Clinical trial NCT03820388
Conditions: Surgery
Keywords: Etomidate Propofol
Sponsor: University of California, Davis
Start date: 2017-12-01; Completion date: 2018-07-13
Enrollment: 75 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Comparison of Etomidate plus Propofol vs. Propofol or Etomidate alone during induction of anesthesia.

Detailed description:
Comparison of Etomidate plus Propofol vs. Propofol or Etomidate alone during induction of anesthesia. The specific aims are testing patient reactions during induction, and in the post-anesthesia care unit (PACU).

Arms: arm 1: Propofol 2 mg/kg arm 2: Etomidate 0.3 mg/kg arm 3: Propofol 1 mg/kg plus Etomidate 0.15 mg/kg
Interventions: intervention 1: Propofol 2mg/kg intervention 2: Etomidate 0.3 mg/kg intervention 3: Propofol 1 mg/kg intervention 4: Etomidate 0.15 mg/kg
Intervention descriptions: intervention 1: 2 mg/kg intervention 2: 0.3 mg/kg intervention 3: 1 mg/kg Propofol intervention 4: 0.15 mg/kg Etomidate

Protocol documents:
ICF_005.pdf: 
Title: Comparison of Etomidate Plus Propofol, Etomidate Alone on Induction of Anesthesia 
NCT03820388 
Document Date: September 26, 2017 


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APPROVED by the Institutional Review
Board at the University of California, Davis
Protocol
APPROVED
909765
September 26, 2017


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
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1&/!0/
!!!


 !"
 
APPROVED by the Institutional Review
Board at the University of California, Davis
Protocol
APPROVED
909765
September 26, 2017



#
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
1/!!).1!
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!H!H
!
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 !/
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
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
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+

$
!/




#CG !C



 !"
 
APPROVED by the Institutional Review
Board at the University of California, Davis
Protocol
APPROVED
909765
September 26, 2017


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
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!E
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'"/0%/%/
1%
/)!./&!
!1
&
!!!/0&
2/
@/
0'$ G
)CC///CCC.
 !
0!
/!/
!!

0!-
/!1
C//
1/!
0!!
E1/*:
*
/

 !"
 
APPROVED by the Institutional Review
Board at the University of California, Davis
Protocol
APPROVED
909765
September 26, 2017




@0
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$!
1/&!
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APPROVED by the Institutional Review
Board at the University of California, Davis
Protocol
APPROVED
909765
September 26, 2017

SAP_004.pdf: 
Title: Comparison of Etomidate Plus Propofol, Etomidate Alone on Induction of Anesthesia 
NCT03820388 
Document Date: September 26, 2017 


Statistical Analysis 
Sample size calculations were based on our pilot study, and we found MAP to be 80.1 (±10.3) 
mmHg, 90.3 (±10.4) mmHg, 91.0 (±11.6) mmHg in group P, PE and E at induction. Using PASS 
15.0 software, a sample size of 20 patients per group would be needed to detect statistically 
significant differences with the power of 0.9 and the alpha level of 0.05. Considering a possible 
20% dropout rate, 25 patients per group were recruited for the study. 
Parametric values were expressed as mean (SD), or percentages of the total number of patients 
(%). Categorical data were analyzed using χ2 or Fisher’s exact test as appropriate. The 
hemodynamic parameters among the three groups were compared using the general linear model 
(GLM). We also considered time of evaluation as a within-subject factor, and the intervention state 
as a between-subject factor. The time groups (interaction terms) were considered group differences 
among the three groups in their responses over time. We used Mauchly’s sphericity test for 
compound symmetry assumption. Differences in hemodynamic variables between the three groups 
at different time points were compared by post hoc Bonferroni test. P<0.05 was considered 
statistically significant. All statistical analyses were performed with SPSS 22.0 (SPSS; Chicago, 
IL, USA). 
 

Prot_003.pdf: 
Title: Comparison of Etomidate Plus Propofol, Etomidate Alone on Induction of Anesthesia 
NCT03820388 
Document Date: March 15, 2017 


PROTOCOL TITLE: Comparison of Etomidate Plus Propofol vs. Propofol, Etomidate 
Alone on Induction of Anesthesia, a Pilot Observational Study 
Page 1 of 9 
 
Revised: March 15, 2017 
1) Protocol Title 
Comparison of Etomidate Plus Propofol vs. Propofol, Etomidate Alone on Induction of 
Anesthesia, a Pilot Observational Study 
Protocol Version Date: 5/2/2017 
2) Objectives 
The purpose of this study is compare of etomidate plus propofol vs. propofol or 
etomidate alone during induction of anesthesia. 
The specific aims or objectives are testing patient reactions during induction, and 
in the post anesthesia care unit (PACU). 
The hypotheses to be tested: induction with etomidate combined with propofol 
when compared to induction with propofol or etomidate alone:  
1. will provide less pain during injection,  
2. less hypotension (compare to propofol), less hypertension (compare to 
etomidate) and better hemodynamics than propofol or etomidate during 
induction, 
3. Similar postoperative nausea and vomiting (PONV) when compared 
with propofol and less PONV when compared with etomidate, 
4. Similar pain score among all three groups 
 
3) Background 
 
Induction of anesthesia is a critical part of anesthesia practice. Sudden hypotension, 
hypertension, arrhythmias, and cardiovascular collapse are threatening complications 
following injection of induction agent in hemodynamically unstable patients. It is 
desirable to use a safe agent with fewer adverse effects for this purpose.  
 
Both etomidate and propofol are the most commonly used induction agents for general 
anesthesia (GA) and both propofol and etomidate have their advantages and 
disadvantages. Propofol has been associated with injection pain, significant 
hemodynamic change (hypotension) during induction and less PONV. Etomidate has 
been associated with more stable hemodynamic and less pain during induction, but more 
myoclonic movements at induction and PONV. However, those findings are still 
controversial and the published results are still inconsistent.  
 
In a large retrospective study, the authors found that anesthetic induction with etomidate, 
rather than propofol, is associated with increased 30-day mortality and cardiovascular 
morbidity after noncardiac surgery. The recommended bolus induction dose is 1.5–2.5 
mg/kg for propofol and 0.15–0.4 mg/kg for etomidate. One study showed that etomidate 
plus propofol had few effects on respiration and circulation in providing sedations for 
patients undergoing gastroscopy and was safer and more effective than propofol alone. In 
another study the authors found that with the etomidate-propofol combination (Etofol), a 


PROTOCOL TITLE: Comparison of Etomidate Plus Propofol vs. Propofol, Etomidate 
Alone on Induction of Anesthesia, a Pilot Observational Study 
Page 2 of 9 
 
Revised: March 15, 2017 
milder hemodynamic response was determined compared to propofol and etomidate used 
alone, both at anesthesia induction and after the intubation. Etofol can be a valuable 
alternative in patients where cardiovascular fluctuations are not wanted. Since there are 
very limited published results available, it is important to provide more evidence and 
address the question of whether etomidate plus propofol is better than propofol or 
etomidate alone on induction of anesthesia. 
 
References: 
1. British Journal of Anaesthesia 110 (3): 388–96 (2013) 
2. Zhou X. et al. Etomidate plus propofol versus propofol alone for sedation during 
gastroscopy: a randomized prospective clinical trial. Surg Endosc. March 22, 2016. DOI 
10.1007/s00464-016-4861-6 
3. J Cardiovasc Thorac Res, 2015, 7(4), 134-140 
4. Anesth Analg. 2013 Dec;117(6):1329-37) 
 
4) Inclusion and Exclusion Criteria 
Patients will be screening for eligibility through local electronic medical record 
(EMR) review using the IRB-approved HIPAA Waiver for Authorization for 
participant identification and recruitment. 
The inclusion criteria are: 
• Patients scheduled for elective non-cardiac surgery 
• ASA physical status of 2 or 3 
• Age equal to or greater than 18 years old 
Patients who do not meet the above criteria or patients who are in the following 
specific populations will be excluded: 
• Adults unable to provide consent 
• Age less than 18 years old 
• Pregnant women 
• Prisoners 
• Difficult airway (Mallampati class 4) 
• Morbid obesity (Body Mass Index (BMI) equal or greater than 40 
• Preoperative sedation use (benzodiazepines, opioids) 
• Severe cardiac (heart block, tachycardia, bradycardia, patient with 
pacemaker/AICD, pulmonary and liver diseases 
• Hypotension and shock 
• Emergency surgeries 
• Allergy to propofol or etomidate 
 


PROTOCOL TITLE: Comparison of Etomidate Plus Propofol vs. Propofol, Etomidate 
Alone on Induction of Anesthesia, a Pilot Observational Study 
Page 3 of 9 
 
Revised: March 15, 2017 
5) Study Timelines 
Patients will be participating in the study for the duration of their surgery and for 
24 hours after induction. 
We anticipated it to take 1 year to enroll all study subjects. 
We anticipate an extra 12 months after completion of the study for the 
investigators to complete the primary analyses. 
6) Study Endpoints 
 
The primary endpoints include:  
1. Blood pressure changes during induction  
2. Heart rate changes during induction 
 
The secondary endpoints include:  
1. Pain at injection 
2. Myoclonic movements  
3. PONV in PACU 
4. Postoperative pain score 
5. Incidence of adverse reactions during induction 
6. Severity of adverse reactions during induction 
7. Dose and frequency of vasoactive agents and other concomitant medications 
used to treat adverse reactions of propofol / etomidate 
8. Sedation depth using bispectral index (BIS) 
9. Eyelash reflex disappear time 
10. Intubation time 
11. Dose and frequency of analgesic and other sedatives used 
 
7) Procedures Involved 
 
This is a non-blinded, randomized, parallel-group study in patients scheduled for elective 
surgery under general anesthesia and orotracheal intubation to compare etomidate plus 
propofol vs. propofol or etomidate alone on induction of anesthesia.  
There will be three cohorts of 25 patients per cohort with one cohort administered 
propofol, one cohort administered etomidate, and one cohort administered propofol 


PROTOCOL TITLE: Comparison of Etomidate Plus Propofol vs. Propofol, Etomidate 
Alone on Induction of Anesthesia, a Pilot Observational Study 
Page 4 of 9 
 
Revised: March 15, 2017 
etomidate. The sample size was calculated with the blood pressure change ± 20 mmHg, 
SD±25 mmHg, power of 0.80 and p value of 0.05 and resulted 25 in each group. 
 
 
 The research team will create 75 envelopes. Each will be numbered, 25 will be in 
propofol group, 25 will be in etomidate group and 25 will be in propofol/etomidate 
group. On the day of surgery, one envelope will be randomly picked for each participant. 
 
Patients in the three cohorts will be administered a 30 second bolus by manual hand push. 
 
Intensive PD and safety assessments will be performed prior to dosing on Day 1 until 24 
hours post-dose (Day 2). There are no plans for long-term follow-up past the 24 hours. 
 
Three cohorts are as follow:  
1. Propofol group: 2 mg/kg propofol 
2. Etomidate group: 0.3 mg/kg etomidate 
3. Propofol plus etomidate group: 1mg/kg propofol plus 0.15mg/kg etomidate.  
Systolic blood pressure, diastolic blood pressure, mean arterial pressure, heart 
rate will be monitored and recorded before induction, at induction and 
intubation followed by 1, 3, 5 and 10 minutes after intubation.  
Pain on injection will be measured using 4 graded scale; 0 --- no pain, 1 --- 
verbal complaint of pain, 2 --- withdrawal of arm, 3 ---both verbal complaint 
and withdrawal of arm.  
The incidence and degree of myoclonic movements also recorded as follows: 0 
= no myoclonic movements, 1 = minor myoclonic movements, 2 = moderate 
myoclonic movements, 3 = major myoclonic movements. 
The medications used in the 3 groups are clinically used already with FDA 
approval for their use. This is an observational study and we will compare the 
effects of the three groups with their medication uses on the parameters we 
listed above: systolic blood pressure, diastolic blood pressure, mean arterial 
pressure, heart rate, pain on injection, myoclonic movements, PONV and BIS 
numbers. 
Non-English speaking participants are still eligible for the study. We will use 
translation services in line with HRP 090 and HRP 091 and the consent short 
form to enroll interested non-English speaking participants. If we find that we 
have enrolled 2 patients of a particular language using the short form as the 
study progressed, we will obtain full translation of the consent form into that 
language through the use of UCD Translation Services. 


PROTOCOL TITLE: Comparison of Etomidate Plus Propofol vs. Propofol, Etomidate 
Alone on Induction of Anesthesia, a Pilot Observational Study 
Page 5 of 9 
 
Revised: March 15, 2017 
 
8) Data and/or Specimen Management and Confidentiality 
 
All data will be summarized using descriptive statistics. Summaries of continuous 
variables will present mean, median, standard deviation, minimum, and maximum; 
summaries of categorical variables will present frequencies and percentages. All data will 
be presented in subject data listings. 
 
Subject enrollment and disposition, including reasons for early withdrawal from the 
study, will summarized by group. 
Demographic variables will be summarized by group for all enrolled subjects. Data will 
be stored up to 3 years after finishing the study. 
This is a pilot study with a proposal to enroll 25 patients into each group for a 
total of 75 patients randomized. 
We expect to complete data analysis on 20 patients in each group for a total of 60 
patients due to patient withdrawal either voluntarily or due to formal withdrawal 
criteria, ie difficulty with securing patient airway. 
9) Provisions to Monitor the Data to Ensure the Safety of Subjects 
 
As this is a minimal risk study, there are no plans to monitor the data. 
 
10) Withdrawal of Subjects 
 
The PI and research team can withdraw subjects from the study without their consent if 
difficulty securing their airway is encountered.   
 
11) Risks to Subjects 
The potential risks are breack to confidentiality and risks associated with the 
study drugs, Propofol and Etomidate. 
In order to safeguard our patient’s confidential data and to lessen the likelihood of 
a breach of confidentiality, the following parameters will be put in place: 
1. The data will be stored in the PI’s password-protected computer in 
his locked office. 
2. We don’t anticipate needing to transport any data, but if need be, 
the data will be transported via a hospital issued, password 
protected IRONKEY. 
3. Patients’ names and medical record numbers will be used initially. 
A numerical number (0001 to 0050) will be assigned to each 
patient.  


PROTOCOL TITLE: Comparison of Etomidate Plus Propofol vs. Propofol, Etomidate 
Alone on Induction of Anesthesia, a Pilot Observational Study 
Page 6 of 9 
 
Revised: March 15, 2017 
4. If the data need to be transmitted, the UCD secured email system 
will be used and the receiving end needs to be same secured email 
system. 
5. Only the research team members can access the data. 
 
Risks associated with Propofol and Etomidate :  
Risk of Etomidate: 
Transient venous pain on injection 
Transient Skeletal muscle movements 
Respiratory System: Hyperventilation, hypoventilation, apnea of short duration, 
laryngospasm, hiccup and snoring suggestive of upper airway obstruction.  
Circulatory System: Hypertension, Hypotension, tachycardia, bradycardia, arrhythmias  
 
Risks of Propofol:  
Cardiovascular: Bradycardia, arrhythmia, tachycardia, hypotension, decreased cardiac 
output 
Central nervous system: movement  
Metabolic/Nutritional: Hyperlipemia   
Respiratory: Apnea, respiratory acidosis during weaning  
Skin and appendages: Rash, pruritus  
 
 
 
 
12) Potential Benefits to Subjects 
Both propofol and etomidate are used in everyday clinical practice. There are still 
controversial over which out of the two is better. By using the combination of 
etomidate and propofol at a reduced dosage in cohort 3, we hope that patients can 
benefit from those drugs through the minimization of side effects.  
We are unable to tell if there will be a direct benefit to the study participant. 


PROTOCOL TITLE: Comparison of Etomidate Plus Propofol vs. Propofol, Etomidate 
Alone on Induction of Anesthesia, a Pilot Observational Study 
Page 7 of 9 
 
Revised: March 15, 2017 
 
13) Multi-Site Research 
N/A 
 
14) Community-Based Participatory Research 
N/A 
 
15) Sharing of Results with Subjects 
There are no plans to share study results with participants. 
 
16) Prior Approvals 
N/A 
 
17) Provisions to Protect the Privacy Interests of Subjects 
Eligible patients will be screened through electronic medical record review up to 
48 hours before their scheduled elective surgery. Patients will be approached on 
the day of the surgery in the UC Davis preoperative holding area of the main 
hospital to gauge for study interest. Research team will obtain consent from 
interested participants and honor any withdrawal requests based off of 
randomization group or time-constraints.  
This observational study does not allow for any interventions nor study 
procedures outside of the patient’s normal care, so we will limit unnecessary 
interactions with the patients to minimize the sense of intrusiveness a subject 
might experience in response to standard questions, examinations, and 
procedures.  
The research team will complete the HIPPA and required CITI training. Only at 
the time of data collection can the research team access the necessary patient’s 
information.   
 
18) Compensation for Research-Related Injury 
 
There is no compensation for participating in this minimal risk study.  
 
19) Economic Burden to Subjects 
 
Both medications are already routinely ordered and administered, and will be billed 
accordingly to the patient’s insurance. 
 
20) Drugs or Devices 
This is an observational study using FDA-approved medications that are used in everyday 
practice for anesthesia induction purpose. 
Medication is routinely stored in PYXIS and will be taken by the anesthesiology. 


PROTOCOL TITLE: Comparison of Etomidate Plus Propofol vs. Propofol, Etomidate 
Alone on Induction of Anesthesia, a Pilot Observational Study 
Page 8 of 9 
 
Revised: March 15, 2017 
 
21) ClinicalTrials.gov Registration 
Section 1:  NIH Funded Studies 
If yes to BOTH, the study must be registered on Clinicaltrials.gov. 
Yes  
 
This study is funded by the NIH. (If this study is not funded by NIH, go to 
Section 2.) 
 
One or more human subjects will be prospectively assigned to one or more 
interventions (which may include placebo or other control) to evaluate the effects 
of those interventions on health-related biomedical or behavioral outcomes. 
 
Section 2:  Studies subject to FDA jurisdiction 
If yes to ANY the study must be registered on Clinicaltrials.gov. 
Yes 
 
 
This is a prospective clinical study of health outcomes in human subjects that 
compares an intervention with an FDA-regulated device against a control. This 
is not a small clinical trial to determine the feasibility of a device, or a clinical 
trial to test prototype devices where the primary outcome measure relates to 
feasibility and not to health outcomes. 
 
This is a pediatric postmarket surveillance of a device as required under section 
522 of the Federal Food, Drug, and Cosmetic Act. 
 
This is a controlled clinical investigation, other than a phase I clinical 
investigation, of a drug subject to section 505 of the Federal Food, Drug, and 
Cosmetic Act or to section 351 of the Public Health Service Act. 
To view a flowchart describing applicable clinical trials subject to FDA jurisdiction click 
here. 
 
Section 3: Publishing the results 
If yes to BOTH the study must be registered on Clinicaltrials.gov. 
Yes  
 
This study prospectively assigns people or a group of people to an intervention, 
with or without concurrent comparison or control groups, to study the cause-and-
effect relationship between a health-related intervention and a health outcome. 
 
The PI has access to and control over all the data from the clinical trial and has 
the right to publish the results of the trial and plans to publish the results in a 
journal that follows the ICMJE recommendations.  
This requirement includes studies of behavioral interventions. 
Section 4: Registration on Clinicaltrials.gov is not required 
Yes  
 
I have read sections 1-3 above and registration on clinicaltrials.gov is not required 
for this research.  
 


PROTOCOL TITLE: Comparison of Etomidate Plus Propofol vs. Propofol, Etomidate 
Alone on Induction of Anesthesia, a Pilot Observational Study 
Page 9 of 9 
 
Revised: March 15, 2017 
22) Criteria for 10 Year Approval  
 
If yes to all items below this research may qualify for a 10-year approval period. 
 
Yes  
 
This research involves no more than minimal risk. 
 
This research does not receive any federal or state government funding or funding 
from a private funder who requires annual review per contract. 
 
This research is not subject to FDA jurisdiction.  
 
This research does not include prisoners as participants. 
 
This research is not part of an IRB reliance. 
 
This research is not subject to SCRO oversight. 
 
This research is not subject to oversight by the Research Advisory Panel of 
California (RAP of C). 
 
This research does not involve identifiable information held by the State of 
California Department or Agency 
 
This research does not involve personnel supported by federal training, center, or 
program grants. 
 
No personnel involved in the design, conduct, or reporting of this research have a 
financial interest (RFI) in this study.