Clinical trial NCT04431206
Conditions: Osteoarthritis, Knee Healthy
Sponsor: Wake Forest University Health Sciences
Start date: 2020-11-04; Completion date: 2020-11-25
Enrollment: 7 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a study of participants that will receive an intravenous (IV) infusion of oxytocin (naturally occurring hormone that is made in the brain).

In this study healthy volunteers and people with knee arthritis so severe that they may need joint replacement are recruited for a one day study. Each study participant will have an IV catheter placed. After placement of the IV catheter oxytocin will be given by IV infusion. Investigators will perform some tests to evaluate how oxytocin changes perceptions on the skin. Investigators will study a painful perception by placing a probe on the skin and heating it to 113 -117 degrees Fahrenheit (F) for 5 minutes. Each study participant will score any pain that is experienced on a 0 to 10 scale, and most people find that pain rises during the 5 minutes, but remains mild, usually around only 1 or 2 on the 0 to 10 scale. The 5 minute heating temperature will be determined according to the subjects pain rating during the screening visit.

The main goal of the study is to determine the effect of oxytocin during and after a fixed rate intravenous infusion on reduction in pain to a sustained heat stimulus in order to generate a model for peripheral analgesia.

Detailed description:
In this study healthy people or those with knee arthritis so severe that they may need joint replacement are recruited for a one day study. Study participants will come to the Clinical Research Unit (CRU) and one intravenous (IV) catheter will be inserted in the forearm for oxytocin infusion. Participants in this study will receive oxytocin at a steady rate for 30 minutes. This information will be analyzed by another group at Stanford University in the Pharmacokinetic/Pharmacodynamic (PK/PD) Core part of this application. Mathematics will be utilized to calculate how quickly oxytocin moves from the blood to where it reduces pain.

Investigators will also do a pain test to determine how much oxytocin reduces pain. For this Investigators will place a probe on the skin and heat it to 113 - 117 degrees for 5 minutes. Study participants will score any pain they feel on a 0 to 10 scale, and most people find that pain rises during the 5 minutes, but remains mild, usually around only 1 or 2 on the 0 to 10 scale.

Arms: arm 1: Verbal pain score is recorded at the end of 5 minutes of heating the skin. In this arm the first score is obtained at 2 minutes after starting the intervention, then every 15 minutes for 60 minutes arm 2: Verbal pain score is recorded at the end of 5 minutes of heating the skin. In this arm the first score is obtained at 5 minutes after starting the intervention, then every 15 minutes for 60 minutes arm 3: Verbal pain score is recorded at the end of 5 minutes of heating the skin. In this arm the first score is obtained at 7 minutes after starting the intervention, then every 15 minutes for 60 minutes arm 4: Verbal pain score is recorded at the end of 5 minutes of heating the skin. In this arm the first score is obtained at 10 minutes after starting the intervention, then every 15 minutes for 60 minutes
Interventions: intervention 1: Oxytocin
Intervention descriptions: intervention 1: Oxytocin, 8.2 IU, administered by 30minute IV infusion starting at time 0

Protocol documents:
Prot_SAP_000.pdf: 
Official Title:  Generate a pharmacodynamic model of oxytocin for peripheral analgesic effects
NCT04431206
IRB Approval Date:  05/18/2022


Protocol version: 5/18/2022 
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Study Title: Generate a pharmacodynamic model of oxytocin for peripheral analgesic effects 
Principal Investigator: James C. Eisenach, M.D., Co-investigator(s): Douglas Ririe, M.D. 
Sponsor or funding source: NIH 
Background, Rationale and Context 
Oxytocin itself is the only tool we have to translate preclinical findings to the clinic, yet we know very 
little about its pharmacology in humans outside of obstetrics.  Most experimental studies utilize the 
intranasal route of administration resulting in minimal serum concentrations and uncertain brain 
penetration.  Until 3 years ago, oxytocin was measured by ELISA and RIA and those values are now 
considered suspect. Rigor of previous pharmacokinetic (PK) modeling is poor, there are no 
pharmacokinetic/pharmacodynamic (PK/PD) models for oxytocin by any route of administration for 
peripheral or central effects and, aside from contracting the pregnant uterus, there are no PD outcome 
measures appropriate to generate PK/PD models. 
This series of studies, submitted to the NIH for funding in Jan, 2020, translates work in animals to 
define peripheral and central PK/PD relationships of oxytocin action in normal volunteers, those with 
advanced knee arthritis, and those recovering from total knee arthroplasty (TKA).  We leverage novel 
hypotheses that light-touch sensitive, low threshold mechanoreceptors (LTMRs) are desensitized and 
nociceptive, A-conducting high threshold mechanoreceptors (A-HTMRs) are sensitized in the pathology 
of pain.  We test these novel ideas with multiple complex or novel pharmacokinetic/pharmacodynamic 
(PK/PD) models.  Together these 8 studies in 226 normal volunteers and patients over 5 years will 
address critical gaps in our understanding of the pharmacology of oxytocin as it relates to sensory 
processing and pain. 
Define oxytocin PK/PD relationships at peripheral sites of somatosensation 
Systemic oxytocin reduces pain from a 5 min, 45°C heat stimulus on the skin and studies suggest 
this effect occurs primarily in the periphery.  We propose a series of studies, each in both healthy 
volunteers and those with painful knee arthritis, using this outcome measure to create and validate a 
PK/PD model for oxytocin action in the periphery. 
GOAL OF THIS STUDY 
We aim to create pharmacokinetic/pharmacodynamic (PK/PD) models for oxytocin action at 
peripheral sites and at central sites as they relate to sensory transmission and pain.  This is the second of 4 
studies to accomplish generation and validation of a PK/PD model for oxytocin in the periphery.  Its goal 
is to generate a PK/PD model by obtaining pharmacodynamic measures (reduction in pain report to 
sustained heat) at frequent intervals during and after a fixed rate intravenous infusion of oxytocin.  Serum 
concentrations will be changing throughout the study as will the degree of pharmacodynamic effect.  It is 
the time relationship between the serum concentration simultaneous to the effect which allows the model 
to be constructed.  The study design assumes that Study 3 will find the 90% maximum serum oxytocin 
concentration to produce analgesia to a sustained heat stimulus is 90 pg/ml and that distribution of 
oxytocin from serum to its site of action in the periphery is rapid (< 5 min), based on our completed 
preliminary pharmacokinetic study. 
GENERAL STUDY DESIGN 
We aim to create pharmacokinetic/pharmacodynamic (PK/PD) models for oxytocin action at 
peripheral sites and at central sites as they relate to sensory transmission and pain.  This is the second of 4 
studies to accomplish generation and validation of a PK/PD model for oxytocin in the periphery.  Its goal 


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2 
is to generate a PK/PD model by obtaining pharmacodynamic measures (reduction in pain report to 
sustained heat) at frequent intervals during and after a fixed rate intravenous infusion of oxytocin.  Serum 
concentrations will be changing throughout the study as will the degree of pharmacodynamic effect.  It is 
the time relationship between the serum concentration simultaneous to the effect which allows the model 
to be constructed.  The study design assumes that Study 3 will find the 90% maximum serum oxytocin 
concentration to produce analgesia to a sustained heat stimulus is 90 pg/ml and that distribution of 
oxytocin from serum to its site of action in the periphery is rapid (< 5 min), based on our completed 
preliminary pharmacokinetic study. 
 
GENERAL STUDY DESIGN 
 
This is a single site study at Wake Forest School of Medicine.  Thirty two 
subjects in total (16 volunteers, 16 subjects with painful knee arthritis), will receive  
a constant iv infusion of oxytocin for 30 minutes with a total dose of 14 μg 
(micrograms), and verbal pain on a 0-10 scale to a 5 minute heating of the lateral 
calf to  45°C - 47 °C will be recorded. We will enroll up to 38 subjects if needed to 
obtain complete data sets for 32 subjects. We will provide this stimulus using an 
FDA-approved, commercially available device (Medoc TSA II). This short period of 
infusion will not result in steady state, but will produce slowly changing effects 
needed to create the pharmacokinetic / pharmacodynamic (PK/PD) model. The 
temperature to be delivered during the 5 minute heating will be determined during 
the screening visit.   The primary outcome measure (pain at the end of 5-min 
heating) will be obtained before infusion and then at 4 times at 15 min intervals 
during and after the 30 min infusion. Subjects will be randomized to begin the first 
5-min outcome measure test 3 min before infusion, at the time the infusion is started, 
or 2 or 5 min after it has begun (n=8 per cohort, n=32 in total).  This staggered time 
of testing will allow the measurement at 5 min to be obtained frequently during 
increasing and decreasing serum concentrations (Figure 1).  A PK/PD model will be 
calculated based on targeted OXT concentrations.  
 
 
RATIONALE FOR USE OF PAIN REPORT TO SUSTAINED HEAT  
 
Aside from contracting the pregnant or early postpartum 
uterus, there is no validated measure of OXT action in the periphery. 
Four lines of evidence suggest that pain intensity report from 
sustained noxious heat is such a stimulus. First, OXT binds to the 
same site in the TRPV1 extracellular domain as the tarantula double 
knot toxin (DkTx) and, like DkTx, mildly gaits, then dramatically 
desensitizes this channel, leading to insensitivity to capsaicin 
injection in rodents [3]. That OXT has a similar effect in humans is 
suggested by our recent study in which pain from a 30 min topical 
application of capsaicin in breast feeding women two weeks after 
delivery was reduced compared to age-matched controls [4].  This 
effect is likely peripheral, since hypersensitivity after capsaicin, 
thought to reflect central sensitization, was no different in the 
postpartum period. Second, pain rating of a 5 min, 45°C stimulus 
was reduced following iv OXT, 17 μg, in our PK study (Fig. 2-left 
panel). Third, intrathecal OXT, 15 μg, also reduces pain to this 
sustained heat stimulus (Fig. 2-middle panel), which is consistent 
with actions on afferent neurons in the DRG or their central 
terminals, although we cannot exclude an action on inhibitory 
Fig. 2. Left) Verbal pain score after 5-min, 45°C 
heating before and 40 min after a 17 μg IV OXT 
infusion (n=10). Middle) Verbal pain score after 5-
min, 45°C heating 40 min after i.t. placebo or OXT, 
15 μg (n=7-8). Right) Verbal pain score after 5-min 
45°C heating in postpartum (Postpart) women vs 
age-matched controls (n=20/group). 
Fig. 1.  Part 1 study design.  Duration 
of testing (bars) and time of 
measurement (vertical line) is shown 
for each cohort of 8 subjects. 
Simulated plasma and effect site OXT 
levels assume an equilibration of 5 
min and an EC90 of 90 pg/ml. 


Protocol version: 5/18/2022 
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dorsal horn neurons [5].  Fourth, pain from this sustained heat stimulus is numerically (although not 
statistically) reduced in lactating, early postpartum women (with estimated serum OXT concentration of 
120 pg/ml at the time of study [6]) compared to controls [4] (Fig. 2-right panel). 
 
WHY THIS STUDY IS NEEDED 
 
A single study of 10 young women used the LC/MS assay for oxytocin to define its 
pharmacokinetics after intramuscular injection [1].  Our long term goal is to examine efficacy of oxytocin 
in outpatient clinic settings (where intravenous infusion is not practical) in older men and women after 
major orthopedic surgery. The dose and timing of intramuscular oxytocin injection in that setting will 
depend on pharmacodynamic studies in this series, but also on knowing the pharmacokinetics in this 
population.   
 
 
Objective 
Main objective  
Determine the effect of oxytocin during and after a fixed rate intravenous infusion on reduction in pain to 
a sustained heat stimulus in order to generate a PK/PD model for peripheral analgesia. 
 
Methods and Measures 
 
METHODS:   
Equal numbers of adult men and women will be recruited from 2 populations.  Sixteen patients with 
advanced knee arthritis being seen in the Orthopedic Clinic in consultation for potential total knee 
arthroplasty will be recruited after their doctor visit if the decision is made not to perform surgery at this 
time.  Sixteen healthy volunteers without pain or taking pain medication will also be studied.  At least 1 
day prior to study subjects will be trained to rate pain in response to heat applied to the lateral calf using a 
Peltier controlled thermode.  
Subjects will return for study visit two in which an intravenous catheter will be inserted, in the 
forearm for drug infusion.  Oxytocin (Pitocin®) will be administered through a constant iv infusion for 30 
minutes with a total dose of 14 micrograms (mcg) and verbal pain on a 0-10 scale to a 5 minute heating of 
the lateral calf to 45°C- 47 °C will be recorded. We will provide this stimulus using an FDA-approved, 
commercially available device (Medoc TSA II). This short period of infusion will not result in steady 
state serum levels, but will produce changing levels and effects needed to create the pharmacokinetic / 
pharmacodynamic (PK/PD) model. The primary outcome measure (pain at the end of 5-min heating) will 
be obtained before infusion and then at 4 times at 15 min intervals during and after the 30 min infusion. 
Subjects will be randomized to begin the first 5-min outcome measure test 3 min before infusion, at the 
time the infusion is started, or 2 or 5 min after it has begun (n=8 per cohort, n=32 in total).   We will 
abandon an individual participant's study and schedule another participant should we be unable to 
successfully place the intravenous catheter. 
 
STUDY DESIGN 
This is an unblinded PK/PD study in which oxytocin is infused constantly and the PD effect of pain relief 
from each level of oxytocin determined. Participants will not be blinded to the experimental plan, 
although they will not be informed when oxytocin levels are changing. 
 
In this study healthy people or those with knee arthritis so severe that they may need joint 
replacement are recruited for two study visits. They will come to the Clinical Research Unit for the first 
study visit; during this visit informed consent will be obtained, a detailed medical history will be recorded 
and vital signs will be taken. Urine pregnancy testing will be performed for appropriate female subjects. 
We will also do a pain test for training purposes. We will perform thermal heat training by applying 
thermal temperatures that range from 100°F to 122 °F with a 5 second presentation of varying 
temperatures to the forearm and then we will place a probe on the skin and heat it to 113 degrees for 5 


Protocol version: 5/18/2022 
4 
minutes.  Subjects will score any pain they feel on a 0 to 10 scale, and most people find that pain rises 
during the 5 minutes, but remains mild, usually around only 1 or 2 on the 0 to 10 scale. However some 
subjects will score the thermal pain less than 1 or zero during the heating of 113 degrees. If this occurs, 
we will move the probe and repeat the 5 minute heating with a 115 degree heating for 5 minutes. If the 
subjects scores this heating less than 1 or zero, we will move the probe again and increase the temperature 
to 117 degrees for 5 minutes. If the subject scores this heating 1 or less they will be excluded from the 
study.  Subjects will come to the Clinical Research Unit for study visit two and one IV inserted in the 
forearm for oxytocin infusion.  Oxytocin will be administered IV by constant rate infusion for 30 min, 
with a total dose of 14 μg. This de-identified data will be analyzed by a pharmacokineticist at Stanford 
University to calculate how quickly oxytocin moves from the blood to where it reduces pain. 
   
We will repeat the thermal testing; 113°F- 117°F temperature for 5 minutes on the lateral calf 5 
additional times at different time points. This temperature will be determined from the training session on 
study visit 1. 
 
 
The research participants will not benefit from this study, but the knowledge we get will be 
important to adjust oxytocin dose to individuals. The sample size we chose is based on getting a good 
estimate for the size of the effect on sensations with each level of oxytocin in blood. This is an unblinded 
study and all subjects will get the same doses of oxytocin. 
 
 
Phase II trials 
The experimental drug or treatment is given to a larger group of people (fewer than 100) to see if it is 
effective and to further evaluate its safety. 
 
Setting 
Study visits will occur on the main campus at Wake Forest Baptist Medical Center in the Clinical 
Research Unit.  
 
Subjects selection criteria 
The study will enroll healthy subjects and subjects with advanced knee arthritis. 
 
Inclusion Criteria:  
1. Male or female > 18 and < 75 years of age, Body Mass Index (BMI) <40. 
2. Generally in good health as determined by the Principal Investigator based on prior medical 
history, American Society of Anesthesiologists physical status 1, 2, or 3. 
3. For healthy volunteers, normal blood pressure (systolic 90-140 mmHg; diastolic 50-90 mmHg) 
resting heart rate 45-100 beats per minute) without medication.  For knee arthritis subjects, normal blood 
pressure or, for those with hypertension, pressure controlled with anti-hypertensives and with a resting 
heart rate 45-100 beats per minute. 
4. Female subjects of child-bearing potential and those < 1 year post-menopausal, must be practicing 
highly effective methods of birth control such as hormonal methods (e.g., combined oral, implantable, 
injectable, or transdermal contraceptives), double barrier methods (e.g., condoms, sponge, diaphragm, or 
vaginal ring plus spermicidal jellies or cream), or total abstinence from heterosexual intercourse for a 
minimum of 1 full cycle before study drug administration. 
Exclusion Criteria:  
1. Hypersensitivity, allergy, or significant reaction to any ingredient of Pitocin® 
2. Any disease, diagnosis, or condition (medical or surgical) that, in the opinion of the Principal 
Investigator, would place the subject at increased risk (active gynecologic disease in which increased tone 
would be detrimental e.g., uterine fibroids with ongoing bleeding), compromise the subject’s compliance 
with study procedures, or compromise the quality of the data 


Protocol version: 5/18/2022 
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3. Women who are pregnant (positive result for urine pregnancy test at screening visit), women who 
are currently nursing or lactating, women that have been pregnant within 2 years 
4. Subjects with neuropathy, chronic pain (located in any extremity other than the knee(s) or any 
other body location that is being treated), diabetes mellitus, or taking benzodiazepines or pain medications 
on a daily basis. 
5. Subjects with current or history of ventricular tachycardia, atrial fibrillation or prolonged QT 
interval. 
6. Subjects with past or current history of hyponatremia or at risk for hyponatremia; anyone taking 
thiazide diuretics, loop diuretics, combination diuretics, lithium,  carbamazepine, enalapril, Ramipril, 
celecoxib, temazepam, gliclazide, glimepiride, glibenclamide, glipizide, omeprazole, pantoprazole, 
desmopressin, SSRI’s, MAOI, or the recreational drug ecstasy. 
7. Subjects with a known latex allergy. 
8. Subjects with a pain score rating of 1 or less during the initial training session to a 5 minute heating 
of 45°C- 47 °C to the lower calf. 
 
 
 
Sample Size 
We request permission to study up to 20 subjects with knee arthritis and 18 healthy volunteers so that 
we will have 32 evaluable subjects, respectively, with complete data at all time periods. 
 
Interventions and Interactions 
Study Visit 1:  The participant will report to the Pain Research Unit at Piedmont Plaza II or the Clinical 
Research Unit (CRU) of the Wake Forest CTSI at least 1 day prior to study visit 2. The participant will 
review and sign the Informed Consent, if not already obtained. After informed consent is adequately 
obtained, a detailed medical history will be obtained from the participant, female participants will provide 
a urine sample to determine pregnancy status.  Vital signs to include blood pressure (BP), heart rate (HR), 
respiratory rate Resp) and peripheral oxygen saturation (POX) will be measured and recorded along with 
height and weight. The research nurse will train the participants to estimate pain quantitatively using a 2 
cm2 Peltier controlled thermode (TSA®) applied to a forearm with 5 sec presentation of stimuli at 39, 41, 
43, 45, 47, 49, and 50°C, using a 11 point numerical verbal scale (NRS) anchored at 0 for no pain and 10 
for the worst pain imaginable.  Typically, the participant is exposed to temperatures between 380 and 510 
C using a random staircase method. After this training, we will ask them to report pain intensity on the 0-
10 NRS scale every minute for 5 minutes upon exposure to a 4 cm2  Peltier controlled thermode at 45°C. 
If the subject scores the thermal pain less than 1 or zero during the heating of 113 degrees, we will move 
the thermal probe and repeat the 5 minute heating with a 115 degree heating for 5 minutes. If the subjects 
scores this heating less than 1 or zero, we will move the probe to a different location and one more 
increase will be made to a 117 degree heating for 5 minutes. If the subject scores this heating 1 or less 
they will be excluded from the study and we will replace them with another subject. 
We have found this training session significantly reduces anxiety and variability in pain and 
hypersensitivity ratings on subsequent study days. The duration of this visit will be approximately 2 
hours. 
 
Study Visit 2  
On the second visit, the participant will report to the CRU, in the morning after having had nothing to eat 
or drink since midnight. Baseline vital signs (BP, HR, Resp, POX) will be obtained for a baseline 
measurement and then at 15, 30, and 60 minutes after the infusion. One intravenous catheter will be 
inserted in the arm for the infusion.  Then oxytocin (Pitocin®), obtained from the research pharmacy will 
be administered through a pump to for 30 minutes. Pain report at the end of a 5-min heating of the skin of 
the lateral calf to 45°C - 47 °C (temperature determined during Study Visit 1) using an FDA approved, 
commercially available device (Medoc, TSA II) will be performed at baseline and then the participant 
will be randomized to have the thermal testing repeated at one of the following time points: 3 minutes 
prior to the infusion, when the infusion begins, 2 minutes after the start of the infusion or 5 minutes after 


Protocol version: 5/18/2022 
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the start of the infusion.  After all data collection the intravenous catheters will be removed and the 
subject discharged from the CRU. The duration for study visit 2 will be approximately 3 hours. 
 
Safety and Monitoring: 
 
Assessment of Side Effects:  Significant side effects are defined as changes > 30% from baseline 
in the mean arterial pressure, HR, or oxyhemoglobin pulse oximetry < 90. Any unexpected or serious side 
effects will be reported to the IRB within 24 hrs. Peripheral oxyhemoglobin saturation, BP and HR will 
be measured non-invasively before and 15, 30, and 60 minutes after intravenous oxytocin injection. If 
either BP or HR change by > 30%, or oxyhemoglobin saturation decreases to less than 90, and require 
treatment, these vital signs will be repeated at 5-minute intervals until vital signs are stabilized. Prior to 
discharge from the study visit  blood pressure and heart rate will need to be within 10% of the baseline 
measurement and the subject will not have any side effects that are worrisome to the study investigators 
such as; nausea, dizziness, lightheadedness, or palpitations. 
 
 
Treatment of Side Effects: Mean blood pressure elevations greater than 30% of baseline will be treated 
with labetalol 5-15 mg IV incrementally until BP elevation is less than 30% elevated. Reductions in mean 
BP > 30% of baseline will be treated with incremental ephedrine 5-20 mg, IV. Heart rate (HR) reductions 
or elevations > 30% of baseline will be treated with incremental glycopyrolate 0.2 mg IV or propranolol 
0.2 mg IV, respectively. Peripheral oxyhemoglobin desaturation (< 90) will be treated with supplemental 
oxygen, nasal cannula, face mask, or non-rebreathing mask depending upon the degree desaturation and 
the response to therapy.  
 
RISKS 
 
Risks include privacy of data from their medical history and the result of the pregnancy test.  
Risks of the intravenous catheter include pain on and after insertion and local bruising.  Risks of oxytocin 
in the nonpregnant individual are allergic responses and, during rapid infusion, transient (<15 min) 
headache and facial flushing.    Additionally the following events have been reported as associated with 
the administration of oxytocin in the laboring female population: 
• 
Anaphylactic reaction 
• 
Postpartum hemorrhage 
• 
Cardiac arrhythmia 
• 
Fatal afibrinogenemia 
• 
Nausea 
• 
Vomiting 
• 
Premature ventricular contractions 
• 
Pelvic hematoma 
• 
Water intoxication 
• 
Subarachnoid hemorrhage 
• 
Hypertensive episode 
• 
Uterine rupture 


Protocol version: 5/18/2022 
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Additional precautions are used in the presence of specific anesthetic medications; we are not 
administering any of these medications during this research study.  
Risks from the heat testing are temporary pain during testing and a superficial burn should the device 
malfunction.  Please note that these devices are used in many pain clinics routinely and have multiple fail-
safe designs to avoid thermal burn. The subject can ask for testing to be stopped at any time and withdraw 
from the study if they are uncomfortable with the thermal heating. 
  
 
Outcome Measure(s) 
Primary Outcome Measure 
 
 
Name: Pharmacodynamics of heat pain after oxytocin 
 
Type: Primary 
 
Time Frame: Before and during infusions of oxytocin lasting 30-105 min 
 
Description: Pain at the end of 5 minutes of heating the skin to 45 – 47 degrees C will be 
determined before, during and after infusions in order to create a PD model and validate the PK/PD 
model. 
 
 
 
Analytical Plan 
This is an unblinded study with primary measure of drug effect to reduce heat pain in order to generate 
and then validate a PK/PD model. In the first study, 4 cohorts will be studied. The use of 4 cohorts is 
dictated by the desire to obtain 4 samples in the first 10 minutes after the beginning and end of infusion 
using a measurement that requires approximately 5 minutes to obtain and cannot be repeated more often 
than every 5 minutes. Staggering the measurements in each cohort provides adequate resolution of the 
time course of drug effect despite the inability to obtain frequent measurements in individual subjects. 
 
 
The figure to the right shows the pain scores 
in the pilot study. The average CV at each time point 
for the pain measurements in the pilot study is 1.26. 
Our desired precision is to reduce the CV to 0.5, 
which requires a study size of 24.1 subjects (1.96 * 
1.253 / 0.5)^2. Six subjects per cohort does not quite 
reach an adequate number (24), and 7 subjects per 
cohort cannot be equally divided between men and 
women, so we propose 8 subjects per cohort (N= 32, 
4 cohorts @ 8 subjects / cohort). 
 
 
The second study will attempt to determine the accuracy of the PK/PD model developed in 
Experiment 2.A and the first part of experiment 2.B. The N is taken from experiment 2.A. 
 
 
Human Subjects Protection 
All studies in volunteers will be performed in the CRU or in the Pain research Unit, which includes 
monitoring and resuscitation equipment and trained nursing support staff, or in in-patient settings of the 
Wake Forest Baptist Medical Center. All studies will be approved by the IRB and written informed 
consent obtained. The Project Investigators have all performed similar studies in volunteers and patients. 
The purpose of the study and all risks will be discussed with each volunteer, and all questions will be 
answered prior to obtaining written informed consent. Risks to be discussed include discomfort with 
needle and catheter insertion. All data acquired will remain confidential with no reference to individuals 
in publications.   


Protocol version: 5/18/2022 
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Subject Recruitment Methods 
Healthy subjects will be recruited from our current database of volunteers BG05-468, word of 
mouth and Be Involved website; the advanced knee arthritis population will be recruited from the 
Orthopedic Clinic at the Davie Medial Center Campus. 
The research nurses; Regina Curry, RN and Vonda McGee, LPN will conduct the recruitment of study 
subjects.  
 
Potential subject from the database will be contacted via phone or email, per their request. 
Potential subjects from the Be Involved website will be contacted according to the information they 
provide.  Potential subjects from the Orthopedic Clinic will be identified through a medical record survey 
of patients schedule for appointments in the Orthopedic Clinic (through a request for a limited waiver of 
HIPAA authorization). Information collected would include, age, medical history, medications and reason 
for visit. This information will be maintained on a secure server and will be destroyed once it has been 
determined a potential subject does not meet inclusion criteria or declines. We will not collect contact 
information; potential subjects will be interviewed in a private room during their scheduled clinic visit. 
 
 
 
Informed Consent 
 
Signed informed consent will be obtained from each subject.  Regina Curry, RN or Vonda McGee, LPN 
will obtain consent. Potential subjects will be consented in the Orthopedic Clinic or in the CRU. A private 
room will be utilized during the consent process and all study visits. 
 
Confidentiality and Privacy 
Confidentiality will be protected by collecting only information needed to assess study outcomes, 
minimizing to the fullest extent possible the collection of any information that could directly identify 
subjects, and maintaining all study information in a secure manner.  To help ensure subject privacy 
and confidentiality, only a unique study identifier will appear on the data collection form.  Any 
collected patient identifying information corresponding to the unique study identifier will be 
maintained on a linkage file, store separately from the data.  The linkage file will be kept secure, with 
access limited to designated study personnel.  Following data collection subject identifying 
information will be destroyed 3 years after closure of the study, in confidential shredding disposal 
bins consistent with data validation and study design, producing an anonymous analytical data set.  
Data access will be limited to study staff.  Data and records will be kept locked and secured, with any 
computer data password protected.  No reference to any individual participant will appear in reports, 
presentations, or publications that may arise from the study. 
 
 
Data and Safety Monitoring 
The principal investigator will be responsible for the overall monitoring of the data and safety of 
study participants.  The principal investigator will be assisted by other members of the study staff. 
 
Data and Safety Monitoring Plan  
 
Security of data and safety for anticipated and unanticipated adverse events will be monitored.  
Vital signs will be recorded during and after oxytocin infusion and adverse events recorded.  An ongoing 
analysis of more than mild anticipated adverse events will be made after completion of each subject. 
Should there be more than 30% more than mild anticipated adverse events in the first 7 subjects, the 
remainder will receive a reduced or no highest planned oxytocin infusion step. Serious adverse events 
(SAEs) will be managed initially with stabilization within the CTSI and then with hospital admission and 
treatment.  The study investigators are anesthesiologists well experienced in acute resuscitation and 


Protocol version: 5/18/2022 
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emergency resuscitation resources are readily available within the CRU of the CTSI.  SAEs will be 
reported within 24 hr to the IRB and the study stopped until a full report and outcome are determined. 
 
We have obtained a waiver for Investigative New Drug (IND) approval for this study from the 
FDA, but will report SAEs to the FDA within 7 days. 
 
An outside expert in oxytocin pharmacology and acute drug effects, Laura Dean, MD, Director, 
Obstetric Anesthesia Service, Wake Forest School of Medicine, will insure that the trial is conducted 
according to the approved protocol and will carry out the DSMP. 
 
Volunteer Payment 
Participants will be paid a total of $300 according to the following payment schedule which we 
have used throughout the last 2 cycles of this grant's protocols. We believe that this payment schedule is 
fair and appropriate, paying for each procedure attempted and an additional payment for completion of 
the entire study.  
Completion of study 1: $25 
Placement of IV: $25 
Completion of entire study: $250 
Volunteer must complete all of the above phases to receive this payment. 
If the subject is excluded from the study during study visit 1 due to the lack of pain felt 
during the thermal testing they will be compensated $25 for this visit. 
 
Long-term Follow-up 
Volunteers will be contacted daily within the following week and questioned about adverse 
events from the study. 
 
 
 
Reporting of Unanticipated Problems, Adverse Events or Deviations 
Any unanticipated problems, serious and unexpected adverse events, deviations or protocol changes 
will be promptly reported by the principal investigator or designated member of the research team to 
the IRB and sponsor or appropriate government agency if appropriate. 
 
Data Share Plan Stanford Pilot Data   
Scope of Work:  Dr. Steven Shafer at Stanford University will establish and direct a 
pharmacokinetic/dynamic (PK/PD) modeling to facilitate future modeling in a NIH grant to be funded 
late 2021/early 2022. The PK/PD modeling will generate a mathematical model of oxytocin uptake, 
distribution, and elimination following intravenous delivery in humans. The PK/PD Core will use these 
mathematical models to describe the relationship between concentration at the site of effect and 
therapeutic response. The models will facilitate dosing regimens for future studies.  The dose effect of 
intramuscular oxytocin will be modeled by the relationship noted on pupil diameter and heart rate 
variability and pupillary hippus measurements. 
 
 
REFERENCES 
1. 
De Groot, A.N., et al., Bioavailability and pharmacokinetics of sublingual oxytocin in male 
volunteers. J Pharm Pharmacol, 1995. 47(7): p. 571-5. 
2. 
Nielsen, E.I., et al., Population Pharmacokinetic Analysis of Vaginally and Intravenously 
Administered Oxytocin in Postmenopausal Women. J Clin Pharmacol, 2017. 57(12): p. 1573-1581. 


Protocol version: 5/18/2022 
10 
3. 
Nersesyan, Y., et al., Oxytocin Modulates Nociception as an Agonist of Pain-Sensing TRPV1. 
Cell Rep, 2017. 21(6): p. 1681-1691. 
4. 
Street, L.M., et al., Capsaicin-induced pain and sensitisation in the postpartum period. Br J 
Anaesth, 2019. 122(1): p. 103-110. 
5. 
Breton, J.D., et al., Oxytocin-induced antinociception in the spinal cord is mediated by a 
subpopulation of glutamatergic neurons in laminas I-II which amplify GABAergic inhibition. Mol.Pain, 
2008. 4(1): p. 19. 
6. 
Jonas, K., et al., Effects of intrapartum oxytocin administration and epidural analgesia on the 
concentration of plasma oxytocin and prolactin, in response to suckling during the second day 
postpartum. Breastfeed Med, 2009. 4(2): p. 71-82. 
7. 
Quintana, D.S., et al., Low-dose intranasal oxytocin delivered with Breath Powered device 
modulates pupil diameter and amygdala activity: a randomized controlled pupillometry and fMRI study. 
Neuropsychopharmacology, 2019. 44(2): p. 306-313. 
8. 
Tanaka, A., et al., Delivery of Oxytocin to the Brain for the Treatment of Autism Spectrum 
Disorder by Nasal Application. Mol Pharm, 2018. 15(3): p. 1105-1111. 
9. 
Liu, R., et al., Perception of social interaction compresses subjective duration in an oxytocin-
dependent manner. Elife, 2018. 7. 
10. 
Tzabazis, A., et al., Oxytocin and Migraine Headache. Headache, 2017. 57 Suppl 2: p. 64-75. 
11. 
Tracy, L.M., et al., Sex-specific effects of intranasal oxytocin on thermal pain perception: A 
randomised, double-blind, placebo-controlled cross-over study. Psychoneuroendocrinology, 2017. 83: p. 
101-110. 
12. 
Rash, J.A., et al., Protocol for a placebo-controlled, within-participants crossover trial 
evaluating the efficacy of intranasal oxytocin to improve pain and function among women with chronic 
pelvic musculoskeletal pain. BMJ Open, 2017. 7(4): p. e014909. 
13. 
Lee, M.R., et al., Oxytocin by intranasal and intravenous routes reaches the cerebrospinal fluid 
in rhesus macaques: determination using a novel oxytocin assay. Mol Psychiatry, 2017. 
14. 
Walum, H., I.D. Waldman, and L.J. Young, Statistical and Methodological Considerations for 
the Interpretation of Intranasal Oxytocin Studies. Biol Psychiatry, 2016. 79(3): p. 251-7. 
15. 
Zunhammer, M., et al., Effects of intranasal oxytocin on thermal pain in healthy men: a 
randomized functional magnetic resonance imaging study. Psychosom Med, 2015. 77(2): p. 156-66. 
16. 
Rash, J.A. and T.S. Campbell, The effect of intranasal oxytocin administration on acute cold 
pressor pain: a placebo-controlled, double-blind, within-participants crossover investigation. Psychosom 
Med, 2014. 76(6): p. 422-9. 
17. 
Mameli, S., et al., Oxytocin nasal spray in fibromyalgic patients. Rheumatol Int, 2014. 34(8): p. 
1047-52. 
18. 
Zhang, H., et al., Treatment of Obesity and Diabetes Using Oxytocin or Analogs in Patients and 
Mouse Models. PLOS ONE, 2013. 8(5): p. e61477. 
19. 
Wang, Y.L., et al., The interaction between the oxytocin and pain modulation in headache 
patients. Neuropeptides, 2013. 47(2): p. 93-7. 
20. 
Striepens, N., et al., Elevated cerebrospinal fluid and blood concentrations of oxytocin following 
its intranasal administration in humans. Sci.Rep., 2013. 3: p. 3440. 
21. 
Leknes, S., et al., Oxytocin enhances pupil dilation and sensitivity to 'hidden' emotional 
expressions. Soc.Cogn Affect.Neurosci., 2013. 8(7): p. 741-749. 
22. 
Kessner, S., et al., Effect of oxytocin on placebo analgesia: a randomized study. JAMA, 2013. 
310(16): p. 1733-1735. 
23. 
Gossen, A., et al., Oxytocin plasma concentrations after single intranasal oxytocin administration 
- a study in healthy men. Neuropeptides, 2012. 46(5): p. 211-215. 
 
 
 
 


Protocol version: 5/18/2022 
11 
 
Appendix 
1. Table of study related events 
2. Data collection form 
3. CRF Face Page 
4. Consent form  

ICF_001.pdf: 
Official Title:  Generate a pharmacodynamic model of oxytocin for peripheral analgesic effects
NCT04431206
IRB Approval Date:  04/10/2023


Page 1 of 10
Adult Consent Form
5/18/2022
Department/Section of Anesthesiology
GENERATING A PHARMACODYNAMIC MODEL OF OXYTOCIN FOR 
PERIPHERAL ANALGESIC EFFECTS
INFORMED CONSENT FORM TO PARTICIPATE IN RESEARCH
James C. Eisenach, M.D., Principal Investigator
SUMMARY
You are invited to participate in a research study. The purpose of this research is to evaluate the 
change of oxytocin in the blood after administration of oxytocin by intravenous (IV) route and 
the effects it may have on thermal testing.  You are invited to be in this study because you are a 
healthy subject or you have been diagnosed with advanced arthritis in your knee(s). Your 
participation in this research will involve 2 visits and last approximately 5 hours (total for both 
visits). 
Participation in this study will involve receiving, IV administration of oxytocin and thermal 
testing.  All research studies involve some risks.  A risk to this study that you should be aware of 
is discomfort from the thermal/sensory testing and IV placement.  Potential risks associated with 
receiving oxytocin are headache, facial flushing and a sensation of your heart pounding 
additional risks that are discussed later in this document.  
Your participation in this study is voluntary.  You do not have to participate in this study if you 
do not want to.  This is not a treatment study and there are no additional choices. You will not 
lose any services, benefits, or rights you would normally have if you choose not to participate. 
The remainder of this form contains a more complete description of this study. Please read this 
description carefully. You can ask any questions if you need help deciding whether to join the 
study. The person in charge of this study is James C. Eisenach, M.D. If you have questions, 
suggestions, or concerns regarding this study or you want to withdraw from the study his/her 
contact information is:  James C. Eisenach, M.D.
   
   
   
If you have any questions, suggestions or concerns about your rights as a volunteer in this 
research, contact the Institutional Review Board at 
 or the Research Subject 
Advocate at Wake Forest at 
.
WFU School of Medicine 
Institutional Review Board 
IRB Number:IRB00066136
Meeting Date Approved 4/10/2023          
Version Valid Until: 4/9/2024


Page 2 of 10
Adult Consent Form
5/18/2022
INTRODUCTION
You are invited to be in a research study. Research studies are designed to gain scientific 
knowledge that may help other people in the future. You are being asked to take part in this 
study because you are a healthy adult or you have advanced arthritis in your knee(s). Your 
participation is voluntary. Please take your time in making your decision as to whether or not 
you wish to participate. Ask your study doctor or the study staff to explain any words or 
information contained in this informed consent document that you do not understand. You may 
also discuss the study with your friends and family.
WHY IS THIS STUDY BEING DONE?
The purpose of this research study is to evaluate the effects oxytocin (naturally occurring 
hormone made in the brain that transmits messages) administered by intravenous (IV) route at a 
set rate may have on thermal testing.  Oxytocin (intravenously or intramuscularly) is commonly 
given to pregnant women to cause labor to start or given after the delivery of an infant to stop the 
mother from bleeding.  In this study we will be administering a dose of oxytocin over a 30 
minute period. Oxytocin is being given to help researchers develop a model for evaluating the 
effect, if any on the response or your parasympathetic nervous system. 
HOW MANY PEOPLE WILL TAKE PART IN THE STUDY?
We will enroll up to 18 people in the healthy subject group and up to 20 people in the advanced 
knee arthritis group. In order to identify the 32 subjects needed, we may need to screen as many 
as 200 because some people will not qualify to be included in the study.
WHAT IS INVOLVED IN THE STUDY?
You will have 2 study visits. Study visit 1 will be conducted in the Pain Research Unit at Piedmont 
Plaza II or the Clinical Research Unit (CRU) at Wake Forest Baptist Medical Center. Study visit 
2 will be conducted in the Clinical Research Unit (CRU) at Wake Forest Baptist Medical Center. 
Study visit 1 will last approximately 2 hours and study visit 2 will last approximately 3 hours.
If you take part in this study, you will have the following tests and procedures:
PROCEDURES
Vital Signs: we will monitor your blood pressure, heart rate, respiratory rate and oxygen 
saturation (amount of oxygen in your blood).  
Laboratory Testing: female participants of child-bearing potential will provide a urine 
sample to determine that they are not pregnant. 
Thermal Heat Testing: we will train you to accurately describe pain from a small (about the 
size of a penny) and a large (about the size of a half dollar) probe. The tip of the heat probe that 
will be applied to the skin on your forearm is about the size of a penny.  The tip of the heat probe 
WFU School of Medicine 
Institutional Review Board 
IRB Number:IRB00066136
Meeting Date Approved 4/10/2023          
Version Valid Until: 4/9/2024


Page 3 of 10
Adult Consent Form
5/18/2022
that will be applied to your calf is about the size of a half dollar. The thermal heat probe will be 
controlled by a computer that is programmed to deliver temperatures that range from skin 
temperature up to a temperature that is hot (122 ºF) and uncomfortable, but does not burn your 
skin.
Intravenous injection of Oxytocin: we will place an intravenous catheter and administer 
oxytocin. 
Study Visit 1
You will report to the (CRU) at least 1 day prior to study visit 2. You will review and sign the 
Informed Consent (if you have not already done so). After informed consent is adequately 
obtained, a detailed medical history will be obtained. During this visit we will measure your 
blood pressure, heart rate, respiratory rate and we will place a clip on your finger which will 
measure the oxygen in your blood. Female participants of child-bearing potential will provide a 
urine sample for a pregnancy test. We will perform thermal heat training by applying thermal 
temperatures that range from 100°F to 122 °F with a 5 second presentation of varying 
temperatures to your forearm. We will ask you to rate each stimuli using an 11 point numerical 
verbal scale (NRS) anchored at 0 for no pain and 10 for the worst pain imaginable.  After this 
training, we will then place a slightly larger probe on your lateral calf and warm the area to a 
temperature of 113F for 5 minutes.  During this five minute warming period we will ask you to 
give a pain rating each minute for any pain you are experiencing. If you do not experience pain 
during the initial thermal heating, we will move the thermal probe to a different location on your 
calf and repeat the testing and deliver a temperature of 115F for 5 minutes. During the five 
minute warming period we will ask you to give a pain rating each minute for any pain you are 
experiencing. If you do not experience pain during this heating, we will move the thermal probe 
to a different location on your calf and repeat the testing and deliver a temperature of 117F for 5 
minutes. During the five minute warming period we will ask you to give a pain rating each 
minute for any pain you are experiencing. 
Study Visit 2 
On the second visit, you will report to the CRU, in the morning after having had nothing to eat or 
drink since midnight. Baseline vital signs (BP, HR, Resp, POX) will be obtained for a baseline 
measurement and then at 15, 30, and 60 minutes after the infusion was started. A peripheral 
intravenous (IV) catheter will be inserted into a vein in your arm and we will begin an IV fluid 
solution for the duration of the study. After obtaining baseline vital signs, we will obtain baseline 
measures from the thermal heat testing that was performed on your lateral calf study visit 1; 
oxytocin will be administered intravenously by pump over a period of 30 minutes. We will 
repeat the thermal testing; 113F- 117F temperature for 5 minutes on your lateral calf 5 
additional times at different time points. This temperature will be determined from your testing 
on study visit 1. We will measure your vital signs 3 more times throughout the study.
HOW LONG WILL I BE IN THE STUDY?
You will be in the study for 2 visits, approximately 5 hours total.
We will call you daily for 5 days after study visit 2.
WFU School of Medicine 
Institutional Review Board 
IRB Number:IRB00066136
Meeting Date Approved 4/10/2023          
Version Valid Until: 4/9/2024


Page 4 of 10
Adult Consent Form
5/18/2022
You can stop participating at any time. If you decide to stop participating in the study we 
encourage you to talk to the investigators or study staff first to learn about any potential health or 
safety consequences. 
WHAT ARE THE RISKS OF THE STUDY?
Being in this study involves some risk to you. You should discuss the risk of being in this study 
with the study staff. Risks and side effects related to the thermal testing and oxytocin we are 
studying include:
Heat Probe 
You may experience brief pain during the thermal heat testing.
Needle Insertions
You may experience discomfort, bruising and/or bleeding where the needle is inserted. 
Occasionally some people become dizzy lightheaded or feel faint. Infection may occur on rare 
occasions.  
Oxytocin
The dose of oxytocin we are using in this study and the route of administration are approved by 
the Food and Drug Administration (FDA). However the indication we are using oxytocin for in 
this study is not approved by the FDA. We will monitor you for many potential problems such as 
changes in your blood pressure, how fast your heart is beating, and your urge to breathe. We will 
treat any side effects that you may experience if the changes are enough to concern us.
There is the possibility of a feeling of being flushed (warm feeling), headache and increased 
heart rate with no significant change in blood pressure during or immediately after the infusion. 
These events have been reported by previous participants but were short lived, lasting 
approximately 12-15 minutes. Additionally the following events have been reported as 
associated with the administration of oxytocin in the laboring female population:
Anaphylactic reaction
Postpartum hemorrhage
Cardiac arrhythmia
Fatal afibrinogenemia
Nausea
Vomiting
Premature ventricular contractions
Pelvic hematoma
Water intoxication
Subarachnoid hemorrhage 
Hypertensive episode 
Uterine rupture
WFU School of Medicine 
Institutional Review Board 
IRB Number:IRB00066136
Meeting Date Approved 4/10/2023          
Version Valid Until: 4/9/2024


Page 5 of 10
Adult Consent Form
5/18/2022
Additional precautions are used in the presence of specific anesthetic medications; we are not 
administering any of these medications during this research study. 
Finally, you cannot participate in this study if you are allergic to latex, as there have been reports 
of allergic reactions to oxytocin injection in women with latex allergies.
In addition, there is a slight risk of a breach of confidentiality.  We will do our best to protect 
your confidential information.  There also may be other side effects that we cannot predict. You 
should tell the research staff about all the medications, vitamins and supplements you take and 
any medical conditions you have. This may help avoid side effects, interactions and other risks.
Taking part in this research study may involve providing information that you consider 
confidential or private.  Efforts, such as coding research records, keeping research records secure 
and allowing only authorized people to have access to research records, will be made to keep 
your information safe.
You may experience discomfort, bruising and/or bleeding where the needle is inserted. 
Occasionally some people become dizzy lightheaded or feel faint. Infection may occur on rare 
occasions.  Frequent donation of blood can result in low iron in your blood (iron deficient 
anemia).  
If you donate blood to the American Red Cross, you should talk with the study doctor about 
whether or not it is safe to do so while participating in this study. You should not donate blood 
more than 2 times per week and no more than approximately one pint (about 500 ml) of blood in 
an eight week period.
Reproductive Risks and other Issues to Participating in Research
Due to known risks and potential harm to the unborn fetus, sexually active women of 
childbearing potential must use a reliable method of birth control while participating in this 
study. Reliable methods of birth control are: abstinence (not having sex), oral contraceptives, 
intrauterine device (IUD), DepoProvera, tubal ligation, or vasectomy of the partner (with 
confirmed negative sperm counts) in a monogamous relationship (same partner). An acceptable, 
although less reliable, method involves the careful use of condoms and spermicidal foam or gel 
and/or a cervical cap or sponge. We encourage you to discuss this issue further with your 
physicians if you have any questions.
Pregnant women are excluded from participation in this study. Because some methods of birth 
control are not 100% reliable, a pregnancy test is required at least 10 days from your last normal 
menstrual period, if you are a sexually active woman of childbearing potential.
 ARE THERE BENEFITS TO TAKING PART IN THE STUDY?
You are not expected to receive any direct benefit from taking part in this research study. We 
hope the information learned from this study will benefit other people in the future.
WFU School of Medicine 
Institutional Review Board 
IRB Number:IRB00066136
Meeting Date Approved 4/10/2023          
Version Valid Until: 4/9/2024


Page 6 of 10
Adult Consent Form
5/18/2022
WHAT OTHER CHOICES ARE THERE?
This is not a treatment study. Your alternative is to not participate in this study.
WHAT ARE THE COSTS?
All study costs, including any study medications and procedures related directly to the study, will 
be paid for by the study. Costs for your regular medical care, which are not related to this study, 
will be your own responsibility.
WILL YOUR RESEARCH RECORDS BE CONFIDENTIAL?
The results of this research study may be presented at scientific or medical meetings or published 
in scientific journals.  Your identity and/or your personal health information will not be disclosed 
unless it is authorized by you, required by law, or necessary to protect the safety of yourself or 
others.  There is always some risk that even de-identified information might be re-identified. 
Participant information may be provided to Federal and other regulatory agencies as required.  
The Food and Drug Administration (FDA), for example, may inspect research records and learn 
your identity if this study falls within its jurisdiction.
This research is covered by a Certificate of Confidentiality from the National Institutes of 
Health. The researchers with this Certificate may not disclose or use information, documents, or 
biospecimens that may identify you in any federal, state, or local civil, criminal, administrative, 
legislative, or other action, suit, or proceeding, or be used as evidence, for example, if there is a 
court subpoena, unless you have consented for this use. Information, documents, or 
biospecimens protected by this Certificate cannot be disclosed to anyone else who is not 
connected with the research except, if there is a federal, state, or local law that requires 
disclosure (such as to report child abuse or communicable diseases but not for federal, state, or 
local civil, criminal, administrative, legislative, or other proceedings, see below); if you have 
consented to the disclosure, including for your medical treatment; or if it is used for other 
scientific research, as allowed by federal regulations protecting research subjects. 
 The Certificate cannot be used to refuse a request for information from personnel of the United 
States federal or state government agency sponsoring the project that is needed for auditing or 
program evaluation by NIH which is funding this project or for information that must be 
disclosed in order to meet the requirements of the federal Food and Drug Administration 
(FDA).  You should understand that a Certificate of Confidentiality does not prevent you from 
voluntarily releasing information about yourself or your involvement in this research. If you 
want your research information released to an insurer, medical care provider, or any other person 
not connected with the research, you must provide consent to allow the researchers to release it.
WILL YOU BE PAID FOR PARTICIPATING?
You will be paid $300 if you complete all the scheduled study visits. If you withdraw for any 
reason from the study before completion you will be paid as follows:   
Completion of study visit 1: $25
Placement of IV: $25
WFU School of Medicine 
Institutional Review Board 
IRB Number:IRB00066136
Meeting Date Approved 4/10/2023          
Version Valid Until: 4/9/2024


Page 7 of 10
Adult Consent Form
5/18/2022
Completion of all study related procedures:  $250
In the event you do not qualify to continue in the study after study visit 1 (due to the thermal 
testing) we will compensate you $25 for your time.
To receive payment, you must provide your social security number, name and address so that we 
can comply with IRS (Internal Revenue Service) reporting requirements.  When payments are 
reported to the IRS we do not let them know what the payment is for, only that you have been 
paid.  If you do not wish to provide this information you can still take part in this study but you 
will not be paid.
The findings from this research may result in the future development of products that are of 
commercial value. There are no plans to provide you with financial compensation or for you to 
share in any profits if this should occur.
WHO IS SPONSORING THIS STUDY?
This study is being sponsored by the National Institutes Health (NIH). The sponsor is providing 
money or other support to Wake Forest University Health Sciences to help conduct this study. 
The researchers do not, however, hold a direct financial interest in the sponsor or the product 
being studied.
WHAT HAPPENS IF YOU EXPERIENCE AN INJURY OR ILLNESS AS A 
RESULT OF PARTICIPATING IN THIS STUDY?
Should you experience a physical injury or illness as a direct result of your participation in this 
study, Wake Forest University School of Medicine maintains limited research insurance 
coverage for the usual and customary medical fees for reasonable and necessary treatment of 
such injuries or illnesses. To the extent research insurance coverage is available under this policy 
the reasonable costs of these necessary medical services will be paid, up to a maximum of 
$25,000. Wake Forest University Baptist Medical Center holds the insurance policy for this 
coverage. It provides a maximum of $25,000 coverage for each claim and is limited to a total of 
$250,000 for all claims in any one year. The Wake Forest University School of Medicine, and 
the North Carolina Baptist Hospitals, Incorporated do not assume responsibility to pay for these 
medical services or to provide any other compensation for such injury or illness. Additional 
information may be obtained from the Medical Center’s Director of Risk and Insurance 
Management, at 
.
If you are injured, the insurer may require information such as your name, social security 
number, and date of birth in order to pay for your care.  This is because the insurer is required by 
law to report any payments made to cover the care of any persons who are members of a 
government insurance plan to the Department of Health and Human Services.
You do not give up any legal rights as a research participant by signing this consent form. For 
more information on medical treatment for research related injuries or to report a study related 
illness, adverse event, or injury you should call James Eisenach at 
 or after hours 
you should call the study coordinator at 
.
WFU School of Medicine 
Institutional Review Board 
IRB Number:IRB00066136
Meeting Date Approved 4/10/2023          
Version Valid Until: 4/9/2024


Page 8 of 10
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5/18/2022
WHAT ABOUT MY HEALTH INFORMATION?
In this research study, any new information we collect from you about your health or behaviors 
is considered Protected Health Information. The information we will collect for this research 
study includes: medical history and medication history.
If this research study involves the diagnosis or treatment of a medical condition, then Protected 
Health Information collected from you during this study may be placed in your medical record, 
and may be used to help treat you, arrange payment for your care, or assist with Medical Center 
operations. 
We will make every effort to keep your Protected Health Information private. We will store 
records of your Protected Health Information in a cabinet in a locked office or on a password 
protected computer. 
Your personal health information and information that identifies you (“your health information”) 
may be given to others during and after the study. This is for reasons such as to carry out the 
study, to determine the results of the study, to make sure the study is being done correctly, to 
provide required reports and to get approval for new products.  
Some of the people, agencies and businesses that may receive and use your health information 
are the research sponsor; representatives of the sponsor assisting with the research; investigators 
at other sites who are assisting with the research; central laboratories, reading centers or analysis 
centers; the Institutional Review Board; representatives of Wake Forest University Health 
Sciences and North Carolina Baptist Hospital; representatives from government agencies such as 
the Food and Drug Administration (FDA) or the Office of Human Research Protections (OHRP), 
the Department of Health and Human Services (DHHS) and similar agencies in other countries.  
Some of these people, agencies and businesses may further disclose your health information. If 
disclosed by them, your health information may no longer be covered by federal or state privacy 
regulations.  Your health information may be disclosed if required by law. Your health 
information may be used to create information that does not directly identify you. This 
information may be used by other researchers. You will not be directly identified in any 
publication or presentation that may result from this study unless there are photographs or 
recorded media which are identifiable.
Any Protected Health Information collected from you in this study that is maintained in the 
research records will be kept for an indeterminate period of time. This authorization does not 
expire. You will not be able to obtain a copy of your Protected Health Information in the 
research records until all activities in the study are completely finished. 
You can tell Dr. James C. Eisenach that you want to take away your permission to use and share 
your Protected Health Information at any time by sending a letter to this address:
James C. Eisenach, M.D.
WFU School of Medicine 
Institutional Review Board 
IRB Number:IRB00066136
Meeting Date Approved 4/10/2023          
Version Valid Until: 4/9/2024


Page 9 of 10
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5/18/2022
  
   
  
However, if you take away permission to use your Protected Health Information you will not be 
able to be in the study any longer. We will stop collecting any more information about you, but 
any information we have already collected can still be used for the purposes of the research 
study.
By signing this form you give us permission to use your Protected Health Information for this 
study.
If you choose to participate in this study, your medical record at Wake Forest University Baptist 
Medical Center will indicate that you are enrolled in a clinical trial.  Information about the 
research and any medications or devices you are being given as a participant may also be 
included in your medical record.  This part of the medical record will only be available to people 
who have authorized access to your medical record.  If you are not a patient at this Medical 
Center, a medical record will be created for you anyway to ensure that this important information 
is available to doctors in case of an emergency.
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 Web site at any time. 
A North Carolina Baptist Hospital (NCBH) medical record will be created for all study 
participants. Information about your participation in the study will be placed in the NCBH 
medical record, along with any routine medical test results that were obtained at NCBH as part 
of this study. 
WHAT ARE MY RIGHTS AS A RESEARCH STUDY PARTICIPANT?
Taking part in this study is voluntary. You may choose not to take part or you may leave the 
study at any time. Refusing to participate or leaving the study will not result in any penalty or 
loss of benefits to which you are entitled. 
If you decide to stop participating in the study we encourage you to talk to the investigators or 
study staff first to learn about any potential health or safety consequences. The investigators also 
have the right to stop your participation in the study at any time. This could be because it is in 
your best medical interest, new information becomes available, you had an unexpected reaction, 
you failed to follow instructions, or because the entire study has been stopped. Information that 
identifies you may be removed from the data or specimens that are collected as part of this study 
and could be used for future research or shared with others without additional consent.
You will be given any new information we become aware of that would affect your willingness 
to continue to participate in the study.
WFU School of Medicine 
Institutional Review Board 
IRB Number:IRB00066136
Meeting Date Approved 4/10/2023          
Version Valid Until: 4/9/2024


Page 10 of 10
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This study will be enrolling students from the Wake Forest University Medical Center campus.  
In addition to your rights as a research participant noted in the previous section, as a student, you 
are under no obligation to participate in this study. You may refuse to participate or withdraw 
from the study at any time and for any reason without affecting your grades, performance 
evaluations, or assignments. You will not be pressured into participating in this research study by 
any statements or implied statements that your grades, performance evaluations or assignments 
will be affected by your willingness to enroll in the study. Your medical records/information will 
not be used by the faculty, administration or study staff to make decisions regarding the status of 
your medical benefits. If you have questions regarding your enrollment in the study and your 
status as a medical student, please contact the Office of Student Services for additional 
information.
WHOM DO I CALL IF I HAVE QUESTIONS OR PROBLEMS?
For questions about the study or in the event of a research-related injury, contact the study 
investigator, Dr. James Eisenach at 
 or after hours you should call the study 
coordinator by calling 
.
The Institutional Review Board (IRB) is a group of people who review the research to protect 
your rights. If you have a question about your rights as a research participant, or you would like 
to discuss problems or concerns, have questions or want to offer input, or you want to obtain 
additional information, you should contact the Chairman of the IRB at 
 or the 
Research Subject Advocate at 
.
You will be given a copy of this signed consent form. 
                                                                                                                                
SIGNATURES
I agree to take part in this study. I authorize the use and disclosure of my health information as 
described in this consent and authorization form.  If I have not already received a copy of the 
Privacy Notice, I may request one or one will be made available to me.  I have had a chance to 
ask questions about being in this study and have those questions answered.   By signing this 
consent and authorization form, I am not releasing or agreeing to release the investigator, the 
sponsor, the institution or its agents from liability for negligence.
Subject Name (Printed):_____________________________
Subject Signature: _________________________________ Date: ________Time:_______ am pm 
Person Obtaining Consent (Printed):_____________________________
Person Obtaining Consent:___________________________ Date:_________ Time:________ am pm
WFU School of Medicine 
Institutional Review Board 
IRB Number:IRB00066136
Meeting Date Approved 4/10/2023          
Version Valid Until: 4/9/2024