Intranasal Cocaine and Temperature Regulation During Exercise
Phase: PHASE1
Conditions: Hyperthermia, Cocaine Use, Exercise
Sponsor: University of Texas Southwestern Medical Center

STUDY PROTOCOL AND STATISTICAL ANALYSIS PLAN 
 
 
 
Official title:  Intranasal cocaine and temperature regulation 
during exercise 
 
NCT number: NCT05809453 
IRB Approved date: 02-07-2024 

Form A 
STU-2023-0094 
 
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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 intranasal cocaine impairs temperature regulation during 
exercise in warm environmental conditions.  
 
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 
Individuals who abuse cocaine for recreational purpose can have excessively elevated core 
temperatures (PMID: 9628710, 7484066, 8010552, 18823733, and 2728444). Using a passive heat 
stress approach, we previously showed that intranasal cocaine administration suppressed skin blood 
flow and sweating (PMID: 12044126).  However, it remains unknown whether suppression of skin 
blood flow and sweating responses to cocaine are sufficient to cause excessive elevations in core 
temperature during exercise.    
 
We propose that cocaine-induced reductions in sweating and skin blood flow will result in excessive 
elevations in core temperature during exercise in warm environmental conditions. Thus, the objective of 
this work is to test the hypothesis that intranasal cocaine impairs core temperature responses during 
mild to moderate intensity exercise while in warm environmental conditions. 
 
b. Current practice 
A cocaine solution, administered in each nostril to achieve analgesia and vasoconstriction, is commonly 
used in rhino-surgical procedures (PMID: 32730351, 16848922, and 26452438). According to the 
product insert, “The total dose for any one procedure or surgery should not exceed 3 mg/kg cocaine 
hydrochloride”, which is the basis for our decision to not administer more than 3 mg/kg cocaine for any 
one procedure.  
 

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A lidocaine solution is also commonly used for related procedures (PMID: 26452438, 24980226, and 
30017430) at doses similar to proposed with the present protocol.   
 
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 cocaine or the placebo (lidocaine) trial first, 
with the other “agent” administered during the subsequent visit. After the administration of either of these 
drugs, the participate will perform mild to moderate intensity exercise in warm environmental conditions (no 
higher than 41 °C).  
 
 
 
 
 
 
 
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
Cocaine
Trial
Placebo 
Trial
Cocaine 
Trial
Placebo 
Trial
randomized
Instrumentation and pre-drug 
baseline measures (~30 minutes)
60 minutes of 
exercise
Post-exercise measures 
and de-instrumentation
Cocaine or Placebo 
Administration
EXPERIMENTAL PROTOCOL
Move into 
heated room

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Inclusion: 
• 
18-50 years of age  
• 
Healthy 
• 
Non-obese (body mass index less than 31 kg/m2) 
• 
Speak English 
• 
Systolic blood pressure <140 mmHg 
• 
Diastolic blood pressure <90 mmHg 
 
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 
• 
Current smokers, as well as individuals who regularly smoked within the past 3 years 
• 
Subjects who cannot speak or read English 
• 
History of drug above within the past 5 years 
• 
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 31 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 cocaine or placebo trial first. During these experimental 
visits, participants will perform mild to moderate-intensity exercise in warm environmental conditions (no 
higher than 41 °C). 
 
The setting for all visits will be the Institute for Exercise and Environmental Medicine. Trials will be conducted 
in controlled laboratory settings. A physician with a license to prescribe schedule II drugs (Noah Jouett DO, 
Satyam Sarma MD, or Tiffany Brazile MD), or a research nurse (with oversight from that physician) will 
administer cocaine (no higher than 3 mg/kg body mass) or placebo (lidocaine, no higher than 3 mg/kg body 
mass) during each experimental visit. We will assess core and skin temperatures, local and whole-body sweat 
rate, brachial blood pressure, heart rate via electrocardiogram, respiration rate (from metabolic cart), 
compensatory reserve via photoplethysmography, and plasma catecholamine concentrations from blood 
samples collected prior to and after exercise (~3 tablespoons per experimental visit). In addition, ratings of 
perceived exertion and thermal perception will be obtained.  
 
Data analysis will be performed as done previously in Dr. Craig Crandall’s laboratory in companion studies 
addressing the same questions but during passive heating rather than exercise (PMID: 12044126). 
Specifically, we will compare thermoregulatory and cardiovascular data (e.g., baseline and end-exercise) 

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between placebo and cocaine trials. All data will be analyzed while blind to condition and with proper co-
variate analyses. 
 
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 30 participants are anticipated to enroll in this study, with a goal of obtaining complete datasets on 20 
individuals. No study has evaluated the effects of cocaine on core temperature responses during exercise in 
warm (or thermoneutral) environmental conditions. The power and sample size estimates are based on 
findings from Dr. Crandall’s laboratory investigating core temperature responses to 60 min of exercise in burn 
survivors. Our rationale for using burn survivors is the expectation that the suppression in sweating in burn 
survivors with 20-40% body surface area burn may be similar to the suppression in sweating caused by 
cocaine. The power analysis was calculated using G*Power [Ttests – Means: Difference between two 
dependent means (matched pairs)] using a projected ~25% heightened increase in core body temperature 
following 60 minutes of exercise with cocaine relative to when participants received placebo (i.e., placebo: 
0.82±0.36 °C, cocaine: 1.02±0.40 °C). These predictions resulted in an effect size of 0.60. With a study 
power=0.81 at an alpha=0.05, yielded an estimated subject size of 19 individuals. That value was inflated to 
20 subjects (10 male and 10 female) to permit an exploratory comparison in the primary responses between 
sexes. Given the potential for subject dropouts, we propose to recruit up to 30 individuals to obtain complete 
datasets from 20 subjects. Since the effects of cocaine on thermoregulatory responses during exercise have 
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. 

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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 
Cocaine/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 4b 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) 
 

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4.c. 
Study Intervention #1 
Cocaine /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 
Identify whether intranasal cocaine impairs temperature regulation 
during exercise in warm environmental conditions 
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   
 

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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 
 
 
 
 
Health history 
assessment 
0 
Once 
 
 
Body height and 
mass 
0 
Once 
 
 
Heart rate and 
rhythm via 12-lead 
ECG 
0 
Once 
 
 
Brachial blood 
pressure 
0 
Approximately 3 times 
 
 
Submaximal exercise 
0 
Once during the screening 
visit 
 
 
Physical activity 
questionnaire (IPAQ) 
0 
Once 
 
2 Other assessments 
 
 
 
 
Core temperatures 
0 
Continuously during the 
experimental visits 
 
 
Skin temperatures 
0 
Continuously during the 
experimental visits 
 
 
Regional sweat rate 
0 
Continuously during the 
experimental visits 
 
 
Whole-body sweat 
rate 
0 
Once per experimental visit  

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Skin blood flow 
0 
Continuously during the 
experimental visits 
 
 
Limb blood flow 
(Doppler ultrasound) 
0 
Approximately 3 times 
 
 
60 minute of exercise 
in warm 
environmental 
conditions 
0 
Once per experimental visit  
 
Assessments of 
perceived exertion 
and thermal 
perception 
0 
Approximately every 10 
minutes during exercise 
 
3 Blood sampling 
 
 
 
 
Blood sampling 
0 
Up to 6 draws (up to 3 
draws per visit; baseline,  
post-drug/placebo 
administration, and post-
exercise). Total blood 
withdrawn for the entire 
study: ~6 tablespoons. 
 
4 Cardiovascular and 
other physiological 
measures 
 
 
 
 
Heart rate and 
rhythm via ECG 
0 
Continuously during the 
experimental visits 
 
 
Brachial blood 
pressure 
0 
Before exercise, 
approximately every 10 
minutes during exercise, 
and after exercise for each 
experimental visit 
 
 
Compensatory 
reserve 
0 
Continuously during the 
experimental visits 
 
 
Cardiac output 
0 
Approximately every 15 
minutes during exercise for 
each experimental visit 
 
 
Urine sample 
0 
Once each visit 
 
 
Ventilation and 
oxygen uptake 
0 
Approximately every 15 
minutes during exercise for 
each experimental visit 
 
 
 
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. 
Cocaine and lidocaine administration: No greater than 3 mg/kg body mass of cocaine or lidocaine will 
be administered once during one each experimental visit. At the administered doses of cocaine or lidocaine 
(doses consistent with procedures performed by an ears, nose, and throat physician in a doctor’s office 
setting) the risks to the participants are minimal. That said, the administered dose of cocaine has the 
potential to slightly elevate arterial blood pressure and heart rate. However, in our prior trial (PMID: 
12044126) cocaine increased resting blood pressure less than 10 mmHg and increased resting heart rate 

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less than 10 bpm, both relative to the placebo (lidocaine) trial. Thus, we do not expect blood pressures or 
heart rates to be excessively elevated. Importantly, in the healthy cohort that will be assessed, such 
increases in arterial blood pressure and heart rate are inconsequential. Importantly, we will monitor the 
patient's vital signs continuously for both the cocaine and lidocaine experimental limbs. A physician licensed 
to precribe schedule II drugs (Noah Jouett DO, Satyam Sarma MD, or Tiffany Brazile MD) will be present 
whenever cocaine is administered to observe and intervene should the patient exhibit the slightest evidence 
distress. Standard “crash cart” equipment (inclusive of a defibrillator) will always be readily available. As 
mentioned above, we performed similar trials, using cocaine and lidocaine (PMID: 12044126) in young 
healthy adults without any complications. 
 
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 an 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   
Sub-maximal exercise in thermoneutral conditions: There are no additional risks involved with 
performing a sub-maximal exercise test beyond that associated with light to moderate-intensity physical 
exertion. Every precaution will be taken to minimize the risk by closely monitoring vital signs (blood 
pressure, heart rate and rhythm) throughout the exercise. This test will be stopped if signs or symptoms of 
cardiac ischemia develop, if excessive hypertension or hypotension develop, or if arrhythmias occur during 
exercise. A research nurse will be present during the sub-maximal exercise test to interpret any danger 
signs and symptoms. 
 
Exercise in warm environmental conditions: Internal body temperature will be monitored throughout 
each experiment. The protocol will stop, and the environmental temperature will be reduced, in the unlikely 
occurrence that internal body temperature exceeds 39.5°C or upon any indication of adverse cardiovascular 
or neurological symptoms (e.g., lightheadedness, hypotension, hypertension, nausea, etc). Our 20+ years 
of experiences reveals that healthy individuals are able to tolerate the exercise bout well. Upon completion 
of each trial, we will ensure that each subject is normothermic and adequately hydrated prior to being 
permitted to leave the laboratory. A research nurse will monitor the participant’s vital signs throughout 
exercise and will stop the exercise, and cool the environment, should any adverse signs or symptoms occur. 
 
Internal temperature (temperature sensor pill): See comments above regarding the internal body 
temperature cut-off (39.5 °C) for all trials. This pill should not be taken if the subject weighs less than 80 
pounds, nor should the subject take this pill if they have or have had any gastrointestinal disease or 
surgery. The research nurse will also check each subject’s medical history prior to the pill being 
swallowed. Should a subject have any contraindications in taking the pill, the pill will not be ingested. 
Rather, rectal temperature will be obtained.  
 
Internal temperature (rectal sensor): If rectal temperature is used, the subject will self-insert a small 
single-use rectal temperature sensor to a pre-marked depth of 15 cm. The rectal thermocouple will not be 
inserted if they have or previously had inflammatory bowel or colon disease and/or rectal or anal surgery. 
They also may not use the probe if they currently have hemorrhoids (internal or external), rectal bleeding, 
diarrhea or fecal impaction in the rectum. Each subject’s medical history will be verified prior to self-
insertion of the rectal probe by the research nurse. 
 
Internal temperature (suppository pill): If a suppository temperature sensing pill is used, with a gloved 
hand the subject will self-insert a lubricated temperature sensor pill (like a suppository) into their rectum. 

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This pill will be discharged through normal defecation. This temperature sensing pill will not be used if the 
subject currently has hemorrhoids (internal or external), rectal bleeding, diarrhea or fecal impaction in the 
rectum. Each subject’s medical history will be verified by the research nurse prior to self-insertion of this 
pill.  
 
Blood draws: Blood draws will be obtained via a “butterfly” needle. No more than 6 tablespoons of blood 
will be withdrawn across all visits. There is a small risk of infection and a still smaller risk of a blood clot. 
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 
needle 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. 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. In addition, physicians and nurses at the Institute for Exercise and Environmental Medicine will 
assist as needed.  A physician licensed to prescribe schedule II drugs (Noah Jouett DO, Satyam Sarma 
MD, or Tiffany Brazile MD) will be present when cocaine is administered. There is a fully stocked “crash 
cart” with a defibrillator and medications within 50 feet of the laboratory. 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 cocaine 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