Conditions: Critical Illness
Keywords: Critical care Emergent Etomidate Hemodynamics Intensive care unit Intubation Ketamine-Propofol admixture
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 160
Healthy volunteers: no

Brief summary:
The hypothesis of this study is that a Ketamine / Propofol mixture will produce more stable hemodynamics as compared to Etomidate during emergent intubations in the intensive care unit. Patients that require a breathing tube to be placed in the ICU will be randomized to receIve either a Ketamine / Propofol mixture or Etomidate for sedation in order to place the breathing tube.

Detailed description:
Endotracheal intubation is a procedure that may cause significant hemodynamic perturbations and can severely impact the outcome of the critically ill. To ensure a safe outcome during this particular procedure, there are many factors that the clinician is faced with. One decision that confronts the critical care physician involves the correct combination of medications with which to facilitate such a safe outcome. Given the reported hemodynamic stability, etomidate is a medication that is chosen by many providers in this particular situation. However, its association with a possible increase in mortality makes it less than ideal for a number of critical care physicians. In recent years, an admixture of propofol and ketamine has been studied that demonstrates hemodynamic stability based on the balancing of the hemodynamic effects of these two individual agents alone. This novel medication combination, sometimes referred to as "ketofol", may offer a valuable alternative to the critical care physician. Therefore, a randomized parallel-group clinical trial of adult critically ill patients admitted to a medical and/or surgical intensive care unit at Mayo Clinic Rochester who meet the criteria designated below for which urgent and/or emergent intubation is needed will receive one of two interventions based on stratified randomization. The "active" intervention arm will receive ketamine/propofol (ketofol) to facilitate endotracheal intubation. The comparison arm will receive etomidate. The primary outcome will focus on hemodynamic data recorded during the first 5 minutes post-administration with secondary outcomes looking at hemodynamic data at 10 and 15 minutes and addressing intensive care unit length of stay, mortality, adrenal function, and vasoactive medication use, among others.

Arms:
arm 1: weight based dose of 0.15mg/kg arm 2: weight based dose of 0.5mg/kg of ketamine and 0.5mg/kg of propofol

Interventions: intervention 1: Ketamine / Propofol Admixture intervention 2: Etomidate
Intervention descriptions: intervention 1: None intervention 2: None

Protocol document:
Prot_SAP_000.pdf: 
1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Ketamine/Propofol Admixture “Ketofol” at Induction in the Critically Ill Against 
Etomidate: KEEP PACE Trial 
 
NCT02105415 
 
PROTOCOL VERSION 12 
30 AUGUST 2018 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


2 
 
 Ketamine/Propofol Admixture “Ketofol” at Induction in the Critically Ill Against 
Etomidate: KEEP PACE Trial 
 
Principal Investigator: 
 
NATHAN J. SMISCHNEY, MD 
 
STATISTICIAN: 
 
DARRELL SCHROEDER 
 
 
 
Co-Investigators: 
 
Brian Pickering M.B., B.Ch, James Onigkeit M.D., Wayne Nicholson M.D., Pharm. D, Vivek 
Iyer M.D. Alice Gallo De Moraes M.D., Philippe Bauer M.D., Ph.D., Mark Keegan M.D., 
Richard Oeckler M.D., Ph.D.,  
 
 
 
 
 
 
PROTOCOL VERSION 12 
30 AUGUST 2018 
 
 
 


3 
 
ABSTRACT 
 
 
Endotracheal intubation is a procedure that may cause significant hemodynamic 
perturbations and can severely impact the outcome of the critically ill.  To ensure a safe 
outcome during this particular procedure, there are many factors that the clinician is faced with.  
One decision that confronts the critical care physician involves the correct combination of 
medications with which to facilitate such a safe outcome.  Given the reported hemodynamic 
stability, etomidate is a medication that is chosen by many providers in this particular situation.  
However, its association with a possible increase in mortality makes it less than ideal for a 
number of critical care physicians.  In recent years, an admixture of propofol and ketamine has 
been studied that demonstrates hemodynamic stability based on the balancing of the 
hemodynamic effects of these two individual agents alone.  This novel medication combination, 
sometimes referred to as “ketofol”, may offer a valuable alternative to the critical care physician.  
Therefore, a randomized parallel-group clinical trial of adult critically ill patients admitted to  St. 
Marys medical ICU (MB-6B/G) or surgical ICU (MB-7D/E) or Methodist medical/surgical ICU (10-
3/10-4) at Mayo Clinic Rochester who meet the criteria designated below for which urgent and/or 
emergent intubation is needed will receive one of two interventions based on stratified 
randomization.  The “active” intervention arm will receive ketamine/propofol (ketofol) to facilitate 
endotracheal intubation.  The comparison arm will receive etomidate.  The primary outcome will 
focus on hemodynamic data recorded during the first 15 minutes post-administration with 
secondary outcomes addressing intensive care unit length of stay, 28 day in-hosptial mortality, 
and vasoactive medication use, among others.   
 
 
 


4 
 
Specific Aims 
 
Critically ill patients often require urgent and/or emergent intubations for diagnostic 
and/or therapeutic interventions.  Preparation and administration of sedation for intubations are 
of vital importance, especially in this patient population where many patients have multiple co-
morbidities.  Etomidate is a medication that was developed to afford hemodynamic stability 
during this process.  With the recent drug shortages across the country, alternatives to this 
medication are necessary and drug combinations may provide an alternative route.1-2  
Furthermore, etomidate's association with adrenal suppression and possibly increased mortality 
among critically ill patients makes it less than ideal for a number of critical care physicians.3-9  
According to a systematic review in 2011, etomidate anesthesia in the intensive care unit 
resulted in an increased relative risk for both adrenal insufficiency (1.64) and mortality (1.19).5  
A second study reported in 2012 on over 700 patients demonstrated and increase in relative risk 
of death (1.20) for patients who received etomidate as compared to an alternative agent.3  
There are other medications that are available but each with its own set of concerns and none 
are reported to offer stable hemodynamics during this process such as etomidate.10-11  In recent 
years, an admixture of propofol and ketamine has been studied that demonstrates 
hemodynamic stability based on the balancing of the hemodynamic effects of these two 
individual agents alone.10,12-13  Most of these studies have taken place in the emergency 
department with focus on continuous infusions and compared with multiple medications.14-
18  The literature is absent with regards to a comparison of this combination against one that is 
purported to afford hemodynamic stability such as etomidate.10,19  
The overall goal of this research proposal is to assess the hemodynamics of a 
particular drug combination (ketamine/propofol) that may be used in critically ill patients in 
urgent and/or emergent need of endotracheal intubation with reduced effects on mortality as 
compared to etomidate.  The objective is to obtain preliminary data on the hemodynamics of 
this combination within the critically ill population.  The central hypothesis is that this 
combination will produce smaller decreases in mean arterial pressure as compared to etomidate 
within the first 15 minutes post-administration.  We are well prepared to undertake the proposed 
research as we have an investigative team with experience in this drug combination.   
 
Primary Specific Aim: To determine if the decrease in mean arterial pressure for the 
ketamine/propofol group at a 1:1 dose ratio is lower as compared to the etomidate group within 
the first 15 minutes post-administration in patients in need of urgent and/or emergent 
endotracheal intubation, as defined by any intubation within the intensive care unit excluding 
intubations for elective procedural events and codes. 
Hypothesis: The decrease in mean arterial pressure for the ketamine/propofol arm will be 
reduced as compared to the etomidate arm during the first 15 minutes post-administration within 
the population of critically ill patients needing urgent and/or emergent endotracheal intubation. 
 
Secondary Specific Aim 1: To determine whether this admixture is associated with 
decreased in-hospital/28-day mortality as compared to etomidate in the critically ill. 
Hypothesis 1: The in-hospital/28 day mortality among patients in the ketamine/propofol 
combination will be decreased as compared to the in hospital/28-day mortality in the etomidate 
arm. 
 
Secondary Specific Aim 2: To determine if this admixture is associated with decreased 
use of vasoactive medication administration (e.g., dopamine, phenylephrine, norepinephrine, 
epinephrine or vasopressin) from time 0 to 24 hours post-administration as compared to 
etomidate in the critically ill. 
Hypothesis 2: The use of vasoactive medications to restore the blood pressure post-
administration will be reduced in the ketamine/propofol combination as compared to the 
etomidate group.  
 
 


5 
 
 
To evaluate the above specific aims, we will randomize 160 critically ill patients in need 
of urgent and/or emergent intubation to one of two arms through a comparison trial.  This study 
will provide insight into a novel drug combination that may be used by some health care 
professionals when facing drug shortages and in need of an equivalent alternative for the 
hemodynamically unstable patient without the cost of increased mortality. 


6 
 
RESEARCH STRATEGY 
A. Significance 
A.1. Ketamine and Propofol 
 
 
Propofol is a non-opioid, non-barbiturate, sedative-hypnotic agent with rapid onset and 
short duration of action.  It reliably produces sedation, amnesia, and general anesthesia but 
because of the associated hemodynamic instability when used alone, its use in the critical care 
setting is limited.  Ketamine is a phencyclidine derivative with fairly rapid onset and short 
duration of action.  It causes little or no respiratory and cardiovascular depression and has 
analgesic properties.  It may, however, cause hemodynamic instability and alterations if given 
alone with propensity of effects that are opposite that of propofol, especially relevant in the 
cardiac and neurological population.11,20 
A.2. Drug Shortages 
 
In recent years, there has been interest in finding alternative medications with which to 
sedate patients for particular procedures.  This has risen in part by the continued drug 
shortages experienced throughout the country.1-2  Due to these drug shortages, various 
medications have been combined in order to reduce waste and conserve already depleted drug 
shortages in the healthcare setting.  However, combining medications can be hazardous with 
issues relating to compatibility and potentiation of individual side effects of the parent drugs. 
A.3. Ketamine/Propofol Admixture Compatibility 
 
One such combination that has gained much interest as of late due to the balancing of 
the individual effects of either drug alone involves the combination of ketamine and 
propofol.  This medication combination has been demonstrated to be safe in specific dose 
combinations.10,12 Furthermore, this particular combination has been tested to assess whether 
there are any precipitation of components or ill effects from combining these two medications.  
These studies have shown stability of ketamine in the presence of propofol.21-22   
 
A.4. Ketamine/Propofol Admixture 
 
 
Much of the work regarding these two agents derives from studies focusing on 
procedural sedation in the emergency department as a continuous infusion.12-15  These studies 
have identified the benefits of both medications while diminishing the side effects from both 
parent compounds when in combination.  A few studies have shown stability of systemic 
hemodynamics.10,12,15-16  Moreover, a recent study demonstrated evidence of ketofol’s stability 
on cerebral hemodynamics as well as on systemic hemodynamic measurements.23  While some 
studies have demonstrated direct comparisons of ketofol to other agents during induction, this 
has been limited.10,19  Therefore, relatively little data arrive at outcomes targeting hemodynamics 
and there are no studies to the authors’ knowledge regarding this admixture with comparison to 
etomidate regarding hemodynamics, or mortality. 10 This is likely due to no standardized 
admixture of ketofol.  A study in 1995 did address a dose response relationship with this 
combination on healthy volunteers with no comparison against another agent.  However, this 
was a homogenous group of patients that involved Asian women.24   
 
 
A.6. Rational for Approach 
 
 
If the proposed aims are achieved, this research will provide clinicians with evidence for 
an alternative medication to use when faced with the unstable critically ill patient in need of 
urgent and/or emergent intubations.  Through accomplishment of the aims, clinicians will not 
feel necessary to use etomidate in the critically ill patient who may become unstable.  According 
to studies previously mentioned, this may result in improved mortality for critically ill patients.  
Moreover, this combination would, in theory, provide pain control and potentially reduce the 
amount of sedatives necessary to keep the patient safe during their intensive care unit stay.  
With the possible reduction in sedative/analgesic medications, this may translate into improved 
patient related outcomes and total reduced cost for the institution.  A follow-up analysis will need 


7 
 
to be performed to assess possible institution cost savings.  This study will provide valuable 
insight into dose response relationships involving this particular medication and will be among 
the first to compare against an agent such as etomidate in the critical care environment.  Lastly, 
this admixture will provide an alternative to hospitals who are in midst of drug shortages.  
Through the use of this medication combination, supplies may be better preserved than with 
each medication used separately in larger doses.    
 
B. INNOVATION 
 
 
The proposed research adds considerably to the field of critical care medicine.  The use 
of a ketamine/propofol admixture as an alternative anesthetic induction agent to provide care to 
the critically ill unstable patient in need of urgent and/or emergent endotracheal intubation is a 
novel concept.  The use of such a drug combination has not been rigorously tested in this 
particular setting.  Data are available on specific dose ratios of this admixture against various 
alternative agents.13,17,19 However, there is no data to the authors’ knowledge that compares this 
drug combination against etomidate. 
 
The weight-based dosing used in this study and in this particular setting has not been 
used in previous studies.  A study comparing various dose ratios based on body weight of this 
admixture was performed in Asian women in the mid 90’s.  However, this study did not use the 
prescribed weight based doses as in this study.24  Therefore, the prescribed doses as used in 
this study protocol along with its use in the critical care environment is novel.   
 
This drug combination is appealing for many reasons.  One important reason relates to 
the question of an ideal anesthetic agent.  An ideal anesthetic agent would include properties of 
sedation, amnesia and analgesia without cardio-respiratory effects.20  Of the approved listed 
medications for induction of anesthesia, ketamine is the only agent reported to provide 
significant pain relief.11,20  The combination of ketamine with propofol yields an admixture that is 
very close to an ideal anesthetic agent without further ill effects on the patient as compared to 
other agents with which to sedate patients during endotracheal intubation.  Therefore, although 
this drug combination has been used for many years, it has only recently been realized that the 
potential benefits of this combination may have a strong positive impact on patient outcomes in 
any given setting.    
 
 
C. APPROACH 
 
C.1. Preliminary Studies 
 
The principal investigator recently completed a comparison of a 1:2 ketamine/propofol 
combination against propofol only at induction in American Society of Anesthesiologists 1-2 
patients and demonstrated improved hemodynamic indices with ketofol as compared to propofol 
only.  In this paper, the authors’ noted that a fixed dose admixture of ketamine and propofol 
against etomidate in the critically ill is warranted.10 Therefore, this is a follow-up study to the 
above mentioned reference. 
 
Limitations of Study: The study had several significant limitations. First, our study was in 
healthy patients and therefore not clinically relevant.  Second, the comparison agent was one 
that is known to cause hemodynamic instability at induction and therefore, the results could 
have been anticipated.  Finally, our primary outcome was a reduction in systolic blood pressure 
specified by a certain percentage and not on absolute mean arterial pressure. 
C.2. Definitions 
1) Ketofol: ketamine and propofol in combination with specified dose ratio; 2) Urgent and/or 
emergent intubation: Any intubation in the intensive care unit excluding elective procedural 
intubations; 3) True emergent situation: any situation that is defined as a code. 4) 28 day in-
hospital mortality:  Mortality that occurs before hospital discharge or hospital day 28, whichever 


8 
 
comes first. 5) Post-menopausal:  12 consecutive months or more since last reported period or 
documented post-menopausal status in EMR.   
C.3. Current Proposal Overview 
 
Stratified Randomized parallel-group clinical trial of adult critically ill patients admitted to 
St. Marys  medical ICU (MB-6B/G) or surgical ICU (MB-7D/E), or Methodist medical/surgical ICU 
(10-3/10-4) at Mayo Clinic Rochester who meet the criteria designated below for which urgent 
and/or emergent intubation was needed and who received one of two interventions based on 
stratified randomization.  The “active” intervention arm will receive ketamine/propofol (ketofol) to 
facilitate endotracheal intubation.  The comparison arm will receive etomidate.  Given that critically 
ill patients may require reduced doses of medications compared to patients presenting electively 
to surgery, induction doses in both groups will be reduced.28  The two groups will receive two 
doses with the reduced dosing stated above and will use the first dose at induction.  The second 
dose will be available as a rescue should the provider need further sedation.  The decision for the 
rescue dose will be made by the provider at the time of induction for intubation based on the 
clinical status of the patient.  Demographic and outcome variables will be collected prospectively 
and analyzed after all patients have completed the study procedures.  
C.4. Participants 
 
Subjects will be eligible to participate if they: 1) are at least 18 years of age; 2) are surgical 
and medical intensive care unit patients requiring endotracheal intubation and treating 
consultant agrees to study plan and will follow drug randomization.  Individuals will be excluded 
from study participation if they: 1) have intracranial pathology such as acute head bleed or 
intracranial mass of significant size causing elevated ICP or acquired head injury documented 
during current hospitalization; 2) have chronic opiate-dependence as defined by those patients 
on methadone, buprenorphine, buprenorphine-naloxone or naltrexone as an outpatient;  3) have 
a severe psychiatric illness defined as currently being treated for bipolar and/or schizophrenia 
disorder; 4) have egg allergies; 5) have any contraindications to fentanyl, midazolam, ketamine, 
propofol or etomidate; 6) have an intubation performed during true emergent situations such as 
codes where standard practice is not to use induction drugs; 7) do not have a documented 
weight and/or are greater than 140kg or less than 30kg;8) have had prior participation in the 
current study; 9) are on continuous infusions of propofol, midazolam, lorazepam, fentanyl or 
dexmedetomidine in the previous 24 hours; 10) undergo a procedural intubation; 11) are of 
child-bearing age, defined as 18-50years, and do not have a documented pregnancy test at our 
institution confirming that they are not pregnant or who do not have a confirmed surgical 
procedure or medical history preventing pregnancy, (i.e., tubal ligation, hysterectomy, post-
menopausal).  The timing of the pregnancy test at which the investigative team will consider a 
subject to be non-pregnant is a documented negative test during current hospitalization or upon 
direct transfer from outside institution during current illness.  If the investigative team does not 
know at the time of emergency intubation that a female of 18-50 years has a documented 
negative pregnancy test, AND they do not have a confirmed surgical procedure or medical 
history preventing pregnancy, she we will not be allowed to participate in the clinical trial.  No 
time will be spent looking for this information in fear of delaying a needed intervention and 
therefore, the female will be excluded.  
 
C.5. Rational for Inclusion/Exclusions 
 
 
After a thorough review of the literature, we have identified specific conditions in which it 
is recommended to avoid the use of the medications under study in certain situations such as 
acute head injury or severe psychiatric illness. 
 
C.6. Randomization  
 


9 
 
 
A computerized randomization schedule will be generated by a statistician not involved 
in determination of patient eligibility, drug administration, or outcome assessment. 
Randomization will be performed using 2 stratification factors (unit: 6B/G,7D/E, 10-3/4; shock 
state: Mean Arterial Pressure (MAP) >/= 65 or MAP <65).  Within each strata, the randomization 
will be performed using blocks of size N=4 to ensure that after every 4th patient is randomized 
within a given strata there are an equal number of patients assigned to each treatment group.  
Randomization will be accomplished by using opaque envelopes.  The randomization envelopes 
will contain a card with the study drug imprinted onto it to which the patient was randomized.  In 
addition, the envelopes will contain a role checklist for the care team, a study subject 
identification number, and a dosing chart for correct drug administration.  The bedside nurse 
along with the core study staff will obtain the correct randomization envelope based on the 
patient’s current MAP vital sign.  The core study staff will evaluate for exclusions prior to 
opening the envelope.  Additionally, the role checklist and dosing chart will be provided to the 
respective units. 
 
C.7. Medication Preparation 
 
 
The medications will be provided through the drug dispensing machine on the respective 
units, the Pyxis machine.  Propofol (one 20ml vial) and ketamine (one 20ml vial) are to be 
aseptically drawn from a standard concentration (10mg/ml) into a 60ml syringe by the assigned 
bedside nurse.  Within the concealed randomization envelope, the nurse will find a dosing chart 
in milliliters to be administered to the patient based on the patient’s weight in kilograms.  The 
syringes used to deliver the study medications will contain the appropriate Investigational New 
Drug (IND) labeling and study subject identification.  Etomidate (two 10ml vials) is to be 
aseptically drawn from a standard concentration (2mg/ml) into a 35ml syringe.  The bedside 
nurse will find a similar dosing chart for etomidate.  The 35ml syringe used to deliver the study 
medication will contain the appropriate IND labeling and study subject identification 
number.  The etomidate dose will be weight based such that it represents 0.15mg/kg of 
etomidate.  The initial 0.15mg/kg will be considered the induction dose and a second dose of 
0.15mg/kg will serve as a rescue dose if deemed clinically necessary.  Should the clinical care 
team need more than 0.3mg/kg of etomidate, they may use the remainder of the study syringe 
as dedicated by the critical care clinician.  We do not anticipate this will happen often given the 
initial prescribed doses.  However, they may not cross over to use ketamine or propofol after 
etomidate has been administered.  The ketofol dose will also be weight based such that it 
represents 0.5mg/kg of ketamine and 0.5mg/kg of propofol.  The initial 1mg/kg (0.5mg/kg of 
ketamine and propofol each) will be considered the induction dose and a second dose of 
1mg/kg will serve as a rescue dose if deemed clinically necessary.  Again, should the clinical 
care team need more than 1mg/kg of ketamine and propofol each, they may use the remainder 
of the study syringe as dedicated by the critical care clinician.  Furthermore, the care team may 
use additional ketamine or propofol only at their discretion.  We do not anticipate this will 
happen often given the initial prescribed doses.  However, they may not cross over to use 
etomidate after ketofol has been administered.  This dose is based on the dose response 
curves from Hui et.al.24  In this study, a 0.5mg/kg dose of ketamine and propofol produced 
anesthesia in roughly 50% of healthy patients who did not receive other sedatives and were not 
critically ill.  We know that the critically ill are provided with additional sedatives for various 
reasons and that certain medications (e.g., propofol) have increased potency in shock patients 
(see reference 28).  If the rescue dose is given in this study, the patient will have received a 
standard induction dose of ketamine.  This is a standard induction dose for an elective surgical 
patient and not a critically ill patient.  Furthermore, the patient will also have been given 
propofol.  The decision to use the rescue dose will be made by the provider at the time of 
induction for intubation.  This decision will be dependent on the clinical status of the patient.  
There are three main conditions in which the critical care provider may need additional 
anesthetic agent during endotracheal intubation.  These include but are not limited to: 1) patient 
movement/purposeful response to the intervention; 2) difficult intubation; 3) or inadvertent 
under-dosing.  Therefore, the only decision made by the provider will center on whether they 
request the rescue dose and/or additional doses.  The bedside nurse will be provided with a 
checklist of tasks to be performed during the urgent and/or emergent intubation.  The checklist 


10 
 
will be contained within the concealed randomization envelope.  The remaining study 
medications will be disposed through Pyxis per usual practice. 
 
C.8. Study Protocol 
 
 
Consent: Given the uncertainty of urgent and/or emergent intubations along with the 
time necessary for preparation of the study drugs and the ethical issue of consenting a potential 
unstable patient to a treatment, we will provide community consultation consisting of meetings 
with community members.  Community consultation plans will involve 4-10 focus group 
sessions, advertisements on the Mayo Clinic external website and informational flyers 
distributed within the community.  Through these plans, the community will be notified of the 
study and the understanding that all patients admitted to the above named critical care units at 
Saint Marys and Methodist Hospital who meet the inclusion/exclusion criteria will be included in 
this study (please refer to consent process development plan document).  Study coordinators 
would then follow up with the patient and/or their legally authorized representative to indicate 
their involvement in the study.  If time allows, consent will be obtained prospectively.  However, 
this will likely not happen for the majority of patients given the issues outlined above.  The 
investigative team will make every effort to prospectively contact the legally authorized 
representative prior to enrolling the patient in the current study.  If the legally authorized 
representative or family member is available at the time the subject is clinically in need of a 
breathing tube, the study coordinators will attempt to contact these members while the bedside 
nurse is preparing the medications.  The study coordinators will explain that a research study 
involving medications used and approved by the FDA for assistance with placement of a 
breathing tube is currently underway.  They will explain that two individual medications already 
in use for this purpose may have beneficial effects when combined together and that the 
investigative team is simply trying to collect data on this unique combination for which no 
approval has been granted by the FDA as of yet.  The legally authorized representative will 
have the opportunity to provide consent or decline participation of the subject at this time.  If 
they declined participation of subject, the study coordinators will notify the bedside nurse 
immediately and the study will cease.  If the legally authorized representative is not available at 
the time of study enrollment, the team will attempt to contact additional family members to 
provide an opportunity to consent to the subject’s participation.  However, as stated previously, 
this will likely not be possible in truly urgent and/or emergent situations.  If the subject has been 
enrolled in the current study without prior contact from the patient, legally authorized 
representative, or additional family members, the investigative team will notify the legally 
authorized representative regarding subject’s enrollment and an opportunity to withdraw the 
subject from the study if they deem it necessary.  Due to the nature of the present study and the 
environment that it will be conducted in, we believe that the only feasible route in performing a 
study such as this is under the emergent use research guidelines as previously published by the 
Food and Drug Administration (www.fda.gov/RegulatoryInformation/Guidances).  Below are the 
conditions that satisfy emergent use research in the document and our responses to each. 
 
1. The human subjects are in a life-threatening situation that necessitates urgent intervention: 
a. Unlike intubations performed outside the intensive care unit, e.g. the operating room, 
placement of an endotracheal tube is done under urgent/emergent conditions and 
rarely electively.  Those intubations that are performed in the intensive care unit 
under elective conditions, e.g. for bronchoscopy/endoscopy, will not be included in 
the current study.  Elective intubations in the intensive care unit are done within the 
context of a stable patient and therefore any anesthetic induction agent may be used 
safely with no need for the above study drug.  The true benefit of the study drug 
involves the critically ill patient who is hemodynamically unstable but is in need of an 
endotracheal tube. 
 
2. Available treatments are unproven or unsatisfactory: 


11 
 
a. There are several alternative anesthetic agents that are available that may be used 
to facilitate placement of an endotracheal tube.  However, these alternatives are 
either unproven or unsatisfactory for the condition at hand.   
1) Etomidate has proven efficacy in providing stable hemodynamics.  As 
referenced above, however, this comes with significant drawbacks with the 
most significant being known adrenal suppression and a potential increase 
in mortality.   
2) Propofol alone is unsatisfactory as the administration of this anesthetic 
agent may lead to dangerously low mean arterial pressures secondary to 
vasodilation and bradycardia, especially within the critically ill patient.  This 
agent is acceptable for those patients who have placement of an 
endotracheal tube for elective purposes, as these patients are not 
hemodynamically unstable.   
3) Ketamine as a sole sedative has some concerns in the intensive care unit 
for routine use.  One study directly comparing ketamine to etomidate in 
critically ill patients did show some benefits of ketamine.  However, the 
ketamine administration was done in a non-critical care setting prior to ICU 
admission.  In addition, this study did involve wavier of consent due to the 
emergent nature of the intervention and the non-feasible alternative of 
obtaining informed consent27.  Ketamine use as a sole agent also has some 
unsatisfactory cardiovascular adverse effects.  Ketamine administration is 
commonly associated with elevations in blood pressure and heart rate.  
Arrhythmias may also occur.  These cardiovascular effects of ketamine are 
dependent on concentration and secondary to central nervous system 
stimulation and inhibition of norepinephrine reuptake11,20,29-31.  These 
elevations in blood pressure and heart rate can have a detrimental effect on 
patients with underlying heart disease32.  Additionally, ketamine possess 
properties that may make intubation attempts difficult due to the increased 
muscular tone at certain dosage levels20.  Evidence suggests that difficult 
intubations lead to increased mortality in critically ill patients from repeated 
airway manipulations33-34.  Finally, an increased risk of emergence delirium 
with ketamine is clearly demonstrated in the product information and 
throughout the literature. Since the above adverse effects are dose related, 
a reduction in dose by using ketamine in a combination with propofol may 
improve these adverse outcomes.  Therefore, the use of smaller rather than 
larger doses is likely to be of benefit as possibly evident in recent case 
reports of septic shock patients suffering cardiac arrest after receiving 
2mg/kg of ketamine35. 
4) Benzodiazepines are unsatisfactory as there is evidence demonstrating 
increased risk of both delirium and mortality with the use of 
benodiazipines36-37.   
5) Barbiturates are unsatisfactory as these agents may also lead to 
unacceptable decreases in mean arterial pressure, secondary to a 
decreased systemic vascular resistance and decreased cardiac output. 
6) Thus, the combination of ketamine and propofol can offset the 
hemodynamic extremes of either drug with the combination resulting in 
potentially more stable hemodynamics and a safer alternative than either 
drug alone. 
 
3. Rationale for therapeutic window: 
a. The interval period under study was chosen due the alpha half-life or redistribution 
half-life from the central compartment of the three drugs.  The redistribution half-life 
of all three drugs is approximately 2-16 minutes, thus the reason for time frame 


12 
 
chosen in the current study.  The alpha half-life is clinically responsible for the 
anesthetic effect seen in medical practice20. 
 
4. Collection of valid scientific evidence is necessary to determine the safety and effectiveness 
of the intervention in this population: 
a. Insufficient evidence exists regarding the safety and efficacy of this drug admixture 
within the critically ill.  As referenced above, a large amount of the data regarding 
ketamine/propofol admixture involves patients in the operating room or the 
emergency department.  Although this drug combination (ketofol) is currently being 
used clinically in several clinical care settings (emergency department, operating 
room, and ICU), data is not available regarding the use of this admixture in the 
critically ill population in an ICU setting. 
 
5. Obtaining informed consent is not feasible because the subjects are not able to give their 
informed consent as a result of their medical condition: 
a. Patients in the intensive care unit requiring placement of an endotracheal tube are 
not in a position to comprehend or sign a document pertaining to clinical research.  
These patients may be in respiratory failure and/or are unstable and to consent this 
patient population would be un-ethical.  Several factors play into the cognitive 
disability of critically ill patients.  For example, delirium is highly prevalent among 
critically ill patients ranging anywhere from 20% to as high as 80%38.  Several 
studies point to the inability of critically ill patients who are unable to consent.  For 
example, a study involving over 400 patients in the intensive care unit utilizing 
pulmonary artery catheters demonstrated that only 2.6% of patients were able to 
consent to this intervention39.  In fact, some studies are not feasible without consent 
wavier due to the critical condition of the patient27,40.  Thus, the process of 
consenting this patient population is questionable. 
 
6. The intervention must be administered before the consent can be obtained from the 
subject’s legally authorized representative: 
a. Emergent endotracheal intubations within the intensive care unit happen quickly and 
oftentimes, a legally appointed representative is not available for several reasons.  In 
an observational trial for traumatic brain injury in 2007, investigators demonstrated 
that the number of patients with relatives available for research authorization was 
only 3% and 25% at 1 and 3 hours post-injury41.  Some critically ill patients lack 
surrogates who might provide informed consent.  When available, surrogates may be 
overwhelmed and desperate, and they may confuse treatment with research thus 
resulting in inconsistencies between their interests/values and that of the patients.  
This was illustrated by a recent article in Critical Care Medicine where both patients 
and surrogate decision makers were presented with hypothetical research scenarios 
of increasing complexity.  The authors noted significant discrepancies between the 
patients and their surrogate decision makers as the risk of the study increased42.  
Federal guidelines are based on a model of patients providing consent, and few state 
laws define the role of surrogates. 
 
7. There is no reasonable way to identify prospectively individuals likely to become eligible for 
participation: 
a. There are no objective measures that are 100% sensitive and specific in anticipating 
who will require mechanical ventilation in the intensive care unit.  There are several 
physiologic variables, e.g. RR>35, Sa02<90%, PaC02>60 that, if present, may result 
in the patient requiring intubation.  However, consenting patients based on these 
variables is neither sensitive nor specific enough to be feasible within the context of 
the current study.  Anticipating who will receive an intervention and who will end-up 
in extremis in the intensive care unit is equivalent to a coin toss.  To prospectively 


13 
 
consent every patient that is admitted to an intensive care unit can potentially result 
in the use of considerable resources and costs, particularly for large studies.  This is 
clearly not feasible.  There are no indicators with 100% sensitivity and 100% 
specificity to establish who will require an intervention and who will not or who will 
become unstable and who will not.  The authors feels that unless the patient can be 
consented prior to the event in a time period deemed feasible and for which the 
event rate is high, wavier of informed consent is likely the only option for study 
completion.  For example, in a study performed at Mayo Clinic involving silver coated 
endotracheal tubes, even for non-urgent intubations that could be anticipated, 266 
patients were consented but only 180 actually ended up intubated.  This means that 
over 30% of the patients identified as likely to be intubated were never intubated in 
actuality [unpublished data]. 
b. Additionally, analyzing our own database reveals that blanket consent is not 
feasible.  The ICU’s that we intend to use for this study had 3,531 unique admissions 
with only 250 unique intubations in 2012.  This is only a 7% intubation rate 
[unpublished data]. 
 
8. Participation in the research holds out the prospect of direct benefit to the subjects: 
a. Critically ill patients requiring emergent intubations are in a life-threatening situation 
and may benefit from the drug admixture regarding maintenance of mean arterial 
pressure.  As referenced above, clinical trials performed in several settings 
demonstrate the potential benefits that this drug admixture may have on 
hemodynamics.  These same studies also address the safety of this admixture both 
from a pharmacokinetic viewpoint and from a patient safety standpoint.  The 
morbidity endpoint of hemodynamic instability, e.g. post-intubation hypotension was 
chosen rather than the mortality endpoint as critically ill patients who develop post-
intubation hypotension of any duration have an associated increased mortality and 
length of stay.  This was demonstrated recently by a retrospective study addressing 
the incidence of post-intubation hypotension and its possible association with in-
hospital mortality.  The authors defined post-intubation hypotension as a systolic 
blood pressure less than 90mmHg occurring within 60 minutes of emergency 
intubation.  Post-intubation hypotension occurred in over 20% of the 465 patients 
who underwent emergent intubations and was associated with significantly higher in-
hospital mortality and longer intensive care length of stay43-44.  The association 
between post-intubation hypotension and mortality has been confirmed by other 
groups upon analysis of respective databases45.  The incidence of post-intubation 
hypotension varies widely and in certain patient populations (sepsis), it is noted to be 
as high as 60%46.  A recent study assessing the incidence of post-intubation 
hemodynamic instability defined as systolic blood pressure less than 90mmHg, a 
decrease in systolic blood pressure of greater or equal to 20%, a decrease in mean 
arterial pressure to less than or equal to 65mmHg, or the initiation of any 
vasopressor within the first 30 minutes following intubation found an incidence of 
44%.  These authors demonstrated an increased mortality and hospital length of stay 
in those patients who developed post-intubation hemodynamic instability47. 
 
9. The clinical investigation could not practically be carried out without the wavier: 
a. It is neither feasible nor practical to obtain consent from all critical care patients 
admitted to the respective intensive care units at Mayo Clinic due to the infrequent 
nature of the intervention, e.g. endotracheal intubation.  Only a small fraction of 
patients admitted to the critical care units at Mayo Clinic will become ill enough to 
receive the above intervention and therefore enrollment would take too long to 
conduct the study in a reasonable amount of time.  Please see above regarding 
unpublished data.  
 


14 
 
 
Intubation Period: Patients will receive standard intensive care unit monitoring consisting 
of electrocardiogram analysis, pulse oximetry and a noninvasive blood pressure cuff.  The 
presence of invasive monitors such as an arterial line will be allowed.  Hemodynamic 
measurements will be based off the noninvasive devices and/or invasive arterial line 
measurements if the noninvasive measurements are not available.  Once the decision to 
intubate the patient is made by the clinical team, both the unit Registered Respiratory Therapist 
(RRT) and the assigned bedside nurse will be informed as per usual practice.  The unit RRT will 
notify the lead RRT and core study staff to immediately be present at the patient’s bedside.  The 
lead RRT or core study staff  will serve as the time/record keeper and will collect the necessary 
information prospectively.  The core study staff will review eligibility and attempt to obtain 
consent, during business hours.  The unit RRT will reset the time intervals on the electronic 
medical record within the patient’s ICU room to record every one minute until 15 minutes after 
successful intubation and then switch to 5 minute intervals for the remaining 45 minutes post 
intubation for a total duration of 60 minutes post-intubation.  They will then assist with the 
intubation per usual practice.  Hemodynamics closest to study drug administration will be 
recorded  prior to induction as a baseline.  To an extent, the anesthetic is to be controlled.  At 
induction, the trial drug will be administered over 60 seconds along with fentanyl at 
50mcg.  Nursing will document the amount of drug administered in the electronic medication 
record.  The dose charted will be verified with the amount recorded by the lead RRT or core 
study staff for accurate study drug reconciliation. Neuromuscular blockade as deemed 
necessary by the critical care provider will be allowed.  Midazolam as deemed necessary by the 
critical care provider will be allowed.  Intubation times will be recorded by the lead RRT or core 
study staff.  The time from study drug administration to intubation will not be standardized.  After 
intubation, sedation is then to be maintained with the choice decided by the critical care 
provider.  Additional narcotics will be allowed as necessary throughout the study period.  If 
necessary, anti-cholinergics, vasoactive and steroid medications are to be allowed as 
well.  Hemodynamics (mean arterial pressure, systolic blood pressure, diastolic blood pressure 
and heart rate) will be recorded every minute until 15 minutes after successful intubation and 
then every 5 minutes up to 60 minutes post-intubation.  Time zero would be defined as time of 
study drug administration.  Emergence from anesthesia will not be controlled by the study 
protocol. 
 
C.9. Study Measures/Assessments 
 
 
Hemodynamic Assessment: Noninvasive blood pressure measurements and/or arterial 
line measurements prior to study drug administration will be obtained and up to one hour after 
successful intubation.  For the first 15 minutes post-administration of study drug measurements 
will be taken every one minute.  Following this interval, the measurements will then be switched 
to intervals of 5 minutes until the time period of one hour has elapsed since successful 
intubation.  Data will be obtained from the chart from the period of 1 hour prior to intubation and 
1 hour after intubation. 
 
Clinical Assessment: General characteristics of the patient including demographics, 
hemodynamics (average of values 60 minutes prior to intubation), cardiovascular medications, 
and APACHE 3 score for the time period of 24 hours prior to study drug administration will be 
obtained.  Final diagnosis is to be recorded.  Interventions including transfusions, total fluid 
volume, urine output, total amount of analgesic/sedative medications utilized, 
vasopressor/steroid administration, intensive care unit-confusion assessment method scores 
and mechanical ventilation parameters will be recorded during the study period of 24 hours pre 
and post-drug administration.   
 
 
Quality Control Measures: The quality of randomization will be accounted for by the 
study coordinator.  They will ensure an accurate record of those participants who received a 
particular intervention.  We will utilize Redcap data management system.  A core set of study 
staff will be trained in the protocol and for study related tasks such as eligibility assessment and 
obtaining consent.  Furthermore, the core study staff will be contacted bi-monthly to review 


15 
 
study progress and concerns voiced to them from the clinical care team.  The study 
coordinators will also schedule routine meetings with the PI to review adverse events and 
protocol deviations. .  The decision to conduct an interim analysis will be governed by the DSMB 
and the DSMB charter.  Regarding ketamine, emergence phenomenon is a concern and this will 
be assessed by recording intensive care unit-confusion assessment method scores in the 
intensive care unit during the follow-up period.  To ensure proper doses of medications given, 
tables will be provided to the bedside nurses within and outside the randomization envelopes 
with the correct dose of both drugs to be given according to the weight of the patient.  The 
weight closest to the intubation will be used to guide drug dosing, unless health care provider 
requests a prior weight to be used, then the reason for using other weight will be documented 
on the recorder form..  The unit nursing team will be provided with education.  Please see 
separate document regarding Data Safety Monitoring Board (DSMB) charter. 
 
C.10. Data Analysis 
 
 
For all analyses, distributional assumptions will be assessed with data transformations or 
non-parametric methods used as appropriate.  For the primary analysis, the change in mean 
arterial pressure from baseline to 5 minutes post induction will be compared between groups 
using analysis of covariance with shock state, dose included as a covariate.  Secondary 
analyses will be performed to compare mean arterial pressure change from baseline at 10 and 
15 minutes as well as the average mean arterial pressure area under the curve over the first 15 
minutes expressed as a change from baseline.  Secondary analyses will also be performed to 
assess whether treatment differences are dependent on stratification factors.  Additional 
endpoints (28 day/in hospital mortality, mechanical ventilation free days at in hospital/day 28, 
vasoactive medication use, transfusions, fluid loading (>/=30cc/kg and intensive care unit free 
days at in hospital/day 28) will be summarized separately for each group and compared 
between groups using appropriate 2-sample methods (e.g., Fisher’s exact test or ANOVA).  
Additionally, we are particularly interested in the subgroup of patients on vasoactive medications 
and those who have received at least 30cc/kg of fluid within three hours prior to intubation.  
Therefore, subgroup analyses will be performed for these two subgroups.  In all cases, two-
tailed tests will be used with p-values of 0.05 or less considered statistically significant. 
• 
Primary Endpoint (Mean Arterial Pressure Over 5 Minutes): The primary outcome of interest is 
change in mean arterial pressure from baseline over the first 5 minutes following induction. Data 
will be recorded at baseline and every minute thereafter.  The primary endpoint will focus on the 
change in mean arterial pressure at 5 minutes post-induction. 
• 
Secondary Endpoint #1 (Mortality Difference): We will analyze differences in 28-day/in-hospital 
mortality between the two groups.  This will be stated as alive or dead at the 28-day mark or 
hospital discharge, whichever comes first and obtained through the medical charts for 
comparison between the two groups using appropriate 2-sample methods. 
• 
Secondary Endpoint #2 (Vasoactive Medication Use): We will analyze the difference in the use 
of vasoactive medications between the two groups.  This will be obtained through the medical 
chart and compared between the two groups using the appropriate 2-sample methods.  
• 
Additional analyses: Additional secondary endpoints will include mechanical ventilation free 
days at day 28, or hospital discharge, whichever comes first, transfusions, fluid loading 
(>/=30cc/kg) and intensive care unit free days at day 28, or hospital discharge, whichever 
comes first. 
• 
Adrenal Assessment: As part of the earlier protocol Version 5, a cosyntropin stimulation test 
was performed by administering 250 mcg cosyntropin at approximately the 4 and 24 hours. 
Serum cortisol levels were drawn at approximately 1 hour before and 1 hour after the 
cosyntropin dose.  We would now like to analyze the results in the subset of 39 patients which 
provided consent and had this testing performed.  The test will be considered normal if the pre-
cosyntropin cortisol is greater than 10 mcg/dL or if the post-cosyntropin cortisol rises by more 
than 9 mcg/dL [48]. 
 
C.11. Sample Size Considerations 
 


16 
 
 
The sample-size for the current study was based on the assumption that the standard 
deviation for the change in mean arterial pressure from baseline to 5 minutes post induction is 
approximately 10 mmHg, and that the mean difference between groups needs to be at least 5 
mmHg in order to be considered clinically relevant.  Based on these assumptions, we have 
determined that a sample-size of N=64 per group will provide statistical power (two-tailed, 
alpha=0.05) of 80% to detect a clinically relevant difference (i.e., difference of 5 mmHg) 
between groups.  We designed the study to have adequate statistical power to detect a 5 mmHg 
difference between groups using a two-sided test. In addition to performing the hypothesis test 
we will also calculate a 95% confidence interval for the difference between groups.  128 is the 
effective sample-size (i.e., the number of subjects we need who have data for the primary 
outcome).  Increasing the sample-size to allow for 20% subject attrition (drop-out) will be 
undertaken given the critical nature in which the study will be conducted. Increasing the sample-
size to 160 would allow for 20% drop-out (i.e. 80% of 160 = 128).  Therefore, we will enroll a 
total of 160 research participants. 
 
D. Protection of Human Subjects 
 
D.1. Consenting 
 
 
Research enrollment in the critical care environment, particularly, due to the nature of 
this study, is likely to include surrogate consent in situations where a surrogate is available and 
the research subject is unable to provide consent because of the degree of their critical illness.  
To ensure that patients are appropriately protected, all patients for which surrogate consent is 
obtained will have the opportunity to provide continuing consent for participation in the study.  In 
cases where continuing consent cannot be obtained, for instance, continued incapacitation or 
death, such reasons for not obtaining continuing consent will be documented in the patients 
study file by the study coordinators with times documented as well.  In addition, because of the 
emergency nature of this study, a community consultation and consent plan have been filed with 
the FDA.  Please see the Community Consultation and Consent Plan Document for further 
information. 
 
All patients enrolled in the trial will have an enrollment note placed in the chart within 72 
hours to confirm they were enrolled.  All patients will be notified within 90 days of trial 
involvement.  After the first contact during the 90 day period, two additional phone calls will be 
made 2 weeks apart.  If on the final attempt, there is still no contact with the patient or patient’s 
legally authorized representative, a certified letter will be sent. 
 
D.2. Data Protection 
 
 
To ensure the protection of patient data, all study data is stored on an encrypted, 
restricted access server maintained behind Mayo Clinic’s firewall.  Only study staff will have 
access to this information.  In the event that paper documentation exists for research subjects, 
their research folders will be maintained in a locked cabinet in a building with restricted access.  
Only study staff will have access to the files.  After data analysis, study records will be stored for 
a duration according to regulation and subsequently destroyed. 
 
D.3. Assessment of Safety Adverse Event Definitions 
 
 
Adverse Event:  Any untoward medical occurrence associated with the use of a drug in 
humans, whether or not considered drug related. 
 
Life-threatening Adverse Event or Life-threatening Suspected Adverse Reaction:  An 
adverse event or suspected adverse reaction is considered "life-threatening" if, in the view of 
either the investigator or sponsor, its occurrence places the patient or subject at immediate risk 
of death. It does not include an adverse event or suspected adverse reaction that, had it 
occurred in a more severe form, might have caused death. 
 
Serious Adverse Event or Serious Adverse Reaction: An adverse event is defined 
"serious" if, in the view of either the investigator or sponsor, it results in any of the following 
outcomes: death, a life-threatening adverse event, inpatient hospitalization or prolongation of 


17 
 
existing hospitalization, a persistent or significant incapacity or substantial disruption of the 
ability to conduct normal life functions, or a congenital anomaly/birth defect. Important medical 
events that may not result in death, be life-threatening, or require hospitalization may be 
considered serious when, based upon appropriate medical judgment, they may jeopardize the 
patient or subject and may require medical or surgical intervention to prevent one of the 
outcomes listed in this definition.  
 
Suspected Adverse Reaction: Any adverse event for which there is a reasonable 
possibility that the drug caused the adverse event. For the purposes of investigational new drug 
(IND) safety reporting, "reasonable possibility" means there is evidence to suggest a causal 
relationship between the drug and the adverse event. Suspected adverse reaction implies a 
lesser degree of certainty about causality than adverse reaction, which means any adverse 
event caused by a drug. 
 
Unexpected Adverse Event or Unexpected Suspected Adverse Reaction: An adverse 
event or suspected adverse reaction is considered "unexpected" if it is not listed in the drug 
package insert or is not listed at the specificity or severity that has been observed. 
 
Patients that are critically ill and requiring intubation with respiratory support sustain multiple adverse 
events as a result of their medical condition.  Therefore, only adverse events that have medical 
importance and/or may have a causal relationship to etomidate, ketamine or propofol will be reported.  
 
 
D.4. IND Safety Reports 
 
 
The study team will notify the FDA in an IND safety report of potential serious risks, from 
clinical trials or any other source, as soon as possible, but in no case later than 15 calendar 
days after the sponsor determines that the information qualifies as “Serious and Unexpected 
Suspected Adverse Reaction”. Results of other studies suggesting significant risk to humans 
exposed to drugs used in this trial, any trials conducted in animals or in-vitro testing that 
suggests significant risk to humans exposed to the drug, or a clinically significant increased rate 
of occurrence of serious suspected adverse reactions will be reported. In each IND safety 
report, the sponsor must identify all IND safety reports previously submitted to FDA concerning 
a similar suspected adverse reaction, and must analyze the significance of the suspected 
adverse reaction in light of previous, similar reports or any other relevant information. Adverse 
events possibly related to etomidate or ketamine / propofol administration include but not limited 
to tachy/bradycardia, hypo/hypertension, nausea/vomiting, hallucinations, disorientation, 
anxiety, myoclonus, seizures, anaphylaxis, arrhythmias, fatal anaphylaxis and anaphylactoid 
reactions, adrenal suppression and pain upon injection. 
 
D.5. Timing of Adverse Event Assessment 
 
     Adverse events (AEs) will be assessed for 72 hours with specific attention to 18 hours after 
enrollment.  In the event that a patient is discharged from the hospital before the 72 hour period 
is up, we will contact the patient by phone.    AEs will be reported to the Mayo Clinic IRB in a 
manner consistent with the site’s institutional policy.   
 
 
D.6. Annual AE and SAE Summaries 
 
 
The study team will ensure that annual reports are submitted to the IRB and will contain 
(a) the number of adverse events and an explanation of how each event was handled, (b) the 
number of complaints and how each complaint was handled, (c) the number of withdrawals of 
study participants and an explanation for each withdrawal, and (d) the number of protocol 
violations and how each was handled.  Summaries of SAEs will be provided to the Data Safety 
Monitoring Board (DSMB) at intervals determined by the DSMB, and DSMB reports and 
communications will be passed onto the Mayo Clinic Institutional Review Board. 
 
 


18 
 
 
D.7. Safety Oversight 
 
 
Safety oversight will be under the direction of a DSMB whose members will be 
independent from the study operations, will regularly review safety data consisting of AEs and 
protocol deviations throughout the study duration.  Full details of the composition and the 
operation of the DSMB and how the safety analyses are to be performed will be detailed in a 
separate DSMB written charter.  Enrollment may not begin, even with IRB and FDA approval, 
until the DSMB has been notified of the current protocol. 
 
D.8. Assessment of Toxicity 
 
           The study team will adopt the grading system toxicity as published by the FDA in 
September of 2007 in the guidance entitled, “Guidance for Industry:  Toxicity Grading Scale for 
Healthy Adult and Adolescent Volunteers Enrolled in Preventative Vaccine Clinical Trials.”  This 
severity scale will apply to any laboratory values or clinical abnormalities that fall outside of the 
institutions normal value range.  The study investigator will sign off on the level of toxicity for any 
abnormal lab value or clinical symptom/sign.  
 
D.9. Assessment of Causality 
 
           The study team will adopt the WHO-UMC system for standardized case causality 
assessment, highlighted in Table 1. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


19 
 
 
Table 1: 
 
 
 
 
D.10. Study Stopping Rules 
 
 
D.10.1. Futility   
 
In order to ensure adequate statistical power for the primary analysis and not jeopardize the 
analyses of secondary outcomes, no interim analyses or early-stopping rules are included. 
 
 
 


20 
 
 
D.10.2. Safety 
 
Judgment concerning the continuation or termination of the study will only be based on 
recommendations from the DSMB. The DSMB will play a valuable role in advising the study 
leadership on the relevance of advances in the diagnosis and treatment of patients. A number of 
therapeutic or diagnostic testing advances may possibly occur during the course of the trial. The 
DSMB will need to help put these advances in proper perspective. If protocol modifications are 
warranted, close consultation among the DSMB, the FDA, and the study Primary Investigator 
will be required.  The principal investigator has the power to stop the study at any time. 
 
D.11. Immediate Study Subject Stopping Rules 
 
The study will not delay intubation in patients.  Clinicians will proceed per standard of 
care.  In the event the study drug is not available by the time of intubation, the procedure will 
proceed in the usual fashion per clinician’s preference.  The study will effectively be stopped in 
such cases.   
In addition, if patients exhibit hemodynamic instability within 5 minutes prior to study 
drug administration, the study will be stopped. The procedure will proceed in the usual fashion 
per clinicians preference.  Hemodynamic instability will be defined as:  
1) Heart rate greater than 160 or less than 50;  
2) Systolic blood pressure greater than 180 or less than 70;  
3) Diastolic blood pressure greater than 120 or less than 30. 
 
E.1. Public Disclosure 
 
The investigator will notify the community of the clinical trial results.  The Center for Clinical and 
Translational Science (CCaTS) will assist with the public disclosure plan.  A public podcast will be held 
to share the clinical trial protocol information, including inclusion population and their characteristics, 
primary and secondary endpoints, adverse events and conclusions. The podcast will be coordinated by 
CCaTS community engagement specialists.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


21 
 
 
 
 
 
 
 
 
 
 
 
Appendix A. Resource Summary 
ST. MARYS HOSPITAL and ROCHESTER METHODIST HOSPITAL 
Mayo Clinic Hospitals: Mayo Clinic is the nation's largest group practice encompassing world 
renowned clinical and surgical expertise with extensive research and educational activities. 
Mayo physicians exclusively staff two large hospitals. Saint Marys (1,157 licensed beds) and 
Rochester Methodist (794 beds), which are part of Mayo Clinic. The organization attends nearly 
half a million patients each year from all regions of the United States and many countries 
abroad, although the majority are from within a 500-mile radius of Rochester. The 213 ICU beds 
and 24/7 intensivist staffing provide unrestricted access to ICU services and life support 
interventions to the Olmsted county community. 
 
 
The Division of Biomedical Statistics and Informatics (BSl) in the Department of Health Sciences 
Research was formed in late 2008 by merging the Division of Biostatistics with the Division of 
Biomedical Informatics to facilitate the linkage of traditional biostatistics and modern 
computational techniques. This division presently comprises more than 200 members, including 
faculty, programmers, contracting personnel, and support personnel. BSl provides integrated 
collaborative research support in both biostatistics and biomedical informatics. This model of 
collaboration was introduced by Joseph Berkson (known for the Berkson bias) in 1932. BSl has 
also supported the integrated medical record at Mayo since 1907 and has organized the 
retrieval indices that have made Mayo an unparalleled resource for clinical research. 
 
BIOSTATISTICS SUPPORT 
Biostatistics expertise is provided by 25 PhD statisticians and 55 statisticians with master's 
degrees, whose activities are facilitated by 75 statisticians with bachelor's degrees (statistical 
programmer analysts), and 20 clerical personnel. In addition to general consulting on over 2,000 
ongoing investigations, the statistical group provides core statistical support for a number of 
program projects. The biomedical informatics activities within the division have two principal 
missions: (1) the indexing and organization of data generated by the clinical practice for search 
and retrieval in support of research and education; and (2) a program of basic research on 
clinical concept representation, information indexing, and database retrieval. This group is 
represented by 11 PhD research investigators, 8 MS or PhD informaticists, 23 analyst 
programmers, and 24 additional support staff. During the past 3 years, the division has 
established a close working relationship with IBM Life Sciences Division to design, prototype, 
and deploy a comprehensive information archive of basic science data, genomic data, clinical 
data, natural language processed documents, and metadata. The division also maintains an 
active statistical research effort, especially in the areas of epidemiologic modeling, survival 
analysis, and statistical genetics and in the design, early stopping, and analysis of clinical trials. 
Recently, four sections were created in BSl to ensure scalability of resources and facilitate 
mentoring. While sections have been created, careful attention has been given to minimize the 
likelihood of forming silos within and among sections. In that spirit, this application will enable 
synergy across the full resources of BSl rather than in only one section. BSl is one of the key 
institutional units integrated into the CTSA. BSl is the academic home for the CTSA BERD 
program and the Biomedical Informatics CTSA component. 


22 
 
 
MINORITY RECRUITMENT RESOURCES 
The Office for Diversity in Clinical Research (ODCR) provides Mayo 
Clinic researchers with information and advice on protocol design, identification of target 
populations, and development of minority recruitment strategies, and assists in the recruitment 
of participants to research protocols throughout the community and nationwide. Its mission is to: 
increase and deepen community relationships with minority populations through outreach; act 
as a liaison between the community and the research teams; honor cultural ways of health and 
healing in education, patient care, and research; communicate medical and scientific concepts 
with culturally relative tools; and, within Mayo's region, identify and attempt to change the social 
and cultural factors that inhibit access to appropriate care and participation in clinical care and 
research opportunities. Mayo's Native American Programs at the Cancer Center provide links to 
local Native American communities; Mayo has established a formal understanding with the 
Indian Health Service to facilitate research on cancer and related health burdens. These two 
offices will help facilitate minority recruitment and representation in our studies. 
 
 
 
 
 
 


23 
 
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