Clinical trial NCT04959812
Conditions: Healthy
Sponsor: University of Texas Southwestern Medical Center
Start date: 2022-03-01; Completion date: 2023-09-08
Enrollment: 46 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
This study will examine how sufentanil (a commonly used pain medication) will alter responses to simulated blood loss in humans. To simulate blood loss in the research laboratory, participants will complete a test with their lower body in a custom-designed vacuum chamber for a brief period of time.

Detailed description:
Pain management on the battlefield is critical for the wellbeing of the soldier. Given that a hemorrhagic injury on the battlefield is virtually always associated with pain, it is paramount that the selected pain medication does not disrupt appropriate physiological mechanisms that are beneficial towards the maintenance of blood pressure and vital organ blood flow during that hemorrhagic insult. Current guidelines for the selection of pain medications of a hemorrhaging soldier are based upon limited scientific evidence, with the vast majority of supporting studies being conducted on anesthetized animals. Thus, the interaction between hemorrhagic shock and pain medications commonly employed on the battlefield is yet to be determined in the conscious humans.

This study will test the hypothesis that sufentanil will impair the capacity for a conscious human to tolerate a hemorrhagic insult.

The obtained data will provide the necessary scientific evidence in humans to support the Committee on Tactical Combat Casualty Care (CoTCCC) guidelines on the analgesic of choice for moderate to severe injuries where the casualty is in hemorrhagic shock. Notably, such data will identify the analgesic that least compromises a human's ability to tolerate a hemorrhagic insult, ultimately providing critical information to the combat medic on which analgesic should be employed for such an injury.

Arms: arm 1: Sufentanil (30 microgram tablet) will be administered via a sublingual pill arm 2: Placebo will be administered via a sublingual pill
Interventions: intervention 1: Sufentanil intervention 2: Placebo
Intervention descriptions: intervention 1: Subjects will receive Sufentanil while the effects of this drug on tolerance to a hemorrhagic insult will be assessed. intervention 2: Subjects will receive a placebo pill while the effects of this placebo on tolerance to a hemorrhagic insult will be assessed.

Protocol documents:
ICF_001.pdf: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
The effects of low-dose analgesics on cardiovascular function (STU-2021-0579) 
NCT04959812 
8/18/2023 
 
 
 


Title of Study: The effects of low-dose analgesics on cardiovascular function 
 
STU2021-0579, Crandall, FormE-Consent, Mod_7, 08-18-23 
 
 
Page 1 of 13 
                           
UTSW Research Consent and Authorization Documents (v January 2019) 
Consent to be part of a Research Study to be conducted at 
The University of Texas Southwestern Medical Center 
Texas Health Resources 
 
Key Information about this Study  
 
The purpose of this research study is to determine whether a commonly used pain medication (sufentanil) 
affects a person’s ability to tolerate a bleeding injury, simulated in the laboratory setting utilizing a lower-body 
negative pressure (LBNP) vacuum chamber. 
 
Sufentanil is given to individuals (including soldiers) who need a pain medication for an injury. In combat 
settings, and in some non-combat settings, pain often accompanies a severe bleeding injury.  It is important 
that the pain medication given to such an individual does not reduce their tolerance to the bleeding injury by 
adversely affecting the control of blood pressure. Therefore, we are studying how sufentanil affects your body’s 
ability to tolerate a simulated hemorrhage injury by altering variables that control your blood pressure. 
 
During this study, you will complete two experimental trials. During one trial, we will administer sufentanil once. 
During the other trial, we will give you a placebo (similar pill as sufentanil but does not have any drug in the 
pill). You will not know whether you are receiving the sufentanil pill or the placebo pill for these trials. During 
these visits, we will measure your nervous system activity, heart function, and blood vessel function. Total 
study duration is approximately 12 hours and will include 3 visits. If you are a healthy individual, between 18 
and 45 years of age, you qualify to participate in this research study. Like all research studies, there are risks 
in participation, though the risks for this study (outlined below) are well controlled and are relatively minor.   
 
This research will help doctors learn more about how sufentanil affects responses that control blood pressure 
during a bleeding injury. If you are interested in learning more about this study, please continue to read below. 
 
Information about this form 
 
You may be eligible to take part in a research study.  This form gives you important information about the 
study.   
 
Please take time to review this information carefully.  You should talk to the researchers about the study and 
ask them any questions you have.  You may also wish to talk to others (for example, your friends, family, or a 
doctor) about your participation in this study.  If you decide to take part in the study, you will be asked to sign 
this form.  Before you sign this form, be sure you understand what the study is about, including the risks and 
possible benefits to you. 
 
Please tell the researchers or study staff if you are taking part in another research study. 
 
Your doctor is a research investigator in this study.  S/he is interested in both your medical care and the 
conduct of this research study.  At any time, you may discuss your care with another doctor who is not part of 
this research study.  You do not have to take part in any research study offered by your doctor. 
 
Voluntary Participation - You do not have to participate if you don't want to.  You may also leave the study at 
any time.  If you decide to stop taking part in this research study, it will not affect your relationship with the UT 
Southwestern staff or doctors.  Whether you participate or not will have no effect on your legal rights or the 
quality of your health care. 
 
If you are a medical student, fellow, faculty, or staff at the Medical Center, your status will not be affected in 
any way. 
 
 
IRB Approved Date: 8/18/2023


Title of Study: The effects of low-dose analgesics on cardiovascular function 
 
STU2021-0579, Crandall, FormE-Consent, Mod_7, 08-18-23 
 
 
Page 2 of 13 
                           
UTSW Research Consent and Authorization Documents (v January 2019) 
General Information – “Who is conducting this research?” 
 
Principal Investigator 
The Principal Investigator (PI) is the researcher directing this study; the PI is responsible for protecting your 
rights, safety, and welfare as a participant in the research.  The PI for this study is Craig Crandall, PhD, 
Department of Internal Medicine at the University of Texas Southwestern Medical Center. 
 
Funding 
The Department of Defense is funding this study. This organization is providing money to the University of 
Texas Southwestern Medical Center so that the researchers can conduct the study. 
 
Purpose – “Why is this study being done?” 
 
Pain management is an important component in the care of an injured soldier. Currently, the four pain 
medications available to a combat medic are morphine, fentanyl, ketamine, and sufentanil. Selection of the 
ideal pain medication is based on the type and level of distress of the soldier. Given that a bleeding injury on 
the battlefield is almost always associated with pain, it is important that the selected pain medication does not 
disrupt responses that are beneficial towards the maintenance of blood pressure and vital organ blood flow 
during a bleeding injury. The procedures outlined below will examine the effects of a recent FDA approved 
version of a pain medication called sufentanil (via pill placed under the tongue; sublingual) on tolerance to a 
simulated bleeding injury in humans. These data will be combined with similar data currently being collected 
using identical techniques but with morphine, fentanyl, and ketamine. Obtaining these data is an important 
step towards an understanding of the potential influence of commonly used pain medications on tolerance to 
a bleeding injury. 
 
You are asked to participate in this research study on the effects of sufentanil on blood pressure control 
during a simulated bleeding condition. This study needs to be done so combat medics will know which pain 
medication is ideal to be given to an injured soldier. 
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by U.S. Law. 
This website will not include information that can identify you. At most, the website will include a summary of 
the results. You can search this website at any time.  
 
Information about Study Participants – “Who is participating in this research?” 
 
You are being asked to be a participant in this study because you are in good health, between the ages of 18-
45 years, and do not have any known specific risks for receiving sufentanil. 
 
How many people are expected to take part in this study?  
• 
This study will enroll approximately  60 study participants. 
 
Information about Study Procedures – “What will be done if you decide to be in the research?” 
 
While you are taking part in this study, you will be asked to attend approximately 3 visits with the researchers 
and study staff. The total time commitment for this study is approximately 12 hours (up to two hours for 
consent/screening and approximately five hours for each of the two experimental trials). 
 
Screening – After you sign this consent to participate, exams, tests, and/or procedures may be done as 
described below to find out if you can continue in the study; this is called screening. We may be able to use the 
results of exams, tests, and/or procedures you completed before enrolling in this study. You will be told which 
results we will obtain and which procedures will not have to be repeated.  All of the procedures described 
below are for research only. 
 
IRB Approved Date: 8/18/2023


Title of Study: The effects of low-dose analgesics on cardiovascular function 
 
STU2021-0579, Crandall, FormE-Consent, Mod_7, 08-18-23 
 
 
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UTSW Research Consent and Authorization Documents (v January 2019) 
Screening Procedures (approximately 2 hours) 
• 
If you are capable of becoming pregnant, a pregnancy test (from one urine sample) may also be done 
before you receive study treatment. 
• 
You may also be asked to provide a urine sample for drug screening. 
• 
We will measure your body height and mass. 
• 
We will ask you to complete a medical history form. 
• 
We will measure your blood pressure. 
• 
We will measure your heart rate and rhythm (12-lead electrocardiogram). 
 
The results of the screening exams, tests, and/or procedures will be reviewed to determine whether you will be 
allowed to continue in the study. If you are not allowed to continue in the study, the researcher will discuss the 
reasons with you (for example, if the urine drug screen comes back positive). We will inform you, and this 
information will not be shared with anyone outside of the study team. 
 
Assignment to Study Groups 
When it is determined that you are eligible for the study, you will be assigned by chance (like flipping a coin) to 
complete either the sufentanil trial first or the placebo trial first. A placebo is an inactive, harmless substance 
that looks like the other study drugs. 
 
If you are randomized to complete the sufentanil trial first, you will complete the placebo trial second. If you are 
randomized to complete the placebo trial first, you will complete the sufentanil trial second. These trials can last 
approximately five hours. 
 
For either visit, neither you nor the researchers will know whether you are receiving sufentanil or the placebo. 
However, the study nurse and anesthesiologist will know if you are receiving sufentanil or placebo. 
 
Study Procedures - as a participant, you will undergo the procedures outlined below.  
 
Visit #1 - approximately two hours: Consent and Screening 
Visit #2 - approximately five hours: First Experimental Visit 
Visit #3 - approximately five hours: Second Experimental Visit 
 
Visit #1 
The following measures and procedures will be performed during visit #1 (see below for descriptions) 
• 
Informed consent/discussion 
• 
Urine sample (pregnancy and drug screening) 
• 
Medical history 
• 
Body height and mass 
• 
Blood pressure (arm) 
• 
Heart rate and rhythm (12-lead electrocardiogram) 
 
Visits 2-3:  
On visits 2 and 3, the procedures performed will be identical, with the exception that during one visit you will 
receive sufentanil (a commonly used pain medication) and during the other visit you will receive the placebo. 
The order of these visits will be randomized.  
 
You will be instrumented and rest quietly by lying down. After a period of resting measurements, we will 
perform two tests (pressure algometry and a cold pressor test). You will then receive sufentanil or placebo 
followed by a rest period prior to initiation of the lower-body negative pressure (LBNP) test. After the LBNP 
test, there will be a rest period followed by a repeat of the pressure algometry and cold pressor tests. 
 
The following measures and procedures may be performed during visits 2 and 3: 
 
IRB Approved Date: 8/18/2023


Title of Study: The effects of low-dose analgesics on cardiovascular function 
 
STU2021-0579, Crandall, FormE-Consent, Mod_7, 08-18-23 
 
 
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UTSW Research Consent and Authorization Documents (v January 2019) 
Procedure 
Description of Procedure 
Duration of 
Procedure 
Urine sample 
You will be asked to urinate into a cup from which we will 
assess the density of your urine, conduct a pregnancy test 
(if applicable), and conduct a drug screening test. Drugs 
that your urine will be screened for include marijuana, 
cocaine, opiates (such as heroin, morphine, hydrocodone, 
oxycodone and methadone), barbiturates, 
benzodiazepines, and methamphetamines. If this drug test 
is positive for one or more of these agents, you will not be 
permitted to participate in the study. A positive drug test will 
not be indicated in your records and this information will 
remain confidential. There is no known significant risk with 
this measure. 
You will be asked to 
urinate into a cup at 
the beginning of each 
visit. 
Body height and 
mass 
You will be asked to stand on a scale. There is no known 
significant risk with this measure. 
Each measurement 
will take about 30 
seconds at the 
beginning of each 
visit. 
Arm blood pressure 
Your blood pressure will be monitored using a cuff placed 
on your upper arm that is inflated and deflated periodically. 
You might feel mild temporary discomfort while the cuff is 
inflated. There is no known significant risk with this 
measure. 
We will measure blood 
pressure several times 
during each visit. 
Limb blood flow 
We will measure blood flow through an artery in one of your 
limbs using Doppler ultrasound. A small amount of gel will 
be placed on an ultrasound probe, with that probe placed 
on the upper limb. There is no known significant risk with 
this measure. 
We will measure limb 
blood flow several 
times during visits 2 
and 3.  
Heart rate and 
rhythm 
(electrocardiogram) 
Sticky pads will be applied to your skin to measure the 
heart’s electrical signals. It is possible that a small amount 
of chest hair may need to be shaved to get the pads to 
stick. You might feel mild temporary discomfort while the 
sticky pads are removed. There is no known significant risk 
with this measure. 
Heart rate and rhythm 
will be measured via 
12-lead 
electrocardiogram 
during visit 1 (usually 
about 10 minutes). 
Heart rate and rhythm 
will be measured 
continuously via six-
lead 
electrocardiogram 
during visits 2 and 3. 
Finger blood 
pressure 
Your blood pressure will be monitored using a cuff placed 
on your finger. You might feel mild temporary discomfort 
when the cuff is “on” (periodically inflating and deflating) for 
too long (over an hour or so). If you feel discomfort, let the 
researchers know and they can turn it “off” for a few 
minutes when there is a break in active data collection. 
There is no known significant risk with this measure. 
This cuff will 
continuously record 
finger blood pressure 
throughout visits 2 and 
3. 
Lower-body negative 
pressure 
This procedure causes fluid in your body to shift from your 
chest and upper body to your lower body. While lying on 
your back, you will be sealed in a box-like chamber from 
the waist down. Suction will be applied inside the box to 
your lower body. The level of suction will increase until the 
This procedure will 
last no more than 30 
minutes. 
IRB Approved Date: 8/18/2023


Title of Study: The effects of low-dose analgesics on cardiovascular function 
 
STU2021-0579, Crandall, FormE-Consent, Mod_7, 08-18-23 
 
 
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UTSW Research Consent and Authorization Documents (v January 2019) 
researchers determine that the test is over, or you request 
to stop. 
Sufentanil 
administration 
Sufentanil will be given by placing a pill under your tongue. 
The pill will rapidly dissolve while it is under your tongue 
The pill will dissolve in 
about 1 minute 
Placebo 
administration 
A placebo pill will be given by placing a pill under your 
tongue. The pill is like the sufentanil pill, but it does not 
contain any sufentanil. The pill will rapidly dissolve while it 
is under your tongue. There is no known significant risk 
with this procedure. 
The pill will dissolve in 
about 1 minute 
Peripheral 
intravenous catheter 
and blood samples 
To collect blood during the experiment (up to approximately 
8 tablespoons per visit), a sterile catheter will be inserted 
into a superficial vein of one of your arms. This procedure 
allows for blood to be taken multiple times with the insertion 
of only one needle. We will measure several hormones 
involved in blood pressure control. 
The catheter will be 
placed at the 
beginning of the visit 
and removed prior to 
discharge. We will 
perform serial blood 
samples (up to five) 
throughout visits 2 and 
3. 
Nervous system 
recording 
(microneurography):   
 
Nerve signals from the nerves in the arm will be measured. 
To locate the nerves, we use ultrasound imaging. When the 
nerve is located, we insert a small sterile needle (an 
electrode about the size of an acupuncture needle) through 
the skin. You may feel some slight discomfort during needle 
insertion. The recording needle is advanced into the nerve. 
When the tip of the needle enters the nerve, you may 
notice a tingling, pins and needles, cramping, or dull achy 
sensation. A second needle serves as a reference 
electrode and is inserted just under the skin, a couple of 
inches away from the nerve. Once the needles are in place 
it is extremely unlikely you will feel any discomfort. This 
method of recording nerve signals in human subjects has 
been used in over 3000 studies since 1979. We have 
performed over 300 recordings in our laboratory without 
any major complications. In rare cases, individuals may 
have tenderness, soreness, or numbness in the nerve 
recording area for a few days that subsides without 
treatment. 
The microneurography 
needle will remain in 
position for the 
duration of visits two 
and three and will be 
removed at the end of 
the study (up to 
approximately five 
hours per visit, up to 
10 hours total). 
Tissue oxygen 
saturation 
A small sensor will be placed on your skin in order to 
measure the amount of oxygen in your muscle or brain. 
There is no known significant risk with this measure. 
The sensor will remain 
in place for the entire 
duration of visits 2 and 
3 (up to approximately 
5 hours per visit, up to 
10 hours total). 
Blood oxygen 
saturation 
 
The amount of oxygen in your blood will be measured by 
pulse oximetry by placing a sensor on your finger. There is 
no known significant risk with this measure. 
Oxygen saturation will 
be measured during 
the entire duration of 
visits 2 and 3 (up to 
approximately 5 hours 
per visit, up to 10 
hours total). 
Compensatory 
reserve indicator 
A small cuff will be placed on one of your fingers to take 
measurements pertaining to the blood flow in your finger. 
There is no known significant risk with this measure. 
The sensor will be 
used during visits 2 
and 3 (up to 
IRB Approved Date: 8/18/2023


Title of Study: The effects of low-dose analgesics on cardiovascular function 
 
STU2021-0579, Crandall, FormE-Consent, Mod_7, 08-18-23 
 
 
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UTSW Research Consent and Authorization Documents (v January 2019) 
approximately 5 hours 
per visit, up to 10 
hours total). 
Brain blood flow 
A gel covered probe will be placed on the side of your 
forehead. Sound waves will be used to record blood flow 
inside your head.  This procedure is similar to standard 
ultrasound tests done to examine the health of babies prior 
to birth. There is no known significant risk with this 
measure. 
The sensor will remain 
in place for the entire 
duration of visits 2 and 
3 (up to approximately 
5 hours per visit, up to 
10 hours total). 
End tidal carbon 
dioxide 
The amount of carbon dioxide that you exhale will be 
monitored from a nasal cannula (a plastic tube that fits 
behind your ears and two small, short prongs that are 
placed in your nostrils). There is no known significant risk 
with this measure. 
The sensor will remain 
in place for the entire 
duration of visits 2 and 
3 (up to approximately 
5 hours per visit, up to 
10 hours total) 
Cold pressor test 
You will place one hand up to the wrist in ice slurry water 
for a period of 2-3 min. You will report the pain that you are 
experiencing on a scale of 0 to 10, 0 being no pain and 10 
being the worst imaginable pain. There is no known 
significant risk with this procedure. 
This test will be 
performed twice 
during visits 2 and 3. 
Pressure algometry 
A digital algometer will be placed on your finger or thumb. 
Pressure to that area will increase until you first start to feel 
discomfort. There is no known significant risk with this 
measure. 
This test will be 
performed twice 
during visits 2 and 3. 
Each test lasts 
approximately 30 
seconds. 
 
Could your participation end early? There are several reasons why the researchers may need to end your 
participation in the study (early withdrawal).  Some reasons are: 
• 
The researcher believes that it is not in your best interest to stay in the study. 
• 
You become ineligible to participate. 
• 
Your condition changes and you need treatment that is not allowed while you are taking part in the study. 
• 
You do not follow instructions from the researchers. 
• 
The study is stopped. 
 
It is possible that this study will identify information about you that was previously unknown, such as disease 
status or risk.  There are no plans to provide this information to you or your physician. 
 
Risks – “What are the risks of participation in the research?” 
 
Risks from the specific research procedures  
There are risks to taking part in this research study. Side effects from this study will usually go away soon by 
the time you are discharged at the end of each visit. In some cases, side effects can be long lasting or may 
never go away. 
 
Everyone taking part in the study will be watched carefully for any side effects.  However, the study doctors 
don’t know all the side effects that may happen.  Be sure to tell your study doctor immediately, about any side 
effects that you may have while taking part in the study. 
 
The following section will describe the risks related to your participation in this research study.  You should talk 
to your study doctor about any side effects or other problems that you have while taking part in the study.    
 
IRB Approved Date: 8/18/2023


Title of Study: The effects of low-dose analgesics on cardiovascular function 
 
STU2021-0579, Crandall, FormE-Consent, Mod_7, 08-18-23 
 
 
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Side effects can range from mild to serious. Mild side effects are those that may be temporarily uncomfortable 
and go away shortly after the procedure and/or do not have the potential for any long-term adverse effects. 
Serious side effects are those that may require hospitalization, are life threatening, or fatal (could cause death). 
The frequency that people experience a certain side effect can range from likely (many), less likely (few), or 
rarely (only one or two).   
 
For more information about risks and side effects, ask one of the researchers or study staff. 
 
Lower-body negative pressure: 
Likely 
In 100 people, approximately (21 to 100 individuals) may have: 
• 
Mild risk: Dizziness, lightheadedness, or nausea that will go away shortly (often immediately) 
after stopping lower-body negative pressure. 
• 
Mild risk: Mild discomfort at the interface between the lower-body negative pressure device and 
your body that will go away immediately upon stopping lower-body negative pressure.  
 
Sufentanil administration:  
Likely 
In 100 people, approximately (21 to 100 individuals) may have: 
• 
Mild risk: Short-term disorientation and changes in vision or hearing 
• 
Mild risk: Short-term tiredness, confusion, or nausea 
 
Less Likely 
In 100 people approximately (2 to 20 individuals) may have: 
• 
Mild risk: Short-term headaches, dizziness, vomiting, or low blood pressure 
 
Rare 
In 1,000 people, approximately (1 or less healthy individuals) may have: 
• 
Mild risk: Elevated or slowed heart rate 
• 
Mild risk: Skin rash or excessive sweating 
• 
Serious risk: Temporary difficulty breathing (very low risk) 
• 
Serious risk: Addiction, abuse, and/or misuse of sufentanil (very low risk) 
 
 
Peripheral intravenous catheter and blood samples: 
Less Likely 
In 100 people, approximately (2 to 20 individuals) may have: 
• 
Mild risk: You may have discomfort, temporary bleeding, redness, mild swelling, and/or bruising. 
• 
Mild risk: You may feel dizzy or faint. 
 
Rare 
In 10,000 people, approximately (1 or less individuals) may have: 
• 
Serious risk: An infection  
• 
Serious risk: A blood clot or breakage of the catheter (very low risk) 
 
Nervous system recording (microneurography):   
Consistent with published guidelines, we will limit the nerve search time to 60 minutes (though most nerve 
searches last less than 30 minutes). Also, we will not record from the same nerve within one 28-day period. 
Likely 
In 100 people, approximately (21 to 100 individuals) may have: 
• 
Mild: Slight short-term discomfort during electrode insertion 
• 
Mild: Slight short-term sensations of tingling, pins and needles, cramping, or dull achy 
IRB Approved Date: 8/18/2023


Title of Study: The effects of low-dose analgesics on cardiovascular function 
 
STU2021-0579, Crandall, FormE-Consent, Mod_7, 08-18-23 
 
 
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Rare 
In 100 people, approximately (1 or less individuals) may have: 
• 
Mild risk: Tenderness, soreness, or numbness near the nerve recording site for a few days that 
spontaneously resolves without treatment 
 
 
 
For more information about risks and side effects, ask one of the researchers or study staff. 
 
We will tell you about any significant new findings which develop during the course of this research which may 
relate to your willingness to continue taking part.   
 
Are there risks related to withdrawing from the study?  
If you decide to withdraw from this study early, please discuss your decision with the principal investigator.  
The researcher may ask you to complete study withdrawal procedures at a final study visit. There is no risk to 
you if you do not complete the final withdrawal procedures and you can choose not to participate in them. 
 
Reproductive Risks 
 
Concerns for sexually active women:  Women should not become pregnant and men should not father a 
baby while taking part in this study because we do not know how the study drugs/procedures could affect a 
man's sperm (for some drugs/procedures, the concern may be that the sperm might be affected and in some 
cases, drugs could be carried by the semen into the vagina and cause harm) or a fetus, if a woman becomes 
pregnant during the study. It is important that you talk to your study doctor about avoiding pregnancy during 
this study. If you think you might have become pregnant or if you believe your female partner has become 
pregnant while you are in this study, you must tell one of the study doctors right away so that management of 
the pregnancy and the possibility of stopping the study can be discussed.   
 
If you are a woman who is pregnant or could be pregnant, you cannot take part in this study because we do 
not know how sufentanil might affect a developing fetus.  We will do a pregnancy test before you start 
treatment to make sure you are not pregnant. 
 
Risks to babies who are being breastfed:   Women who are breastfeeding cannot take part in this study 
because we do not know what effect the drugs/procedures might have on their breast milk.  
 
Are there risks if you also participate in other research studies? 
Being in more than one research study at the same time, or even at different times, may increase the risk to 
you.  It may also affect the results of the studies.  You should not take part in more than one study without 
approval from the researchers.   
 
What if a research-related injury occurs?  
The researchers have taken steps to minimize the known or expected risks.  However, you may still 
experience problems or side effects, even though the researchers are careful to avoid them.  In the event of a 
research-related injury or if you experience an adverse reaction, please immediately contact your study doctor.  
See the section “Contact Information” for phone numbers and additional information.  You may also need to tell 
your regular doctors. 
 
If you are injured or made sick from taking part in this research study, medical care will be provided. This care 
may be billed to you or your insurance. Depending on the circumstances, this care may be provided at no cost 
to you. We have no plans to give you money if you are injured. The investigator can provide you with more 
information. 
 
If you sign this form, you do not give up your right to seek additional compensation if you are harmed as a 
IRB Approved Date: 8/18/2023


Title of Study: The effects of low-dose analgesics on cardiovascular function 
 
STU2021-0579, Crandall, FormE-Consent, Mod_7, 08-18-23 
 
 
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result of being in this study. 
 
Benefits – “How could you or others benefit from your taking part in this study?” 
The possible benefit of your participating in this study is related to research monitoring procedures (such as the 
assessment of blood pressure) which is likely to contribute to your well-being.   
 
You may not receive any personal benefits from being in this study. 
 
We hope the information gained from this research will lead to better treatment and management of individuals 
involved with traumatic injuries in the pre-hospital setting, e.g., traffic collisions or injured soldiers. 
 
Alternative procedures– “What other options are there to participation in this study?” 
 
Your participation is completely voluntary. You do not have to take part in this research. 
 
Payments – Will there be any payments for participation? 
 
Individuals eligible to participate will be compensated at the rate of $35 per hour of time in the laboratory. This 
compensation will be provided via a check in the mail within approximately six weeks of the final experimental 
visit completion. Your name, address, date of birth and social security number will be shared with a third-party 
solely for the purposes of compensation processing. All information will be stored in a secure fashion. 
 
If required, you will be reimbursed for your transportation to and from the research center (for example cab or 
bus fare). To receive reimbursement, you will need to turn in all your receipts to the research coordinator. 
 
Please note that if you are on record as owing money to the State of Texas, such as for back child support or a 
delinquent student loan, the payment may be applied to that debt.  
 
An IRS Form 1099 will be sent to you if your total payments are $600 or more in a calendar year, unless it’s a 
reimbursement.  
 
Costs – Will taking part in this study cost anything? 
 
There will be no costs to you in taking part of any of the procedures associated with this study. 
 
Confidentiality – How will your records be kept confidential? 
 
Information we learn about you in this study will be handled in a confidential manner, within the limits of the 
law.  If we publish the results of the study in a scientific journal or book, we will not identify you.  The 
Institutional Review Board and other groups that have the responsibility of monitoring research may want to 
see study records which identify you as a subject in this study.    
 
Certificate of Confidentiality: 
To help us further protect your information, the investigators will obtain a Certificate of Confidentiality from the 
U.S. Department of Health and Human Services (DHHS).  This Certificate adds special protections for 
research information that identifies you and will help researchers protect your privacy.   
 
With this Certificate of Confidentiality, the researchers cannot be forced to disclose information that may 
identify you in any judicial, administrative, legislative, or other proceeding, whether at the federal, state, or local 
level.  There are situations, however, where we will voluntarily disclose information consistent with state or 
other laws, such as: 
• 
to DHHS for audit or program evaluation purposes; 
• 
information regarding test results for certain communicable diseases to the Texas Department of State 
IRB Approved Date: 8/18/2023


Title of Study: The effects of low-dose analgesics on cardiovascular function 
 
STU2021-0579, Crandall, FormE-Consent, Mod_7, 08-18-23 
 
 
Page 10 of 13 
                           
UTSW Research Consent and Authorization Documents (v January 2019) 
Health Services, including, but not limited to HIV, Hepatitis, Anthrax, and Smallpox; 
• 
if you pose imminent physical harm to yourself or others; 
• 
if you pose immediate mental or emotional injury to yourself; 
• 
if the researchers learn that a child has been, or may be, abused or neglected; or 
• 
if the researchers learn that an elderly or disabled person has been, or is being, abused, neglected or 
exploited. 
 
The Certificate of Confidentiality does not prevent you or a member of your family from voluntarily releasing 
information about your involvement in this research study.  In addition, the researchers may not use the 
Certificate to withhold information about your participation in this research study if you have provided written 
consent to anyone allowing the researchers to release such information (including your employer or an 
insurance company).  This means that you or your family must also actively protect your privacy. 
 
A Certificate of Confidentiality does not represent an endorsement of this research project by the Department 
of Health & Human Services or any other Federal government agency. 
 
How will my information and/or tissue samples be used? 
With appropriate permissions, your samples and collected information may also be shared with other 
researchers here, around the world, and with companies. 
 
By agreeing to participate in this study, your information or tissue samples could be used for future research 
studies or sent to other investigators for future research studies without additional consent from you. The 
information that identifies you will first be removed from your information or tissue samples. If you do not want 
your information or tissue samples to be used for future research studies without your consent, you should not 
participate in this study. 
 
Research policies require that private information about you be protected and this is especially true for your 
health information.  However, the law sometimes allows or requires others to see your information.  The 
information given below describes how your privacy and the confidentiality of your research records will be 
protected in this study. Medical information collected during this study and the results of any test or procedure 
that may affect your medical care may be included in your medical record. The information included in your 
medical record will be available to health care providers and authorized persons including your insurance 
company. 
 
What is Protected Health Information (PHI)?   
Protected Health Information is information about a person’s health that includes information that would make it 
possible to figure out whose it is.  According to the law, you have the right to decide who can see your 
protected health information.  If you choose to take part in this study, you will be giving your permission to the 
investigators and the research study staff (individuals carrying out the study) to see and use your health 
information for this research study.  In carrying out this research, the health information we will see and use 
about you will include:  
• 
Demographic information: Name, Address, Phone Number, Date of Birth 
• 
Medical History: What medical conditions you have and information about them 
• 
Screening information (information that is obtained during your screening visit) 
• 
Information that is collected during study testing 
 
We will get this information by asking you, reviewing medical records in UTSW or THR electronic medical 
record, requesting medical records from your doctors or collecting this information through study procedures. 
 
How will your PHI be shared?   
Because this is a research study, we will be unable to keep your PHI completely confidential.  We may share 
your health information with people and groups involved in overseeing this research study including: 
IRB Approved Date: 8/18/2023


Title of Study: The effects of low-dose analgesics on cardiovascular function 
 
STU2021-0579, Crandall, FormE-Consent, Mod_7, 08-18-23 
 
 
Page 11 of 13 
                           
UTSW Research Consent and Authorization Documents (v January 2019) 
• 
Members of the local research team. 
• 
The Institutional Review Board, Human Research Protection Program Office and the Compliance Office 
of the University of Texas Southwestern Medical Center, and other groups that oversee how research 
studies are carried out. 
• 
Department of Defense and other U.S. and international governmental regulatory agencies involved in 
overseeing research. 
• 
A Data Safety Monitoring Board is the committee that checks the study data on an ongoing basis, to 
determine if the study should be stopped for any reason 
• 
The Food and Drug Administration (FDA) and other U.S. and international governmental regulatory 
agencies involved in overseeing drug or device research. 
• 
The Research offices at the University of Texas Southwestern Medical Center and Texas Health 
Resources.  
• 
Representatives of domestic and foreign governmental and regulatory agencies may be granted direct 
access to your health information for oversight, compliance activities, and determination of approval for 
new medicines, devices, or procedures. 
 
If you decide to participate in this study, you will be giving your permission for the groups named above to 
collect, use and share your health information.  If you choose not to let these groups collect, use and share 
your health information as explained above, you will not be able to participate in the research study. 
 
Parts of your PHI may be photocopied and sent to a central location or it may be transmitted electronically, 
such as by e-mail or fax. The groups receiving your health information may not be obligated to keep it private.  
They may pass information on to other groups or individuals not named here.   
 
How will your PHI be protected?   
In an effort to protect your privacy, the study staff will use code numbers instead of your name, to identify your 
health information. Initials and numbers will be used on any photocopies of your study records, and other study 
materials containing health information that are sent outside of our laboratory for review or testing. If the results 
of this study are reported in medical journals or at meetings, you will not be identified. 
 
Do you have to allow the use of your health information? 
You do not have to allow (authorize) the researchers and other groups to see and share your health 
information.  If you choose not to let the researchers and other groups use your health information, there will 
be no penalties but you will not be allowed to participate in the study.   
 
After you enroll in this study, you may ask the researchers to stop using your health information at any time.  
However, you need to say this in writing and send your letter to Craig Crandall, Institute for Exercise and 
Environmental Medicine, 7232 Greenville Avenue, Dallas, TX 75231. If you tell the researchers to stop using 
your health information, your participation in the study will end and the study staff will stop collecting new 
health information from you and about you for this study.  However, the study staff will continue to use the 
health information collected up to the time they receive your letter asking them to stop. 
 
Can you ask to see the PHI that is collected about you for this study?   
The federal rules say that you can see the health information that we collect about you and use in this study.   
 
Contact the study staff if you have a need to review your PHI collected for this study. 
 
Because of the type of research, you can only access your PHI when the study is done.  At that time, you have 
the right to see and copy the medical information we collect about you during the study, for as long as that 
information is kept by the study staff and other groups involved. 
 
How long will your PHI be used?   
By signing this form, you agree to let us use and disclose your health information for purposes of the study until 
IRB Approved Date: 8/18/2023


Title of Study: The effects of low-dose analgesics on cardiovascular function 
 
STU2021-0579, Crandall, FormE-Consent, Mod_7, 08-18-23 
 
 
Page 12 of 13 
                           
UTSW Research Consent and Authorization Documents (v January 2019) 
the end of the study.  This permission to use your personal health information expires when the research ends 
and all required study monitoring is over. 
 
Contact Information – Who can you contact if you have questions, concerns, comments or 
complaints? 
 
If you have questions now, feel free to ask us.  If you have additional questions, concerns, comments or 
complaints later or you wish to report a problem which may be related to this study please contact: 
 
Primary contact: 
Research Nurse: Courtney Hakes, BSN, RN can be reached at 214-345-6502 or 
CourtneyHakes@TexasHealth.org. 
 
If primary is not available, contact Craig Crandall, PhD at 972-522-8859. 
 
The University of Texas Southwestern Medical Center Human Research Protection Program (HRPP) oversees 
research on human subjects.  HRPP and Institutional Review Board (IRB) representatives will answer any 
questions about your rights as a research subject, and take any concerns, comments or complaints you may 
wish to offer.  You can contact the HRPP by calling the office at 214-648-3060. 
 
 
IRB Approved Date: 8/18/2023


Title of Study: The effects of low-dose analgesics on cardiovascular function 
 
STU2021-0579, Crandall, FormE-Consent, Mod_7, 08-18-23 
 
 
Page 13 of 13 
                           
UTSW Research Consent and Authorization Documents (v January 2019) 
Research Consent & Authorization Signature Section 
If you agree to participate in this research and agree to the use of your protected health information in this 
research, sign this section.  You will be given a copy of this form to keep.  You do not waive any of your legal 
rights by signing this form. 
 
 
SIGN THIS FORM ONLY IF THE FOLLOWING STATEMENTS ARE TRUE: 
• 
You have read (or been read) the information provided above. 
• 
Your questions have been answered to your satisfaction about the research and about the collection, 
use and sharing of your protected health information. 
• 
You have freely decided to participate in this research or you are voluntarily giving your consent for 
another person to participate in this study because you believe this person would want to take part if 
able to make the decision and you believe it is in this person’s best interest.   
• 
You understand that a copy of this signed consent document, information about this study, and the 
results of any test or procedure that may affect your medical care, may be included in your medical 
record. Information in your medical record will be available to health care providers and authorized 
persons including your insurance company. 
• 
You authorize the collection, use and sharing of your protected health information (another person’s 
protected health information) as described in this form. 
 
Adult Signature Section  
 
 
 
 
 
 
 
AM 
PM 
Printed Name of Participant 
 
 
 
Signature of Participant 
 
 
 
Date 
 
Time 
 
 
 
 
 
 
 
AM 
PM 
Printed Name of Person 
Obtaining Consent 
 
Signature of Person Obtaining 
Consent  
 
 
Date 
 
Time 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blind or Illiterate Signature Section  At the time of consent, also complete this section if consent is obtained from 
an individual who is unable to read and/or write but can otherwise communicate and/or comprehend English (e.g., 
blind, physically unable to write, etc.)  
 
Declaration of witness: 
By signing below, I confirm I was present for the entire consent process. The method used for communication 
(e.g., verbal, written, etc.) with the subject was:                                      .   
 
The specific means (e.g., verbal, written, etc.) by which the subject communicated agreement to participate  
was:                                             .          
 
 
 
 
 
 
 
 
AM 
PM 
Printed Name of Witness 
 
 
Signature of Witness 
 
 
Date 
 
Time 
 
 
 
IRB Approved Date: 8/18/2023

Prot_SAP_002.pdf: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
The effects of low-dose analgesics on cardiovascular function (STU-2021-0579) 
NCT04959812 
8/18/2023 
 
 
 


Form A 
STU-2021-0579 
 
STU2021-0579, Crandall, FormA-Protocol, Mod_7, 08-18-23 
 
1 
V2Mar2018 
PROTOCOL FORM / RESEARCH DESCRIPTION 
 
If an item does not apply to your research project, indicate that the question is "not applicable” – do not leave 
sections blank 
 
Click once on the highlighted entry in each box to provide your response.  Click the item number/letter or 
word, if hyperlinked, for detailed instructions for that question.  If your response requires inserting a table, 
picture, etc, you may need to first delete the box that surrounds the answer and then insert your table or other 
special document. 
 
1.  Purpose and objectives.           List the purpose and objectives: 
 
The objective of this study is to identify whether sublingual sufentanil decreases tolerance to a simulated 
hemorrhagic insult in humans.  
 
2.  Background. 
• 
Describe past experimental and/or clinical findings leading to the formulation of your study.   
• 
For research involving investigational drugs, describe the previously conducted animal and human 
studies.   
• 
For research that involves FDA approved drugs or devices, describe the FDA approved uses of 
this drug/device in relation to your protocol.   
• 
Attach a copy of the approved labeling as a product package insert or from the Physician’s Desk 
Reference.   
You may reference sponsor’s full protocol or grant application (section number and/or title) or if none, 
ensure background includes references. 
 
Please respond to all components of this item, or clearly indicate which components are not applicable. 
 
a. Background 
Hemorrhage is the leading cause of battlefield and civilian trauma deaths.  In the early stages of a 
hemorrhagic injury, autonomic compensatory mechanisms are engaged that are vital to maintain blood 
delivery to vital organs.  
 
Hemorrhagic injuries are virtually always accompanied with pain. Pain management of an injured 
soldier is a critical component of the medical care of that casualty. It is critical that the employed 
analgesic not compromise autonomic responses requisite to maintain arterial blood pressure, and thus 
blood flow, in a hemorrhaging individual.  Sublingual sufentanil was recently approved by the FDA and 
is being deployed on the battlefield as and analgetic. No studies have evaluated the effects of 
analgesic doses of sufentanil on tolerance to a simulated (or actual) hemorrhagic insult in humans.   
 
We propose that if sufficient doses of commonly employed analgesics are administered to humans, 
otherwise appropriate cardiovascular responses to the hemorrhagic insult will be suppressed, thereby 
reducing the ability of the individual to tolerate that insult.  That said, the effects of analgesic doses of 
such agents (i.e., doses that are recommended for the pre-hospital setting) on physiological responses 
necessary to preserve tolerance to a hemorrhagic insult in humans is entirely unknown. Thus, the 
objective of this work is to identify the effects of sublingual sufentanil on tolerance to a simulated 
hemorrhagic challenge in humans. 
 


Form A 
STU-2021-0579 
 
STU2021-0579, Crandall, FormA-Protocol, Mod_7, 08-18-23 
 
2 
V2Mar2018 
b. Current practice 
A 30 microgram dose of sufentanil (trade name: Dsuvia) is administered sublingually for the 
management of acute pain. 
 
3.  Study Design.  
Describe the study design (e.g., single/double blind, parallel, crossover, etc.)  Consider inserting a scheme 
to visually present the study design. 
 
We will conduct a double-blind, placebo-controlled, crossover study. Following informed consent and 
screening, eligible participants will be randomized to complete the sufentanil or the placebo trial first, with the 
other “agent” administered during the subsequent visit. During these experimental visits, we will administer 
two assessments of pain perception (described in greater detail below), then administer sufentanil 
sublingually or a placebo pill also sublingually, perform the simulate hemorrhagic tolerance assessment 
(lower-body negative pressure), and then re-assess the measures of pain perception. The graphics below 
depicts the study design and experimental protocol, respectively.  
 
 
 
 
 
 
 
4.  Research Plan / Description of the Research Methods:   
4.a.  Provide a comprehensive narrative describing the research methods.   
     1) Provide the order in which tests/procedures will be performed,  
     2) Provide the setting for these events and a description of the methods used to protect privacy 
during the study.   
     3) Provide the plan for data analysis (include as applicable the sample size calculation) 
 
Please respond to all components of this item, or clearly indicate which components are not applicable. 
 
Consent, 
Screening, 
Questionnaires
Sufentanil 
Trial
Placebo 
Trial
Sufentanil 
Trial
Placebo 
Trial
randomized
Instrumentation and quiet rest 
(30-90 minutes)
Pre-drug baseline & 
pain assessments
Progressive LBNP 
tolerance test
Post-LBNP recovery, pain assessments, 
and de-instrumentation
Sufentanil or Placebo 
Administration
EXPERIMENTAL PROTOCOL
~30 min wait


Form A 
STU-2021-0579 
 
STU2021-0579, Crandall, FormA-Protocol, Mod_7, 08-18-23 
 
3 
V2Mar2018 
Inclusion: 
• 
18-45 years of age  
• 
Healthy 
• 
Body mass index less than 33 kg/m2 
• 
Body mass greater than or equal to 60 kg 
• 
Speak English 
 
Exclusion: 
• 
Subjects not in the defined age range 
• 
Subjects who have cardiac, respiratory, neurological and/or metabolic illnesses 
• 
Any known history of renal or hepatic insufficiency/disease 
• 
Pregnancy or breast feeding 
• 
Body mass less than 60 kg 
• 
Current smokers, as well as individuals who regularly smoked within the past 3 years 
• 
Subjects who cannot speak or read English 
• 
Positive urine drug screen 
• 
Currently taking pain modifying medication(s) 
 
Although this study requires relatively uncomplicated procedures, inclusion of non-English speaking subjects 
would compromise subject safety. Consequently, it is imperative that the research and medical staff can 
communicate instantly and effectively with subjects, without the need of a translator. Therefore, the 
investigators feel that inclusion of non-English speakers would markedly and unnecessarily increase the risk 
to those participants. 
 
Healthy adults will be recruited via online and paper flyers, emails to the Texas Health System (reaches over 
18,000 people), local universities (inclusive of UTSW), and our institutional participant database. Participants 
must be free from underlying serious medical conditions (detailed via medical history, physical exam), non-
smokers, have a body mass index less than 33 kg/m2, and will be excluded if they have any current 
cardiometabolic diseases (e.g., diabetes, heart disease). Individuals who are pregnant, planning to become 
pregnant, or breastfeeding will be excluded. We will also exclude those with a history of drug abuse. 
 
As described above, all participants will complete an informed consent and screening for eligibility. 
Participants will be randomized to complete either the sufentanil or placebo trial first. During these 
experimental visits, we will administer two assessments of pain perception (described in greater detail below), 
then administer sufentanil sublingually or a placebo pill also sublingually, perform the simulate hemorrhagic 
tolerance assessment (lower-body negative pressure), and then re-assess the measures of pain perception. 
 
The setting for all visits will be the Institute for Exercise and Environmental Medicine. Trials will be conducted 
in controlled laboratory settings. During the experimental visits (sufentanil and placebo), we will record 
baseline cardiovascular measures. UT-Southwestern anesthesiologist Joseph Hendrix, MD, or a research 
nurse (with direct oversight from Dr. Hendrix) will administer sufentanil (30 microgram tablet) or placebo tablet 
during each experimental visit (i.e., participants will receive only one 30 microgram tablet of sufentanil).  We 
will assess brachial blood pressure, nervous system activity via ultrasound-guided microneurography from 
the upper arm, beat-to-beat arterial blood pressure via photoplethysmography, cerebral perfusion via 
transcranial Doppler, limb blood flow via Doppler ultrasound, heart rate via electrocardiogram, respiration rate 
and end-tidal CO2 via capnography from a nasal cannula, peripheral oxygen saturation via pulse oximetry, 
compensatory reserve via photoplethysmography, and plasma catecholamine concentrations from serial 
blood samples collected throughout the visit (~4 tablespoons per experimental visit). In addition, both before 
and after sufentanil/placebo administration, pain perception will be accessed via a cold pressor test (2-3 


Form A 
STU-2021-0579 
 
STU2021-0579, Crandall, FormA-Protocol, Mod_7, 08-18-23 
 
4 
V2Mar2018 
minutes of a hand placed in a water/ice slurry) and via a pressure algometer assessment (pressure applied 
to the hand to the point if discomfort). 
 
Data analysis will be performed as done previously in Dr. Craig Crandall’s laboratory in companion studies 
addressing the same questions but with ketamine (STU 092017-068), fentanyl (STU 092017-069), and 
morphine (STU 092017-070). Specifically, we will compare cardiovascular data (inclusive of nervous system 
activity data) between time points (baseline and post-drug/placebo administration) and conditions.  We will 
also assess tolerance to the simulated hemorrhage challenge between sufentanil and placebo trials. All data 
will be analyzed while blind to condition and with proper co-variate analysis 
 
Personal health information (PHI) that is collected will be kept in a key-lock filing cabinet in a key-lock room 
only accessible to study team members within a numeric-padlocked laboratory. As described in the eIRB 
portal, a coded number system will be used in place of the participants name to de-identify their research 
information collected. A participant ID key, only accessible to study team members, will link the participants 
‘information with the coded number. Additionally, we follow all applicable University of Texas Southwestern 
IRB and Institute of Exercise and Environmental Medicine (i.e., where the research will take place) guidelines 
for protecting research participant privacy. 
 
Up to 60 participants are anticipated to enroll in this study. No study has evaluated the effects of sufentanil 
on lower-body negative pressure (LBNP) tolerance in humans.  The power and sample size estimates are 
based on findings from Dr. Crandall’s laboratory showing reduced LBNP tolerance in the heat-stressed 
individuals. In that study heat stressed reduced LBNP tolerance by ~70% (P<0.001).  Though we expect 
sufentanil to likewise reduce LBNP tolerance, we do not anticipate as large of a reduction as that observed 
with heat stress. The power analysis was calculated using G*Power [Ttests – Means:  Difference between 
two dependent means (matched pairs)] using an estimated reduction in the cumulative stress index to 
sufentanil of 25% relative to LBNP tolerance of a normothermic subjects taking a placebo (i.e., placebo: 
988±402 units; sufentanil: 741±300 units).  These predictions resulted in an effect size of 0.68.  Having a 
correlation of 0.5, with a study power=0.80 at an adjusted alpha=0.05, yielded an estimated subject size of 
15 individuals.  That value was inflated to 30 subjects (15 male and 15 female) to permit a comparison in the 
primary responses within sexes. Given the potential for subject dropouts, we propose to recruit up to  60 
individuals to obtain complete datasets from 30 subjects. Since the effects of sufentanil on LBNP tolerance 
has never been assessed, the indicated values are estimates and thus interim power analyses will be 
performed, with the number of required subjects adjusted based upon the variance of the obtained data. 


Form A 
STU-2021-0579 
 
STU2021-0579, Crandall, FormA-Protocol, Mod_7, 08-18-23 
 
5 
V2Mar2018 
 
4.b.  List of the study intervention(s) being tested or evaluated under this protocol 
 N/A -  this study does not test or evaluate an intervention.    Skip to item 4.d. 
# 
Study intervention(s) being tested or evaluated under the 
protocol 
 
 
 
Add or delete rows as needed 
 
Affiliate 
 
Place a check 
next to 
institution(s) 
where the  
intervention will 
be performed 
Local 
Standard 
Practice?  
Indicate 
whether the 
intervention is 
considered 
acceptable 
practice locally 
for applicable 
institutions 
1 
Sufentanil/Placebo administration  
☐ UTSW 
☐ Yes 
☐ PHHS 
☐ Yes 
☐CMC 
☐ Yes 
☒THR 
☐ Yes 
☐TSRH 
☐ Yes 
☐ Other: _____ 
☐ Yes 
 
 
4.c.  Risk:Benefit Analysis of study interventions being tested or evaluated under this protocol 
For each study intervention identified in section 6b above, complete a risk:benefit analysis table. 
 
(Two tables are provided, copy & paste additional tables as needed or delete both tables if this study does 
not test an intervention) 
 


Form A 
STU-2021-0579 
 
STU2021-0579, Crandall, FormA-Protocol, Mod_7, 08-18-23 
 
6 
V2Mar2018 
4.c. 
Study Intervention #1 
Sufentanil/Placebo Trials 
List each group exposed to this 
intervention on a separate line. 
(e.g., experimental, control, Arm A, 
Arm B, etc) 
Or state All Groups/Subjects 
For each group, list the benefits of this intervention.  (Benefits can 
be directly from the intervention or from a monitoring procedure 
likely to contribute to the subject’s well being).  If there are no 
benefits, state “none”. 
All subjects 
Learning of screening information (e.g., resting blood pressure) may 
positively contribute to the participant’s well being 
If you are requesting a Waiver of Informed Consent, complete the table below. 
 
If you have a consent form, list the reasonably foreseeable risks in the consent form (and do not 
complete this section).   
 
List the risks according to the probability (likely, less likely or rare) and magnitude (serious or not serious). 
(include: 1) expected adverse events; 2) rare and serious adverse events; 3) all other psychological, social, 
legal harms) 
Do not delete frequency.  Frequency must be estimated because it will assist you with determining which 
adverse events will require prompt reporting.   
 
Not serious 
Serious  
Likely 
These risks are expected to 
occur in more than 20 out of 
100 subjects. 
• 
N/A 
• 
N/A   
 
Not serious 
Serious 
Less likely  
These risks are expected to 
occur in 5-20 subjects or less 
out of 100 subjects. 
• 
N/A   
• 
N/A   
 
 
Serious 
Rare  
These risks are expected to 
occur in less than 5 subjects 
out of 100  
 
• 
N/A   
 


Form A 
STU-2021-0579 
 
STU2021-0579, Crandall, FormA-Protocol, Mod_7, 08-18-23 
 
7 
V2Mar2018 
 
4.d. List ALL other research procedures or components not listed in table 4.b. 
        The combination of Tables 4b and 4d should account for all of the 
research procedures that will take place during this study. 
 
Consider grouping similar procedures under a single component (e.g., blood 
work, CT = safety assessments) 
 
 
 
# Research 
component 
• 
individual 
procedures 
 
example: 
Eligibility 
Assessments 
• 
History and 
physical 
• 
Questionnaire 
• 
Laboratory 
tests 
Add or delete rows 
as needed 
Column A 
Local Standard 
Practice Indicate 
the number of 
times each 
procedure will be 
performed as 
stipulated in the 
research plan 
that would be 
performed if the 
participant were 
not 
participating in 
the study. 
Column B 
Research Only  
Indicate the number of 
times each procedure will 
be performed solely for 
research purposes 
(meaning that the 
participant would not 
undergo the same number 
of procedures or would not 
undergo the procedure(s) 
at the same frequency if 
they were not participating 
in the study) 
Column D 
Risks 
If you are requesting a 
Waiver of Informed Consent, 
complete the table below. 
 
List the reasonably expected 
risks for each procedure or 
group of procedures under the 
following categories as 
appropriate: 
• Serious and likely; 
• Serious and less likely; 
• Serious and rare; 
• Not serious and likely; 
• Not serious and less likely 
1 Eligibility 
assessments 
 
 
 
 
Body height and 
mass, waist and hip 
circumference 
0 
Body height = 1, body 
mass recorded at each 
visit, waist and hip 
circumference = 1 
 
 
Heart rate and 
rhythm via 12-lead 
ECG 
0 
1 
 
 
Brachial blood 
pressure 
0 
Usually 3 to 5 measures 
 
2 Other assessments 
 
 
 
 
Health history 
assessment 
0 
1 
 
 
Lower-body negative 
pressure tolerance 
assessment 
0 
2 
 
3 Blood sampling 
 
 
 
 
Blood sampling 
0 
Up to 10 draws (up to 5 
draws per visit; baseline, 
and up to 4 time points 
post-drug/placebo 
administration). Total blood 
withdrawn: ~8 tablespoons. 
 


Form A 
STU-2021-0579 
 
STU2021-0579, Crandall, FormA-Protocol, Mod_7, 08-18-23 
 
8 
V2Mar2018 
4 Cardiovascular and 
other physiological 
measures 
 
 
 
 
Heart rate and 
rhythm via ECG 
0 
continuous throughout 
visits 
 
 
Brachial blood 
pressure 
0 
several throughout visits, 
several in the 24-hour 
period after experimental 
visits 
 
 
Finger blood 
pressure 
0 
continuous throughout 
visits 
 
 
Microneurography for 
nervous system 
activity assessment 
0 
continuous throughout 
visits (needles placed at 
beginning of visits and 
removed before discharge) 
 
 
Brain blood flow 
0 
continuous throughout 
visits 
 
 
Limb blood flow 
0 
several throughout the 
experimental visits 
 
 
End-tidal carbon 
dioxide 
0 
continuous throughout 
visits 
 
 
Pulse oximetry 
0 
continuous throughout 
visits 
 
 
Tissue oxygen 
saturation 
0 
continuous throughout 
visits 
 
 
Urine sample 
0 
once each visit 
 
5 Sufentanil 
Administration 
0 
Once 
 
 
 
 
5.  Safety Precautions.  (Describe safeguards to address the serious risks listed above.) 
a.  Describe the procedures for protecting against or minimizing any potential risks for each of the more 
than minimal risk research procedures listed above. 
Sufentanil administration: 30 micrograms of sufentanil will be administered once during one of the two 
experimental visits. The product that will be used will be a DsuviaTM sublingual tablet, or similarly packaged 
placebo. 
Risks and their mitigation: After sufentanil administration, it is possible participants will temporarily (e.g., 
to several minutes) experience low blood pressure, high heart rate, disorientation, become tired or dizzy, 
and/or develop a headache. While some individuals may feel discomfort from one or more of these 
sensations, it is expected that they will subside within a few minutes. In rare cases subjects may become 
nauseous or vomit. In extremely rare conditions individuals may have difficulty breathing. In such extreme 
cases, when medical treatment is needed, we will immediately stop testing and monitor the participant 
until all vital signs are within safe limits. Naloxone will completely reverse all opioid effects within 2 
minutes of IV administration and 5 minutes of intramuscular administration. However, at the dose in the 
study proposed, we do not expect that significant respiratory depression will occur.  We will monitor the 
patient's vital signs continuously.  We will monitor pulse oximetry and end tidal carbon dioxide 
continuously. These two monitors will provide sufficient accuracy and robustness to administer this 
medication safely.  An anesthesiologist will be present whenever sufentanil is administered to observe 
and intervene should the patient exhibit the slightest evidence of respiratory depression well before any 


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patient danger should arise.  Standard airway intervention equipment will always be readily available. We 
have safely performed similar trials, using identical experimental procedures, with ketamine (STU 
092017-068), fentanyl (STU 092017-069), and morphine (STU 092017-070) administrations without major 
complications in 40+ young adults in the previous two years. 
 
Upon the conclusion of the protocol, subjects will not be permitted to leave the laboratory until all of the 
following discharge variables are met:  
• 
The subject presents with an Aldrete score (post-anesthesia discharge scoring system) matching 
baseline,  
• 
The subject demonstrates a awareness of time, person, and place and is able to answer 
questions appropriately 
• 
The subject is able to stand up and walk for 5 minutes without assistance (supervised) 
• 
The subject is able to drink water and eat crackers without reports of nausea 
• 
The subject able to void   
To be consistent with THR/UTSW hospital guidelines—the subject will be required to have a responsible 
adult bring them home.  The responsible adult can either drive the subject home or accompany the 
subject home using ground transportation (bus, train, uber, or taxi service).  The subject will also receive 
the recommendation to have someone observe them for the rest of the day and overnight. 
 
Lower-body negative pressure (LBNP): LBNP to pre-syncope will be used to simulate a hemorrhagic 
injury. LBNP is performed by the subject lying on a table with their lower body (from iliac crest) inside an 
airtight container.  A vacuum source is connected to that container.  40 mmHg negative pressure will 
initially be applied to the chamber for 3 min, with this pressure decreasing by 10 mmHg every 3 min until 
signs and/or symptoms of pre-syncope are observed (e.g., bradycardia, sustained systolic blood pressure 
<80 mmHg, nausea, lightheadedness, and/or diaphoresis). This approach is a validated method to 
simulate a hemorrhagic challenge (see PMID: 15016789). Dr. Crandall’s laboratory has performed this 
procedure on hundreds of individuals (inclusive of 40+ individuals who received ketamine, morphine, or 
fentanyl) without any adverse incidents.  
Risks and their mitigation: The possible risks of this procedure are light-headedness, feeling faint, nausea 
and rarely a subject may faint. If this occurs, the procedure will be stopped and the subject will begin to 
feel better almost immediately. 
 
Cold pressor test:  This widely used technique for pain assessment presents minimal risk.  For this test, 
immersion of the hand in ice cold water will elicit painful sensations as well as an increase in blood 
pressure.   
Risks and their mitigation: These typical responses are immediately reduced to pretest levels with the 
removal of the subject’s hand from the ice water.  The maximum duration for this test is three minutes and 
the subject can voluntarily remove the hand from the ice water at any time.   
 
Pressure algometry: This pain assessment technique is conducted by applying the rubber tip of a hand-
held digital algometer on the subject’s digit.  Force will be gradually increased and the peak force is 
recorded when the subject first reports a painful sensation.   
Risks and their mitigation: Removal of the applied pressure immediately relieves the painful sensation, 
and the subject can voluntarily stop the test at any time. A pre-set maximum of 3 kg of pressure will 
ensure there is no damage to the tissue.    
 
Microneurography: Nerve signals from the nerves in the arm [i.e. median nerve (inside portion of the 
middle part of the arm), radial nerve (inside portion of the forearm), or posterior cutaneous nerve (outside 
portion of the forearm)] will be measured. To locate the nerves, we use ultrasound imaging. When the nerve 
is located, we insert a small sterile needle (an electrode about the size of an acupuncture needle) through 
the skin. The participant may feel some slight discomfort during needle insertion. The recording needle is 
advanced into the nerve. When the tip of the needle enters the nerve, the participant may notice a tingling, 


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pins and needles, cramping, or dull achy sensation. A second needle serves as a reference electrode and 
is inserted just under the skin, a couple of inches away from the nerve. Once the needles are in place it is 
extremely unlikely the participant will feel any discomfort. This method of recording nerve signals in human 
participants has been used in over 3000 studies since 1979. We have performed over 300 recordings in 
our laboratory without any major complications. In rare cases, individuals may have tenderness, soreness, 
or numbness in the nerve recording area for a few days that subsides without treatment. 
Risks and their mitigation: Consistent with published guidelines for microneurography, we will limit the nerve 
search time (from needle insertion until an adequate signal is acquired) to 60 minutes. Also, we will not 
record from the same nerve within one 28-day period. While not anticipated, we will stop this technique if 
they feel too much discomfort from microneurography. Participants will be instructed not to perform heavy 
lifting and to avoid rubbing/massaging the upper arm for ~24 hours to reduce the potential for inflammation-
related acute neuropathy (occurs in fewer than 1% of cases). 
 
Blood draws: A sterile catheter will be inserted into an arm vein for blood collection of plasma 
catecholamine concentrations. A total of ~8 tablespoons of blood will be withdrawn across all visits.  
Risks and their mitigation: There is a small risk of infection and a still smaller risk of a blood clot or breakage 
of the catheter. The likelihood of these complications is remote (less than 1 in 10,000) when the procedure 
is carried out by trained personnel and proper equipment is used, as during this study. There is also a small 
risk of the catheter perforating the vein or not being inserted into a blood vessel. The participant may have 
discomfort, bleeding, and/or bruising and on rare occasions, a person may feel dizzy or faint. 
 
Health history assessment: Participants will fill out a survey related to their physical well-being. 
Risks and their mitigation: It is possible individuals may feel uncomfortable while completing this survey. 
We will ensure all participants are aware of this procedure during the informed consent visit. If a participant 
is uncomfortable completing all of the survey, they will be reminded that 1) their participation is entirely 
voluntary, 2) that only study investigators will have access to the surveys and their results, and 3) only de-
identified results will be shared in scientific meetings and/or in future scientific manuscripts. 
 
 
b.  Where appropriate, discuss provisions for ensuring necessary medical or professional intervention in 
the event of adverse events, or unanticipated problems involving subjects. 
When the participant is undergoing any testing, they will be supervised by an ACLS trained nurse and/or 
physician. Of note, a board-certified anesthesiologist will always be present when sufentanil is 
administered. There is a fully stocked “crash cart” with a defibrillator and medications (including naloxone) 
within 50 feet of the laboratory. IV anti-arrhythmic medications are rapidly available if a sustained but not 
life-threatening arrhythmia were to occur. Airway management equipment is also stocked in that cart. 
Furthermore, the Texas Health Resource Emergency Room is minutes away if an escalation of care is 
required. 
 
Upon screening, participants will be given contact information for a nurse to contact in case any adverse 
event occurs following discharge from experimental days. However, this is unlikely to occur given the 
short-acting effects of sufentanil and the fact that participants are not discharged until vital signs are 
similar to that of baseline values. 
 
c.  Will the safeguards be different between/among groups?   
 
Yes 
 
No 
 
 
 


Statistical Analysis 
Data was assessed for normality and are presented as means ± SD or medians [interquartile 
ranges], when appropriate. Based on our prior data investigating pharmacologic agents’ effects 
on tolerance to LBNP (12, 24, 25), a sample size of n = 15 was estimated, but to maintain 
consistency with the previous studies, we recruited 29 individuals. Paired t-tests or Wilcoxon 
Signed-Rank tests were used for all paired comparisons (e.g., Urine-specific gravity, CSI, pain 
ratings, differences in CSI between the sexes etc.). Plasma catecholamine concentrations were 
compared between trials (placebo vs. sufentanil) using mixed-effects model analyses. 
Cardiovascular and cerebrovascular responses were evaluated every 30 seconds for the cold 
pressor test [time x trial], and the last minute of each LBNP stage [LBNP stage x trial], with the 
variables with each challenge compared using repeated-measures two-way ANOVAs or mixed-
effects model. If a significant interaction was identified, a post hoc Šidák multiple comparison 
test was employed. Α < 0.05 was considered statistically significant. Data were analyzed using 
GraphPad Prism 9 (GraphPad Software Inc., La Jolla, CA, USA).