS-L): final results. Stroke. 2010 Oct; 41(10):2265-70. 
23. Kornbau C, Lee KC, Hughes GD, Firstenberg MS. Central line complications. International 
Journal of Critical Illness and Injury Science. 2015;5(3):170-178. doi:10.4103/2229-
5151.164940. 
24. Moler FW, Silverstein FS, Holubkov R, Slomine BS, Christensen JR, Nadkarni VM, et al. 
Therapeutic hypothermia after out-of-hospital cardiac arrest in children. N Engl J Med. 2015 
May 14;372(20):1898-908. 
25. The Hypothermia after Cardiac Arrest Study Group. Mild therapeutic hypothermia to 
improve the neurologic outcome after cardiac arrest. N Engl J Med. 2002;346:549–556 
26. An international randomized trial comparing four thrombolytic strategies for acute 
myocardial infarction. The GUSTO investigators. N Engl J Med. 1993 Sep 2;329(10):673-
82. 

Version:  26Mar2018 
 
Page 16 of 23 
 

Version:  26Mar2018 
 
Page 17 of 23 
Appendix 1 – Schedule of Study Activities 
 
 
Baseline 
18-24 hours (after 
randomization) 
48-96 hours (after 
randomization) 
30-day 
Follow-Up 
90-day 
Follow-Up 
Informed Consent 
X 
 
 
 
 
Review Medial History 
X 
 
 
 
 
Review Medication History 
X 
 
 
 
 
Height and Weight 
X 
 
 
 
 
Vital Signs a 
X 
X 
X 
 
 
Echocardiogram (TTE) 
X 
X 
X 
 
 
Electrocardiogram (ECG) 
X 
X 
X 
 
 
Hemodynamics b 
X 
X 
X 
 
 
Blood Tests c 
X 
X 
X 
 
 
Vasoactive Medication  Dosing 
 
X 
 
 
 
Potassium (pts randomized to 
cooling) 
 
Q 4 hours 
 
 
Glucose Checks (pts randomized to 
cooling) 
 
Q 1 hour 
 
 
Urine Output 
X 
X 
X 
 
 
Randomization 
X 
 
 
 
 
Adverse Events 
 
X 
X 
X d 
X d 
a blood pressure, heart rate, temperature (bladder or esophageal), respiratory rate 
b RA pressures, RV pressures, PA pressures, pulmonary capillary wedge pressure (PCWP), Fick cardiac output and cardiac index, 
systemic vascular resistance (SVR), pulmonary vascular resistance (PVR), cardiac power and cardiac power index, mixed venous 
saturation (MVO2) 
c serum lactate level, basic metabolic panel, hepatic function, coagulation parameters, complete blood count (CBC), arterial blood gas 
(ABG), and optional blood samples for future research 
d to be completed in clinic, when possible, or by phone 
eitems to be charged to research during cooling include: meperidine 

Version:  26Mar2018 
 
Page 18 of 23 
Appendix 2 – DSMB Charter 
 
1. Introduction 
This Charter is for the Data and Safety Monitoring Board (DSMB) for Cardiogenic Shock 
Intravascular Cooling Trial (CHILL-SHOCK). The DSMB will consist of a team of clinical 
researchers who are unaffiliated with this project. The members of the DSMB will not be 
investigators in this study and will be experienced in conducting and interpreting clinical trials. 
Their responsibilities will include reviewing the efficacy and safety endpoints at the set times 
points, as stated below. The Charter is intended to be a living document.  The DSMB may wish 
to review it at regular intervals to determine whether any changes in the procedure are necessary. 
 
2. Responsibilities of the DSMB 
The DSMB is responsible for safeguarding the interests of study participants, assessing the safety 
and efficacy of study procedures, and for monitoring the overall conduct of the study. 
 
The DSMB is an independent group advisory to the study PI and is required to provide 
recommendations about starting, continuing, and stopping the study.  In addition, the DSMB is 
asked to make recommendations, as appropriate, to/about: 
• 
Selection, recruitment, and retention of participants 
• 
Adherence to protocol requirements 
• 
Completeness, quality, and analysis of measurements 
• 
Amendments to the study protocol and consent forms 
• 
Confirmation of the PI’s assessment of adverse events 
• 
Final adjudication of all adverse events, as defined by Table A below 
• 
Participant safety 
• 
Notification of and referral for abnormal findings 
 
3. DSMB Members 
DSMB Chair: 
Gabe Sayer, MD 
University of Chicago 
Medicine 
Department of Medicine 
Section of Cardiology 
Assistant Professor of 
Medicine 
Mardi Gomberg-Maitland, 
MD, MSc 
Inova Health System 
Department of Medicine 
Section of Cardiology 
Professor of Medicine 
Gene Kim, MD  
University of Chicago 
Medicine 
Department of Medicine 
Section of Cardiology 
Assistant Professor of 
Medicine 
 
4. Scheduling, Timing, and Organization of Meetings: Data and Safety Monitoring 
Meetings 
The DSMB will meet (in person or via telephone conference) a minimum of 3 times: 
• 
after treatment of the first 4 subjects (2 in the TH arm and 2 in the control arm) 
• 
after treatment of the first 10 subjects (5 in the TH arm and 5 in the control arm) 
• 
at the conclusion of the study 
 
The DSMB may convene additional meetings if necessary to ensure the ongoing monitoring and 
safety of the subjects treated with TH. 

Version:  26Mar2018 
 
Page 19 of 23 
A quorum of at least two (2) DSMB members needs to be present for a meeting to commence.  
Members may either be present in person or have the option to phone-in if unable to arrive at the 
meeting location. 
 
All DSMB members will receive an agenda prior to the meeting.  In the event that a DSMB 
member is unable to attend a meeting, that member will receive minutes, as well as any 
additional notes, with the opportunity to share any additional thoughts on the distributed 
information. 
 
5. Grading and Attribution Methods for Adverse Events 
Grading Scale 
The DSMB and the study team will utilize the Adverse Event Grading Scale provided in Table 
A.  All adverse events will be graded according to this scale, the PI will prepare data regarding 
adverse events for review by the DSMB prior to meeting, and any additional details will be 
provided to the DSMB by the PI, as necessary. 
 
Table A – Safety Reporting Definitions 
Term 
Definition 
Adverse Event (AE) 
 
Ref: ISO 14155-2011 
 
Ref: MEDDEV 2.7/3 12/2010 
 
Any untoward medical occurrence, unintended disease or injury, 
or any untoward clinical signs (including an abnormal laboratory 
finding) in subjects, users or other persons, whether or not related 
to the investigational medical device. 
This definition includes events related to the procedures involved 
(any procedure in the clinical investigation plan). 
Adverse Device Effect 
(ADE) 
 
Ref: ISO 14155-2011 
 
Ref: MEDDEV 2.7/3 12/2010 
Adverse event related to the use of an investigational medical 
device 
NOTE 1: This definition includes any adverse event resulting 
from insufficient or inadequate instructions for use, the 
deployment, the implantation, the installation, the operation, or 
any malfunction of the investigational medical device. 
NOTE 2: This definition includes any event resulting from use 
error or from intentional misuse of the investigational medical 
device. 
Serious Adverse Event 
(SAE) 
 
Ref: ISO 14155-2011 
 
Ref: MEDDEV 2.7/3 12/2010 
Adverse event that: 
• 
Led to death, 
• 
Led to  serious deterioration in the health of 
the subject, that either resulted in: 
o a life-threatening illness or injury, or 
o a permanent impairment of a body structure or a body 
function, or 

Version:  26Mar2018 
 
Page 20 of 23 
Table A – Safety Reporting Definitions 
Term 
Definition 
o in-patient  or prolonged hospitalization of existing 
hospitalization, or 
o medical or surgical intervention to prevent life-threatening 
illness or injury or permanent impairment to a body structure 
or a body function 
• 
Led to fetal distress, fetal death, or a 
congenital abnormality or birth defect. 
NOTE: Planned hospitalization for a pre-existing condition, or a 
procedure required by the clinical investigational plan, without 
serious deterioration in health, is not considered a serious adverse 
event.  
Serious Adverse Device 
Effect (SADE) 
 
Ref: ISO 14155-2011 
 
Ref: MEDDEV 2.7/3 12/2010 
 
Adverse device effect that has resulted in any of the consequences 
characteristic of a serious adverse event. 
Unanticipated Adverse 
Device Effect (UADE) 
 
Ref: 21 CFR Part 812 
 
Any serious adverse effect on health or safety or any life-
threatening problem or death caused by, or associated with, a 
device, if that effect, problem, or death was not previously 
identified in nature, severity, or degree of incidence in the 
investigational plan or application (including a supplementary 
plan or application), or any other unanticipated serious problem 
associated with a device that relates to the rights, safety, or 
welfare of subjects.   
Device Deficiency 
 
Ref: ISO 14155-2011 
 
Ref: MEDDEV 2.7/3 12/2010 
A device deficiency is any inadequacy of a medical device with 
respect to its identity, quality, durability, reliability, safety or 
performance. 
NOTE: Device deficiencies include malfunctions, misuse or use 
errors, and inadequate labeling. 
Abbreviations: EC=Ethics Committee; IRB=Institutional Review Board 
 
Underlying diseases are not reported as AEs unless there is an increase in severity or frequency 
during the course of the investigation. 
 
Relationship to Study Device(s) and Reporting Requirements 
The Investigator will assess the relationship of the AE to the study device as related or unrelated. 
 

Version:  26Mar2018 
 
Page 21 of 23 
Table B – Criteria for Assessing Relationship of Study Device to Adverse Event 
Classification 
Description 
Unrelated 
The adverse event is determined to be due to a concurrent illness or effect 
of another device/drug and is not related to the investigational product. 
Related 
• The adverse event is determined to be potentially related to the 
investigational product, and an alternative etiology is equally or less 
likely compared to the potential relationship to investigational product, 
or 
• There is a strong relationship to investigational product, or recurs on re-
challenge, and another etiology is unlikely, or 
• There is no other reasonable medical explanation for the event. 
 
Table C – Adverse Event Reporting 
Event Classification 
Event Recording 
Communication to FDA 
Communication to IRB 
Adverse Event 
• 
Event reviewed 
and classified 
by PI 
• 
Event recorded 
in Oncore 
Adverse event 
database 
Detail of all AE’s will be 
given at time of annual 
report. 
Details provided at time 
of annual review, per 
IRB policy. 
Serious Adverse Event 
including Serious 
Adverse Device 
Effects 
• 
Event reviewed 
and classified 
by PI 
• 
Event recorded 
in Oncore 
Adverse event 
database 
Reported via From 3500 
within 48 hours of PI 
knowledge. 
Details provided at time 
of annual review, per 
IRB policy (as these are 
not unanticipated 
events). 
Unanticipated Adverse 
Device Effect / 
Unanticipated Serious 
Adverse Device Effect 
• 
Event reviewed 
and classified 
by PIStudy will 
be halted if 
event presents a 
significant or 
unreasonable 
risk to subjects 
enrolled in the 
study 
• 
Event recorded 
Reported as soon as 
possible, but within 48 
hours of PI knowledge, 
via From 3500. 
UADE reported within 
10 days of PI knowledge 
USADE reported 
directly to IRB 
Chairman upon PI 
knowledge, followed by 
formal reporting to the 
IRB within 48 hours. 
Study will be halted if 
event presents a 

Version:  26Mar2018 
 
Page 22 of 23 
Table C – Adverse Event Reporting 
Event Classification 
Event Recording 
Communication to FDA 
Communication to IRB 
in Oncore 
Adverse event 
database 
significant or 
unreasonable risk to 
subjects enrolled in the 
study 
Device Deficiencies 
(including but not 
limited to failures, 
malfunctions, and 
product 
nonconformities) 
Note:  Any 
Investigational Device 
Deficiency that might 
have led to a serious 
adverse event if a) 
suitable action had not 
been taken or b) 
intervention had not 
been made or c) if 
circumstances had 
been less fortunate is 
considered a 
reportable event. 
• 
Event reviewed 
and classified 
by PI 
• 
Event recorded 
in Oncore 
Adverse event 
database 
Investigational Device 
Deficiency that might 
have led to a serious 
adverse event if a) 
suitable action had not 
been taken or b) 
intervention had not been 
made or c) if 
circumstances had been 
less fortunate is 
considered a reportable 
event and will be 
reported to the FDA 
within 48 hours of PI 
knowledge, via Form 
3500. 
All other device 
deficiencies will be 
reported within 10 days. 
Investigational Device 
Deficiency that might 
have led to a serious 
adverse event if a) 
suitable action had not 
been taken or b) 
intervention had not 
been made or c) if 
circumstances had been 
less fortunate is 
considered a reportable 
event will be reported to 
the IRB within 10 days 
of PI knowledge. 
 
6. Example of Format for Minutes 
 
Data and Safety Monitoring Meeting Minutes 
 
Date:  
 
Title of Protocol/IRB Number:  
 
Principal Investigator/Designee:   
 
Recommendations: 
 
□ Continue the trial without modification 
 
□ Accrual: 
□ Recommend study be closed because of slow accrual 
□ Continue to monitor study, but consider closure because of slow accrual 
 
□ Recommend study is amended/changed: 
□ For patient safety reasons 

Version:  26Mar2018 
 
Page 23 of 23 
□ Rate of adverse events 
□ To extend accrual because of an event rate slower than expected 
 
□ Other: _________________________________________________________ 
 
 
Signature of Principal Investigator: _______________________________________________ 
 
Signature of DSMB 
Chair:_____________________________________________________________ 
 
The DSMB will review adverse event data, other safety data, quality and completeness of study 
data, and enrollment data at each meeting to ensure proper trial conduct.   
 
6. Reports of DSMB Deliberations and Reporting 
Initial summary:  The DSMB Chair is responsible for assuring the accuracy and transmission of 
a brief summary of the DSMB’s discussion and recommendations to study PI 
and team within 7 days of the meeting or call.  The study team will review this 
summary and either approve recommendation(s), or request additional 
information until agreement is reached. 
Formal minutes:  The DSMB Chair is responsible for the accuracy and transmission of the 
formal DSMB minutes for the Study PI within 30 days of the meeting or call.  
These minutes are prepared accordingly to summarize the key points of the 
discussion and debate (with the first priority being safety evaluation), requests 
for additional information, response of the investigators to previous 
recommendations, and the recommendations from the current meeting.