Clinical trial NCT04764630
Conditions: Healthy Subjects Opioid Antagonist Pharmacokinetics
Keywords: Opioid antagonist Intranasal naloxone Pharmacokinetics
Sponsor: Food and Drug Administration (FDA)
Start date: 2021-03-01; Completion date: 2021-03-20
Enrollment: 21 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
Intranasal (IN) naloxone is available as 2 mg or 4 mg dose with the indication to re-administer additional doses every 2 to 3 minutes (using alternating nostrils) if needed until emergency medical assistance arrives. The 4 mg dose is distributed in packages of two nasal sprays (1 dose per nasal spray), but additional doses can be administered if needed and available.

While the pharmacokinetics of IN naloxone have been determined following administration of a 4 mg dose in each nostril concurrently, the pharmacokinetics have not been determined following multiple doses when there is a 2-3 minute delay between doses and when doses are re-administered to the same nostril.

Obtaining data with repeat dosing will inform if and how fast naloxone plasma concentrations can be reached to be able to reverse highly-potent opioid overdoses. This study will be a randomized, unblinded, three-way crossover study to determine naloxone plasma concentration after administration of multiple doses:

A. Four 4 mg IN naloxone doses (1 dose every 2.5 minutes) B. Four 4 mg IN naloxone doses (2 doses every 2.5 minutes) C. Two 4 mg IN naloxone doses (1 dose every 2.5 minutes)

Detailed description:
Naloxone, a fast-acting mu-opioid antagonist, is a treatment commonly used in reversing opioid overdose. Naloxone is available in multiple formulations, including for injection intravenously, intramuscularly or subcutaneously, and more recently as a spray administered intranasally (IN). The IN naloxone formulation, which was approved in 2015, is of particular interest as there is a need for naloxone formulations for community use by caregivers and first responders/law enforcement who do not have medical training. It is critical to administer naloxone as quickly as possible to prevent irreversible brain damage and death.

The U.S. Food and Drug Administration (FDA), Center for Drug Evaluation and Research (CDER), Division of Applied Regulatory Science (DARS) has conducted modeling and simulation, evaluating how many doses of IN naloxone may be needed to reverse opioid-induced respiratory depression from fentanyl and fentanyl derivates under a range of overdose scenarios. These analyses have suggested that more than two doses of IN naloxone are sometimes required to reverse the effects of highly potent opioids (e.g., certain fentanyl derivatives). Experience with intranasal formulations for other products has shown that repeat administration of doses given in close proximity to the same nostril can influence drug exposure due to run-off from the application site, limited absorption, or other factors. While the pharmacokinetics of IN naloxone have been determined following administration of a 4 mg dose in each nostril concurrently, the pharmacokinetics have not been determined following multiple doses according to the FDA product label:

* Administer a single spray intranasally into one nostril.
* Administer additional doses using a new nasal spray with each dose, if the patient does not respond or responds and then relapses into respiratory depression, additional doses may be given every 2 to 3 minutes until emergency medical assistance arrives.

This involves a 2-3 minute delay between each dose and re-administering to a previously dosed nostril starting with the 3rd dose, which may result in a less than dose-proportional increase in naloxone plasma concentration and/or delayed increase in naloxone exposure compared to the first 2 doses. Obtaining data with repeat dosing will inform if and how fast naloxone plasma concentrations can be reached to be able to reverse highly-potent opioid overdoses.

This study will be a randomized, unblinded, three-way crossover study to determine naloxone plasma concentration after administration of multiple doses:

A. Four 4 mg IN naloxone doses (1 dose every 2.5 minutes) B. Four 4 mg IN naloxone doses (2 doses every 2.5 minutes) C. Two 4 mg IN naloxone doses (1 dose every 2.5 minutes)

The above 3 treatments will be evaluated in a randomized order over 3 treatment periods. Healthy subjects will be randomized to one of six treatment sequences (i.e., ABC, ACB, BAC, BCA, CAB, CBA). Subjects will report to the study site for screening from Days -28 to -2 and then will return to the site on Day -1 for baseline assessments and check-in. After check-in (Day -1), subjects will receive dosing for the 3 respective treatment periods on Days 1, 4 and 7. There will be two days of washout between each treatment period. Participants will be confined in the study clinic from Day -1 until the morning of Day 8. On dosing days, dosing will occur as per the treatment description and pharmacokinetic (PK) assessments will occur at 16 different time points.

Arms: arm 1: Four 4 mg IN naloxone doses (left nostril at 0 min, right nostril at 2.5 min, left nostril at 5 min, right nostril at 7.5 min) arm 2: Four 4 mg IN naloxone doses (left and right nostrils at 0 min, left and right nostrils at 2.5 min) arm 3: Two 4 mg IN naloxone doses (left nostril at 0 min, right nostril at 2.5 min)
Interventions: intervention 1: Four naloxone nasal spray doses (1 every 2.5 min) intervention 2: Four naloxone nasal spray doses (2 every 2.5 min) intervention 3: Two naloxone nasal spray doses (1 every 2.5 min)
Intervention descriptions: intervention 1: Four 4 mg IN naloxone doses (left nostril at 0 min, right nostril at 2.5 min, left nostril at 5 min, right nostril at 7.5 min intervention 2: Four 4 mg IN naloxone doses (left and right nostrils at 0 min, left and right nostrils at 2.5 min) intervention 3: Two 4 mg IN naloxone doses (left nostril at 0 min, right nostril at 2.5 min)

Protocol documents:
ICF_000.pdf: 
Study Title: Clinical Study to Investigate the Pharmacokinetics of Multiple 
Repeated Doses of Intranasal Naloxone 
 
Document Title: Informed Consent Form – Study No. SCR-011 
 
Document Date : 23 February 2021 
 
NCT Number: NCT04764630 


U.S. Food and Drug Administration / Protocol Number SCR-011 
Page 1 of 22 
 
 
Jennifer Deering, MSN, APNP 
Advarra IRB Approved Version 23 Feb 2021 
 
 
CONSENT TO TAKE PART IN A CLINICAL RESEARCH STUDY 
AND 
AUTHORIZATION TO DISCLOSE HEALTH INFORMATION 
 
Sponsor / Study Title: 
  
U.S. Food and Drug Administration / “Clinical study to 
investigate the pharmacokinetics of multiple repeated doses of 
intranasal naloxone” 
 
Protocol Number: 
 
SCR-011 
 
Principal Investigator: 
Study Doctor 
 
Jennifer Deering, MSN, APNP 
Carlos Sanabria, MD 
Telephone: 
 
(800)597-4507  
(855)622-8100 (24-Hour) 
 
Address: 
Spaulding Clinical 
525 S. Silverbrook Drive 
West Bend, WI    53095 
 
SUBJECT SCREENING #_______ 
 
Please read this form carefully. Take time to ask the study doctor or study staff as many 
questions about the study as you would like. The study doctor or study staff can explain words or 
information that you do not understand. Reading this form and talking to the study doctor or 
study staff may help you decide whether to take part or not. If you decide to take part in this 
study, you must sign your name and date at the end of this form. You cannot take part in this 
research study until you sign and date this form. 
 
CLINICAL STUDY SUMMARY: 
 
Purpose of this clinical 
study 
You are being asked to take part in a research study which will 
look at how different repeated doses of the study drug 
(naloxone nasal spray) affects the level of naloxone in the 
blood. Naloxone nasal spray is used to treat patients with 
known or suspected opioid overdoses.  
 
Your participation in this clinical study is voluntary. 
Duration of participation 
You can be expected to be confined at the research institution 
for a total of 9 days, 8 nights. 
Risks and/or discomforts 
from the study drug (as 
seen in previous clinical 
studies using this study 
drug) 
• Increased blood pressure 
• Constipation 
• Toothache 
• Muscle spasms 
• Musculoskeletal pain 
• Headache 


U.S. Food and Drug Administration / Protocol Number SCR-011 
Page 2 of 22 
 
 
Jennifer Deering, MSN, APNP 
Advarra IRB Approved Version 23 Feb 2021 
 
 
• Nasal dryness 
• Nasal edema (swelling) 
• Nasal congestion 
• Nasal inflammation/bleeding 
• Rhinalgia (pain in the nose) 
• Xeroderma (dryness of the skin or nose) 
Other foreseeable risks 
and/or discomforts 
Risks of taking blood may include: 
• Fainting 
• Pain 
• Bruising 
• Rarely, there may be a small blood clot or infection at 
the site of the needle puncture 
 
The blood pressure cuff may also cause discomfort or bruising 
to the upper arm.  
Benefits to your 
participation in this clinical 
study 
You will not receive direct medical benefit from receiving the 
study drug. You may benefit by having your medical history 
recorded, undergoing a physical examination, and having 
blood and urine tests as they apply to this research study.   
 
By taking part in this research study, you may be helping 
future patients by providing important information about the 
study drug and by contributing to medical knowledge. 
Stipend 
If you complete the screening process for this study, you will 
receive up to $55. 
 
If you are selected for participation in this study and complete 
the entire study (Day -1 to Day 8), you will receive up to 
$3,645.00 
 
 
WHAT IS A VOLUNTEER INFORMED CONSENT? 
 
Please read this consent form carefully. This consent form provides important information about 
participating in a research study to help you decide whether or not you would like to participate 
as a research subject. This form contains important information about what you will be asked to 
do during the study, about the risks and benefits of the study, and about your rights as a research 
subject. You may discuss your decision with your family, your friends and/or your doctor. If you 
decide to take part in this study, you must sign your name and date at the end of this form. Your 
participation is entirely voluntary. If you choose to participate you can change your mind at any 
time and withdraw from the study. You will not be penalized in any way or lose any benefits to 
which you would otherwise be entitled if you choose not to participate in this study or if you 
choose to withdraw. You cannot take part in this research study until you sign and date this form. 
A copy of the signed and dated form will be provided to you for your record. 
 


U.S. Food and Drug Administration / Protocol Number SCR-011 
Page 3 of 22 
 
 
Jennifer Deering, MSN, APNP 
Advarra IRB Approved Version 23 Feb 2021 
 
 
You are being asked to take part in a research study which will look at the following:  
 
• How different repeated doses of the study drug (naloxone) affect the level of naloxone in 
the blood. 
• Determine the impact of multiple doses of naloxone on the mean time to rescue patients 
from opioid overdoses using a pre-determined model. 
 
Naloxone (trade name Narcan) has been approved by the U.S. Food and Drug Administration 
(FDA) and is commonly used in reversing opioid overdose.  Naloxone is available in multiple 
formulations, including intravenous, intramuscular, and intranasal (inhaled through the nose).  In 
this study, the administration of naloxone will be intranasal.  
 
Before you decide to take part, you should understand the possible benefits and risks associated 
with this study. This process is known as informed consent and means that you will: 
 
• 
Receive detailed information about this research study. 
• 
Have a chance to ask and receive answers to any questions you may have. 
• 
Be asked to read and sign and date this informed consent, once you understand the study 
and wish to take part. 
• 
Be given a signed and dated copy of this informed consent to keep. 
 
Taking part in this study is entirely voluntary. 
 
WHY IS THIS STUDY DRUG BEING STUDIED? 
 
Naloxone is a fast-acting drug that is commonly used in reversing opioid overdose.  The use of 
intranasal (through the nose) naloxone is of interest as there is a need for naloxone formulations 
for community use by caregivers and first responders/law enforcement who do not have medical 
training.  It is critical to administer naloxone as quickly as possible in the event of an opioid 
overdose to prevent irreversible brain damage and death. 
 
There is a need to assess the body’s exposure to naloxone when given intranasally over multiple 
doses.  Your contribution to the study is of major importance to agencies like the U.S. Food and 
Drug Administration to understand how the body processes multiple repeated doses of intranasal 
naloxone. 
 
HOW WILL THIS STUDY BE DONE? 
 
This study will be conducted in one part, with three treatment periods.  Approximately 20 
healthy subjects will be enrolled who will receive study drug treatment according to the table 
below.  Subjects will receive study treatment (study treatment group A, B, or C) in a random 
order on days 1, 4, and 7 with a washout period (meaning no study drug is given) of two days in 
between each dosing day.  There will be no placebo used in this study. The table below describe 
the 3 dose regimens that you will get in random order. 
 
 


U.S. Food and Drug Administration / Protocol Number SCR-011 
Page 4 of 22 
 
 
Jennifer Deering, MSN, APNP 
Advarra IRB Approved Version 23 Feb 2021 
 
 
 
Study 
Treatment  
Description 
A 
Four 4 mg IN naloxone doses (1 dose every 2.5 min; L at 0 min, R at 2.5 
min, L at 5 min, R at 7.5 min) 
B 
Four 4 mg IN naloxone doses (2 doses every 2.5 min; L and R at 0* min, L 
and R at 2.5* min) 
C 
Two 4 mg IN naloxone doses (L at 0 min, R at 2.5 min) 
IN = intranasal, L = Left Nostril, R = Right Nostril, *L and R doses will be ~5 seconds apart 
(one after the other) 
 
For this study, you will be confined at Spaulding Clinical from Day -1 through the morning of 
Day 8 (a total of 9 days). 
 
WHO IS BEING ASKED TO TAKE PART IN THIS STUDY? 
 
Approximately 20 healthy male and female adult subjects, who meet the requirements following 
a screening visit, will be enrolled in the study.  
 
You have been asked to take part in this study because you are in general good health, are 
between 18 and 55 years of age, have no history of heart or liver disease, no history of allergies, 
no symptoms consistent with coronavirus disease of 2019 (COVID-19), no underlying medical 
conditions that put you at higher risk for COVID-19 complications and have not participated in 
another research study for an experimental drug (or a medical device) within 30 days of the first 
dose of study drug.  
 
HOW MUCH TIME IS REQUIRED TO TAKE PART IN THE STUDY? 
 
If you decide to take part in the study, you will be asked to attend a screening visit. If you pass 
the screening visit, you will return to the clinic for one study treatment period of 9 days and 8 
nights. 
 
INFORMATION FOR FEMALE SUBJECTS 
 
You should not screen for this study if: 
 
• There is any possibility that you may become, or are pregnant, 
• You have given birth in the last 3 months, or 
• You are breast feeding. 
 


U.S. Food and Drug Administration / Protocol Number SCR-011 
Page 5 of 22 
 
 
Jennifer Deering, MSN, APNP 
Advarra IRB Approved Version 23 Feb 2021 
 
 
You may screen for this study if:  
 
• You have had a hysterectomy (uterus removed) or bilateral oophorectomy (ovaries 
removed), confirmed with documentation, or 
• You are of post-menopausal age and have not had a menstrual period for 2 years, 
confirmed with hormone level (FSH blood test) at screening, or 
• You have a vasectomized partner who has been documented to no longer produce sperm, 
or 
• You are using TWO highly effective methods of contraception to avoid pregnancy at 
least 1 month before study entry, throughout the study, and for at least 1 month after last 
study drug administration. Highly effective methods of birth control include: 
 
o Hormonal implants/patch,  
o Oral hormonal contraceptives,  
o Injectable hormones,  
o Intrauterine device (IUD), 
o Approved cervical ring,  
o Diaphragm with spermicide or condom (female or male) with spermicide 
 
One of the methods of birth control used must be a barrier method. The use of spermicide alone 
and condom alone are not acceptable methods of contraception.  
 
Except for continuous abstinence (no sexual intercourse with a male partner), no method of birth 
control can be considered 100% reliable in preventing pregnancy. Although the risk of becoming 
pregnant is low with many methods, unplanned pregnancies may occur with all birth control 
methods. Most occur because of improper or irregular use of the birth control method. If you are 
usually not sexually active but become sexually active, you must follow the advice documented 
above regarding contraceptive methods. 
 
All females enrolled in the study will have a pregnancy test performed at screening, at check-in 
on Day -1 and check out on Day 8. 
 
Please be aware that a pregnancy test may not be positive until 12 days after conception 
(fertilization of the egg by sperm). Therefore, if you do not follow the study birth control 
requirements and/or your birth control method has failed, you will not be able to count on a 
negative test to confirm that you are not pregnant. 
 
If you know that you have not followed the study birth control requirements outlined above, then 
you must immediately inform us. You must not take any dose of the study drug if you have not 
followed these requirements. If you become pregnant, your pregnancy will be followed to 
document the outcome.  All live births must be followed for a minimum of 30 days or until the 
first well-baby visit. 
 


U.S. Food and Drug Administration / Protocol Number SCR-011 
Page 6 of 22 
 
 
Jennifer Deering, MSN, APNP 
Advarra IRB Approved Version 23 Feb 2021 
 
 
INFORMATION FOR MALE SUBJECTS 
 
The effect of the study drug on male sperm is unknown. Therefore, it is recommended to avoid 
fathering a child for 30 days after the last dose of the study drug. 
 
Male subjects must ensure that TWO acceptable methods of contraception are used for the entire 
duration of the study, one of which must be a barrier method, up to the study follow-up visit, if 
applicable. 
 
Periodic abstinence and withdrawal are not acceptable methods of contraception. 
 
HOW WILL YOU KNOW IF YOU ARE ELIGIBLE TO TAKE PART? 
 
You will NOT need to fast prior to your arrival at Spaulding Clinical Research, LLC. for your 
screening visit. You may eat and drink as normal prior to arrival.  
 
At the beginning of the Screening visit, Informed Consent will be obtained. 
 
Before starting the study, the following screening procedures will be performed:  
 
• A complete medical history and physical examination (including height and weight 
measurements for Body Mass Index (BMI, a way to tell if your weight is proportional to 
your height). 
• Assessment of vital signs including blood pressure, respiratory rate, heart rate, and oral 
temperature. 
• A complete history of relevant allergies or drug sensitivities. 
• An electrocardiogram (ECG), (a painless recording of the electrical activity of your 
heart). 
• You will be asked if you have taken any medication recently. 
• You will be asked if you have been feeling ill recently. 
• Clinical laboratory tests (urine and blood samples), including screening for drugs, 
alcohol, and pregnancy tests (all female subjects); blood sample to measure FSH (for 
postmenopausal female subjects only); and testing for HIV, hepatitis B and C. Positive 
results of HIV or hepatitis tests will be reported to local health authorities as required by 
state law. 
If you meet the “entry criteria” of the study, according to the study doctor, you will be tested 
again when you are admitted to Spaulding Clinical Research, LLC. You will have the entry 
criteria reviewed again to ensure that you still are eligible for the study.  
In addition, prior to admission you will have a diagnostic test performed to detect severe acute 
respiratory syndrome coronavirus 2 (called “coronavirus” from now on), which is the virus that 
causes COVID-19. Depending on the time required to return results, this may be performed ~2 
days before check-in or may be performed on the check-in day. You will only be allowed to be 
admitted if your coronavirus test is negative. In addition, when entering the building for 
screening and check-in, triage for COVID-19 will take place. The exact details of what will 
occur at triage may change as additional information or testing is available, however as of now it 


U.S. Food and Drug Administration / Protocol Number SCR-011 
Page 7 of 22 
 
 
Jennifer Deering, MSN, APNP 
Advarra IRB Approved Version 23 Feb 2021 
 
 
is planned to include asking about any potential contacts with COVID-19, signs and symptoms 
associated with COVID-19, temperature monitoring and antibody screening for coronavirus. 
 
WHAT TESTS AND PROCEDURES WILL BE USED IN THE STUDY? 
 
1. Check-in (Day -1) 
 
Upon admission to Spaulding Clinical Research, LLC., you will be given an identity band to 
wear throughout your entire stay in the unit. 
 
You will NOT need to fast prior to your arrival meaning you should eat and drink as normal.  
 
The following admission procedures will be performed:  
 
• Perform/review results from coronavirus test  
• Medical history updates 
• Physical examination 
• Weight collection 
• Clinical laboratory tests (urine and blood samples), including screening for drugs, 
alcohol, and pregnancy tests (all female subjects) 
• Assessment of vital signs including blood pressure, respiratory rate, heart rate, and oral 
temperature 
• An electrocardiogram (ECG), (a painless recording of the electrical activity of your heart) 
• You will be asked for details of any medication taken since the screening or previous 
visit 
• You will be asked if you have been ill since the screening or previous visit 
• You will be asked if you complied with study restrictions 
• You will be provided meals 
• Inclusion/Exclusion assessment and preparation for randomization 
 
The results from these tests will help the study staff determine whether you are still eligible to 
enter the study.  
 
2. Study Treatment (Days 1, 4, and 7) 
 
• Adverse event assessment (check for side effects) and changes in concomitant 
medications (medicines you are currently taking). 
• Randomization (assignment to an order of study treatments) 
• Collection of 3 electrocardiograms (ECG) at pre-dose, 1 hour, and 6 hour time points.  
• Assessment of vital signs including blood pressure, respiratory rate, heart rate, and oral 
temperature at pre-dose, 0.5 hour, 1 hour, and 6 hour time points. 
• Administration of study drug. 
• Blood collection to look at levels of study drug in your blood. 
• Meals. 
• Nasal irritation assessment. 


U.S. Food and Drug Administration / Protocol Number SCR-011 
Page 8 of 22 
 
 
Jennifer Deering, MSN, APNP 
Advarra IRB Approved Version 23 Feb 2021 
 
 
 
3. Washout (Days 2, 3, 5, and 6) 
 
• Adverse event assessment (check for side effects) and changes in concomitant 
medications (medicines you are currently taking). 
• Assessment of vital signs including blood pressure, respiratory rate, heart rate, and oral 
temperature. 
• Meals. 
 
4. Check-out (Day 8) 
 
• Adverse event assessment (check for side effects) and changes in concomitant 
medications (medicines you are currently taking). 
• Physical examination. 
• Weight collection. 
• Clinical laboratory tests (urine and blood samples), including screening for drugs, 
alcohol, and pregnancy tests (all female subjects).  
• Assessment of vital signs including blood pressure, respiratory rate, heart rate, and oral 
temperature. 
• An electrocardiogram (ECG) 
• You will be asked for details of any medication taken since the screening or previous 
visit. 
• You will be asked if you have been ill since the screening or previous visit. 
• You will be asked if you complied with study restrictions. 
 
INFORMATION OBTAINED DURING THE STUDY 
 
Blood Sampling 
 
Blood samples will be collected for measurement of levels of study drug at the following times: 
 
• On dosing days (Day 1, 4, and 7) at: 0 (pre-dose), 2, 4.5, 7, 10, 12.5, 15, 20, 30, 45, 60, 
120, 180, 240, 360, and 720 minutes after dosing for a total of 48 blood collections for 
determining study drug levels. 
Blood samples will be collected for measurement of proteins and other constituents of your 
blood at the following times: 
• Screening 
• Check-in: Day -1 
• Check-out: Day 8 
• Total of 3 blood collections for measuring proteins and other constituents of your blood 
 
You will have numerous blood samples drawn during the entire study as shown above.  The 
blood samples may be taken by individual needle sticks into one of your arm veins, or, if 
necessary, by an indwelling catheter (a thin plastic tube placed in a vein in your arm).  
 


U.S. Food and Drug Administration / Protocol Number SCR-011 
Page 9 of 22 
 
 
Jennifer Deering, MSN, APNP 
Advarra IRB Approved Version 23 Feb 2021 
 
 
The total amount of blood taken will be approximately 480 ml or about 2 cups. 
 
Urine Sampling 
 
You will have urine samples collected at screening, Day -1 (Check-in), and the last study day 
(Check-out). These will be used to screen for either alcohol or drugs or for routine safety 
analysis.  
 
ECG Measurements 
 
Safety ECG measurements will occur at your screening visit, Day -1 (Check-in), Day 1, 4, 7, and 
Day 8 (Check-out). There will be periods of time where you will need to lie very still to get 
precise readings of your heart’s rhythm. 
 
Some individuals may develop redness, irritation, or discoloration of the skin at the site of ECG 
electrodes placed on the chest/body. This may develop due to sensitivity to the electrodes or to 
our skin preparation procedure. In order to get the quality results needed, it is necessary for us to 
lightly scrub the skin with an abrasive pad to remove any skin impedance such as oil, dead skin 
cells and lotions. We may trace each electrode site with a permanent marker to assure electrodes 
are placed in the same place on the body for each ECG event to maintain quality and consistent 
results. This tracing may occur as often as once a day during confinement. 
 
Nasal Irritation Assessment 
 
You will have nasal irritation assessments at different timepoints during study drug 
administration. A trained observer will use a pen light to look in your nostrils for signs of 
irritation or bleeding. 
 
WHAT ARE YOUR RESTRICTIONS DURING THE STUDY? 
 
You will need to avoid the following while taking part in this study, and most importantly from 
the time of your screening visit until you check in:  
 
 
Restricted Item: 
Duration: 
Alcohol 
48 hours before dose until the end of study 
visit 
Caffeine or other xanthine-containing products 
(for example, coffee, tea, cola or chocolate) 
48 hours before dose until the end of study 
visit  
Grapefruit or grapefruit juice 
48 hours before dose until the end of study 
visit 
Nicotine-containing products 
6 weeks prior to screening until end of study 
visit  
Prescription or non-prescription medication 
(except for oral contraceptives) – note this 
includes:  
14 days prior to dose 


U.S. Food and Drug Administration / Protocol Number SCR-011 
Page 10 of 22 
 
 
Jennifer Deering, MSN, APNP 
Advarra IRB Approved Version 23 Feb 2021 
 
 
• Aspirin or NSAIDs (Ibuprofen, 
Naproxen)  
• Any intranasal medication 
Other intranasal spray products  
48 hours before dose until the end of study 
visit. 
You will receive a diet that does not contain any alcohol or caffeine. You must eat all of each 
meal that is served to you and eat at a reasonable pace (within 25 minutes).  
 
You may eat only meals and snacks that are provided to you during the periods of your stay. 
After checking out of the clinic, there are no dietary restrictions.  
 
You must be willing to comply with study rules, including the meal schedule (25 minutes to eat), 
attempting to void at specified times, remaining quiet, awake, undistracted, motionless, and 
seated during specified times (for example during ECG extraction times), and avoiding vigorous 
exercise as directed throughout the duration of the study. 
 
You must be able to take the study drug intranasally and should not have a deviated septum or 
any previous nasal surgeries that would impact administration of the intranasal drug.  
 
You must remain fully supine for approximately one hour after study drug administration. You 
will be instructed to not breathe through the nose during administration of the nasal spray into 
the nose. You will be asked to leave your masks off for twenty minutes after study drug 
administration. 
 
Due to current precautions being taken for COVID-19, the following restrictions will be in place: 
 
• You must always wear a mask except when in your bed with a curtain drawn in the room 
or for a limited time for a study procedure (for example, study drug administration when 
instructed by the study staff).  
• You must practice social distancing. Common areas will be closed. You will eat meals 
socially distanced in the hallway. You will spend most of your time in your rooms except 
for specified times for walking in the halls (with masks). 
• You must practice regular handwashing with soap and water, scrubbing hands for at least 
20 seconds or with approved hand sanitizer as supplied by study staff.  
 
If new information becomes available, there could be other precautions that lead to additional 
restrictions. 
 


U.S. Food and Drug Administration / Protocol Number SCR-011 
Page 11 of 22 
 
 
Jennifer Deering, MSN, APNP 
Advarra IRB Approved Version 23 Feb 2021 
 
 
ARE THERE RISKS TO YOU IF YOU ARE IN THIS STUDY? 
 
Please be advised that non-pharmacological treatments (such as heating pack, stretches, 
hydration, etc.) are our first line of therapy for mild adverse events. The study doctor will be 
notified if a subsequent medication may be needed to treat an adverse event. Following the study 
plan guidelines, the study doctor will assess your adverse event and develop a treatment plan. 
 
The following adverse reactions were observed in a naloxone nasal spray clinical study similar to 
this one: 
 
• Increased blood pressure 
• Constipation 
• Toothache 
• Muscle spasms 
• Musculoskeletal pain 
• Headache 
• Nasal dryness 
• Nasal edema (swelling) 
• Nasal congestion 
• Nasal inflammation/bleeding 
• Rhinalgia (pain in the nose) 
• Xeroderma (dryness of the skin or nose) 
 
Additionally, there is a risk of precipitation of severe opioid withdrawal in subjects who are 
opioid-dependent characterized by the following signs/symptoms: 
 
• Body aches 
• Diarrhea 
• Tachycardia (increased heart rate) 
• Fever 
• Runny nose 
• Sneezing 
• Piloerection (goose bumps) 
• Sweating 
• Yawning 
• Nausea or vomiting 
• Nervousness 
• Restlessness or irritability 
• Shivering or trembling 
• Abdominal cramps 
• Weakness 
• Increased blood pressure 
 


U.S. Food and Drug Administration / Protocol Number SCR-011 
Page 12 of 22 
 
 
Jennifer Deering, MSN, APNP 
Advarra IRB Approved Version 23 Feb 2021 
 
 
However, opioid-dependent individuals are excluded from this study as subjects cannot use 
prescription or nonprescription drugs within at least 14 days of study drug administration and a 
urine drug screen will check for opioids at screening and check-in.  
  
Problems or side effects that are not now known could also occur. You will be given any new 
information that may affect your willingness to start or continue in the study. 
 
The tests done at each visit are standard medical tests. The most unpleasant is often having blood 
samples taken. The risks of taking blood may include: 
• Fainting 
• Pain 
• Bruising 
• Rarely, there may be a small blood clot or infection at the site of the needle puncture 
 
The blood pressure cuff may also cause discomfort or bruising to the upper arm.  
 
In rare instances where a study nurse, a study doctor, or a study technician, sustains an exposure 
to your blood, tissue or body fluids by needle stick, cut or splash to mucosa or damaged skin, it 
may be necessary to test your blood, tissue, or body fluid sample for certain viral infections 
including Hepatitis B and C and HIV on the sample already available. This is to enable that 
person to receive appropriate counseling, monitoring and treatment if necessary. In this instance, 
the study doctor or designee will offer you the information relevant to your health and advise you 
on the next steps. Confidentiality of your data will be respected at all times according to the state 
law. 
 
Unknown Risks 
 
As with any drug, it is possible that you could experience an allergic reaction to the study drug 
used in this study. Symptoms of any allergic reaction can include: 
• Rash  
• Hives  
• Itching 
• Angioedema:  
o Difficulty breathing 
o Closing of the throat  
o Swelling of the lips, tongue or face 
• Rarely, death 
 
If you think you are having a severe allergic reaction, while outside the study center call 9-
1-1 and seek medical attention immediately. 
 
It is very important that you tell the study doctor and the study staff about any side effects that 
you might experience. 
 


U.S. Food and Drug Administration / Protocol Number SCR-011 
Page 13 of 22 
 
 
Jennifer Deering, MSN, APNP 
Advarra IRB Approved Version 23 Feb 2021 
 
 
You may experience side effects or discomforts that are not listed on this form. Tell your study 
doctor or study staff immediately if you have any problems. Your safety will be our priority and 
closely monitored throughout the study. 
 
For ECG Monitoring 
 
It is possible to be sensitive to the adhesives used on the electrodes that are applied to your chest 
when having an ECG performed. If this is the case, you could develop a temporary redness, 
irritation, or discoloration of the skin where the electrodes were applied. 
 
HIV and Hepatitis B and C Testing 
 
The risks of HIV and hepatitis B and C testing include psychological and social risks. A positive 
test can lead to restrictions in freedom of travel to some countries and possible prejudices in job 
employment, insurance eligibility, housing and other forms of discrimination. Positive HIV and 
hepatitis B and C test results must be reported to health authorities under state law. A positive 
HIV and/or hepatitis B or C result will exclude you from participation in the study. 
 
Reproductive Risks 
 
The effects of the study drug on human pregnancy and the unborn child (fetus) are unknown. 
Therefore, it is very important that you do everything within your power not to become pregnant, 
or father a child during this study and for 30 days following the last dose. Please ensure that you 
follow the study birth control requirements outlined in the sections regarding information for 
male and female subjects above. 
 
If you become pregnant during the course of the study, you will be withdrawn from the study 
immediately. Neither Spaulding Clinical Research, LLC. nor the sponsor will be responsible for 
the cost of any obstetric or related care, or for your child's care. Female subjects are agreeing, by 
signing and dating this form, that information about your pregnancy and birth of your child may 
be collected. The information collected will include your health and the health of your unborn 
child during pregnancy, pregnancy outcome (miscarriage, termination, live birth, etc.), and the 
health of the baby after it is born (for a minimum of 30 days or until the first well-baby visit). 
 
COVID-19 Risks 
 
Despite the extra precautions (for example, COVID-19 triage at screening/check-in, coronavirus 
testing, mandatory masks for study subjects and study staff, social distancing, extra hand 
washing) that will be in place, there is still a risk of developing COVID-19 just as there is when 
you are not at Spaulding Clinical. Tell your study doctor or study staff about any new symptoms 
you develop during the study.  
 


U.S. Food and Drug Administration / Protocol Number SCR-011 
Page 14 of 22 
 
 
Jennifer Deering, MSN, APNP 
Advarra IRB Approved Version 23 Feb 2021 
 
 
The U.S. Centers for Disease Control and Prevention (CDC) currently highlights that people 
with the following symptoms may have COVID-19: 
• Cough 
• Shortness of breath or difficulty breathing 
• Fever or chills 
• Fatigue 
• Muscle or body aches 
• Headache 
• Sore throat 
• New loss of taste or smell 
• Congestion or runny nose  
• Nausea or vomiting 
• Diarrhea 
 
It is important to note that COVID-19 can also present with other symptoms and just because 
you develop any of the above symptoms does not mean that you have COVID-19. Your study 
doctor will evaluate if your symptoms warrant further isolation from other study subjects, study 
staff, additional coronavirus testing, and/or any treatment. 
 
NEW FINDINGS 
 
Your study doctor will tell you of any information learned during the course of the study that 
might cause you to change your mind about taking part in the study. You may contact the study 
doctor at any time after your participation ends to find out if any new information about this 
study has become available. 
 
WHAT IS THE ALTERNATIVE TO BEING IN THE STUDY? 
 
Since this is a study involving healthy subjects, your alternative is not to take part. 
 
WILL YOU BENEFIT FROM TAKING PART IN THE STUDY? 
 
You will not receive direct medical benefit from receiving the study drug. You may benefit by 
having your medical history recorded, undergoing a physical examination, and having blood and 
urine tests as they apply to this research project.  
 
Just by taking part in this research study, you may be helping future patients by providing 
important information about the study drug and by contributing to medical knowledge. 
 
WHO IS PAYING FOR THIS STUDY? 
 
The U.S. Food and Drug Administration is the Sponsor of the study. The U.S. Food and 
Drug Administration pays the study doctor to run this study. 
 
The study drug and all tests, procedures and visits required by the study are provided at no cost 
to you. The sponsor, the U.S. Food and Drug Administration pays for them. 


U.S. Food and Drug Administration / Protocol Number SCR-011 
Page 15 of 22 
 
 
Jennifer Deering, MSN, APNP 
Advarra IRB Approved Version 23 Feb 2021 
 
 
 
Information about this study is confidential. This information belongs to the U.S. Food and Drug 
Administration. We ask that you keep it private. You can discuss this information in private with 
your doctor or family to talk about your healthcare or to decide about taking part in this study. 
 
WILL YOU BE PAID FOR BEING IN THIS STUDY? 
 
Compensation for screening is as follows: 
 
• $55.00 if you qualify and take part in a study. $55.00 for your time and inconvenience if 
you do not qualify for this study.  
• If the results of the drug and alcohol tests are positive, or if you attempt to falsify your 
drug screen you will not receive any compensation. 
• If you screen for the study, qualify and are enrolled, your screening payment will be 
included in your first stipend payment. If you are not accepted into the study your 
screening payment will be processed and mailed within 7 calendar days of study 
enrollment. 
 
Compensation for this study is as follows: 
 
For subjects that complete the entire study (Day -1 to Day 8), you will receive up to 
$3,645.00.  This payment will be made in two separate payments as follows: 
 
• $3,000.00 will be paid after all check out procedures have been completed at the end of 
day 8. 
• The remaining $645.00 will be paid after the follow up visit/call, and any additional 
follow up procedures are completed, and all results are reviewed. 
 
If you withdraw from the study early, you will only be paid for the visits you completed. You 
will receive $100.00 for each full day that you were in-house. 
 
NOTE: You may be required to return to the clinic for repeat blood test or other assessments 
(for example, ECG, physical, vital signs) after the final check out. This is considered part of the 
study and no additional compensation is available. Your final payment will not be released until 
all follow up procedures have been completed and accepted by the study doctor. Once follow up 
procedures have been completed and accepted by study doctor, your final payment will be 
processed and mailed within 14 calendar days. 
 
NOTE: If you meet eligibility criteria you may be asked to be an alternate subject. Alternate 
subjects are eligible subjects that are in addition to the number of subjects in the event an 
enrolled subject drops out before their dose can take place or in the event it is not safe for a 
subject to move forward with dosing. If you are selected as an alternate subject and you agree to 
participate as an alternate subject, you may receive up to $250 if you are not needed to dose. If 
you are needed to replace a subject, you will be paid as stated for participating in and completing 
the study. If you agree to be an alternate subject, you will have all the pre-dose procedures as the 


U.S. Food and Drug Administration / Protocol Number SCR-011 
Page 16 of 22 
 
 
Jennifer Deering, MSN, APNP 
Advarra IRB Approved Version 23 Feb 2021 
 
 
enrolled subjects so that if you are needed, you will be ready to participate. If you are not needed 
you will be discharged shortly after completion of the dosing round. 
 
No deductions for any state or federal withholding or any other similar taxes will be made, and 
you are solely responsible for reporting such payments on your state and federal income tax 
returns.  
 
If you need to stay at Spaulding Clinical Research, LLC. for a longer period of time for safety 
reasons, you will be compensated at a rate proportional to the entire compensation for the study. 
 
If you are dismissed from the study for medical reasons OR if the study is temporarily or 
permanently halted, your compensation will be proportional to the time you spend in the study at 
the rate of approximately $365 a day. 
 
If you are dismissed from the study because you have not complied with the instructions of the 
study staff, no compensation is available. Non-compliance includes, but is not limited to, 
improper conduct, taking alcohol and/or any drugs (including recreational drugs), tampering with 
the study drug, or consuming any foods/beverages not allowed in the study. 
Subjects may be reimbursed for travels expenses depending on need and Sponsor approval. 
 
By signing and dating this consent, you expressly agree that you are an Independent Contractor 
for Spaulding Clinical Research, LLC. As an Independent Contractor, you will receive a 1099 
form from Spaulding Clinical Research, LLC. The 1099 form shall document and report all 
payments and/or study stipends you received as an Independent Contractor for Spaulding 
Clinical Research, LLC. In addition, because you are an Independent Contractor and will be 
receiving payments and/or study stipends, those earnings are subject to wage garnishment. If 
Spaulding Clinical receives an Earnings Garnishment Notice (or similar) from a State or Federal 
legal entity, we will adhere to that garnishment.  
 
COMPENSATION FOR INJURY 
 
It is important that you follow carefully all the instructions given by the study doctor and his/her 
study staff regarding this study.  
 
If you become ill or are physically injured as a result of participation in this study, please contact 
the study doctor right away at the telephone number listed on page one of this consent form. 
He/she will treat you or refer you for treatment. 
 
Spaulding Clinical Research, LLC. and/or its affiliated institutions has not set aside funds to 
provide you with financial compensation or reimbursement for the cost of care provided to treat 
a research-related injury or for other expenses arising from a research-related injury. You or your 
insurer will be responsible for the payment of any medical treatments for research related injuries 
or illness. By signing and dating this consent form, you are not giving up any legal rights. If this 
research study is conducted in a negligent manner and you are injured as a direct result, you may 
be able to recover the costs of care and other damages from the individuals or organizations 


U.S. Food and Drug Administration / Protocol Number SCR-011 
Page 17 of 22 
 
 
Jennifer Deering, MSN, APNP 
Advarra IRB Approved Version 23 Feb 2021 
 
 
responsible for your injury as you still have the right to seek compensation for injury related to 
malpractice, negligence, fault, guilt or blame of those involved in the research. 
 
PROTECTING THE PRIVACY OF YOUR HEALTH DATA 
 
Unless required by law, your name will not be disclosed outside the research clinic. Your name 
will be available only to the following people or agencies: the study doctor and study staff; and 
authorized representatives of the study doctor; Advarra Institutional Review Board, health 
authority inspectors, such as the U.S. Food & Drug Administration and the European Medicines 
Agency; study monitors and auditors; and authorized Clinical Research Organization 
representatives. The above mentioned individuals will use the personal information collected as 
part of this study, including your medical records (“study information”) to check that the study is 
conducted correctly and to ensure the accuracy of the study information. These people are all 
obligated to maintain confidentiality by the nature of their work, or are bound by confidentiality 
agreements. If required, the study doctor may contact your personal doctor to collect additional 
medical information and your past medical history. 
 
The study doctor may only share your study information with people whom you have permitted 
to see it. However once your study information is shared as authorized, it may no longer be 
protected by federal law and may be re-disclosed without your permission. 
 
While participating in this study, the study doctor will replace your name with a special code that 
identifies you. This code, along with your study information, will be used by the study sponsor, 
the U.S. Food and Drug Administration and their representatives, for the study purposes 
mentioned above and to help establish whether the study drug is safe and effective. The U.S. 
Food and Drug Administration may share your coded information, as necessary, with the U.S. 
Food and Drug Administration affiliates who work within the scope of this consent; Advarra IRB 
and Regulatory agencies such as the National Health Authorities, and the European Medicines 
Agency. 
 
You should be aware that some countries may not offer the same level of privacy protection as 
you are used to in the country where you live or where this study is conducted. However, the US 
Food and Drug Administration will keep any information it receives to the same standard of 
confidentiality as far as permitted by applicable local law. The US Food and Drug 
Administration has also entered into agreements with third parties working for the US Food and 
Drug Administration to secure adequate protection of your data and samples.  
 
The study information will be kept confidential within the limits of the law. The U.S. Food and 
Drug Administration may keep study samples and data collected for future research. Identifiers 
might be removed from your identifiable private information or identifiable biospecimens 
collected during this study and could then be used for future research studies or distributed to 
another investigator for future research studies without additional informed consent. No 
additional participation time or procedures will be required beyond what is described above for 
the primary study. Study samples and data will be de-identified (stripped of identifiers such as 
name, address, or account number) so that the data cannot be linked to you. The de-identified 
data from the study may be released to a data warehouse (location that will store the data) or 


U.S. Food and Drug Administration / Protocol Number SCR-011 
Page 18 of 22 
 
 
Jennifer Deering, MSN, APNP 
Advarra IRB Approved Version 23 Feb 2021 
 
 
used as part of a publication. It may be shared broadly for research purposes outside of the U.S. 
Food and Drug Administration and Spaulding Clinical Research, LLC. Other study doctors will 
have access to limited clinical and biological data such as age, gender, and disease status. Your 
samples will only be used for research purposes and will not benefit you. It is also possible that 
your samples and data will never be used. Results of research done on your samples and data will 
not be available to your study doctor. If the results of this study are published or presented in a 
meeting, you will not be named and no one will be able to tell that you were in the study from 
the publication or presentation.  
 
WHOM TO CONTACT ABOUT THIS STUDY 
During the study, if you experience any medical problems, suffer a research-related injury, or 
have questions, concerns or complaints about the study, please contact the study doctor at the 
telephone number listed on the first page of this consent document. If you seek emergency care, 
or hospitalization is required, alert the treating physician that you are participating in this 
research study.  
 
An institutional review board (IRB) is an independent committee established to help protect the 
rights of research subjects. If you have any questions about your rights as a research subject, 
and/or concerns or complaints regarding this research study, contact: 
 
• By mail: 
Study Subject Adviser 
Advarra IRB 
6940 Columbia Gateway Drive, Suite 110 
Columbia, MD 21046 
• or call toll free:    877-992-4724 
• or by email:          adviser@advarra.com 
 
Please reference the following number when contacting the Study Subject Adviser: 
Pro00049858. 
 
IS YOUR PARTICIPATION VOLUNTARY? 
 
Yes, your participation in this study is strictly voluntary. You may refuse to take part in it, or you 
may stop participating at any time, even after signing and dating this informed consent. There 
will be no penalty or loss of benefits to which you are otherwise entitled. However, if you decide 
to leave the study before it ends, the study doctor will need to see you before you are released 
from the study. 
 
The study doctor, U.S. Food and Drug Administration or Advarra IRB may also decide to 
remove you from the study at any time without your consent. The study doctor may choose to 
take you out of the study because of unexpected or serious side effects, or for other scientific, 
technical, or safety considerations. 
 
 
 


U.S. Food and Drug Administration / Protocol Number SCR-011 
Page 19 of 22 
 
 
Jennifer Deering, MSN, APNP 
Advarra IRB Approved Version 23 Feb 2021 
 
 
Examples why you may be taken out of the study are: 
• Staying in the study would be harmful 
• You need treatment not allowed in this study 
• You failed to follow instructions 
• You become pregnant 
• The study is cancelled 
• Your study treatment arm is stopped 
If your participation ends for any reason, you will return to the study site for the following study 
procedures: 
• Serum pregnancy test (female subjects only) 
• Adverse events and concomitant medications 
• Alcohol and drug screening 
• Clinical laboratory (blood) tests and urine collection for urinalysis 
• Measurement of vital signs including blood pressure, heart rate, respiratory rate, pulse 
oximetry and oral body temperature) 
• ECG 
• Complete physical exam including weight 
If you should decide to leave the study you should tell the study doctor or study staff. They will 
make sure that proper procedures are followed and a final visit is made for your safety. 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
by U.S. Law. This Web site will not include information that can identify you. At most, the Web 
site will include a summary of the results. You can search this Web site at any time. 
 
 
 


U.S. Food and Drug Administration / Protocol Number SCR-011 
Page 20 of 22 
 
 
Jennifer Deering, MSN, APNP 
Advarra IRB Approved Version 23 Feb 2021 
 
 
STATEMENT OF CONSENT  
 
I have read this form and its contents were explained to me. I agree to be in this research study 
for the purposes listed above. All my questions were answered to my satisfaction. I will receive a 
signed and dated copy of this form for my records. I am not giving up any of my legal rights by 
signing and dating this form.  
 
___________________________________ 
 
____/____/____ 
Signature of Research Subject 
 
Date 
 
___________________________________  
 
 
 
_______________ 
Printed Name of Research Subject 
 
 
 
 
 
Time (24hr) 
 
STATEMENT OF PERSON OBTAINING INFORMED CONSENT  
I have carefully explained to the subject the nature and purpose of the above study. There has 
been an opportunity for the subject to ask questions about this research study. I have been 
available to answer any questions that the subject has about this study. 
 
                                                                                          
 
____/____/____ 
Signature of Person Obtaining Informed Consent 
 
Date 
 
 
___________________________________  
 
 
 
_______________ 
Printed Name of Person Obtaining Informed Consent 
 
 
 
Time (24hr) 
 
 


U.S. Food and Drug Administration / Protocol Number SCR-011 
Page 21 of 22 
 
 
Jennifer Deering, MSN, APNP 
Advarra IRB Approved Version 23 Feb 2021 
 
 
HIPAA Authorization Agreement 
Permission to Review, Use and Release Information about You 
 
If you decide to be in this study, the study doctor and research team will use and share health 
data about you to conduct the study. Health data may include: 
 
• Your name. 
• Address.  
• Phone number. 
• Date of birth. 
• Medical history. 
• Information from your study visits, including all test results.  
 
Health data may come from your study records or from existing records kept by your doctor or 
other health care workers.  
 
For this study, the research team may share health data about you with authorized users. 
Authorized users may include: 
 
• Representatives of the U.S. Food and Drug Administration 
• Representatives of Spaulding Clinical Research, LLC. 
• Representatives of Advarra IRB (an Institutional Review Board that reviews this study). 
• Other US governmental agencies. 
• Government agencies to whom certain diseases (like HIV, hepatitis, and STIs) must be 
reported. 
• Governmental agencies of other countries. 
• Labs working with the sponsor on this study. 
• Other authorized users. 
 
The sponsor and those working for the sponsor may use the health data sent to them: 
 
• To see if the study drug works and is safe. 
• To compare the study drug to other drugs. 
• For other research activities related to the study drug. 
 
Once your health data has been shared with authorized users, it may no longer be protected by 
federal privacy laws.  
 
Your permission to use and share health data about you will not end unless required by state law.  
 
You may take back your permission to use and share health data about you at any time by 
writing to the study doctor at the address listed on page one of this consent form. If you do this, 
you will not be able to stay in this study. No new health data that identifies you will be gathered 
after your written request is received. However, health data about you that has already been 
gathered may still be used and given to others as described in this form.  


U.S. Food and Drug Administration / Protocol Number SCR-011 
Page 22 of 22 
 
 
Jennifer Deering, MSN, APNP 
Advarra IRB Approved Version 23 Feb 2021 
 
 
Your right to access your health data in the study records will be suspended during the study to 
keep from changing the study results. When the study is over, you can access your study health 
data. 
 
If you decide not to sign and date this form, you will not be able to take part in the study. 
 
STATEMENT OF AUTHORIZATION 
 
I have read this form and its contents were explained. My questions have been answered. I 
voluntarily agree to allow study staff to collect, use and share my health data as specified in this 
form. I will receive a signed and dated copy of this form for my records. I am not giving up any 
of my legal rights by signing and dating this form.  
 
 
 
 
 
____/____/____ 
Signature of Research Subject 
 
 
Date 
 
___________________________________  
 
 
_______________  
Printed Name of Research Subject 
 
 
 
 
 
Time (24hr) 
 
 
 
 
 
 
 
STATEMENT OF PERSON OBTAINING AUTHORIZATION 
 
I have carefully explained to the subject the nature and purpose of this form. I have been 
available to answer any questions that the subject has about this form. 
 
                                                                       
 
 
 
____/____/____ 
Signature of Person Obtaining Authorization 
 
 
Date 
 
___________________________________  
 
 
 
_______________ 
Printed Name of Person Obtaining Informed Consent 
 
 
 
Time (24hr) 
 
 
 
 
 
 
 

SAP_002.pdf: 
Study Title: Clinical study to investigate the pharmacokinetics of multiple 
repeated doses of intranasal naloxone 
 
Document Title: Statistical Analysis Plan – Study No. SCR-011 
 
Document Date: 10 March 2021 
 
NCT Number: NCT04764630 


Statistical Analysis Plan 
SCR-011: Clinical Study to Investigate the Pharmacokinetics of 
Multiple Repeated Doses of Intranasal Naloxone
Page 1 of 18
Statistical Analysis Plan 
SCR-011: Clinical Study to Investigate the Pharmacokinetics 
of Multiple Repeated Doses of Intranasal Naloxone
Sponsor:
U.S. Food and Drug Administration
White Oak Building #64, Room 2072
10903 New Hampshire Avenue
Silver Spring, MD 20993
Sponsor Study Lead:
David Strauss, MD, PhD
Director, Division of Applied Regulatory Science 
U.S. Food and Drug Administration
Telephone: 301-796-6323
Email: david.strauss@fda.hhs.gov
Sponsor Medical 
Monitor:
Keith Burkhart, MD
U.S. Food and Drug Administration
Telephone: 301-796-2226
Email: keith.burkhart@fda.hhs.gov
Project Manager:
Jeffry Florian, PhD
U.S. Food and Drug Administration
Telephone: 301-796-4847
Email: jeffry.florian@fda.hhs.gov
Study Monitor:
Jill Brown
FDA IRB Project Manager
U.S. Food and Drug Administration
Version of SAP:
1.0
Date of SAP:
10 Mar 2021
CONFIDENTIAL
The concepts and information contained in this document or generated during the study are 
considered proprietary and may not be disclosed in whole or in part without the expressed 
written consent of the U.S. Food and Drug Administration.


Statistical Analysis Plan 
SCR-011: Clinical Study to Investigate the Pharmacokinetics of 
Multiple Repeated Doses of Intranasal Naloxone
Page 2 of 18
Sponsor Signatures Page 
Prepared by
Victoria Gershuny, PhD
Biologist, Division of Applied Regulatory 
Science
U.S. Food and Drug Administration
Date
Prepared by
Jeffry Florian, PhD
General Health Scientist, Division of 
Applied Regulatory Science
U.S. Food and Drug Administration
Date
Reviewed by
Robbert Zusterzeel, MD, PhD
Contractor, Division of Applied Regulatory 
Science 
U.S. Food and Drug Administration 
Date
Approved by
David Strauss, MD, PhD
Director, Division of Applied Regulatory 
Science 
U.S. Food and Drug Administration
Date


Statistical Analysis Plan 
SCR-011: Clinical Study to Investigate the Pharmacokinetics of 
Multiple Repeated Doses of Intranasal Naloxone
Page 3 of 18
Contents 
Sponsor Signatures Page.......................................................................................................... 2 
Contents.................................................................................................................................. 3 
Abbreviations and definitions................................................................................................... 5 
Change Log ......................................................................................................................... 6 
1. 
Introduction...................................................................................................................... 7 
2. 
Study Objectives .............................................................................................................. 7 
3. 
Study Overview................................................................................................................ 7 
3.1 
Study Design ............................................................................................................. 7 
4. 
Study Endpoints ............................................................................................................... 8 
4.1 
Primary Endpoint....................................................................................................... 8 
4.2 
Secondary Endpoints ................................................................................................. 8 
4.3 
Exploratory Endpoint................................................................................................. 9 
4.4 
Sample Size............................................................................................................... 9 
5. 
Analysis Populations .......................................................................................................10 
6. 
Data Screening and Acceptance .......................................................................................11 
6.1 
Handling of Missing and Incomplete Data .................................................................11 
7. 
General Statistical Considerations ....................................................................................11 
7.1 
Subject Disposition...................................................................................................11 
7.2 
Demographic and Baseline Characteristics.................................................................11 
7.3 
Pharmacokinetic Analyses ........................................................................................12 
7.3.1 
Naloxone Concentration Comparisons ...................................................................12 
7.3.2 
Dose Proportionality..............................................................................................13 
7.3.3 
Plasma Pharmacokinetics ......................................................................................13 
7.4 
Additional Secondary Analyses.................................................................................14 
7.4.1 
PK/PD Modeling of Time to Reversal of Opioid Induced Respiratory Depression ...14 
7.5 
Safety Analyses........................................................................................................15 
7.5.1 
Adverse Events .....................................................................................................15 
7.5.2 
Clinical Laboratory Tests.......................................................................................15 
7.5.3 
Vital Sign Measurements.......................................................................................15 


Statistical Analysis Plan 
SCR-011: Clinical Study to Investigate the Pharmacokinetics of 
Multiple Repeated Doses of Intranasal Naloxone
Page 4 of 18
7.5.4 
Safety 12-lead Electrocardiograms.........................................................................15 
7.5.5 
Physical Examinations...........................................................................................15 
7.5.6 
Nasal Irritation Score Analyses..............................................................................15 
7.5.7 
Other Safety Data..................................................................................................16 
8. 
Data Quality Assurance ...................................................................................................16 
9. 
Appendices .....................................................................................................................17 
9.1 
Randomization schedule ...........................................................................................17 
10.
References...................................................................................................................18 


Statistical Analysis Plan 
SCR-011: Clinical Study to Investigate the Pharmacokinetics of 
Multiple Repeated Doses of Intranasal Naloxone
Page 5 of 18
Abbreviations and definitions 
AE
Adverse event
AUC0-inf
Area under the plasma concentration time curve from time 0 extrapolated 
to infinity
AUC0-t
Area under the concentration-time curve from 0 to last quantifiable 
concentration
Clast
Last quantifiable concentration
Cmax 
Maximum observed plasma concentration
CV
Coefficient of variation
ECG
Electrocardiogram
eCFRs
Electronic case report forms
FDA
Food and Drug Administration
IN
Intranasal
inf
Infinity
Kel
Elimination rate constant
pAUC
partial area under the curve
PD
Pharmacodynamic
PK 
Pharmacokinetic
SAP 
Statistical analysis plan
SD
Standard deviation
t1/2
Terminal half-life
TEAE
Treatment-emergent adverse event
Tmax
Time of maximum concentration (Cmax)


Statistical Analysis Plan 
SCR-011: Clinical Study to Investigate the Pharmacokinetics of 
Multiple Repeated Doses of Intranasal Naloxone
Page 6 of 18
Change Log 
Version / Date
Section
Summary of Changes
1.0 /
10 Mar 2021
General 
Developed initial statistical analysis plan
 


Statistical Analysis Plan 
SCR-011: Clinical Study to Investigate the Pharmacokinetics of 
Multiple Repeated Doses of Intranasal Naloxone
Page 7 of 18
1. Introduction 
This document outlines the proposed statistical methods for data analysis of data collected from 
Protocol ‘SCR-011: Clinical study to investigate the pharmacokinetics of multiple repeated doses 
of intranasal naloxone’.
The following statistical analysis plan (SAP) provides the framework for the summarization of 
the data from this study. The SAP may change due to unforeseen circumstances. Any changes 
made to the SAP will be documented in a change log within the SAP along with a rationale for 
the changes.
2. Study Objectives 
The study objectives are:
1. To determine and compare the pharmacokinetics of intranasal (IN) naloxone between the 
4-dose naloxone arms and the 2-dose naloxone arm.
2. To use the pharmacokinetic data from each of the 3 naloxone dosing schedules/doses to 
predict the time to reverse opioid-induced respiratory depression following different 
overdose scenarios based on pharmacokinetic/pharmacodynamic (PK/PD) models
3. Study Overview 
3.1 Study Design 
This study will be a randomized, unblinded, three-way crossover study to determine naloxone 
plasma concentration after administration of multiple doses of intranasal (IN) naloxone.
Table 3-1:Study Schedule
Day -1
Day 1
Days 2-3
Day 4
Days 5-6
Day 7
Day 8
Check-in
Treatment
Period 1
Washout
Treatment
Period 2
Washout
Treatment
Period 3
Check-out
The following 3 treatments will be evaluated in a randomized order over the 3 treatment periods.
Table 3-2:Study Treatments


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Page 8 of 18
Treatment 
Description
A
Four4 mg IN naloxone doses (1 dose every 2.5 min; L at 0 min, R at 2.5 min, L at 5 
min, R at 7.5 min)
B
Four 4 mg IN naloxone doses (2 doses every 2.5 min; L and R at 0* min, L and R at 
2.5* min)
C
Two 4 mg IN naloxone doses (Lat 0 min, R at 2.5 min)
L = Left Nostril, R = Right Nostril, * doses will be ~5 seconds apart (one after the other)
Healthy subjects will be randomized to one of six treatment sequences (i.e., ABC, ACB, BAC, 
BCA, CAB, CBA). FDA will prepare the randomization schedule. Subjects will report to the 
study site for screening from Days -28 to -2 and then will return to the site on Day -1 for baseline 
assessments and check-in. After check-in (Day -1), subjects will receive dosing for the 3 
respective treatment periods on Days 1, 4 and 7. There will be two days of washout between each 
treatment period. Participants will be confined in the study clinic from Day -1 until the morning of 
Day 8. On dosing days, dosing will occur as per the treatment description and PK assessments 
will occur at the following time points: 
PK assessment: 0 (pre-dose), 2, 4.5, 7, 10, 12.5, 15, 20, 30, 45, 60, 120, 180, 240, 360, and 
720 minutes
The subject should remain fully supine for approximately one-hour post-dose. Subjects should be 
instructed not to breathe through the nose during administration of the nasal spray into the nose.
Subjects will be instructed to leave their masks off for twenty minutes after drug administration.
A summary of all assessments prior to and following study drug administration on Day 1, is 
described in the Protocol, Schedule of Events. 
Subjects will be discharged from the study after completion of all study procedures. If a subject 
discontinues from the study prematurely, all procedures scheduled for the end of the study will 
be performed.
4. Study Endpoints 
4.1 Primary Endpoint 
First time point when there is a higher naloxone plasma concentration in the 4-dose
naloxone arms compared to the 2-dose naloxone arm
4.2 Secondary Endpoints 


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1.
First time point when there is a higher naloxone plasma concentration in the 4-dose
naloxone arm B (2 doses every 2.5 minutes) compared to the 4-dose naloxone arm A (1 
dose every 2.5 minutes)
2.
Dose-proportionality of the 4-dose naloxone arms in reference to the 2 -dose naloxone 
arm based on Cmax, AUC0-inf, and AUC0-t
3.
Predicted time to rescue a patient from simulated opioid-induced respiratory depression 
from fentanyl and carfentanil following medium and high overdose scenarios 
4.3 Exploratory Endpoint 
Naloxone Cmax, AUC0-inf, AUC0-t, tmax, and partial AUC [pAUC] within the first 30 minutes 
of dosing
4.4 Sample Size 
Twenty healthy participants are planned for enrollment with up to 4 replacements. Naloxone 
plasma concentration profiles and variabilities were calculated based on summary 
pharmacokinetic data from the IN naloxone product label. Predicted naloxone concentrations 
were determined for each of the proposed dosing treatments based on principles of superposition 
(i.e., for linear pharmacokinetics the total concentration of a drug in circulation is the sum of 
remaining concentration from each administered dose prior to the current measurement time) 
with a focus on comparing plasma concentrations at early timepoints. Power calculations were 
based on the ratio between concentrations for each of the two primary comparisons (Treatment A 
vs Treatment C and Treatment B vs Treatment C). Of the comparisons, the power for the 4-dose 
naloxone arm A (test) versus the 2-dose naloxone arm C (reference) was expected to be lower 
than the 4-dose naloxone arm B (test) versus the 2-dose naloxone arm C (reference). For the 
different proposed treatments, the ratio in concentrations and the coefficient of variation (CV) at 
each timepoint based on principles of superposition are shown in Table 4-1.


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Table 4-1:Predicted concentration ratio and CV between treatments at different timepoints and power 
calculation at a 0.0221 significance level
Comparison
Time (min)
Concentration
Ratio
CV
Power (n=18) at 
p = 0.0221
Primary Endpoint (comparisons of 4-dose treatment arms vs. 2-dose treatment arm reference)
Treatment A vs Treatment C
10
1.36
68
49
12.5
1.57
58
91
15
1.78
48
100
Treatment B vs Treatment C
4.5
2
111
86
7
2
90
94
10
2
68
99
Secondary Endpoint (comparison between the 4-dose treatment arms)
Treatment B vs Treatment A
4.5
2
111
86
7
1.85
90
88
10
1.47
68
68
As the intent of administering naloxone is rapid reversal of an overdose, the planned primary 
analysis is a comparison of naloxone concentrations between treatment arms across pre-specified 
consecutive time points. Each of the paired comparisons was assumed to include three pre-
specified timepoints (timepoints correspond to those listed in Table 4-1). The time points will be 
evaluated sequentially with adjustments for multiplicity using Pocock boundaries (Pocock, 
1977). For three pre-specified assessments, this would correspond to assessments at a 0.0221 
significance level for comparisons at individual time points to maintain an overall 0.05 
significance level. 
Based on these considerations and the concentration ratios and CVs in Table 4-1, a sample size 
was determined so that at least one of the planned time points would have greater than 90% 
power at a 0.0221 significance level for a one sided, log-transformed paired comparison (for the 
primary endpoint). For concluding an increase in naloxone concentration for Treatment A 
compared to Treatment C at 15 minutes, at least 12 subjects would be necessary assuming a 
1.78-fold increase in exposure and 48% CV for the treatments. For concluding an increase in 
naloxone concentration for Treatment B compared to Treatment C at 10 minutes, at least 12 
subjects would have the desired power assuming a 2-fold increase in exposure and 68% CV for 
the treatments. The sample size was further increased to 20 subjects to account for 
discontinuations and situations where the CV values in Table 4-1 may be underestimated for 
repeat naloxone dosing.
5. Analysis Populations 
The PK population will include all subjects who receive study drug and have at least one 
estimable PK parameter after dosing. The safety population will include all subjects who receive 


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at least 1 dose of the study drug. The analysis population will include all subjects in the PK 
population with sufficient data to calculate PK parameters. Only subjects with results from two 
or more periods will be included in comparisons. Treatment in all analysis populations will be 
assigned based upon the treatment which the subjects actually received.
6. Data Screening and Acceptance 
6.1 Handling of Missing and Incomplete Data 
The following approaches will be used for the handling of missing and incomplete data:
Missing PK data (e.g., skipped plasma sample collected) will not be imputed.
Missed dose, dose administered outside the window, or other issues with dose 
administration (e.g., product delivery fails) will result in PK data from that period for that 
subject being excluded from all treatment arm comparisons and summary statistics from 
that time point forward. Other situations, such as a subject sneezing in close proximity to 
dosing will be carefully documented by study staff and handling of these cases will be 
determined and documented before any concentration data is available.  
PK samples collected outside the protocol-defined sampling window (i.e., more than ± 
0.5 minute from the scheduled time for the first 15 minutes of collections) will be 
excluded from analyses comparing naloxone concentrations at the specific time point that 
is outside the window.
PK measurements below the lower limit of quantification will be set to zero for all 
analyses.
7. General Statistical Considerations 
All data will be presented in data listings. Data from subjects excluded from an analysis 
population will be presented in the data listings, but not included in the calculation of summary 
statistics. Demographic and baseline characteristics will be summarized overall and by treatment 
for all subjects.
7.1 Subject Disposition 
The number of subjects who enroll in the study and the number and percentage of subjects who 
complete each assessment will be presented. The frequency and percentage of subjects who 
withdraw or discontinue from the study and the reason for withdrawal or discontinuation will be 
summarized.
7.2 Demographic and Baseline Characteristics 
Continuous demographic and baseline characteristic variables (age, height, weight, and body 
mass index) will be summarized overall and by treatment using descriptive statistics (number of 
subjects, mean, standard deviation [SD], median, minimum, and maximum). The number and 
percentage of subjects in each class of categorical demographic and baseline characteristic 
variables will also be summarized.


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7.3 Pharmacokinetic Analyses
7.3.1 Naloxone Concentration Comparisons  
The primary endpoint is the first timepoint when there is a higher naloxone plasma concentration 
in the 4-dose naloxone arms compared to the 2-dose naloxone arm. Separate comparisons will be 
performed with the 4-dose naloxone arm A (test) versus the 2-dose naloxone arm C (reference) 
and the 4-dose naloxone arm B (test) versus the 2-dose naloxone arm C (reference). No 
adjustment for multiplicity is planned for these separate comparisons.
Secondary endpoints will include determination of the first time point when there is a higher 
naloxone plasma concentration in the 4-dose naloxone arm B (2 doses every 2.5 minutes) as test 
compared to the 4-dose naloxone arm A (1 dose every 2.5 minutes) as reference. The same 
approach outlined for the primary endpoint analysis above will be used for this secondary 
endpoint comparison. The secondary endpoint analysis will be conducted regardless of the
primary endpoint results.
Table 7-1:Pre-specified Timepoints and p-value Threshold for Comparing Naloxone Concentrations Across 
Treatments (Maintain Overall p-value Per Comparison at 0.05) (Pocock, 1977)
Comparison
Time (min)
Interim Analysis
p-value Threshold
Treatment A vs Treatment C(primary)
10
1
0.0221
12.5
2
0.0221
15
3 (final)
0.0221
Treatment B vs Treatment C(primary)
4.5
1
0.0221
7
2
0.0221
10
3 (final)
0.0221
Treatment B vs Treatment A (secondary)
4.5
1
0.0221
7
2
0.0221
10
3 (final)
0.0221
For both the primary and secondary analyses, up to three different time points have been pre-
specified for each comparison. Time points will be evaluated from earliest to latest time (Table 
7-1). Testing will be conducted sequentially along planned interim analyses (i.e., start at the
initial time and progress forward, stopping if success is achieved) at a 0.0221 significance level.
Testing will proceed through each time point until either one passes (reported as the earliest time 
where a difference in concentration is observed) or all pre-specified time points fail (no 
difference in naloxone concentrations between treatments for the selected time points).
For comparing treatment A to treatment C, the analysis will use naloxone concentration data 
collected at 10, 12.5, and 15 min. For both the treatment B to treatment C comparison and the 
treatment B to treatment A comparison, the pre-specified time points are 4.5, 7, and 10 min. All 


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subjects contributing naloxone concentration measures from both treatments at the pre-specified 
time points will be included in the analysis. At each of these timepoints, subject-level naloxone 
concentration will be log-transformed. Naloxone concentration values that are below the lower 
limit of quantification (i.e., zero) will result in that time point from that subject being removed
for comparisons involving that treatment arm.  
A paired Student’s t-test will be used for comparing naloxone concentrations between 
treatments. To demonstrate an increase in naloxone concentration with the test compared to 
reference, it is necessary that the lower bound of the one-sided 97.79% interval for the geometric 
mean ratio excludes 1. The results will be transformed back to the original scale by 
exponentiation to provide treatment geometric means.
Normality assumption will be verified using the Shapiro-Wilke test for normality and 
homogeneity of variances will be verified using Levene’s test. If either assumption is not valid, a 
Mann-Whitney-U test will be used for the comparisons rather than a t-test.
7.3.2 Dose Proportionality 
Dose proportionality based on Cmax, AUC0-t, and AUC0-inf will be compared between each of the 
three naloxone treatments as secondary endpoints. The 4-dose naloxone arms (separate 
comparisons for 1 dose every 2.5 minutes and 2 doses every 2.5 minutes) will be compared with 
the 2-dose naloxone arm (1 dose every 2.5 minutes). An additional comparison will be 
performed between the 4-dose naloxone arm B (2 doses every 2.5 minutes) as test and 4-dose
naloxone arm A (1 dose every 2.5 minutes) as reference. 
Dose-adjusted values for Cmax, AUC0-t, and AUC0-inf will be calculated based on 
noncompartmental PK parameter results, normalized to per mg of naloxone administered. Using 
linear mixed-effects modeling, comparisons of log-transformed dose-adjusted PK parameters
will be performed. Treatment will be a fixed effect. Subject will be included as a random effect 
on the intercept. Treatment differences on the log-scale will be estimated for the PK parameters.
Geometric mean ratio and 90% CIs will be obtained by exponentiation of the treatment effect 
and 90% CIs based on the log-transformed scale. Dose-proportionality will be concluded if the 
confidence interval includes 1.
7.3.3 Plasma Pharmacokinetics 
The following PK parameters will be determined for naloxone for each subject across all 
treatments:
AUC from time 0 to the sampling time corresponding to the last quantifiable 
concentration (Clast) (AUC0-t)
AUC0-t will be calculated according to the linear trapezoidal rule from time 0 minutes to 
the last quantifiable concentration.
AUC from time 0 extrapolated to infinity (AUC0-inf)


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AUC0-t will be extrapolated to infinity from the AUC from time 0 to the sampling time 
corresponding to the last quantifiable concentration plus the last quantifiable 
concentration divided by Kel, as follows:
AUC0-inf = AUC0-t + Clast/Kel
Partial AUCs (pAUC) over time intervals of 0 to 7 (pAUC0-7), 0-10 (pAUC0-10), 0-
12.5 (pAUC0-12.5), 0-15 (pAUC0-15), 0-20 (pAUC0-20), and 0-30 (pAUC0-30) minutes
pAUC will be calculated according to the linear trapezoidal rule from time 0 minutes to 
7, 10, 12.5, 15, 20, and 30 minutes after time from first dose
Maximum concentration (observed peak drug concentration) (Cmax)
Cmax will be read directly from the observed concentrations.
Time at which Cmax occurs (Tmax)
Tmax will be read directly from the observed concentrations as the blood sampling time 
corresponding to Cmax. The earlier time will be reported in cases where the same Cmax
value is observed for a subject at multiple time points
Terminal half-life (t1/2)
The terminal half-life will then be calculated using the elimination rate constant as:
t1/2=ln(2)/Kel
Kel
The terminal elimination rate constant, which will be determined from the terminal slope 
of the log-concentration curve using linear regression 
The PK parameters will be analyzed using noncompartmental methods based on actual sampling 
times. Plasma concentrations below the limits of quantification will be set to zero for the purpose 
of this analysis (see Section 6). AUC0-inf, t1/2, and Kel for naloxone by treatment and subject will 
only be included if the subject has 3 or more concentration values on the terminal portion of the 
pharmacokinetic curve and with an adjusted coefficient of determination (R2) greater than 0.80. 
These PK parameters will be summarized using descriptive statistics (number of subjects, mean, 
SD, CV, median, minimum, and maximum) for naloxone.
All parameters will be calculated using R software. Mean and individual concentration-time 
profiles will be presented in graphs.
7.4 Additional Secondary Analyses 
7.4.1 PK/PD Modeling of Time to Reversal of Opioid Induced Respiratory 
Depression 


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PK data from this study will be used to update the naloxone PK model in a previously developed 
PK/PD model for opioid-induced respiratory depression. The updated model will be used to 
predict the mean time to rescue a patient from simulated opioid induced respiratory depression 
from fentanyl and carfentanil following a range of overdose scenarios (e.g. low, medium and 
high). Full details of the analysis will be described in a separate Modeling Analysis Plan (MAP).
7.5 Safety Analyses 
7.5.1 Adverse Events
All adverse events (AEs) will be coded using the latest version of the Medical Dictionary for 
Regulatory Activities (MedDRA). The incidence of treatment-emergent adverse event (TEAEs), 
organized by system organ class and frequency, will be summarized by seriousness, severity, 
relationship to treatment, and by treatment at onset of the TEAE. A detailed listing of serious 
AEs and TEAEs leading to withdrawal will also be provided.
7.5.2 Clinical Laboratory Tests 
Clinical laboratory results (hematology, serum chemistry, and urinalysis) will be summarized 
using descriptive statistics (number of subjects, mean, SD, minimum, median, and maximum). 
Clinical laboratory results will be classified as normal or abnormal, according to the reference 
ranges of the individual parameter. The number and percentage of subjects with abnormal 
laboratory results will be provided. No statistical testing will be performed on clinical laboratory 
data.
7.5.3 Vital Sign Measurements 
Vital sign measurements and changes from baseline will be summarized using descriptive 
statistics (number of subjects, mean, SD, minimum, median, and maximum) by treatment and 
timepoint.
7.5.4 Safety 12-lead Electrocardiograms 
Abnormal 12-lead ECG findings will be recorded as AEs (not planned for each treatment period)
in a data listing.
7.5.5 Physical Examinations 
Abnormal physical examination findings will be recorded as AEs (not planned for each treatment 
period).
7.5.6 Nasal Irritation Score Analyses 
Nasal Irritation Score is an examination of the nasal passage conducted by a trained observer to 
evaluate evidence of irritation to the nasal mucosa. These results will be summarized using 
descriptive statistics for all treatment groups.


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7.5.7 Other Safety Data 
All concomitant medication usage and medications that changed in daily dose, frequency, or 
both since the subject provided informed consent will be summarized for each subject.
8. Data Quality Assurance 
Completed eCRFs are required for each subject randomly assigned to treatment. Electronic data 
entry will be accomplished through the ClinSpark® remote electronic data capture system, which 
allows for on-site data entry and data management. This system provides immediate, direct data 
transfer to the database, as well as immediate detection of discrepancies, enabling site 
coordinators to resolve and manage discrepancies in a timely manner. Each person involved with 
the study will have an individual identification code and password that allows for record 
traceability. Thus, the system, and subsequently any investigative reviews, can identify 
coordinators, investigators, and individuals who have entered or modified records.
Furthermore, the investigator retains full responsibility for the accuracy and authenticity of all 
data entered into the electronic data capture system. The completed dataset and their associated 
files are the sole property of the sponsor and should not be made available in any form to third 
parties, except for appropriate governmental health or regulatory authorities, without written 
permission of the sponsor. 


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9. Appendices 
9.1 Randomization schedule 
This is a 3-period, unblinded, crossover study where approximately 20 subjects will be enrolled 
to receive either two or four administrations of 4 mg intranasal naloxone following different 
administration schedules. Healthy subjects will be randomized to one of six treatment sequences 
(i.e., ABC, ACB, BAC, BCA, CAB, CBA), where treatment codes are summarized in the table 
below. The first 18 subjects enrolled will be randomized in blocks of 6. The remaining two 
subjects will be randomly placed in 2 of the 6 treatment sequences. The study plans for 1:1 
enrollment of males and females, but the randomization will not account for sex and treatment 
sequence interactions.
Table 9-1: Treatment Codes and Treatment Names
Treatment Code
Treatment Name
A
Four4 mg IN naloxone doses (1 dose every 2.5 min; L at 0 
min, R at 2.5 min, L at 5 min, R at 7.5 min)
B
Four 4 mg IN naloxone doses (2 doses every 2.5 min; L 
and R at 0* min, L and R at 2.5* min)
C
Two 4 mg IN naloxone doses (Lat 0 min, R at 2.5 min)


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10.References 
NARCAN Nasal Spray Label, dated 08/06/2020. Obtained from 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/208411Orig1s004lbl.pdf
Pocock, S. (1977). Group Sequential Methods in the Design and Analysis of Clinical 
Trials. Biometrika,64(2), 191-199.

Prot_001.pdf: 
Study Title: Clinical study to investigate the pharmacokinetics of multiple 
repeated doses of intranasal naloxone 
 
Document Title: Clinical Study Protocol – Study No. SCR-011 
 
Document Date: 15 February 2021 
 
NCT Number: NCT04764630 


U.S. FOOD AND DRUG ADMINISTRATION 
CDER / Office of Translational Sciences / Office of Clinical 
Pharmacology / Division Applied Regulatory Science
Protocol Number: SCR-011 (Version: 1.0)
CONFIDENTIAL
Page 1 of 54
CLINICAL STUDY PROTOCOL
Clinical study to investigate the pharmacokinetics of multiple repeated doses 
of intranasal naloxone
PROTOCOL NO. SCR-011
Sponsor:
U.S. Food and Drug Administration
White Oak Building #64, Room 2072
10903 New Hampshire Avenue
Silver Spring, MD 20993
Sponsor Study Lead:
David Strauss, MD, PhD
Director, Division of Applied Regulatory Science 
U.S. Food and Drug Administration
Telephone: 301-796-6323
Email: david.strauss@fda.hhs.gov
Sponsor Medical 
Monitor:
Keith Burkhart, MD
U.S. Food and Drug Administration
Telephone: 301-796-2226
Email: keith.burkhart@fda.hhs.gov
Project Manager:
Jeffry Florian, PhD
U.S. Food and Drug Administration
Telephone: 301-796-4847
Email: jeffry.florian @fda.hhs.gov
Version of Protocol:
1.0
Date of Protocol:
15 February 2021
CONFIDENTIAL
The concepts and information contained in this document or generated during the study are 
considered proprietary and may not be disclosed in whole or in part without the expressed 
written consent of the U.S. Food and Drug Administration.


U.S. FOOD AND DRUG ADMINISTRATION 
CDER / Office of Translational Sciences / Office of Clinical 
Pharmacology / Division Applied Regulatory Science
Protocol Number: SCR-011 (Version: 1.0)
CONFIDENTIAL
Page 2 of 54
SPONSOR SIGNATURE PAGE
This study will be conducted with the highest respect for the individual participants in 
accordance with the requirements of this clinical study protocol and also in accordance with the 
following:
The ethical principles that have their origin in the Declaration of Helsinki;
International Council for Harmonisation (ICH) harmonised tripartite guideline E6 (R2): Good 
Clinical Practice; and
All applicable laws and regulations, including without limitation, data privacy laws and 
compliance with appropriate regulations, including human subject research requirements set 
forth by the Institutional Review Board (IRB).
David Strauss, MD, PhD
Director, Division of Applied Regulatory 
Science 
U.S. Food and Drug Administration
Date




U.S. FOOD AND DRUG ADMINISTRATION 
CDER / Office of Translational Sciences / Office of Clinical 
Pharmacology / Division Applied Regulatory Science
Protocol Number: SCR-011 (Version: 1.0)
CONFIDENTIAL
Page 4 of 54
TABLE OF CONTENTS
PROTOCOL SYNOPSIS ............................................................................................................................ 7 
1. INTRODUCTION ............................................................................................................................... 18 
2. STUDY OBJECTIVES .......................................................................................................................... 19 
3. STUDY ENDPOINTS .......................................................................................................................... 19 
3.1 PRIMARY ENDPOINT ............................................................................................................................................... 19
3.2 SECONDARY ENDPOINTS .......................................................................................................................................... 19
3.3 EXPLORATORY ENDPOINT......................................................................................................................................... 19
4. INVESTIGATIONAL PLAN .................................................................................................................. 19 
4.1 STUDY DESIGN....................................................................................................................................................... 19
4.1.1 Risk/Benefit ............................................................................................................................................... 20
4.2 SELECTION OF STUDY POPULATION ............................................................................................................................ 22
4.2.1 Inclusion Criteria ........................................................................................................................................ 22
4.2.2 Exclusion Criteria ....................................................................................................................................... 23
4.3 SCREENING FAILURES .............................................................................................................................................. 24
4.4 TERMINATION OF STUDY OR INVESTIGATIONAL SITE...................................................................................................... 25
4.4.1 Criteria for Termination of the Study ........................................................................................................ 25
4.4.2 Criteria for Termination of the Investigational Site ................................................................................... 25
4.5 CRITERIA FOR SUBJECT WITHDRAWAL ........................................................................................................................ 25
4.5.1 Handling of Withdrawals .......................................................................................................................... 26
4.5.2 Replacement of Subjects ........................................................................................................................... 27
4.6 STUDY VISITS ........................................................................................................................................................ 27
4.6.1 Recruitment ............................................................................................................................................... 27
4.6.2 Compensation ........................................................................................................................................... 27
4.6.3 Screening ................................................................................................................................................... 28
4.6.4 Study Periods ............................................................................................................................................. 28
4.6.5 Washout .................................................................................................................................................... 30
4.6.6 Discharge (or Early Termination) .............................................................................................................. 30
4.7 STUDY PROCEDURES............................................................................................................................................... 30
4.7.1 Pharmacokinetic Assessments .................................................................................................................. 30
4.7.2 Safety Assessments ................................................................................................................................... 32
4.7.3 Demographics and Medical History .......................................................................................................... 36
4.8 STUDY TREATMENTS ............................................................................................................................................... 36
4.8.1 Treatments Administered and Schedule ................................................................................................... 36
4.8.2 Dose Selection ........................................................................................................................................... 37
4.8.3 Method of Assigning Subjects to Treatment Sequence ............................................................................. 37
4.8.4 Identity of Study Drug ............................................................................................................................... 38
4.8.5 Management of Clinical Supplies .............................................................................................................. 39
4.8.6 Blinding ..................................................................................................................................................... 39
4.8.7 Treatment Compliance .............................................................................................................................. 39
4.8.8 Prior and Concomitant Medications .......................................................................................................... 40
4.8.9 Subject Restrictions ................................................................................................................................... 40
4.9 STATISTICAL METHODS............................................................................................................................................ 41
4.9.1 Sample Size ................................................................................................................................................ 41
4.9.1 Analysis Populations .................................................................................................................................. 41
4.9.2 General Statistical Considerations ............................................................................................................ 42
4.9.3 Subject Disposition .................................................................................................................................... 42


U.S. FOOD AND DRUG ADMINISTRATION 
CDER / Office of Translational Sciences / Office of Clinical 
Pharmacology / Division Applied Regulatory Science
Protocol Number: SCR-011 (Version: 1.0)
CONFIDENTIAL
Page 5 of 54
4.9.4 Demographics and Baseline Characteristics ............................................................................................. 42
4.9.5 Pharmacokinetic Analysis .......................................................................................................................... 42
4.9.6 PK/PD Modeling ........................................................................................................................................ 43
4.9.7 Safety Analyses ......................................................................................................................................... 43
4.9.8 Missing Data ............................................................................................................................................. 44
4.10 DATA QUALITY ASSURANCE ................................................................................................................................... 44
4.11 DATA SHARING .................................................................................................................................................... 45
5. ETHICAL CONSIDERATIONS.............................................................................................................. 45
5.1 ETHICAL CONDUCT OF THE STUDY ............................................................................................................................. 45
5.2 INSTITUTIONAL REVIEW BOARD (IRB) ........................................................................................................................ 45
6. ADMINISTRATIVE PROCEDURES ....................................................................................................... 46 
6.1 RESPONSIBILITIES OF THE INVESTIGATOR ..................................................................................................................... 46
6.1.1 Form FDA 1572 .......................................................................................................................................... 46
6.1.2 Adherence to Protocol ............................................................................................................................... 46
6.1.3 Reporting Requirements ............................................................................................................................ 46
6.1.4 Source Documentation .............................................................................................................................. 46
6.1.5 Retention of Records ................................................................................................................................. 46
6.1.6 Financial Disclosure and Obligations ......................................................................................................... 47
6.2 CONFIDENTIALITY AND DISCLOSURE OF DATA .............................................................................................................. 47
6.3 SUBJECT CONSENT ................................................................................................................................................. 48
6.4 DATA COLLECTION ................................................................................................................................................. 48
6.5 PUBLICATIONS ....................................................................................................................................................... 48
7. STUDY MANAGEMENT .................................................................................................................... 49 
7.1 MEDICAL MONITOR ............................................................................................................................................... 49
7.2 STUDY MONITORING .............................................................................................................................................. 49
7.3 MANAGEMENT OF PROTOCOL AMENDMENTS AND DEVIATIONS...................................................................................... 49
7.3.1 Modification of the Protocol ..................................................................................................................... 50
7.3.2 Protocol Violations and Deviations ........................................................................................................... 50
8. REFERENCE LIST ............................................................................................................................... 51 
9. APPENDICES .................................................................................................................................... 52 
9.1 APPENDIX A – SCHEDULE OF EVENTS ......................................................................................................................... 52
9.2 APPENDIX B – LIST OF ABBREVIATIONS ....................................................................................................................... 53
9.3 APPENDIX C – PROTOCOL REVISION HISTORY .............................................................................................................. 54


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LIST OF TABLES
TABLE 4-1: STUDY SCHEDULE ................................................................................................................................... 20
TABLE 4-2: STUDY TREATMENTS ............................................................................................................................... 20
TABLE 4-3: CLINICAL LABORATORY TESTS & DIAGNOSTIC SCREENING TESTS ......................................................................... 35 
TABLE 4-4: STUDY TREATMENTS & DOSE SCHEDULE ...................................................................................................... 37 
TABLE 9-1: SCHEDULE OF EVENTS.............................................................................................................................. 52


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PROTOCOL SYNOPSIS
Protocol Number:
SCR-011
Title:
Clinical study to investigate the pharmacokinetics of multiple repeated 
doses of intranasal naloxone
Investigators:
Principal Investigator: Jennifer Deering, MSN, APNP
Study Physician: Carlos Sanabria, MD
Study Phase:
1
Study Period:
The duration of study participation will be approximately 9 days 
(excluding the screening period).
Study Site:
Spaulding Clinical Research Unit, West Bend, Wisconsin
Background and 
Motivation:
Naloxone, a fast-acting mu-opioid antagonist, is a treatment commonly 
used in reversing opioid overdose. Naloxone is available in multiple 
formulations, including for injection intravenously, intramuscularly or 
subcutaneously, and more recently as a spray administered intranasally
(IN). The IN naloxone formulation, which was approved in 2015, is of 
particular interest as there is a need for naloxone formulations for 
community use by caregivers and first responders/law enforcement who do 
not have medical training. It is critical to administer naloxone as quickly as 
possible to prevent irreversible brain damage and death.
The U.S. Food and Drug Administration (FDA), Center for Drug 
Evaluation and Research (CDER), Division of Applied Regulatory Science 
(DARS) has conducted modeling and simulation to evaluate how many 
doses of IN naloxone may be needed to reverse opioid-induced respiratory 
depression from fentanyl and fentanyl derivates under a range of overdose 
scenarios. These analyses have suggested that more than two doses of IN 
naloxone would be required to reverse the effects of highly potent opioids 
(e.g., carfentanil). Experience with intranasal formulations for other 
products has shown that repeat administration of doses given in close 
proximity or to the same nostril can influence drug exposure due to run-
off from the application site, limited absorption, or other factors. While 
the pharmacokinetics of IN naloxone have been determined following 
administration of a 4 mg dose in each nostril concurrently, the 
pharmacokinetics have not been determined following multiple doses 
according to the FDA product label: 


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Administer a single spray of NARCAN Nasal Spray to adults or 
pediatric patients intranasally into one nostril. 
Administer additional doses of NARCAN Nasal Spray, using a new 
nasal spray with each dose, if the patient does not respond or 
responds and then relapses into respiratory depression, additional 
doses of NARCAN Nasal Spray may be given every 2 to 3 minutes 
until emergency medical assistance arrives. 
This involves a 2-3 minute delay between each dose and re-administering 
to a previously dosed nostril starting with the 3rd dose, which may result in 
a less than dose-proportional increase in naloxone plasma concentration 
and/or delayed increase in naloxone exposure compared to the first 2 
doses. Obtaining data with repeat dosing will inform if and how fast 
naloxone plasma concentrations can be reached to be able to reverse 
highly-potent opioid overdoses. 
This study will be a randomized, unblinded, three-way crossover study to 
determine naloxone plasma concentration after administration of multiple 
doses of IN naloxone: 
A. Four 4 mg IN naloxone doses (1 dose every 2.5 minutes)
B. Four 4 mg IN naloxone doses (2 doses every 2.5 minutes)
C. Two 4 mg IN naloxone doses (1 dose every 2.5 minutes)
IN naloxone (NARCAN Nasal Spray)
Intranasal naloxone is available as a 2 mg or 4 mg dose of naloxone 
hydrochloride in 0.1 mL with the indication to re-administer additional 
doses every 2 to 3 minutes (using alternating nostrils) if needed until 
emergency medical assistance arrives. The 4 mg drug is distributed in 
packages of two nasal sprays (1 dose per nasal spray), but additional doses 
can be administered if needed and available.
Objectives and 
Endpoints:
The objectives of this study are:
Objectives:
1.
To determine and compare the pharmacokinetics of IN naloxone 
between the 4 naloxone dose arms and the 2 naloxone dose arm
2.
To use the pharmacokinetic data from each of the 3 naloxone 
dosing schedules/doses to predict the time to reverse opioid-
induced respiratory depression following different overdose 


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scenarios based on pharmacokinetic/pharmacodynamic (PK/PD) 
models
The endpoints for this study are:
Primary Endpoint
1.
First timepoint when there is a higher naloxone plasma 
concentration in the 4 naloxone dose arms compared to the 2
naloxone dose arm 
Secondary Endpoints
1.
First timepoint when there is a higher naloxone plasma 
concentration in the 4 naloxone dose arm B (2 doses every 2.5
minutes) compared to the 4 naloxone dose arm A (1 dose every 
2.5 minutes)
2.
Dose-proportionality of the 4 naloxone dose arms in reference to 
the 2 naloxone dose arm based on Cmax, AUC0-inf, and AUC0-t
3.
Predicted time to rescue a patient from simulated opioid-induced 
respiratory depression from fentanyl and carfentanil following 
medium and high overdose scenarios
Exploratory Endpoint
1.
Naloxone Cmax, AUC0-inf, AUC0-t, tmax, and partial AUC [pAUC] 
within the first 30 minutes of dosing
 
Study Design:
This study will be a randomized, unblinded, three-way crossover study to 
determine naloxone plasma concentration after multiple IN naloxone 
doses. 
Study Schedule:
Day -1
Day 1
Days 2-3
Day 4
Days 5-6
Day 7
Day 8
Check-
in
Treatment 
Period 1
Washout
Treatment 
Period 2
Washout
Treatment 
Period 3
Check-
out


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The following 3 treatments will be evaluated in a randomized order over 
the 3 treatment periods. 
Study Treatments:
Treatment 
Description
A
Four 4 mg IN naloxone doses (1 dose every 2.5 min; L at 0 min, 
R at 2.5 min, L at 5 min, R at 7.5 min)
B
Four 4 mg IN naloxone doses (2 doses every 2.5 min; L and R at 
0* min, L and R at 2.5* min)
C
Two 4 mg IN naloxone doses (L at 0 min, R at 2.5 min)
L = Left Nostril, R = Right Nostril, * doses will be ~5 seconds apart (one after the other)
Healthy subjects will be randomized to one of six treatment sequences 
(i.e., ABC, ACB, BAC, BCA, CAB, CBA). FDA will prepare the 
randomization schedule.
Subjects will report to the study site for screening from Days -28 to -2 and 
then will return to the site on Day -1 for baseline assessments and check-in. 
After check-in (Day -1), subjects will receive dosing for the 3 respective 
treatment periods on Days 1, 4 and 7. There will be two days of washout 
between each treatment period. Participants will be confined in the study 
clinic from Day -1 until the morning of Day 8. On dosing days, dosing will 
occur as per the treatment description and PK assessments will occur at the 
following timepoints: 
PK assessment: 0 (pre-dose), 2, 4.5, 7, 10, 12.5, 15, 20, 30, 45, 60, 
120, 180, 240, 360, and 720 minutes
A summary of all assessments prior to and following study drug 
administration on Day 1, is described in the Schedule of Events (Table 9-
1). 
Subjects will be discharged from the study after completion of all study 
procedures. If a subject discontinues from the study prematurely, all 
procedures scheduled for the end of the study will be performed.
Subject 
Population:
Approximately 20 healthy subjects are planned for enrollment. Every 
effort will be made to maintain an approximate 50:50 male-to-female sex 
distribution. Up to 4 subjects may be qualified as replacements. Thus, a 
maximum of 24 subjects may be exposed to study drug and procedures 
during the study.


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Study and 
Reference Drugs, 
Dosage, and Route 
of Administration:
NARCAN (naloxone hydrochloride) intranasal sprays (4 mg/0.1 mL) will 
be obtained. On Days 1, 4, and 7 starting at 0 hr subjects will receive 2 or 
4 doses of IN naloxone according to the following schedules:
IN Naloxone Doses
Schedule
4 doses of 4 mg IN
L at 0 min, R at 2.5 min, L at 5 min, R at 7.5 min
4 doses of 4 mg IN
L and R at 0* min, L and R at 2.5* min
2 doses of 4 mg IN
L at 0 min, R at 2.5 min
L = Left Nostril, R = Right Nostril, * doses will be ~5 seconds apart (one after the other)
Inclusion Criteria:
Subjects who meet all the following inclusion criteria will be eligible to 
participate in the study: 
1. Subject signs an IRB-approved written informed consent and privacy 
language as per national regulations (e.g., Health Insurance 
Portability and Accountability Act authorization [HIPAA]) before any 
study-related procedures are performed. 
2. Subject is a healthy, non-smoking man or woman, 18 to 55 years of 
age, inclusive, who has a body mass index of 18.5 to 32 kg/m2,
inclusive, at screening.
3. Subject has normal medical history findings, clinical laboratory 
results, vital sign measurements, 12 lead ECG (Electrocardiogram)
results, and physical examination findings at screening or, if 
abnormal, the abnormality is not considered clinically significant (as 
determined and documented by the investigator or designee).
4. Subject must have a negative test result for alcohol and drugs of 
abuse at screening and check-in (Day -1). 
5. Subject must test negative for severe acute respiratory syndrome 
coronavirus (SARS-CoV-2) by a molecular diagnostic test at check-in 
(Day -1). If a subject’s test comes back inconclusive, it can be 
repeated.
6. Female subjects must be of non-childbearing potential or, if they are 
of childbearing potential, they must: 1) have been strictly abstinent 
for 1 month before check-in (Day -1) and agree to remain strictly 
abstinent for the duration of the study and for at least 1 month after 
the last application of study drug; OR 2) be practicing 2 highly 
effective methods of birth control (as determined by the investigator 
or designee; one of the methods must be a barrier technique) from at 


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least 1 month before check-in (Day -1) until at least 1 month after the 
end of the study. 
7. Male subjects must agree to practice 2 highly effective methods of 
birth control (as determined by the investigator or designee) from at 
least 1 month before check-in (Day -1) until at least 1 month after the 
last application of study drug.
8. Subject is highly likely (as determined by the investigator) to comply 
with the protocol defined procedures and to complete the study.
Exclusion 
Criteria:
Subjects who meet any of the following exclusion criteria will not be 
eligible to participate in the study:
1. Subject has a deviated septum or previous nasal surgeries or need to 
use another nasal spray product during study that would impact 
administration of the intranasal study drug.
2. Subject has had an episode of epistaxis or an upper respiratory 
infection in the previous month.
3. Subject has used any prescription or nonprescription drugs (including 
aspirin or NSAIDs and excluding oral contraceptives and 
acetaminophen) within 14 days or 5 half-lives (whichever is longer) 
or complementary and alternative medicines within 28 days before 
the first dose of study drug.
4. Subject is currently participating in another clinical study of an 
investigational drug or has been dosed with any investigational drug 
within 30 days or 5 half-lives (whichever is longer) of dosing for this 
study.
5. Subject has used nicotine-containing products (e.g., cigarettes, cigars, 
chewing tobacco, snuff) within 6 weeks of screening.
6. Subject has consumed alcohol, xanthine-containing products (e.g., 
tea, coffee, cola), caffeine, grapefruit, or grapefruit juice within 24 h
of check-in. Subjects must refrain from ingesting these throughout the 
study. 
7. Subject has any underlying disease or surgical or medical condition 
(e.g., cancer, human immunodeficiency virus [HIV], severe hepatic or 
renal impairment) that could put the subject at risk or would normally 
prevent participation in a clinical study. This includes subjects with 


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any underlying medical conditions that the Investigator believes 
would put subjects at increased risk of severe illness from COVID-19
based on the Centers for Disease Control and Prevention (CDC) 
guidelines. The CDC lists cancer, chronic kidney disease, chronic 
obstructive pulmonary disease, immunocompromised state from solid 
organ transplant, severe obesity, serious heart conditions, sickle cell 
disease, pregnancy, smoking and type 2 diabetes mellitus as 
conditions that put subjects at increased risk. Additionally, the CDC 
lists asthma (moderate-to-severe), cerebrovascular disease, cystic 
fibrosis, hypertension, immunocompromised state or immune 
deficiencies, neurologic conditions such as dementia, liver disease, 
pulmonary fibrosis, thalassemia, overweight, type 1 diabetes mellitus 
as conditions that might put subjects at increased risk.
8. Subject has any signs or symptoms that are consistent with COVID-
19 per CDC recommendations. These include subjects with fever or 
chills, cough, shortness of breath or difficulty breathing, fatigue, 
muscle or body aches, headache, new loss of taste or smell, sore 
throat, congestion or runny nose, nausea or vomiting, or diarrhea may 
have COVID-19. In addition, the subject has any other findings 
suggestive of COVID-19 risk in the opinion of the investigator.
9. Subject has known or suspected allergies or sensitivities to the study 
drug.
10. Subject has clinical laboratory test results (hematology, serum 
chemistry and urinalysis) at screening or check-in that are outside the 
reference ranges provided by the clinical laboratory and considered 
clinically significant by the investigator.
11. Subject has a positive test result at Screening for HIV 1 or 2 antibody, 
hepatitis C virus antibodies, or hepatitis B surface antigen.
12. Subject is unable or unwilling to undergo multiple venipunctures for 
blood sample collection because of poor tolerability or is unlikely to 
complete the trial due to poor venous access.
13. Female subject is pregnant or lactating before enrollment in the study.


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Sample Collection
The following samples should be collected and processed as follows. 
Number of samples collected throughout the study can be found in the 
Schedule of Events (Table 9-1):
The pharmacokinetic blood samples (8 mL each) will be collected into 
10 mL tubes containing K2EDTA, inverted several times to mix the blood 
with the anticoagulant, and placed in an ice bath. Within 30 minutes of 
collection, the samples will be centrifuged for 10 minutes, at 
3000 revolutions per minute, at 4°C, by a study team member.
The plasma will be separated using a disposable plastic pipette and 
approximately half of the plasma will be transferred into duplicate 
cryotube vials (2 mL polypropylene tubes) labeled as Aliquot A (primary) 
and Aliquot B (backup). The plasma samples will be appropriately labeled 
and stored frozen at –70°C or below until shipment. Temperature 
monitoring logs should be maintained and accessible for review by the 
study monitor.
Pharmacokinetic 
Assessments:
Samples will be collected as described above and in the Schedule of 
Events (Table 9-1) for determination of naloxone in blood. The following 
naloxone PK parameters will be determined for each subject:
Plasma
Concentrations at specified times after the first dose 
Maximum concentration (observed peak drug concentration) 
(Cmax) on the specified day
Partial AUCs (pAUC) over time intervals of 0 to 7 (pAUC0-7), 0-
10 (pAUC0-10), 0-12.5 (pAUC0-12.5), 0-15 (pAUC0-15), 0-20
(pAUC0-20), and 0-30 (pAUC0-30) minutes. 
AUC from time 0 extrapolated to infinity (AUC0-inf)
AUC from time 0 to the sampling time corresponding to the last 
quantifiable concentration (Clast) (AUC0-t)
Time at which Cmax occurs (tmax)
Elimination rate constant (Kel)
Terminal half-life (t1/2)
Apparent clearance (CL/F)


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Safety 
Assessments:
Safety will be evaluated in terms of adverse events (AEs), clinical 
laboratory results (hematology, serum chemistry, and urinalysis), vital 
sign measurements (blood pressure, heart rate, respiratory rate, and oral 
body temperature), safety 12-lead ECG, and physical examination 
findings.
An examination of the nasal passage will be conducted by a trained 
observer to evaluate evidence of irritation to the nasal mucosa. This nasal 
irritation assessment will be taken at the following timepoints during 
study drug administration:
0 (pre-dose), 4.5, 10, 30, 60, 240 minutes
Sample Size and 
Threshold 
Determination:
Approximately 20 healthy participants are planned for enrollment. The 
study is intended to obtain information regarding the pharmacokinetics 
and dose-proportionality of IN naloxone following different dosing 
schedules. The number of subjects was determined to have greater than 
80% power for comparisons between treatment arms across prespecified 
consecutive timepoints (different timepoints for each comparison). These 
power calculations are based on 18 subjects with each comparison, 
allowing for potential dropouts. These analyses adjust for multiplicity 
using Pocock boundaries for assessing the same endpoint at multiple 
timepoints. Coefficient of variations and effects sizes for different 
treatment scenarios were determined using modeling and simulation from 
previous naloxone studies. Up to 4 subjects may be qualified as 
replacements, if needed.
Statistical 
Methods:
All data will be presented in data listings. Data from subjects excluded 
from the PK population will be presented in the data listings but not 
included in the calculation of summary statistics. The number of subjects 
who enroll in the study and the number and percentage of subjects who 
complete each assessment will be presented. The frequency and 
percentage of subjects who withdraw or discontinue from the study and 
the reason for withdrawal or discontinuation will be summarized. 
Demographic and baseline characteristics will be summarized overall and 
by treatment for all subjects.
Descriptive statistics will be used to summarize demographic and baseline 
subject characteristics. For continuous variables, the mean, median, 
standard deviation (SD), minimum, and maximum values will be reported. 


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For categorical (nominal) variables, the number and percentage of 
subjects (or observations) will be reported.
The PK population will include all subjects who receive study drug and 
have at least one on-study sample. The analysis population will include all 
subjects in the PK population with calculated PK parameters Only 
subjects with results from two or more periods will be included in 
comparisons.
Pharmacokinetics: Concentrations will be determined at specified 
timepoints. The primary endpoint is the first timepoint when there is a 
higher naloxone plasma concentration in the 4 naloxone dose arms
compared to the 2 naloxone dose arm. Secondary endpoints will include 
determination of the first timepoint when there is a higher naloxone 
plasma concentration in the 4 naloxone dose arm B (2 doses every 2.5 
minutes) compared to the 4 naloxone dose arm A (1 dose every 2.5 
minutes). Additional PK measures will be summarized and compared as 
exploratory endpoints. These include, but are not limited to measures 
listed under Pharmacokinetic Assessments. Details of the PK analysis will 
be included in the Statistical Analysis Plan (SAP).
Dose Proportionality: Dose proportionality based on Cmax, AUC0-t, and 
AUC0-inf will be compared between each of the three naloxone treatments
as secondary endpoints. The 4 naloxone doses arms (separate comparisons 
for 1 dose every 2.5 minutes and 2 doses every 2.5 minutes) will be 
compared with the 2 naloxone dose arm (1 dose every 2.5 minutes). An 
additional comparison will be performed between the 4 naloxone arm B (2
doses every 2.5 minutes) as test and 4 naloxone dose arm A (1 dose every 
2.5 minutes) as reference.
PK/PD Modeling: PK data from this study will be used to update the 
naloxone PK model in a previously developed PK/PD model for opioid-
induced respiratory depression. The updated model will be used to predict 
the mean time to rescue a patient from simulated opioid induced 
respiratory depression from fentanyl and carfentanil following a range of 
overdose scenarios (e.g. low, medium and high: to be described in the 
modeling analysis plan). 
Safety: The safety population will include all subjects who receive at least 
1 dose of the study drug. All AEs will be coded using the Medical 
Dictionary for Regulatory Activities (MedDRA). The incidence of AEs, 


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organized by system organ class and preferred term, will be summarized 
with a focus on treatment-emergent AEs. Vital sign measurements will be 
summarized using descriptive statistics by time point. All values will be 
evaluated for clinically notable results. Data for additional safety 
parameters (e.g., physical examination findings) will be listed.
Date of Protocol:
15 February 2021


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1. INTRODUCTION
Naloxone, a fast-acting mu-opioid antagonist, is a treatment commonly used in reversing opioid 
overdose. Naloxone is available in multiple formulations, including for injection intravenously,
intramuscularly or subcutaneously, and more recently as a spray administered intranasally (IN). 
The IN naloxone formulation, which was approved in 2015, is of particular interest as there is a 
need for naloxone formulations for community use by caregivers and first responders/law 
enforcement who do not have medical training. It is critical to administer naloxone as quickly as 
possible to prevent irreversible brain damage and death.
The U.S. Food and Drug Administration (FDA), Center for Drug Evaluation and Research 
(CDER), Division of Applied Regulatory Science (DARS) has conducted modeling and 
simulation to evaluate how many doses of IN naloxone may be needed to reverse opioid-induced
respiratory depression from fentanyl and fentanyl derivates under a range of overdose scenarios. 
These analyses have suggested that more than two doses of IN naloxone would be required to 
reverse the effects of highly potent opioids (e.g., carfentanil). Experience with intranasal 
formulations for other products has shown that repeat administration of doses given in close 
proximity or to the same nostril can influence drug exposure due to run-off from the application 
site, limited absorption, or other factors. While the pharmacokinetics of IN naloxone have been 
determined following administration of a 4 mg dose in each nostril concurrently, the 
pharmacokinetics have not been determined following multiple doses according to the FDA 
product label: 
Administer a single spray of NARCAN Nasal Spray to adults or pediatric patients 
intranasally into one nostril. 
Administer additional doses of NARCAN Nasal Spray, using a new nasal spray with each 
dose, if the patient does not respond or responds and then relapses into respiratory 
depression, additional doses of NARCAN Nasal Spray may be given every 2 to 3 minutes 
until emergency medical assistance arrives. 
This involves a 2-3 minute delay between each dose and re-administering to a previously dosed 
nostril starting with the 3rd dose, which may result in a less than dose-proportional increase in 
naloxone plasma concentration and/or delayed increase in naloxone exposure compared to the 
first 2 doses. Obtaining data with repeat dosing will inform if and how fast naloxone plasma 
concentrations can be reached to be able to reverse highly-potent opioid overdoses. 
This study will be a randomized, unblinded, three-way crossover study to determine naloxone 
plasma concentration after administration of multiple doses of IN naloxone: 
A. Four 4 mg IN naloxone doses (1 dose every 2.5 minutes)
B. Four 4 mg IN naloxone doses (2 doses every 2.5 minutes)
C. Two 4 mg IN naloxone doses (1 dose every 2.5 minutes)


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IN naloxone (NARCAN Nasal Spray)
Intranasal naloxone is available as a 2 mg or 4 mg dose of naloxone hydrochloride in 0.1 mL with 
the indication to re-administer additional doses every 2 to 3 minutes (using alternating nostrils) if 
needed until emergency medical assistance arrives. The 4 mg drug is distributed in packages of 
two nasal sprays (1 dose per nasal spray), but additional doses can be administered if needed and 
available.
2. STUDY OBJECTIVES
1. To determine and compare the pharmacokinetics of IN naloxone between the 4 naloxone 
dose arms and the 2 naloxone dose arm.
2. To use the pharmacokinetic data from each of the 3 naloxone dosing schedules/doses to 
predict the time to reverse opioid-induced respiratory depression following different 
overdose scenarios based on pharmacokinetic/pharmacodynamic (PK/PD) models
3. STUDY ENDPOINTS
3.1 Primary Endpoint
1. First timepoint when there is a higher naloxone plasma concentration in the 4 naloxone 
dose arms compared to the 2 naloxone dose arm.
3.2 Secondary Endpoints
1. First timepoint when there is a higher naloxone plasma concentration in the 4 naloxone 
dose arm B (2 doses every 2.5 minutes) compared to the 4 naloxone dose arm A (1 dose 
every 2.5 minutes)
2. Dose-proportionality of the 4 naloxone dose arms in reference to the 2 naloxone dose arm 
based on Cmax, AUC0-inf, and AUC0-t
3. Predicted time to rescue a patient from simulated opioid-induced respiratory depression 
from fentanyl and carfentanil following medium and high overdose scenarios 
3.3 Exploratory Endpoint
1. Naloxone Cmax, AUC0-inf, AUC0-t, tmax, and partial AUC [pAUC] within the first 30 
minutes of dosing
4. INVESTIGATIONAL PLAN
4.1 Study Design


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This study will be a randomized, unblinded, three-way crossover study to determine naloxone 
plasma concentration after administration of multiple doses of IN naloxone.
Table 4-1: Study Schedule
Day -1
Day 1
Days 2-3
Day 4
Days 5-6
Day 7
Day 8
Check-in
Treatment
Period 1
Washout
Treatment
Period 2
Washout
Treatment
Period 3
Check-out
The following 3 treatments will be evaluated in a randomized order over the 3 treatment periods.
Table 4-2: Study Treatments
Treatment 
Description
A
Four 4 mg IN naloxone doses (1 dose every 2.5 min; L at 0 min, R at 2.5 min, L at 5 
min, R at 7.5 min)
B
Four 4 mg IN naloxone doses (2 doses every 2.5 min; L and R at 0* min, L and R at 
2.5* min)
C
Two 4 mg IN naloxone doses (L at 0 min, R at 2.5 min)
L = Left Nostril, R = Right Nostril, * doses will be ~5 seconds apart (one after the other)
Healthy subjects will be randomized to one of six treatment sequences (i.e., ABC, ACB, BAC, 
BCA, CAB, CBA). FDA will prepare the randomization schedule. Subjects will report to the 
study site for screening from Days -28 to -2 and then will return to the site on Day -1 for baseline 
assessments and check-in. After check-in (Day -1), subjects will receive dosing for the 3 
respective treatment periods on Days 1, 4 and 7. There will be two days of washout between each 
treatment period. Participants will be confined in the study clinic from Day -1 until the morning of 
Day 8. On dosing days, dosing will occur as per the treatment description and PK assessments 
will occur at the following timepoints: 
PK assessment: 0 (pre-dose), 2, 4.5, 7, 10, 12.5, 15, 20, 30, 45, 60, 120, 180, 240, 360, and 
720 minutes
The subject should remain fully supine for approximately one hour post-dose. Subjects should be 
instructed not to breathe through the nose during administration of the nasal spray into the nose.
Subjects will be instructed to leave their masks off for twenty minutes after drug administration.
A summary of all assessments prior to and following study drug administration on Day 1, is 
described in the Schedule of Events (Table 9-1). 
Subjects will be discharged from the study after completion of all study procedures. If a subject 
discontinues from the study prematurely, all procedures scheduled for the end of the study will 
be performed.
4.1.1 Risk/Benefit


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Subjects will be informed that participation in a human clinical pharmacology study like the 
present one cannot be of benefit to healthy volunteers. Nevertheless, the information from the 
physical examination, vital sign measurements, and ECG results may be shared with the 
subject’s personal physician if this is the subject’s choice. Subjects will be informed that it is 
also their choice to inform their personal physician that they are participating in this research 
study.
Subjects will be informed that their contribution to the study is of major importance to agencies 
like the FDA to understand how the body processes multiple repeated doses of IN naloxone.
However, since this is a study involving healthy volunteers, subjects will be informed that they 
have the option not to participate.
Subjects will be informed that they may be exposed to risks associated with the pharmacological 
properties of the study drug and the study procedures. The following summary of potential AEs 
for the study drug will be provided to and discussed with the subjects:
IN naloxone (NARCAN Nasal Spray Label, dated 08/06/2020)
The following adverse reactions were observed in a NARCAN Nasal Spray clinical study: 
increased blood pressure, constipation, toothache, muscle spasms, musculoskeletal pain, 
headache, nasal dryness, nasal edema, nasal congestion, nasal inflammation, rhinalgia, and 
xeroderma. 
Additionally, abrupt reversal of opioid effects in persons who were physically dependent on 
opioids has precipitated an acute withdrawal syndrome. Signs and symptoms have included: 
body aches, fever, sweating, runny nose, sneezing, piloerection, yawning, weakness, shivering or 
trembling, nervousness, restlessness or irritability, diarrhea, nausea or vomiting, abdominal 
cramps, increased blood pressure, tachycardia. In some patients, there may be aggressive 
behavior upon abrupt reversal of an opioid overdose. However, opioid-dependent individuals are 
excluded from this study as subjects cannot use prescription or nonprescription drugs within at 
least 14 days of study drug administration and a urine drug screen will check for opioids at 
screening and check-in.
The study drug will not be administered to anyone who is pregnant. All women must take a 
pregnancy test before receiving any study drug in this study. All women of childbearing potential 
enrolled on this study will be informed that they must use effective birth control methods 
(abstinence, intrauterine device, and contraceptive foam and a condom [i.e., double-barrier 
method]) during treatment. Subjects will be informed that they must notify the investigator if 
they or their female partners become pregnant during the course of the study. If a subject 
becomes pregnant, she will be informed that neither Spaulding Clinical Research nor the sponsor
will be responsible for the cost of any obstetric or related care, or for the child’s care.
Subjects will be informed that insertion of an IV catheter may be required for blood sample 
collection and, during insertion of the catheter, soreness, bruising, or infection at the insertion 


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site are possible but unlikely. Subjects will also be informed that dizziness and lightheadedness 
may occur during direct venipuncture, insertion of the IV catheter, or during blood collection.
Subjects will be informed that the confidentiality of their data will be respected at all times 
according to state law, and the study personnel handling their study data are bound by 
confidentiality agreements.
Subjects will be informed that extra precautions will be put in place, including required 
screening tests, that will limit the risk of COVID-19. All precautions related to COVID-19 will 
be documented in a COVID-19 Business Continiuity Plan as well as a study-specific COVID-19
Procedure Plan. Subjects will be informed that despite the extra precautions there is still a risk of 
them contracting COVID-19. Any changes to the COVID-19 precautions (e.g., due to updated 
CDC recommendations or new testing becoming available) will be documented in the COVID-
19 Business Continiuity Plan and study specific COVID-19 Procedure Plan. 
Subjects will be informed that the study drug and all tests, procedures, and visits required by the 
study are provided at no cost to them. If subjects become ill or physically injured because of 
participation in this study, they will be informed that costs of treatment will not be covered by 
the sponsor.
4.2 Selection of Study Population
Subjects will be screened, and the data collected will be reviewed by the principal investigator. 
Only those subjects who meet all the eligibility criteria will be enrolled. Approximately
20 healthy subjects are planned for enrollment. Up to 4 subjects may be qualified as 
replacements. Thus, a maximum of 24 subjects may be exposed to study drug and procedures 
during the study. Every effort will be made to maintain an approximate 50:50 male-to-female sex 
distribution.
4.2.1 Inclusion Criteria
Subjects who meet all of the following inclusion criteria will be eligible to participate in the 
study:
1. Subject signs an IRB-approved written informed consent and privacy language as per 
national regulations (e.g., Health Insurance Portability and Accountability Act 
authorization) before any study-related procedures are performed. 
2. Subject is a healthy, non-smoking man or woman, 18 to 55 years of age, inclusive, who 
has a body mass index of 18.5 to 32 kg/m2, inclusive, at screening.
3. Subject has normal medical history findings, clinical laboratory results, vital sign 
measurements, 12 lead ECG results, and physical examination findings at screening or, if 
abnormal, the abnormality is not considered clinically significant (as determined and 
documented by the investigator or designee).


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4. Subject must have a negative test result for alcohol and drugs of abuse at screening and 
check-in (Day -1). 
5. Subject must test negative for severe acute respiratory syndrome coronavirus (SARS-
CoV-2) by a molecular diagnostic test at check-in (Day -1). If a subject’s test comes back 
inconclusive, it can be repeated.
6. Female subjects must be of non-childbearing potential or, if they are of childbearing 
potential, they must: 1) have been strictly abstinent for 1 month before check-in (Day -1)
and agree to remain strictly abstinent for the duration of the study and for at least 1month 
after the last application of study drug; OR 2) be practicing 2 highly effective methods of 
birth control (as determined by the investigator or designee; one of the methods must be a 
barrier technique) from at least 1 month before check-in (Day -1) until at least 1 month 
after the end of the study. 
7. Male subjects must agree to practice 2 highly effective method of birth control (as 
determined by the investigator or designee) from at least 1 month before check-in (Day -
1) until at least 1 month after the last application of study drug.
8. Subject is highly likely (as determined by the investigator) to comply with the protocol 
defined procedures and to complete the study.
4.2.2 Exclusion Criteria
Subjects who meet any of the following exclusion criteria will not be eligible to participate in 
the study:
1. Subject has a deviated septum or previous nasal surgeries or need to use another nasal 
spray product during study that would impact administration of the intranasal study drug.
2. Subject has had an episode of epistaxis or an upper respiratory infection in the previous 
month.
3. Subject has used any prescription or nonprescription drugs (including aspirin or NSAIDs 
and excluding oral contraceptives and acetaminophen) within 14 days or 5 half-lives 
(whichever is longer) or complementary and alternative medicines within 28 days before 
the first dose of study drug.
4. Subject is currently participating in another clinical study of an investigational drug or 
has been dosed with any investigational drug within 30 days or 5 half-lives (whichever is 
longer) of dosing for this study.
5. Subject has used nicotine-containing products (e.g., cigarettes, cigars, chewing tobacco, 
snuff) within 6 weeks of screening.


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6. Subject has consumed alcohol, xanthine-containing products (e.g., tea, coffee, cola), 
caffeine, grapefruit, or grapefruit juice within 24 h of check-in. Subjects must refrain 
from ingesting these throughout the study. 
7. Subject has any underlying disease or surgical or medical condition (e.g., cancer, human 
immunodeficiency virus [HIV], severe hepatic or renal impairment) that could put the 
subject at risk or would normally prevent participation in a clinical study. This includes 
subjects with any underlying medical conditions that the Investigator believes would put 
subjects at increased risk of severe illness from COVID-19 based on the Centers for 
Disease Control and Prevention (CDC) guidelines. The CDC lists cancer, chronic kidney 
disease, chronic obstructive pulmonary disease, immunocompromised state from solid 
organ transplant, severe obesity, serious heart conditions, sickle cell disease, pregnancy, 
smoking and type 2 diabetes mellitus as conditions that put subjects at increased risk. 
Additionally, the CDC lists asthma (moderate-to-severe), cerebrovascular disease, cystic 
fibrosis, hypertension, immunocompromised state or immune deficiencies, neurologic 
conditions such as dementia, liver disease, pulmonary fibrosis, thalassemia, overweight, 
type 1 diabetes mellitus as conditions that might put subjects at increased risk.
8. Subject has any signs or symptoms that are consistent with COVID-19 per CDC 
recommendations. These include subjects with fever or chills, cough, shortness of breath 
or difficulty breathing, fatigue, muscle or body aches, headache, new loss of taste or 
smell, sore throat, congestion or runny nose, nausea or vomiting, or diarrhea may have 
COVID-19. In addition, the subject has any other findings suggestive of COVID-19 risk 
in the opinion of the investigator.
9. Subject has known or suspected allergies or sensitivities to the study drug.
10. Subject has clinical laboratory test results (hematology, serum chemistry and urinalysis) 
at screening or check-in that are outside the reference ranges provided by the clinical 
laboratory and considered clinically significant by the investigator.
11. Subject has a positive test result at Screening for HIV 1 or 2 antibody, hepatitis C virus 
antibodies, or hepatitis B surface antigen.
12. Subject is unable or unwilling to undergo multiple venipunctures for blood sample 
collection because of poor tolerability or is unlikely to complete the trial due to poor 
venous access.
13. Female subject is pregnant or lactating before enrollment in the study.
4.3 Screening Failures


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Subjects who sign and date the informed consent form but who fail to meet the inclusion and 
exclusion criteria are defined as screening failures. A screening log, which documents the subject 
initials and reason(s) for screening failure, will be maintained by the investigator for all 
screening failures. A copy of the log should be retained in the investigator’s study files.
If a subject fails the screening process because of an abnormal laboratory result, they can receive 
a copy of the results upon request. The investigator will determine if follow-up for the abnormal 
laboratory result is needed and will encourage the subject to follow-up with his or her personal 
physician as appropriate. All subjects will be informed as to the reason(s) they are excluded from 
study participation, even if follow-up is not required. If a subject fails the screening process 
because of a positive test result for human immunodeficiency virus or hepatitis, the positive 
result will be reported to local health authorities as required by law.
4.4 Termination of Study or Investigational Site
4.4.1 Criteria for Termination of the Study
The study will be completed as planned unless one of the following criteria is satisfied that 
requires early termination of the study.
New information regarding the safety or efficacy of the study drug that indicates a change in 
the known risk profile for the study drug, such that the risk is no longer acceptable for 
subjects participating in the study.
Significant violation of Good Clinical Practice (GCP) that compromises the ability to achieve 
the primary study objective or compromises subject safety.
4.4.2 Criteria for Termination of the Investigational Site
The study site may be terminated if the site (including the investigator) is found in significant 
violation of GCP, the protocol, the contractual agreement, or is unable to ensure adequate 
performance of the study.
In the event that the sponsor elects to terminate the study or the investigational site, a study-
specific procedure for early termination will be provided by the sponsor; the procedure will be 
followed by the applicable investigational site during the course of termination.
4.5 Criteria for Subject Withdrawal
Subjects may withdraw from the study at any time at their own request, or they may be 
withdrawn by the investigator without the approval of the subject based on the investigator’s 
clinical judgment. A subject is not required to provide a written request to withdraw from the 
study; however, a written request is required if a subject withdraws consent for his or her 
personal data to be used for study-related purposes.


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A subject may be discontinued for any of the following reasons:
AE: The subject has experienced an AE that, in the opinion of the investigator, requires early 
termination. The appropriate electronic case report form (eCRF) must be completed for each 
AE. If a subject is discontinued from the study due to an AE, the investigator is required to 
follow-up with the subject until the event resolves or becomes stable. If a subject dies during 
the study, the cause of death must be reported as a serious AE (SAE), with an outcome of 
death noted in the eCRF.
Protocol Violation: The subject failed to meet protocol entry criteria or did not adhere to 
protocol requirements, and continued participation poses an unnecessary risk to the subject’s 
health.
Withdrawal by Subject: The subject (or other responsible individual [e.g., caregiver]) wishes 
to withdraw from the study in the absence of a medical need.
NOTE: Withdrawal due to an AE should not be recorded in the “voluntary withdrawal” 
category.
Study Terminated by Sponsor: The sponsor, IRB, FDA, or other regulatory agency 
terminates the study.
Pregnancy: The subject is found to be pregnant.
NOTE: If the subject is found to be pregnant, the subject must be withdrawn immediately. 
The pregnancy will be followed-up to term, and the outcome, including any premature 
termination will be recorded. All live births must be followed for a minimum of 30 days or 
until the first well-baby visit.
Other.
NOTE: This category records withdrawals caused by an accidental or a medical emergency, 
unblinding, and other rare cases. The specific reason should be recorded in the comment 
space of the eCRF.
4.5.1 Handling of Withdrawals
The investigator may terminate a subject’s study participation at any time during the study when 
the subject meets the criteria described in Section 4.5. In addition, a subject may discontinue his 
or her participation without giving a reason at any time during the study. Subjects will be 
informed that their participation in the study is voluntary, that refusal to participate will involve 
no penalty or loss of benefits to which the subject is otherwise entitled, and that the subject may 
discontinue participation at any time without penalty or loss of benefits to which the subject is 
otherwise entitled.


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Should a subject’s participation be discontinued, the primary reason for termination must be 
recorded. In addition, efforts should be made to perform all procedures scheduled for the early 
termination visit. Any data and samples collected before subject withdrawal will become the
property of the sponsor.
If a subject sneezes after dosing, a blood sample will be collected and, if the subject sneezes
immediately after dosing, the sponsor will be consulted regarding a decision to continue the 
subject in the study. Under no circumstances will a dose of the study drug be repeated.
4.5.2 Replacement of Subjects
Approximately 20 healthy subjects are planned for enrollment and will be randomized to one of 
the six treatment sequences. Up to 4 subjects may be qualified as replacements and replacement 
subjects (if needed) must complete the treatment period. A replacement subject will receive the 
same treatment as the subject being replaced. Thus, a maximum of 24 subjects will be exposed to 
study drug and procedures during the study. 
4.6 Study Visits
4.6.1 Recruitment
Recruitment materials (e.g., internet, radio, and print advertisements, social media posts) will be 
approved by the local IRB before telephone screening. The sponsor is responsible for registration 
of the study on clinicaltrials.gov. Recruitment (including telephone screening) may not occur 
until the study is fully registered on clinicaltrials.gov.
4.6.2 Compensation
Subjects will be offered payment for Screening; however, if the results of their alcohol and drug 
screening tests are positive, they will not be compensated. Subjects who complete the entire 
study will receive payment according to the schedule provided in the informed consent form. No 
special incentives are offered. Final payment will not be released until all follow-up procedures 
have been completed and accepted by the investigator.
If a subject chooses to withdraw from the study prematurely, he or she will only be compensated 
for completed days. If subjects are withdrawn for medical reasons or if the study is halted 
temporarily or permanently, the subjects will receive compensation proportional to the time 
spent in the study. No compensation will be provided if a subject is dismissed from the study for 
noncompliance (e.g., improper conduct, ingesting alcohol and/or drugs [including recreational 
drugs], tampering with the study drug, consuming any prohibited foods or beverages).
If subjects are required to stay in the clinic for a longer period for safety reasons, they will be 
compensated at a rate proportional to the entire compensation for the study. If a subject becomes 


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ill or physically injured because of participation in this study, the subject will be referred for 
treatment.
4.6.3 Screening 
The following procedures and assessments will be performed at Screening (Days -28 to -2):
Obtain informed consent/HIPAA authorization. The informed consent process will be 
performed by a clinical research nurse in a private room. The subject will be given unlimited 
time to ask questions regarding study participation, and each subject will be questioned to 
ensure their understanding.
After informed consent is obtained:
Review inclusion/exclusion criteria to confirm subject eligibility
Record demographic information
Measure height, weight, and calculate body mass index
Perform serology screening (HIV antigen/antibody [Ag/Ab] Combo 1/2, HepC antibody, 
HBsAg)
Record medical history
Perform alcohol and drug screening (amphetamines, barbiturates, benzodiazepines, 
cannabinoids, cocaine, alcohol, opiates, phencyclidine, propoxyphene, and methadone)
Perform a serum pregnancy test (female subjects only)
Perform FSH measuring (postmenopausal [i.e., without menses for two years] female 
subjects only)
Record prior medications
Monitor for AEs
Perform clinical laboratory tests (hematology, serum chemistry, and urinalysis)
Measure vital signs (blood pressure, heart rate, respiratory rate, and oral body temperature)
Perform a safety 12-lead ECG
Perform a complete physical examination
4.6.4 Study Periods
This is a crossover study with three treatment periods. Subjects will be kept in the study clinic 
between these three periods. Subjects will check-in on Day -1 and will check-out on the morning 
of Day 8. 


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4.6.4.1 Check-In
The following procedures and assessments will be performed at Check-in (Day -1):
Perform/review results from SARS-CoV-2 molecular test (may be performed ~2 days before 
check-in to allow time for results)
Review inclusion/exclusion criteria to confirm subject eligibility
Measure weight
Review medical history
Perform alcohol and drug screening (amphetamines, barbiturates, benzodiazepines, 
cannabinoids, cocaine, alcohol, opiates, phencyclidine, propoxyphene, and methadone)
Perform a serum pregnancy test (female subjects only)
Admit subject to the study clinic
Randomization (after completion of check-in procedures on Day -1 or just before dosing on 
Day 1) 
Record concomitant medications
Monitor for AEs
Perform clinical laboratory tests (hematology, serum chemistry, and urinalysis)
Measure vital signs (blood pressure, heart rate, respiratory rate, and oral body temperature)
Perform a safety 12-lead ECG
Perform a comprehensive physical examination
4.6.4.2 Treatment
The following procedures and assessments will be performed during the treatment period 
according to the Schedule of Events (Table 9-1):
Monitor for AEs
Record concomitant medications
Perform a safety 12-lead ECG at 0 (pre-dose), 1h, and 6h timepoints. If scheduled for the 
same time, safety 12-lead ECGs will always be performed before vital sign measurement and 
blood sample collection
Measure vital signs at 0 (pre-dose), 0.5h, 1h, and 6h timepoints (blood pressure, heart rate, 
respiratory rate, and oral body temperature). If vital signs are scheduled at the same time as 
another event, vital signs will be measured after the ECG, but before blood sample collection


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Administer study drug according to the randomization schedule following all other pre-dose 
examinations and specimen collection
Collect PK blood samples (8 mL) at the timepoints specified in Section 4.1
Perform nasal irritation assessment at 0 (pre-dose), 4.5, 10, 30, 60 and 240 minutes as 
described in Section 4.7.2.6
4.6.5 Washout
There will be two washout days (72h from dose to dose) between the treatment periods. The 
following procedures and assessments will be performed during washout period:
Monitor for AEs
Measure vital signs (blood pressure, heart rate, respiratory rate, and oral body temperature)
4.6.6 Discharge (or Early Termination)
The following procedures and assessments will be performed before the subject is discharged 
from the study or at early termination:
Perform a serum pregnancy test (female subjects only)
Record concomitant medications
Monitor for AEs
Perform alcohol and drug screening (amphetamines, barbiturates, benzodiazepines, 
cannabinoids, cocaine, alcohol, opiates, phencyclidine, propoxyphene, and methadone)
Perform clinical laboratory tests (hematology, serum chemistry, and urinalysis)
Measure vital signs (blood pressure, heart rate, respiratory rate, and oral body temperature)
Perform a safety 12-lead ECG 
Perform a complete physical examination
Measure weight
Discharge subject from the study clinic after completion of all study procedures
4.7 Study Procedures
4.7.1 Pharmacokinetic Assessments
4.7.1.1 Pharmacokinetic Sample Collection 


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For this study, PK blood samples will be collected on Day 1 of each treatment period
(i.e., dosing days). Blood samples will be collected by direct venipuncture or by inserting an 
IV catheter into the subject’s forearm region. A single PK blood sample (8 mL) will be collected 
at the following timepoints within each period: 0 (i.e., immediately before dosing), 2, 4.5, 7, 10,
12.5, 15, 20, 30, 45, 60, 120, 180, 240, 360, and 720 minutes after dosing on Days 1, 4 and 7 
(Table 9-1). The target time of the PK blood collection is considered the most critical. If the 
collection time is more than ± 0.5 minute from the scheduled time for the first 15 minutes of 
collections or more than ± 2 minutes from scheduled timepoints, thereafter, this will be 
considered a protocol deviation.
Each blood sample will be labeled with subject number, study number, study day, time point, 
event, and a barcode that matches that belonging to the subject.
4.7.1.2 Specimen Handling
The PK blood samples (8 mL each) will be collected into 10 mL tubes containing K2EDTA, 
inverted several times to mix the blood with the anticoagulant, and placed in an ice bath. Within 
30 minutes of collection, the samples will be centrifuged for 10 minutes, at 3000 revolutions per 
minute, at 4°C, by a study team member.
The plasma will be separated using a disposable plastic pipette and approximately half of the 
plasma will be transferred into duplicate cryotube vials (2 mL polypropylene tubes) labeled as 
Aliquot A (primary) and Aliquot B (backup). The plasma samples will be appropriately labeled 
and stored frozen at –70°C or below until shipment. Temperature monitoring logs should be 
maintained and accessible for review by the study monitor.
The Aliquot A samples (primary) will be shipped first, on dry ice, to the bioanalytical laboratory 
specified by the sponsor for processing when requested by the sponsor. The Aliquot B samples 
(backup) will be held for a second shipment at a time after the completion of all Aliquot A
sample shipment(s) and the timing of the Aliquot B shipment communicated by the sponsor. 
None of the PK blood samples will be stored at clinical facility for future use. De-identified
samples may be stored by the sponsor for additional exploratory analyses.
Plasma concentrations of naloxone will be assayed using a validated liquid chromatography with 
tandem mass spectrometry method.
4.7.1.3 Pharmacokinetic Parameters
The following PK parameters will be determined for each subject: 
Plasma
Concentrations at specified times after the first dose 
Maximum concentration (observed peak drug concentration) (Cmax) on the specified day


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AUC from time 0 extrapolated to infinity (AUC0-inf)
AUC from time 0 to the sampling time corresponding to the last quantifiable 
concentration (Clast) (AUC0-t)
Partial AUCs (pAUC) over time intervals of 0 to 7 (pAUC0-7), 0-10 (pAUC0-10), 0-12.5 
(pAUC0-12.5), 0-15 (pAUC0-15), 0-20 (pAUC0-20), and 0-30 (pAUC0-30) minutes. 
Time at which Cmax occurs (tmax)
Elimination rate constant (Kel)
Terminal half-life (t1/2)
Apparent clearance (CL/F)
4.7.2 Safety Assessments
Safety will be evaluated in terms of AEs, clinical laboratory results (hematology, serum 
chemistry, and urinalysis), vital sign measurements (blood pressure, heart rate, respiratory rate, 
and oral body temperature), safety 12-lead ECG results, and physical examination findings. 
An examination of the nasal passage will be conducted by a trained observer to evaluate 
evidence of irritation to the nasal mucosa. This nasal irritation assessment will be taken at the
following timepoints during study drug administration 0 (pre-dose), 4.5, 10, 30, 60, 240 minutes.
4.7.2.1 Adverse Events
4.7.2.1.1 Adverse Event Definitions
An AE is defined as any untoward and/or unintended sign, including an abnormal clinical 
laboratory finding, symptom, or disease temporally associated with the use of a study drug, 
whether or not considered related to the study drug. Events or conditions that increase in 
frequency or severity during or as a consequence of use of a drug in human clinical trials will 
also be considered AEs.
A treatment-emergent adverse event (TEAE) is defined as an AE that begins after study drug 
administration.
An unexpected AE is any AE having a specificity or severity not consistent with the current 
investigator’s brochure for the study drug(s).
A serious adverse event (SAE) is defined as any AE occurring at any dose that meets the 
following criteria:
Results in death,
Is life threatening,


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Requires hospitalization or prolongation of existing hospitalization,
Results in persistent or significant disability or incapacity,
Results in a congenital anomaly/birth defect due to exposure prior to conception or during 
pregnancy, or
Is an important medical event that may not meet the previous criteria but, based upon 
appropriate medical judgment, jeopardizes the subject or requires medical or surgical 
intervention to prevent one of the outcomes listed previously.
4.7.2.1.2 Adverse Event Reporting
The recording of AEs will begin after the subject signs the informed consent form and will 
continue until discharge (or early termination). All AEs, whether serious or nonserious and 
whether or not related to the study drug, must be recorded in the eCRF. Study subjects will be 
instructed to warn study staff if he or she has any unexpected symptoms. In addition, all subjects 
will receive a reminder telephone call approximately 24 h before check-in.
Any SAE (whether expected or unexpected) must be entered into the eCRF system and reported 
by email to the sponsor or designee using the SAE Reporting Form within 24 h of the 
investigator or study clinic staff becoming aware of the event. It is the responsibility of the 
investigator to report all SAEs to the sponsor, to provide the most complete report possible, and 
to assess each SAE for its relationship to the study drug. The investigator is responsible for 
obtaining follow-up information on all SAEs and submitting follow-up SAE data. Any 
unexpected SAEs must be reported promptly to the investigator’s IRB as per the IRB’s 
requirements.
In the event of a fatal or life-threatening SAE, the sponsor will notify the appropriate FDA 
authorities within 7 calendar days of receipt of the report. The sponsor will follow all 7-day alert 
reports with a written report within 10 working days of receipt of the case. Serious AE cases that 
concern nonfatal, nonlife-threatening events that are unexpected and at least possibly related to 
the study drug will be submitted in writing to the FDA within 10 working days of receipt.
Furthermore, any AEs that are not expected, occur at a higher frequency, or would require 
modification of the study protocol and/or informed consent must be reported to the FDA within 
10 working days.
AEs that are assessed by the investigator as possibly or probably related to the study drug will be 
followed until they resolve or stabilize. All SAEs will be followed until resolution.
4.7.2.1.3 Assessment of Severity
The investigator will assess the severity of each AE using the following scale:


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Mild: The subject is aware of the AE but is still able to perform all activities; minimal or no 
medical intervention or therapy is required.
Moderate: The subject has to discontinue some activities due to the AE; minimal or no 
medical intervention or therapy is required.
Severe: The subject is incapacitated by the AE and is unable to perform normal activities; 
significant medical intervention or therapy is required, and hospitalization is possible.
4.7.2.1.4 Assessment of Causality
The investigator will assess the causal relationship/relatedness of each AE to the study drug 
using the following scale:
Not Related: Onset of the AE has no reasonable temporal relationship to administration of 
the study drug, a causal relationship to administration of the study drug is biologically 
implausible, or the event is attributed to an alternative etiology.
Unlikely Related: Onset of the AE has a reasonable temporal relationship to study drug 
administration and although a causal relationship is unlikely, it is biologically plausible.
Possibly Related: Onset of the AE has a strong temporal relationship to administration of the 
study drug, cannot be explained by the subject’s clinical state or other factors, and a causal 
relationship is biologically plausible.
Probably Related: Onset of the AE shows a distinct temporal relationship to administration of 
the study drug that cannot be explained by the subject’s clinical state or other factors, the AE 
is a known reaction to the product or chemical group, or can be predicted by the product’s 
pharmacology.
4.7.2.1.5 Pregnancy
A serum pregnancy test will be performed for female subjects at the timepoints presented in the 
Schedule of Events (Table 9-1). If a subject becomes pregnant while on the study, this should be 
reported immediately to the investigator and sponsor and the subject will be withdrawn from the 
study. The subject will be instructed to follow-up with his or her personal physician. All 
pregnancies are to be reported as an AE and followed for outcome.
4.7.2.2 Clinical Laboratory Tests
Clinical laboratory and diagnostic screening tests will be performed at the timepoints presented 
in the Schedule of Events (Table 9-1) and will be collected in accordance with acceptable 
laboratory procedures. Clinical laboratory testing will be performed by the clinical study 
contractor(s). The clinical laboratory tests that will be performed are presented in Table 4-3.
Unused clinical laboratory test samples will not be stored for future use.


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Table 4-3: Clinical Laboratory Tests & Diagnostic Screening Tests
4.7.2.3 Vital Sign Measurements
Vital signs (blood pressure, heart rate, respiratory rate, and oral body temperature) will be 
measured using an automated device on days presented in the Schedule of Events (Table 9-1). 
The subject should be in a supine position, if possible, for a minimum of 5 minutes before vital 
signs are measured. 
4.7.2.4 Safety 12-lead Electrocardiograms
Hematology
Serum Chemistry
Urinalysis
Hematocrit
Hemoglobin
Platelet count
Red blood cell count
White blood cell count (with 
automated differential)
Alanine aminotransferase
Albumin
Alkaline phosphatase
Aspartate aminotransferase
Bicarbonate
Bilirubin (total, direct, and indirect)
Blood urea nitrogen
Calcium
Chloride
Creatinine (including calculated 
creatinine clearance – Cockcroft 
Gault)
Glucose
Lactate dehydrogenase
Magnesium
Phosphorus
Potassium
Sodium
Total protein
Uric acid
Appearance
Bilirubin
Blood
Color
Glucose
Ketones
Leukocyte esterase
Microscopic examination: red blood 
cells, white blood cells, epithelial cells, 
bacteria, crystals, and casts (if present)
Nitrite
pH
Protein
Specific gravity
Urobilinogen
Diagnostic Screening Tests:
Serum
Urine
Other
Serology (human 
immunodeficiency virus 
Ag/Ab Combo 1/2, hepatitis 
C virus antibody, and 
hepatitis B surface antigen)
Female Subjects Only
Human chorionic 
gonadotropin (for pregnancy)
Drug screen including: 
amphetamines, barbiturates, 
benzodiazepines, cannabinoids, 
cocaine, alcohol, opiates, 
phencyclidine, propoxyphene, and 
methadone
SARS-CoV2 molecular test


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12-lead ECGs will be obtained with the subjects in the supine position for a minimum of 5 
minutes before recording. ECGs will be overread by a physician. If an abnormality is observed, 
the subject will be instructed to follow-up with his or her personal physician.
4.7.2.5 Physical Examinations
A complete physical examination will be performed on the days presented in the Schedule of 
Events (Table 9-1).
The complete physical examination will include, but not be limited to, assessments of the head, 
eyes, ears, nose, throat, skin, thyroid, nervous system, respiratory system, cardiovascular system, 
abdomen (liver and spleen), lymph nodes, and extremities. Height, weight (without shoes and 
wearing the lightest possible clothing), and calculation of body mass index will be performed at 
Screening and check-out.
If a clinically significant abnormality is observed upon physical examination, the subject will be 
instructed to follow-up with his or her personal physician.
4.7.2.6 Nasal Irritation Assessment
Nasal irritation (erythema, edema, and erosion) will be evaluated by a trained observer during 
study drug administration at the following timepoints: 0 (pre-dose), 4.5, 10, 30, 60 and 240 
minutes. If a PK sample corresponds to the nasal irritation assessment the nasal assessment will 
be performed after the PK sample is obtained.
Nasal Irritation Scale 
1 - Inflamed mucosa, no bleeding 
2 - Minor bleeding which stops within 1 minute 
3 - Minor bleeding, taking 1-5 minutes to stop 
4 - Substantial bleeding for 4-60 minutes, does not require medical intervention 
5 - Ulcerated lesions, bleeding which requires medical intervention
4.7.3 Demographics and Medical History
Demographic data (date of birth, gender, race, and ethnicity) will be collected at Screening. Each
subject will provide a complete medical history at Screening that will be reviewed at check-in. 
Specific information relating to any prior or existing medical conditions/surgical procedures will 
be recorded in the subject’s eCRF.
4.8 Study Treatments
4.8.1 Treatments Administered and Schedule


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Subjects will receive each of the following treatments (Table 4-4) according to the 
randomization schedule. Drug administration will occur on Day 1, 4 and 7 with a 2 day washout 
period in between. 
Table 4-4: Study Treatments and Dose Schedule 
Treatment 
Description
Dose Schedule
A
4 doses of 4 mg IN naloxone doses
1 dose every 2.5 min; L at 0 min, R at 2.5 
min, L at 5 min, R at 7.5 min
B
4 doses of 4 mg IN naloxone doses 
2 doses every 2.5 min; L and R at 0* min, 
L and R at 2.5* min
C
2 doses of 4 mg IN naloxone doses 
L at 0 min, R at 2.5 min
L = Left Nostril, R = Right Nostril, * doses will be ~5 seconds apart (one after the other)
Subjects will be randomized to one of six treatment sequences (i.e., ABC, ACB, BAC, BCA, 
CAB, CBA). Study drug will be administered by a clinical research nurse on the study clinic 
floor at the subject’s bedside. The pharmacist and investigator will be available if needed during 
study drug administration. The subject should remain fully supine for approximately one hour 
post-dose. Subjects should be instructed not to breathe through the nose during administration of 
the nasal spray into the nose. Subjects will be instructed to leave their masks off for twenty 
minutes after drug administration.
IN naloxone doses will be administered as a 4 mg IN spray at the times specified above. No 
treatments will include placebo.
4.8.2 Dose Selection
IN naloxone is available as a single-dose spray containing 4 mg of naloxone hydrochloride in 0.1 
mL. The 4 mg drug is distributed in packages of two nasal sprays (1 dose per spray), but 
additional doses can be administered if needed and available. IN naloxone labeling includes 
instructions to readminister additional doses using alternating nostrils, every 2 to 3 minutes (new 
nasal spray for each dose) if the patient does not respond or responds and then relapses into 
respiratory depression until medical assistance arrives. This may result in multiple doses of 
naloxone being required to achieve reversal, however, there is only PK data of IN naloxone 
following administration of 2 IN naloxone doses (in each nostril) at the same time. In this study, 
doses of IN naloxone (4 mg) were selected to compare administration of multiple doses of IN 
naloxone. The model-predicted naloxone exposures from 4 IN naloxone doses as will be 
administered in this study are Cmax 19 ng/mL and AUC0-inf 31 hr•ng/mL. These naloxone 
exposures are lower than exposures observed with intravenous administration of naloxone up to 
10 mg IV (predicted: AUC0-inf 40-50 hr•ng/mL for 5 x 2 mg IV; predicted Cmax 25-30 ng/mL 
for 2 mg IV), which are covered by labeling and clinical use (Naloxone Hydrocholride Injection 
Generic Label, dated 03/18/2020; Tylleskar et al., 2017; McDonald et al., 2018).
4.8.3 Method of Assigning Subjects to Treatment Sequence


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4.8.3.1 Randomization Process
The project biostatistician will create the specifications that will be used to generate the 
randomization schedule. The specifications will be based on the protocol requirements and 
appropriate statistical programming with consideration for study design, number of treatments, 
number of subjects planned for enrollment, stratification, and blocking.
Based on these specifications, the project biostatistician (or designee) will generate a dummy 
randomization schedule. The schedule is generated in R. 
The project biostatistician (or designee) distributes the ‘dummy’ randomization schedule to 
specified personnel for review. Any change (e.g., change in block size, change in stratification 
levels) that requires an update to the specifications will reset this process. Minor changes (e.g., 
display formatting) will not require a change to the specifications.
After the approval of the ‘dummy’ randomization schedule, the project biostatistician (or 
designee) will generate the final randomization schedule. The output is sent only to designated 
recipients, who will maintain a secured digital and printed copy for their use.
Archival of the programs and output is accomplished by the creation of an encrypted, password-
protected ZIP file containing the program and output file(s). The ZIP file is copied to a secure 
storage drive on the sponsor’s site.
Randomization will occur after informed consent is obtained either after completion of check-in 
procedures on Day -1 or just before dosing on Day 1. Approximately 20 healthy subjects are 
planned for enrollment and up to 4 subjects may be qualified as replacements. Thus, a maximum 
of 24 subjects will be exposed to study drug and procedures during the study.
Enrolled subjects will be randomly assigned to one of the six different treatment sequences as
mentioned in Section 4.8.2.
All randomization information will be secured and housed in a locked storage area.
4.8.4 Identity of Study Drug
NARCAN Nasal Spray (referred to throughout this document as IN naloxone) is indicated for the 
emergency treatment of known or suspected opioid overdose, as manifested by respiratory and/or 
central nervous system depression. NARCAN Nasal Spray is intended for immediate 
administration as emergency therapy in settings where opioids may be present and is available as 
a 2 mg or 4 mg single dose of naloxone hydrochloride in 0.1 mL with the indication to re-
administer additional doses every 2 to 3 minutes (using alternating nostrils) if needed until 
emergency medical assistance arrives. NARCAN Nasal Spray is a pre-filled, single dose 
intranasal spray. Chemically, naloxone hydrochloride has a molecular weight of 363.84 and 
molecular formula C19H21NO4 HCl. Naloxone hydrochloride, an opioid antagonist, occurs as a 


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white to slightly off-white powder, and is soluble in water, in dilute acids, and in strong alkali; 
slightly soluble in alcohol; practically insoluble in ether and in chloroform. (NARCAN Nasal 
Spray label, dated 08/06/2020)
4.8.5 Management of Clinical Supplies
4.8.5.1 Study Drug Packaging and Storage
The active study drug will be obtained from commercial sources. Storage instructions for the 
active study drug are as follows (NARCAN Nasal Spray label, dated 08/06/2020):
Store NARCAN Nasal Spray in the blister and cartons provided. Store below 77°F ( 
25°C). Excursions permitted up to 104°F (40°C). Do not freeze or expose to excessive 
heat above 104°F (40°C). Protect from light.
NARCAN Nasal Spray freezes at temperatures below 5°F (-15°C). If this happens, the 
device will not spray. However, NARCAN Nasal Spray may be thawed by allowing it to 
sit at room temperature for 15 minutes, and it may still be used if it has been thawed after 
being previously frozen.
4.8.5.2 Study Drug Accountability
Good clinical documentation practices will be employed to record the receipt, storage conditions, 
accountability, and use or return of the study drug. The study drug will be stored in a secure 
location with access to the study personnel who will be managing the storage, dispensing, and 
accountability of the study drug.
Upon completion or termination of the study, final accountability review by the study monitor, 
and written authorization from the sponsor, all unused and/or partially used study drug should be 
returned or destroyed at the study clinic. It is the investigator’s responsibility to ensure that the 
sponsor has provided written authorization for study drug disposal, the disposal process follows 
the study clinic’s standard operating procedures, and appropriate records of the disposal are 
documented and maintained. No unused study drug may be disposed until fully accounted for by 
the study monitor (or designee). Documentation of unused study drug should include subject 
number, medication identity (medication #, period #), date, and quantity of study drug used.
4.8.6 Blinding
The study will be unblinded as the product is administered IN and different arms will have a 
different number of administrations at different times. 
4.8.7 Treatment Compliance
At Screening, as part of the inclusion criteria, it will be confirmed that subjects are able to 
comply with the protocol-defined procedures including administration of an intranasal study 


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drug. All doses of the study drug will be administered in the study clinic by clinic personnel and 
recorded in the eCRF. If a subject sneezes after dosing, the event will be documented. The 
decision to replace any subject who sneezes after dosing will be made as described in 
Section 4.5.1.
4.8.8 Prior and Concomitant Medications
Subjects are prohibited from using any prescription or nonprescription drugs (including aspirin 
or non-steroidal anti-inflammatory drugs [NSAIDs] and excluding oral contraceptives and 
acetaminophen) within 14 days or 5 half-lives (whichever is longer), or complementary and 
alternative medicines within 28 days before the first dose of study drug. Subjects will be asked if 
they have used any of these substances and their responses will be recorded on the eCRF.
Subjects are also prohibited from currently participating in another clinical study of an 
investigational drug and may not have been treated with any investigational drug within 30 days 
or 5 half-lives (whichever is longer) of the compound.
Subjects must be instructed not to take any medications, including over-the-counter products, 
without first consulting with the investigator.
4.8.9 Subject Restrictions
Subjects are not allowed to use nicotine-containing products (e.g., cigarettes, cigars, chewing 
tobacco, snuff) within 6 weeks before screening. In addition, subjects are not allowed to ingest 
alcohol, xanthine-containing products (e.g., tea, coffee, chocolate, cola), caffeine, grapefruit, or 
grapefruit juice for 48 h before dosing and throughout the study. 
Subjects must be able to tolerate a controlled, quiet study conduct environment, including 
avoidance of music, television, movies, games, and activities that may cause excitement, 
emotional tension, or arousal during prespecified times (e.g., before and during ECG extraction 
windows) throughout the duration of the study.
Subject must be able to take the drug intranasally and should not have a deviated septum or any 
previous nasal surgeries that would impact administration of the intranasal drug. Additionally, 
subjects must refrain from using any other nasal spray product beginning 48 h before dosing 
until completion of the study.
Subjects must be willing to comply with study rules; attempting to void at specified times; 
remaining quiet, awake, undistracted, motionless, and supine during specified times; and 
avoiding vigorous exercise as directed throughout the duration of the study.
Standardized meals will be served at consistent times relative to dosing, and no food or fluids 
will be served containing caffeine. Subjects must only eat meals and snacks that are provided 
during periods of their stay in the study clinic, and must consume all of each meal that is served 


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at a reasonable pace (within 25 minutes). Outside of meal times, the subjects will only be 
allowed to intake water, which will be available ad libitum.
Due to current precautions being taken for COVID-19, the following restrictions will be in place:
Subjects must always wear masks except when in their beds with a curtain drawn 
between subjects or for a limited time for a study procedure (e.g. study drug 
administration or eating) when instructed by staff. 
Subjects must practice social distancing, which will include having 2 subjects per room 
for overnight stays and having common areas closed. Subjects will eat meals socially 
distanced in the hallway. Subjects will spend most of their time in their rooms except for 
specified times for walking in the halls (with masks).
Subjects must practice regular handwashing with soap and water, scrubbing hands for at 
least 20 seconds or with approved hand sanitizer as supplied by study staff. 
Designated isolation rooms will be set up to segregate any participant(s) that develop any 
symptoms of concern while housed in the unit and COVID-19 testing will be done when deemed 
necessary by the Investigator. If new information becomes available, there could be other 
precautions that lead to additional restrictions that will be documented in the COVID-19
Business Continuity Plan and the study specific COVID-19 Procedure Plan.
4.9 Statistical Methods
4.9.1 Sample Size
Up to 24 healthy subjects will be enrolled (including 4 potential replacement subjects). The 
number of subjects was determined to have greater than 80% power for comparisons between 
treatment arms across prespecified consecutive timepoints (different timepoints for each 
comparison). These power calculations are based on 18 subjects with each comparison, allowing 
for potential dropouts. These analyses adjust for multiplicity using Pocock boundaries for 
assessing the same endpoint at multiple timepoints. Coefficient of variations and effects sizes for 
different treatment scenarios were determined using modeling and simulation from previous 
naloxone studies.
4.9.1 Analysis Populations
The PK population will include all subjects who receive study drug and have at least 
one estimable PK parameter after dosing.
The safety population will include all subjects who receive at least one dose of the study drug.
The analysis population will include all subjects in the PK population with sufficient data to calculate 
PK parameters. Only subjects with results from two or more periods will be included in 
comparisons.


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The details of the PK analysis will be included in the Statistical Analysis Plan (SAP). In any 
situation where the SAP and protocol differ regarding planned analyses, the language in the SAP 
supercedes descriptive text in the protocol. 
4.9.2 General Statistical Considerations
All data will be presented in data listings. Data from subjects excluded from an analysis 
population will be presented in the data listings, but not included in the calculation of summary 
statistics. Demographic and baseline characteristics will be summarized overall and by treatment 
for all subjects.
4.9.3 Subject Disposition
The number of subjects who enroll in the study and the number and percentage of subjects who 
complete each assessment will be presented. The frequency and percentage of subjects who 
withdraw or discontinue from the study and the reason for withdrawal or discontinuation will be 
summarized.
4.9.4 Demographics and Baseline Characteristics
Descriptive statistics will be used to summarize demographic and baseline subject 
characteristics. For continuous variables, the mean, median, standard deviation (SD), minimum, 
and maximum values will be reported. For categorical (nominal) variables, the number and 
percentage of subjects (or observations) will be reported.
4.9.5 Pharmacokinetic Analysis
Pharmacokinetics: Concentrations will be determined at specified times. The primary endpoint 
is the first timepoint when there is a higher naloxone plasma concentration in the 4 naloxone 
dose arms compared to the 2 naloxone dose arm. The comparisons will consider multiple, pre-
specified timepoints and adjust for multiplicity using Pocock boundaries. Separate comparisons 
will be performed looking at the 4 naloxone dose arm A (test) versus the 2 naloxone dose arm C
(reference) and the 4 naloxone dose arm B (test) verus the 2 naloxone dose arm C (reference). 
Different timepoints will be selected for each comparison and timepoints will be evaluated from 
earliest to latest time. 
Secondary endpoints will include determination of the first timepoint when there is a higher 
naloxone plasma concentration in the 4 naloxone dose arm B (2 doses every 2.5 minutes) as test
compared to the 4 naloxone dose arm A (1 dose every 2.5 minutes) as reference. The same 
approach as outlined for the primary endpoint analysis above will be used for this comparison. 
Additional PK measures (i.e., Cmax, AUC0-inf, AUC0-t, pAUC, Tmax, half-life, elimination rate) 
will be exploratory endpoints and determined for each subject using non-compartmental 


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methods. All parameters will be calculated using SAS or R software and will be reported with 
standard descriptive statistics including the mean and coefficient of variation. Calculation of PK 
parameters will be performed using actual sampling times. Additional details of the PK analysis 
will be included in the SAP.
Dose Proportionality: Dose proportionality based on Cmax, AUC0-t, and AUC0-inf will be 
compared between each of the three naloxone treatments as secondary endpoints. The 4 naloxone 
doses arms (separate comparisons for 1 dose every 2.5 minutes and 2 doses every 2.5 minutes) 
will be compared with the 2 naloxone dose arm (1 dose every 2.5 minutes). An additional 
comparison will be performed between the 4 naloxone arm B (2 doses every 2.5 minutes) as test
and 4 naloxone dose arm A (1 dose every 2.5 minutes) as reference.
4.9.6 PK/PD Modeling
PK data from this study will be used to update the naloxone PK model in a previously developed 
PK/PD model for opioid-induced respiratory depression. The updated model will be used to 
predict the mean time to rescue a patient from simulated opioid induced respiratory depression 
from fentanyl and carfentanil following a range of overdose scenarios (e.g. low, medium and 
high). Full details of the analysis will be described in a separate Modeling Analysis Plan (MAP).
4.9.7 Safety Analyses
4.9.7.1 Adverse Events
All AEs will be coded using the latest version of the Medical Dictionary for Regulatory 
Activities. The incidence of TEAEs, organized by system organ class and frequency, will be 
summarized by seriousness, severity, relationship to treatment, and by treatment at onset of the 
TEAE. A detailed listing of serious AEs and TEAEs leading to withdrawal will also be provided.
4.9.7.2 Clinical Laboratory Tests
Clinical laboratory results will be reviewed by the investigator or designee together with data in 
the eCRF. Any values outside the reference range will be evaluated for clinical significance. If a 
value is determined to be clinically significant, the subject will be instructed to follow-up with 
his or her personal physician. The investigator or designee may repeat the clinical laboratory 
tests if deemed appropriate. The investigator will maintain a copy of the laboratory accreditation 
and the reference ranges for the laboratory used.
Clinical laboratory results (hematology, serum chemistry, and urinalysis) will be summarized 
using descriptive statistics (number of subjects, mean, SD, minimum, median, and maximum). 
Clinical laboratory results will be classified as normal or abnormal, according to the reference 
ranges of the individual parameter. The number and percentage of subjects with abnormal 


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laboratory results will be provided. No statistical testing will be performed on clinical laboratory 
data.
4.9.7.3 Vital Sign Measurements
Vital sign measurements and changes from baseline will be summarized using descriptive 
statistics (number of subjects, mean, SD, minimum, median, and maximum) by treatment and 
time point.
4.9.7.4 Safety 12-lead Electrocardiograms 
12-lead ECGs will be obtained with the subjects in the supine position for a minimum of 5 
minutes before recording. ECGs will be overread by a physician. If an abnormality is observed, 
the subject will be instructed to follow-up with his or her personal physician.
4.9.7.5 Physical Examinations
Physical examination findings will be presented in a data listing, and abnormal physical 
examination findings will be recorded as AEs.
4.9.7.6 Nasal Irritation Score Analyses
Nasal Irritation Score is an examination of the nasal passage conducted by a trained observer to 
evaluate evidence of irritation to the nasal mucosa. This measures will provide an assessment of 
how much nasal irritation the subject is caused by each treatment during the study. These results
will be summarized using descriptive statistics for all treatment groups. 
4.9.7.7 Other Safety Data
All concomitant medication usage and medications that changed in daily dose, frequency, or 
both since the subject provided informed consent will be summarized for each subject.
4.9.8 Missing Data
Missing data will not be imputed. Data that are excluded from the descriptive or inferential 
analyses will be included in the subject data listings. This will include data from subjects not in 
the particular analysis population, measurements from unscheduled visits, or extra measurements 
that may arise from 2 or more analyses of the biofluid sample at the same time point. Details on 
the handling of missing data will be further described in the SAP.
4.10 Data Quality Assurance
Completed eCRFs are required for each subject randomly assigned to treatment. Electronic data 
entry will be accomplished through the ClinSpark® remote electronic data capture system, which 
allows for on-site data entry and data management. This system provides immediate, direct data 


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transfer to the database, as well as immediate detection of discrepancies, enabling site 
coordinators to resolve and manage discrepancies in a timely manner. Each person involved with 
the study will have an individual identification code and password that allows for record 
traceability. Thus, the system, and subsequently any investigative reviews, can identify 
coordinators, investigators, and individuals who have entered or modified records.
Furthermore, the investigator retains full responsibility for the accuracy and authenticity of all 
data entered into the electronic data capture system. The completed dataset and their associated 
files are the sole property of the sponsor and should not be made available in any form to third 
parties, except for appropriate governmental health or regulatory authorities, without written 
permission of the sponsor.
4.11 Data Sharing
De-identified subject-level data may be released to other researchers (including through a data 
warehouse or as a part of a publication) to enable secondary research. Additional secondary 
research may also be performed by the sponsor.
5. ETHICAL CONSIDERATIONS
5.1 Ethical Conduct of the Study
This study will be performed in accordance with the recommendations guiding physicians in 
biomedical research involving human subjects adopted by the 18th World Medical Association 
General Assembly, Helsinki, Finland, 1964 and later revisions, as well as, United States Title 45
Code of Federal Regulations (CFR) Part 46 GCP, and International Council for Harmonisation 
(ICH) guidelines describing technical requirements for registration of pharmaceuticals for human 
use.
5.2 Institutional Review Board (IRB)
The FDA Project Lead or investigator will provide the designated IRB with all required 
documents, including the study protocol and informed consent form. The study will not be 
initiated until appropriate IRB approval is obtained from the designated IRB. The investigator 
will provide the FDA Project Lead with copies of the approval documents for the protocol, 
informed consent form, and all recruiting materials. The designated IRB will also receive copies 
of any original or amended information sheets or pamphlets given to the study subject in support 
of the informed consent process and any advertisements or other recruitment material. Such
materials will not be employed in the study before approval by the designated IRB.
Subjects will be informed that they have the right to contact the IRB or Office for Human 
Research Protections if they have any questions, concerns, complaints, or believe they have been 


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harmed by the participation in this research study as a result of investigator negligence. Subjects 
will be given the address and phone number of the IRB.
6. ADMINISTRATIVE PROCEDURES
6.1 Responsibilities of the Investigator 
The following administrative items are meant to guide the investigator in the conduct of the 
study but may be subject to change based on industry and government standard operating 
procedures, working practice documents, or guidelines. Changes may be reported to the IRB but 
will not result in protocol amendments.
6.1.1 Form FDA 1572
The investigator will complete and sign the Form FDA 1572.
6.1.2 Adherence to Protocol
The investigator agrees to conduct the study as outlined in this protocol in accordance with the 
ICH E6(R2) and all applicable guidelines and regulations.
6.1.3 Reporting Requirements
By participating in this study, the investigator agrees to submit reports of SAEs according to the 
time line and method outlined in the protocol (Section 4.7.4.1.2). In addition, the investigator 
agrees to submit reports to the IRB as appropriate. The investigator also agrees to provide the 
sponsor with an adequate report shortly after completion of the investigator’s participation in the 
study.
6.1.4 Source Documentation
By participating in this study, the investigator agrees to maintain adequate case histories for the 
subjects treated as part of the research under this protocol. The investigator agrees to maintain 
accurate eCRFs and source documentation as part of the case histories.
6.1.5 Retention of Records
The investigator agrees to keep the records stipulated in this protocol and those documents that 
include (but are not limited to) the study-specific documents, identification log of all 
participating subjects, medical records, source worksheets, all original signed and dated informed 
consent forms, subject authorization forms regarding the use of personal health information (if 
separate from the informed consent form), copies of all eCRFs, query responses, and detailed 
records of drug disposition, to enable evaluations or audits from regulatory authorities, the 
sponsor, or its designees.


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Furthermore, ICH 4.9.5 requires the investigator to retain essential documents specified in 
Section 8 of ICH E6 (R2) until at least 2 years after the last approval of a marketing application 
for a specified drug indication being investigated or, if an application is not approved, until at 
least 2 years after the investigation is discontinued and regulatory authorities are notified. In 
addition, ICH 4.9.5 states that the study records should be retained until an amount of time 
specified by applicable regulatory requirements or for a time specified in the clinical study site 
agreement between the investigator and sponsor.
Refer to the clinical study site agreement for the sponsor’s requirements on record retention. The 
investigator should contact and receive written approval from the sponsor before disposing of 
any such documents.
6.1.6 Financial Disclosure and Obligations
The investigator is required to provide financial disclosure information to allow the sponsor to 
submit the complete and accurate certification or disclosure statements required under 
45 CFR 46. In addition, the investigator must provide to the sponsor a commitment to update this 
information promptly if any relevant changes occur during the course of the investigation and for 
1 year after the completion of the study.
Neither the sponsor nor the study clinic is financially responsible for further testing or treatment 
of any medical condition that may be detected during the screening process.
6.2 Confidentiality and Disclosure of Data
All subjects will sign a HIPAA-compliant authorization form containing the mandated core 
elements and requirements before participation in this clinical study. The sponsor and designees 
affirm and uphold the principle of the subject’s right to protection against invasion of privacy. 
Throughout this study, a subject’s source data will only be linked to the sponsor’s electronic data 
capture system database or documentation via a unique identification number. As permitted by 
all applicable laws and regulations, limited subject attributes such as gender, age or date of birth, 
and subject initials may be used to verify the subject and accuracy of the subject’s unique 
identification number.
To comply with ICH Guidelines for GCP and to verify compliance with this protocol, the 
sponsor requires that the investigator allow review of the subject’s original medical records 
(source data or documents) by the study monitor, representatives from any regulatory authority 
(e.g., FDA), the sponsor’s designated auditors, and the appropriate IRB. These medical records 
will include, but will not be limited to, clinical laboratory test result reports, ECG reports, 
admission and discharge summaries for hospital admissions occurring during a subject’s study 
participation, and autopsy reports. Access to a subject’s original medical records requires the 
specific authorization of the subject as part of the informed consent process.


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Copies of any subject source documents that are provided to the sponsor must have certain 
personally identifiable information removed (i.e., subject name, address, and other identifier 
fields not collected in the subject’s eCRF).
Data will be maintained and backed up in the electronic data capture system. All access to the 
data is protected by username and password, and each staff member and all sponsor staff will 
have separate access that requires a separate username and password. Access is only given to site 
staff and requested sponsor staff who have completed the appropriate training.
6.3 Subject Consent
Written informed consent in compliance with 45 CFR 46 will be obtained from each subject 
before entering the study or performing any unusual or nonroutine procedure that involves risk to 
the subject. An informed consent template may be provided by the sponsor to the study clinic. If 
any institution-specific modifications to study-related procedures are proposed or made by the 
study clinic, the consent should be reviewed by the sponsor or its designee or both before IRB 
submission. Once reviewed, the consent will be submitted by the investigator to the IRB for 
review and approval before the start of the study. If the informed consent form is revised during 
the course of the study, all active participating subjects must sign the revised form.
Before enrollment, each prospective subject will be given a full explanation of the study and be 
allowed to read the approved informed consent form. The informed consent process will be 
performed by a clinical research nurse in a private room. The subject will be given unlimited 
time to ask questions regarding study participation, and each subject will be questioned to ensure 
their understanding. Once the investigator is assured that the subject understands the implications 
of participating in the study, the subject will be asked to give consent to participate in the study 
by signing the informed consent form.
The investigator will provide a copy of the signed informed consent form to the subject. The 
original form will be maintained in the subject’s medical records at the site.
6.4 Data Collection
Full details of procedures for data collection and handling will be documented in the data 
management plan, which is initiated with the final protocol receipt. The data management plan is 
a changing document that evolves over the course of the study and is finalized by database lock.
6.5 Publications
No information related to or generated by this study will be released to the public until it has 
been reviewed by the sponsor. The sponsor shall own intellectual rights for the data and analysis 
resulting from this study. Authorship on publications will be determined by standard journal 
requirements.


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7. STUDY MANAGEMENT
7.1 Medical Monitor
As outlined in ICH E6(R2) Section 5.3, the sponsor’s designated medical monitor will be readily 
available to advise on trial-related medical questions or problems.
7.2 Study Monitoring
The sponsor or its designee will monitor the study to ensure that it is being conducted according 
to the protocol, GCP standards, and applicable region-specific requirements, and to ensure that 
study initiation, conduct, and closure are adequate. The investigators and the study clinic staff 
will be expected to cooperate fully with the study monitors and personnel or agents of the 
sponsor and be available during monitoring visits to answer questions sufficiently and to provide 
any missing information. The investigators and their institutions will permit direct access to 
source data/documents for study-related monitoring activities, audits, IRB reviews, and 
regulatory inspections.
During any on-site visits, the study monitor will: 
Check and assess the progress of the study
Review all informed consent forms
Review study data collected
Conduct source document verification
Identify any issues and address their resolution
Verify that the facility remains acceptable
Conduct study drug accountability
These monitoring activities will be done in order to verify that the: 
Data are authentic, accurate, and complete.
The safety and rights of the subjects are being protected.
The study is being conducted in accordance with the currently approved protocol (including 
any amendments), GCP, and all applicable regulatory requirements.
In addition, the sponsor, designated auditors, and government inspectors must be allowed access 
to eCRFs, source documents, and other study files that may be required to evaluate the conduct 
of the study.
7.3 Management of Protocol Amendments and Deviations


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7.3.1 Modification of the Protocol
Any changes in this research activity, except those necessary to remove an apparent immediate 
hazard to the subject, must be submitted to the sponsor or designee and reviewed and approved 
by the local IRB before implementation. Amendments to the protocol must be submitted in 
writing to the investigator’s IRB for approval before subjects are enrolled into an amended 
protocol.
7.3.2 Protocol Violations and Deviations
Any significant protocol deviations that the investigator or study clinic staff believes are of major 
importance (e.g., incorrect randomizations, subject enrolled but not eligible) should be reported 
to the sponsor and the investigator’s IRB as soon as possible. Significant protocol deviations 
may include the following:
Deviations from the inclusion/exclusion criteria that may affect subject safety
Deviations (omission or delay) of safety monitoring procedures
Deviations in the administration of the study drug
Deviations in obtaining informed consent
All subjects who are enrolled and receive the study drug, regardless of whether they have a 
major protocol violation, must continue to be followed for safety for all follow-up study visits.


U.S. FOOD AND DRUG ADMINISTRATION 
CDER / Office of Translational Sciences / Office of Clinical 
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Protocol Number: SCR-011 (Version: 1.0)
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8. REFERENCE LIST
1. NARCAN Nasal Spray Label, dated 08/06/2020. Obtained from 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/208411Orig1s004lbl.pdf.
2. Naloxone Hydrochloride Injection Generic Label, dated 03/18/2020. Obtained from
https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=b1303f15-c48b-a44d-b28a-
72f370094e02
3. Tylleskar I, Skulberg AK, Nilsen T, Skarra S, Jansook P, Dale O. Pharmacokinetics of a 
new, nasal formulation of naloxone. Eur J Clin Pharmacol. 2017;73(5):555-562. doi: 
10.1007/s00228-016-2191-1
4. McDonald R, Lorch U, Woodward J, et al. Pharmacokinetics of concentrated naloxone 
nasal spray for opioid overdose reversal: Phase I healthy volunteer study. Addiction.
2018;113(3):484-493. doi:10.1111/add.14033


U.S. FOOD AND DRUG ADMINISTRATION 
CDER / Office of Translational Sciences / Office of Clinical 
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Protocol Number: SCR-011 (Version: 1.0)
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9. APPENDICES
9.1 Appendix A – Schedule of Events
Table 9-1: Schedule of Events


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9.2 Appendix B – List of Abbreviations
LIST OF ABBREVIATIONS
Abbreviation
Definition
AE
adverse event
AUC0-inf
area under the concentration-time curve from 0 to infinity
AUC0-t
area under the concentration-time curve from 0 to last quantifiable 
concentration
CFR
Code of Federal Regulations
Cmax
maximum observed concentration
COVID-19
CDER
DARS
coronavirus disease of 2019
Center for Drug Evaluation and Research
Division of Applied Regulatory Science
ECG
Electrocardiogram
eCRF
electronic case report form
FDA
Food and Drug Administration
GCP
Good Clinical Practice
HBsAg
hepatitis B surface antigen
HepC
hepatitis C 
HIPAA
Health Insurance Portability and Accountability Act
HIV
human immunodeficiency virus
ICH
International Council for Harmonisation
IRB
Institutional Review Board
IN
Intranasal
Kg
kilogram
MAP
modeling analysis plan
MedDRA
Medical Dictionary for Regulatory Activities
Mg
milligram
NSAID
nonsteroidal anti-inflammatory drug
pAUC
partial area under the curve
PD
Pharmacodynamic
PK
Pharmacokinetic
SAE
serious adverse event
SAP
statistical analysis plan
SARS-CoV-2
SD
severe acute respiratory syndrome coronavirus 2
standard deviation
t1/2
terminal half-life
TEAE
treatment-emergent adverse event
tmax
time of Cmax


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9.3 Appendix C – Protocol Revision History
PROTOCOL REVISION HISTORY
Protocol 
Number
Version
Effective Date
Summary of Changes
SCR-011
1.0
15 Feb 2021
Developed initial protocol