Clinical trial NCT04314713
Conditions: Medical Countermeasures Organophosphate Poisoning
Keywords: Scopolamine
Sponsor: Battelle Memorial Institute
Start date: 2020-06-02; Completion date: 2021-05-06
Enrollment: 32 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
To characterize the safety and tolerability profile of ascending doses of scopolamine hydrobromide trihydrate (Scopolamine HBT) administered by intramuscular (IM) injection. And characterize the pharmacokinetics (PK) of ascending doses of Scopolamine HBT administered by IM injection

Detailed description:
This is a double-blinded, randomized, placebo-controlled, in-clinic, Phase 1, single-dose, IM, sequential dose-escalation study in healthy adults aged 18-55. Healthy volunteers will be assigned to 1 of 5 cohorts of Scopolamine HBT dosage groups: 0.005, 0.007, 0.011, 0.014, or 0.021 mg/kg, or will receive the placebo administered by IM injection to the anterior thigh. In each cohort, 6 to 9 subjects will receive active drug and 2 to 3 subjects will receive placebo. Each cohort will have at least 3 male and 3 female subjects enrolled among the first 8 subjects in the dosing group to ensure that at least 1 male subject and 1 female subject in each dosing group receive active drug. If nonextreme dose-limiting toxicities are observed in any of the cohorts, 4 additional subjects, 3 active and 1 placebo, may be added to each cohort.

Arms: arm 1: Dose of Scopolamine 0.005mg/kg verses Placebo arm 2: Dose of Scopolamine 0.007mg/kg verses Placebo arm 3: Dose of Scopolamine 0.011mg/kg verses Placebo arm 4: Dose of Scopolamine 0.014mg/kg verses Placebo arm 5: Dose of Scopolamine 0.021mg/kg verses Placebo arm 6: Placebo controlled
Interventions: intervention 1: Scopolamine Hydrobromide Trihydrate
Intervention descriptions: intervention 1: Scopolamine Hydrobromide Trihydrate Intramuscular Injection

Protocol documents:
ICF_002.pdf: 
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Informed Consent Document 
 
PROTOCOL NUMBER AND TITLE OF STUDY:  S-16-14; 
“A 
Phase 
1, 
Double-Blind, 
Randomized, 
Placebo-Controlled, 
Dose-
Escalation Study to Evaluate the Safety, 
Tolerability, 
and 
Pharmacokinetics 
of 
Intramuscular Administration of Scopolamine 
Hydrobromide Trihydrate, Injection” 
 
SPONSOR:  
The Surgeon General, Department of the Army 
(TSG-DA) 
 
NAME OF PERSON IN CHARGE OF THE  
RESEARCH STUDY (STUDY DOCTOR/ 
INVESTIGATOR):  
 
 
 
 
 
 
 
 
Paolo DePetrillo, M.D. 
 
DAYTIME TELEPHONE:  
 
 
 
 
 
 
410-706-8801 
AFTER WORK HOURS:   
 
 
 
 
 
 
301-961-5667 
 
CONTACT INFORMATION:  
 
The contact information is a resource if you have questions about the study, your participation in the 
study, the investigational drug used in the study, any side effect, possible payment for participation in the 
study, your rights as a study participant, and your safety. You may also withdraw your Health Insurance 
Portability and Accountability Act (HIPAA) Authorization  by contacting the study doctor, who is known 
as the Principal Investigator (PI). 
 
The PI should be contacted for questions about an injury related to the research study, side effects, the 
study drug, payment due to injury, or to revoke in writing the HIPAA Authorization. 
 
The study will be conducted at Pharmaron by Dr. Paolo DePetrillo. The sponsor of the study is The 
Surgeon General, Department of the Army (TSG-DA).  
 
The Joint Program Executive Office for Chemical, Biological, Radiological, and Nuclear Defense is 
funding this research. Pharmaron is being paid to conduct this study. 
 
You must be honest with the investigator about your health history or you may harm yourself by 
participating in this study. 
 
You are being asked to participate in this research study because you are a healthy adult male or female 
living in the greater Baltimore area. 
 
The following table summarizes some key points about the study. After reading this summary, if you 
think you might be interested in participating, please read the rest of the consent form for more details 
about the study. 
 
 
 
 


Protocol number S-16-14 
 
Paolo DePetrillo, M.D. 
Informed Consent 
 
 
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Research Study Summary 
Informed Consent 
It is important that you understand what will be done in this research study, 
as well as the possible risks to you, so you can make an informed decision 
about participation. This process is called informed consent. 
 
Please ask questions about anything you do not understand. 
 
The study staff will explain anything you do not understand, 
including the study procedures and risks. 
 
Take as much time as you need to review this document. 
 
Feel free to talk with your family, friends, or others before you make 
a decision. 
 
After your questions have been answered, you will be asked if you 
want to participate. If you agree, you will sign this consent form. 
 
After signing, you will be given a test to ensure you understand the 
study and procedures. You will have three tries to pass the test. In 
between tries, the study staff will discuss any incorrect answers with 
you. 
 
You will be given a copy of this form to keep for reference. 
 
The study staff will talk with you about the information in this 
consent form at any time during the study. 
Voluntary 
Participation 
You do not have to take part in this research. It is your choice. 
 
You can choose to withdraw (stop participating) at any time during 
the study. 
 
Your refusal to participate or withdrawal will involve no penalty or 
loss of any benefits to which you are otherwise entitled. 
Purpose 
 
The main purpose of this study is to evaluate the safety and 
tolerability of an investigational drug. 
 
Another purpose is to evaluate how much of the drug remains in 
your system over time. 
Study Duration 
You will be in this study for about 2 months, including the screening period. 
Main 
Study 
Procedures 
While you are in the study, the main procedures are: 
 
One screening visit, one inpatient stay of 4 days and 3 nights 
followed by 2 follow-up telephone calls, and 1 outpatient visit. 
 
One injection (shot) of active study drug or placebo (inactive or 
“dummy” drug) into one of your thighs. 
 
Safety testing to monitor your physical and mental health throughout 
the study. 
 
Blood and urine collection for standard lab tests to check your health 
and measure how much study drug stays in your system. 
 
See “What Is Involved in Being in This Study” for a complete 
description of procedures and tests by study day. 


Protocol number S-16-14 
 
Paolo DePetrillo, M.D. 
Informed Consent 
 
 
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Research Study Summary 
Investigational Drug 
The investigational drug in this study is Scopolamine Hydrobromide 
Trihydrate, Injection (Scopolamine HBT, Injection). Scopolamine is  
approved by the US Food and Drug Administration (FDA) for use as a skin 
patch where the drug is absorbed through the skin to treat nausea and 
vomiting.  However, Scopolamine HBT has not been approved by the FDA 
to be given as an intramuscular injection, or to treat conditions other than 
nausea and vomiting. Therefore, the Scopolamine HBT you will receive 
during this study is considered an investigational drug. 
Main Study Risks 
The main risks from being in this study are: 
 
Local reactions at the site of injection: pain, itching, rashes, tingling 
or numbness, tenderness, redness, swelling, bruising, muscle 
stiffness, or feeling of burning, warmth or coldness. 
 
Systemic reactions due to the study drug include: 
o Dry mouth, thirst, difficulty swallowing, decreased sweating, 
and/or dry skin 
o Dilation of the pupils and blurred vision 
o Cognitive and memory disturbances (including disorientation or 
mental confusion), euphoria, and amnesia 
o Dizziness, headaches, restlessness, tremors, fatigue, and gait 
disturbances (such as stumbling) 
o See “Non Local Reactions” for a complete description 
Benefits 
There is no direct benefit to you for participating in this study. 
Compensation 
You may receive compensation for participating in this study. 
ClinicalTrials.gov 
A 
description 
of 
this 
clinical 
study 
will 
be 
available 
on 
http://www.ClinicalTrials.gov, as required by US 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. 
 
Why Is This Investigational Drug Being Offered? 
 
As part of the continued search for better treatment options, the US Army Medical Research and 
Development Command (USAMRDC) is developing this drug as an additional therapy for the treatment 
of chemical warfare nerve agent exposure. Nerve agents are organic chemicals that attack the nervous 
system of the human body by disrupting the way your nerves send messages to your organs. You will not 
be exposed to any nerve agents during your participation in this research study. 
 
What Is the Purpose of the Study? 
 
The main purpose of this study is to evaluate the safety and tolerability of this investigational drug. 
Another purpose is to evaluate how much of the drug remains in your system over time (this is called 
pharmacokinetics). 
 
 In this study, "Investigational" means the study drug formulation being tested is not approved by the 
FDA for intramuscular injection, or to treat chemical warfare nerve agent exposure. 
 
 


Protocol number S-16-14 
 
Paolo DePetrillo, M.D. 
Informed Consent 
 
 
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In this document, you may see the terms “medication,” “treatment,” and “treatment period;” these are 
terms used in research studies as mentioned above and does not mean that you will be receiving medical 
treatment for any condition.  These terms apply to the study drug and parts of the study where you will 
receive the investigational product. 
   
What Is the Design of the Study? 
 
This is a dose-escalation study and involves a total of 5 dose levels (or groups). Dose escalation means 
that the first group of participants will be randomly (by chance) assigned to receive the lowest dose of the 
active study drug or placebo (inactive or dummy drug), and the second group will be randomly assigned 
to receive the next higher dose of the active study drug or placebo. After all participants in the first group 
are dosed, the findings for the entire group will be evaluated. If no concerning side effects are seen, the 
second group of participants will be enrolled. This procedure will be repeated until all 5 groups have been 
enrolled. 
 
A minimum of 40 and a maximum of 60 participants will be enrolled in this study. Overall, up to 240 
subjects may be screened for this study. In each group, 6 participants will receive the active study drug 
and 2 will receive the inactive placebo. If certain side effects are seen in any of the groups, 4 additional 
subjects (3 active and 1 placebo) may be added to each group. Each group will have at least 3 female and 
3 male subjects enrolled. 
 
You have a 3 to 1 chance of receiving the active study drug. You will not have a choice as to which dose 
level (group) you are assigned nor will you have a choice as to the assignment of active drug or placebo. 
Neither you nor the study staff will know if you are assigned to receive the active study drug or the 
placebo. This information can be obtained if it becomes medically necessary. 
 
One screening visit is required within 30 days of the start of the study. The purpose of the screening visit 
is to make sure that you are qualified (eligible) and willing to participate in the study. If the study doctor 
determines that you are eligible and you agree to participate, the study will require one inpatient clinic 
stay of 4 days and 3 nights followed by 2 follow-up telephone calls and 1 outpatient visit. 
 
What Is the Length of Study Participation? 
 
The length of your participation in this study is approximately 2 months, including the screening period. 
 
What Is the Investigational Product? 
 
The investigational drug in this study is scopolamine hydrobromide trihydrate, injection (Scopolamine 
HBT, Injection).   
 
How Will the Drug Be Given? 
 
Scopolamine HBT or placebo will be given as an injection (shot) into the muscle of one of your thighs. 
Each participant will receive one injection. 


Protocol number S-16-14 
 
Paolo DePetrillo, M.D. 
Informed Consent 
 
 
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What Are the Requirements to Be in the Study? 
 
To be eligible for this research study, you must meet the following requirements: 
 
 
Male or female, 18 to 55 years of age 
 
Able to read, speak, and comprehend English and willing to sign this informed consent 
 
A body mass index (BMI) of ≥ 19.0 and ≤ 30.0 
 
A weight range of 55.0 to 85.0 kg 
 
Generally healthy and medically cleared for participation by a study doctor based on a physical exam, 
medical history review, and laboratory, neuropsychiatric and other tests 
 
Negative results on drug and alcohol tests at screening and prior to study drug administration 
 
Non-smoker and a non-tobacco/nicotine product (including e-cigarette) user within 3 months of 
dosing and throughout the study period 
 
If female, nonpregnant and nonbreastfeeding with a negative blood pregnancy test at screening and 
prior to dosing. Females should also not plan to become pregnant for the duration of the study. 
 
If female of childbearing potential, must have been using adequate contraception for at least 3 months 
prior to drug administration and agree to use an adequate method of contraception for at least 30 days 
following drug administration 
 
If female of nonchildbearing potential, must be postmenopausal (no menstrual period for 24 months) 
or surgically sterile (bilateral tubal ligation [both tubes cut], bilateral removal of ovaries, or total 
hysterectomy [uterus removed]) 
 
If male with a female partner of childbearing potential, must agree to use a barrier method of 
contraception (defined as condoms with spermicide) for at least 30 days following drug 
administration 
 
Must not have received any other investigational drug within 30 days prior to drug administration 
 
Must not have donated > 480 mL of blood within 8 weeks of drug administration 
 
To be eligible for this study, you must agree to the following restrictions: 
 
 
May not consume Seville orange (bitter orange), grapefruit, grapefruit juice, other grapefruit-
containing products, or starfruit within 7 days prior to dosing and through Day 3 
 
May not consume alcohol within 72 hours prior to dosing and through Day 3 
 
May not consume caffeine or other xanthine-containing products (such as chocolate) within 7 days 
prior to dosing and through Day 3 
 
May not do strenuous physical activity of any kind (such as lifting weights, working out, or dancing) 
from 48 hours prior to admission on Day -1 and until after the Day 8 visit 
 
May not take antimuscarinic drugs, such as phenothiazines, tricyclic antidepressants, antihistamines 
(including meclizine), meperidine, or other anticholinergics that have weak antimuscarinic activity or 
that cause drowsiness, including antidepressants, benzodiazepines, alcohol, sedatives (used to treat 
insomnia), pain relievers, anxiety medicines, and muscle relaxants within 72 hours prior to dosing 
 
May not take any prescription or nonprescription medication (including home remedies, herbal 
supplements, or nutritional supplements) within 14 days of planned dosing. Note: hormonal birth 
control methods are allowed  
 
May not donate blood or other blood components for 8 weeks after completion of the study 
 


Protocol number S-16-14 
 
Paolo DePetrillo, M.D. 
Informed Consent 
 
 
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What Is the Potential Benefit of the Study, and Is There an Alternative to Participating? 
 
There is no direct benefit to you for participating in this study. The alternative to participating is to choose 
not to participate. 
 
What Are the Potential Risks and Discomforts of the Study Drug? 
 
If you do not understand what any of these side effects mean, please ask the investigator or study 
staff to explain these terms to you.  
 
Because this drug is investigational, all of its side effects may not be known.  There may be rare and 
unknown side effects. Some of these may be life threatening. 
 
You must tell the investigator or study staff about all side effects that you have. If you are not honest about 
your side effects, you may harm yourself by staying in this study. 
 
Until you know how the drug(s) will affect you, you should use caution by avoiding stairs, not 
driving a car or working with machinery. 
 
Local Injection site Reactions:  
 
Potential risks associated with the injection of Scopolamine HBT or placebo with a syringe may include 
the following local effects at the site of injection: pain (which may be severe), itching, rashes, tingling or 
numbness, tenderness, redness, swelling, bruising, muscle stiffness, or a feeling of burning, warmth, or 
coldness. 
 
Non local Reactions:  
 
Typically, dry mouth is the first notable reaction followed by dry skin. Thirst and difficulty in swallowing 
may occur when the mouth and esophagus become sufficiently dry. Decreased sweating occurs, which 
also may cause flushing and limit your body’s ability to tolerate heat; this can lead to heat exhaustion or 
heat stroke in a hot environment. Dilation of the pupils of the eyes is expected; sensitivity to light and 
blurring of vision are effects of this dilation. At the same time your pupils dilate, the muscles that allow 
your vision to accommodate may be impaired, which also leads to blurred vision. In susceptible persons, 
especially the elderly, the impaired function of the eye muscles may contribute to an elevation of eye 
pressures. Difficulty in urination and urinary retention may occur. Tachycardia (ie, rapid heart rate) is a 
common side effect. Bradycardia (ie, low heart rate) at lower doses, hypotension (low blood pressure), 
and arrhythmias (irregular heart rhythms) may also occur. Scopolamine HBT reduces salivary secretion, 
gastric secretion (both the volume and acid content), and also inhibits the motor activity of the stomach 
and intestines, which may lead to constipation that may be severe. Nausea and vomiting may also occur. 
 
Scopolamine HBT also often causes cognitive and memory disturbances (including disorientation or 
mental confusion), euphoria (a feeling or state of intense excitement and happiness), amnesia (a partial or 
total loss of memory), and dreamless sleep with a reduction in rapid-eye-movement sleep. Scopolamine 
HBT may cause drowsiness, fatigue, dizziness, headaches, tremors, and gait disturbances (such as 
stumbling). Less commonly, Scopolamine HBT may cause excitement, restlessness, insomnia (inability to 
sleep), delirium (altered mental status), hallucinations, and/or paranoia (suspicion and mistrust of people), 
especially in the presence of severe pain. 


Protocol number S-16-14 
 
Paolo DePetrillo, M.D. 
Informed Consent 
 
 
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Rarely, Scopolamine HBT may cause neuroleptic malignant syndrome (includes seizures and fever) and 
the risk of seizures. Emergency equipment and rescue medications will be available at the bedside in case 
of seizures or other side effects. 
 
A specific rescue medication to treat Scopolamine HBT effects will be available. This medication is 
called physostigmine, a drug that has been used to reverse the side effects of Scopolamine HBT, such as 
memory disturbances, paranoia, and hallucinations. After receiving your injection of Scopolamine HBT 
or placebo, you will be monitored carefully by a study doctor. Depending on your symptoms, the study 
doctor will determine whether you need to receive a dose of physostigmine to relieve the side effects. If 
used, medical staff will administer one dose of physostigmine intravenously (IV). Three more doses may 
be given every 5 minutes (for a total of 4 doses), if needed to relieve the symptoms.  
 
Additional rescue medications, atropine and a benzodiazepine (diazepam or lorazepam), will be available 
at the bedside. 
 
Allergic Reaction:  
 
As with any study drug administration and no matter what precautions are taken, there is always the risk 
of a more serious, or even life-threatening, allergic reaction. Emergency equipment is available in the 
clinic to handle emergencies per standard medical practice. For these reactions, initial emergency medical 
treatment will begin in the clinic, and if indicated, 911 will be called for further treatment and possible 
transport to a local hospital emergency room. 
 
What Are the Potential Risks and Discomforts of the Study Procedures? 
 
Needle Stick:  
 
Blood sampling carries a minimal risk of minor discomfort, the possibility of minor bruising at the needle 
puncture site, and the possibility of lightheadedness or fainting. Rarely, there is also the possibility of 
infection at the needle puncture site or inflammation of the vein. 
 
ECG:  
 
The adhesive on the ECG patches may cause a skin reaction such as redness or itching. You may also 
experience localized skin discomforts and/or hair loss associated with the placement and removal of ECG 
leads. 
 
Blood Oxygen Level:  
 
A finger clip sensor will be used to measure the amount of oxygen in your blood. The clip will fit snugly 
on your index finger and should cause minimal, if any, discomfort. While causing minimal discomfort, 
you should be aware that your oxygen levels will be monitored for 24 hours after you receive the study 
drug. 


Protocol number S-16-14 
 
Paolo DePetrillo, M.D. 
Informed Consent 
 
 
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Are There Unknown Risks to Participating in This Study? 
 
Unknown/Unforeseeable Risks:  
 
As with all research, there is the remote possibility of risks that are unknown or that cannot be foreseen 
based on current information. 
 
You will be informed in a timely manner both verbally and in writing of any new information, findings, 
or changes to the way the research will be performed that might influence your willingness to continue 
your participation in this study. 
 
Risks to the Unborn:  
 
The effects of the study drug on an unborn child are unknown and may be hazardous. You should not 
receive this investigational drug if you are pregnant, or think you may be pregnant, and you should not 
become pregnant for at least 30 days after drug administration. 
 
If you think that you have become pregnant during the study it is important that you inform the study 
doctor immediately. If you become pregnant or think that you may be pregnant, you will be removed 
from the study and the study doctor will refer you to seek obstetric care, the cost of which will be your 
responsibility. The study staff will follow your pregnancy to term for safety reasons via periodic 
telephone contact. The updates you provide to study staff on your pregnancy and pregnancy outcome 
(delivery or other outcome) will be reported to the sponsor and the Institutional Review Board (IRB). 
There is a possibility that it may be necessary to access your medical records in order to obtain more 
information about your pregnancy and/or pregnancy outcome. 
 
The birth control requirements for males and females who participate in this study are described below. 
 
Birth Control Requirements: 
 
Females:  
 
You may not participate in this study if you are pregnant or breastfeeding. As part of giving your consent 
you must agree to have a serum (blood) pregnancy test at screening, prior to dosing, and at the end of the 
study, regardless of your childbearing potential. You must also agree to use an acceptable means of birth 
control during this study unless you are post-menopausal for at least 2 years or are surgically sterile (have 
had a bilateral oophorectomy [both ovaries removed], bilateral tubal ligation [both tubes cut], or total 
hysterectomy [uterus removed]). 
 
Acceptable means of birth control for females include the regular use of hormonal contraceptives (ie, oral, 
implant, injection, patch, or vaginal ring), barrier methods with spermicide (ie, condom, diaphragm, 
cervical cap with spermicidal gel, cream, or foam), or an intrauterine device (IUD). If you are using an 
acceptable means of birth control, you must have been using the same method for at least 3 months prior 
to receiving the study drug, and you must continue this method for at least 30 days after study drug 
administration. 
 
Please note that birth control methods such as the use of condoms, a diaphragm or cervical cap, birth 
control pills, IUDs, or sperm-killing products are not completely effective in preventing pregnancy. 


Protocol number S-16-14 
 
Paolo DePetrillo, M.D. 
Informed Consent 
 
 
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Males:  
 
As part of giving your consent, you must agree to use a barrier form of birth control (ie, condoms with 
spermicide) from the time of screening to 30 days after study drug administration. 
 
A pregnancy test isn’t always right, especially in the early stages of pregnancy. If you or your partner are 
pregnant, become pregnant, or breastfeed during the study, the study drug may have unforeseen effects on 
the unborn or breastfed baby. 
 
What Is Involved in Being in This Study? 
 
Screening Visit and Tests:  
 
After all of your questions have been answered, and if you are interested in participating and sign the 
informed consent form, the following screening tests and activities will be done: 
 
 
Complete medical and surgical history, including past and current medications and treatments, and 
past and current illnesses (including psychiatric history) 
 
Complete physical exam including weight, height, body mass index (BMI) calculation, and vital signs 
(blood pressure, heart rate, respiration rate, body temperature, and blood oxygen level) 
 
Electrocardiogram (ECG): measures the electrical activity of your heart and monitors your heart 
rhythm) 
 
Brief Psychiatric Rating Scale: you will be asked a set of questions about how you are feeling. This 
will only take a few minutes and study staff and will note your answers.  
 
Suicidality Rating Scale: you will be asked questions to determine if you have ever had any wishes to 
harm yourself, or if you have made any attempts to harm yourself in the past. The interview will take 
only a few minutes and study staff will note your responses. 
 
Structured Clinical Interview (done at Day -1 admission): clinical staff will ask you questions relating 
to your mental health.  The interview may take up to approximately one hour.   
 
Digit Symbol Substitution Test  is a short ‘paper and pencil test’ administered by study staff to help 
determine if the study drug has caused any changes to your cognitive or memory functions.  The test 
takes around 3 minutes. 
 
Blood samples (fasting [no food] ≥ 8 hours) for standard lab tests to check your health, (includes 
hepatitis B and C, HIV, and syphilis testing), and pregnancy testing for all females regardless of 
childbearing potential 
 
Urine sample for urinalysis and drugs of abuse screening 
 
Alcohol breath test 
 
Review of inclusion/exclusion criteria 
 
Discussion of study restrictions 
 
You will be told at the end of the screening visit if any of the completed tests will exclude you from the 
study. If you are not excluded during the screening visit, you will be contacted by telephone a few days 
later and told whether you qualify for the study (after all test results have been reviewed). If you do not 
qualify at any time, you will be told the reason(s) for your exclusion. 


Protocol number S-16-14 
 
Paolo DePetrillo, M.D. 
Informed Consent 
 
 
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If you are found to be positive for hepatitis B or C, HIV, or syphilis you will be asked to return to the 
study site to discuss the results with a study doctor. You will be given counseling and referrals to the 
appropriate healthcare providers. Please be aware that any positive results from these tests will be 
reported to the local health department, as required by state law. 
 
Inpatient Stay and Dosing:  
 
If you are eligible after all screening test results have been reviewed, you will be asked to return to the 
study site for an inpatient stay of 4 days and 3 nights. You will be considered an alternate for this study 
until such time as you receive the study drug. 
 
Day -1:  
 
You will check into the study site on the day before dosing (Day -1) to begin your inpatient stay. Blood 
and urine samples will be collected for laboratory tests, screening for drugs of abuse, and pregnancy 
testing for all females. Breath alcohol testing, three ECGs, vital signs, and a physical exam including 
weight with BMI calculation will be done. The Brief Psychiatric Rating Scale, Suicidality Rating Scale, 
the Digit Symbol Substitution Test, and the Structured Clinical Interview will be administered, and you 
will be asked if you have taken any medications since the screening visit. Your medical history will be 
reviewed and your eligibility will be assessed again. 
 
If you are still eligible, starting on the evening of Day -1, you will be asked to fast overnight (no food for 
at least 8 hours prior to dosing), but water and clear liquids will be allowed. 
 
Eligible subjects who are not dosed on Day 1 may be asked to return for dosing on another day. If this 
happens, your Day-1 tests will be repeated (except for the Structured Clinical Interview). 
 
Day 1:  
 
You will continue to fast for 1 hour after dosing (total fast of at least 9 hours). Liquids will be allowed 
until 1 hour before dosing and again at 1 hour after dosing. Prior to dosing, you will be placed on 
continuous cardiovascular (heart and vital signs) monitoring for approximately 24 hours, a blood sample 
will be collected, and three ECGs and vital sign measurements will be done. You will begin to collect all 
of your urine for the next 24 hours in containers provided by the study staff. You will then receive your 
dose of study drug as an injection in your thigh, and you will be asked to rate any injection site symptoms 
(pain, itching, tingling, or numbness) using a scale of 0 to 10. 
 
Following dosing, you will have pharmacokinetic blood samples taken 11 times over the next 12 hours to 
see how much study drug is in your blood stream. Periodically during the next 24 hours, your vital signs 
will be measured, and ECGs and physical exams will be performed. You will be asked how you are 
feeling, if you are experiencing any injection site symptoms, and if you have taken any medications. The 
Brief Psychiatric Rating Scale will be administered and you will be monitored for any potential side 
effects. The study staff will also monitor your injection site. 
 
Note: You will not be able to shower during the 24-26 hours you are on continuous cardiovascular 
monitoring (starting 1-2 hours prior to dosing on Day 1 and until after the morning activities on Day 2). 


Protocol number S-16-14 
 
Paolo DePetrillo, M.D. 
Informed Consent 
 
 
Page 11 of 17 
APPROVED BY 
INTEGREVIEW IRB 
SEPTEMBER 4, 2020 
 
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Note: To ensure that you stay hydrated, you will be asked to drink at least 1000 mL (1 liter) of water 
within 24 hours prior to administration of study drug and 1000 mL (1 liter) during the 24 hours following 
the administration of study drug. 
 
Days 2 and 3:  
 
The continuous cardiovascular monitoring will end on the morning of Day 2. On Days 2 and 3, blood and 
urine samples will be collected, and ECGs and vital sign measurements will be done. You will be asked 
how you are feeling, if you are experiencing any injection site symptoms, and if you have taken any 
medications. On Day 3, you will also have a physician exam and the Brief Psychiatric Rating Scale and 
the Digit Symbol Substitution Test will be administered again. You will be discharged from the clinic 
after you have completed all of the study procedures on Day 3. Before you leave, study staff will schedule 
your follow-up telephone calls and outpatient visit, and remind you about the birth control requirements 
and all applicable study restrictions. 
 
The study doctor may determine that you require longer observation in the clinic or additional laboratory 
testing based on the effects of the drug or the results of the laboratory tests as necessary. 
 
Day 4:  
 
You will be contacted for a follow-up telephone call. Study staff will ask how you are feeling, if you are 
experiencing any injection site symptoms, and if you have taken any medications since your last visit. 
You will be reminded about the Day 8 follow-up visit, birth control requirements, and all applicable study 
restrictions. 
 
Day 8:  
 
You will return to the research center for an outpatient visit. You will have a physical exam and an ECG, 
and vital signs including blood oxygen level will be measured. Blood and urine samples will be collected 
for clinical laboratory tests, and your urine will be tested for drugs of abuse. A pregnancy test will be 
performed for all women, regardless of childbearing potential. You will be asked how you are feeling, if 
you are experiencing any injection site symptoms, and if you have taken any medications since the Day 4 
telephone call. The Brief Psychiatric Rating Scale, Suicidality Rating Scale, and Digit Symbol 
Substitution Test will be administered. You will be reminded about the Day 30 follow-up telephone call, 
birth control requirements, and all applicable study restrictions. 
 
Day 30:  
 
You will be contacted for a follow-up telephone call. Study staff will ask how you are feeling, if you are 
experiencing any injection site symptoms, and if you have taken any medications since your last visit. 
You will be reminded to refrain from donating blood or other blood components for 8 weeks after study 
completion. 
 
Withdrawal Procedures:  
 
If you withdraw early from the study, for any reason, you will be asked to complete the lab testing and 
discharge procedures described previously in the Day 8 study procedures. 
 


Protocol number S-16-14 
 
Paolo DePetrillo, M.D. 
Informed Consent 
 
 
Page 12 of 17 
APPROVED BY 
INTEGREVIEW IRB 
SEPTEMBER 4, 2020 
 
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Meals:  
 
Standardized meals and snacks will be served at regular times during your clinic stay except when fasting 
is required or otherwise noted. Please tell study staff if you have any dietary requirements or if you do not 
eat certain foods. 
 
Blood Sampling:  
 
The total amount of blood to be collected in this study is approximately 250 milliliters (a little more than 
1 cup). This amount includes tests to check your health and pharmacokinetic testing to see how much of 
the drug is in your blood stream. For comparison, a standard blood donation is about 2 cups of blood. 
Additional blood may be drawn during the study if the study doctor considers it necessary for monitoring 
your health. It is possible that more than one attempt to obtain a blood sample may be necessary. 
 
During your inpatient stay, an intravenous catheter (a small flexible tube) may be inserted into a vein (by 
a needle) in your arm to collect blood samples without sticking you multiple times. The catheter will be 
checked, maintained, and may be changed if necessary. 
 
What Happens if I Am Injured as a Result of Taking Part in This Treatment Protocol? 
 
You may choose to seek care under your own health insurance, and it is also possible that you may have 
workers’ compensation/disability coverage that applies to your injury. No reimbursement will be offered 
if you incur medical expenses to treat research-related injuries. No compensation will be offered for 
research-related injuries. If you believe you have sustained a research-related injury, please contact the PI.  
 
Please be aware that some insurance plans may not pay for research-related injuries.  You should contact 
your insurance company for more information. 
 
You should understand that this does not constitute a waiver or release of legal rights. 
 
What Happens if I Want to Leave the Study? 
 
Your participation in this study is completely voluntary. You may choose not to take part at all, or you 
may choose to stop your participation at any time after you have begun the study. If you stop participating 
in this study, you will not be penalized or lose any benefits to which you are otherwise entitled. If you 
decide to leave this study early, we ask that you notify the PI or a designee as soon as possible. You may 
be asked to schedule a clinic visit. 
 
The investigator, the sponsor company, IntegReview, or the FDA, if applicable, may take you out of the 
study without your permission, at any time, for the following reasons: 
 
 
If you do not follow the investigator’s instructions  
 
If we find out you should not be in the study 
 
If the study is stopped 
 
If it becomes harmful to your health 


Protocol number S-16-14 
 
Paolo DePetrillo, M.D. 
Informed Consent 
 
 
Page 13 of 17 
APPROVED BY 
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SEPTEMBER 4, 2020 
 
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If you leave the study or if you are taken out of the study, you may be asked to return for a final visit to 
have some end of study evaluations or tests.  If information generated from this study is published or 
presented, your identity will not be revealed.  If you leave the study, no more information about you will 
be collected for this study.  However, all of the information you gave us before you left the study will still 
be used. 
 
What Are the Safeguards for My Protection? 
 
All study procedures will be performed by qualified, trained study personnel. 
 
Volunteer Registry Data Sheet:  
 
USAMRDC requires that data sheets (Volunteer Registry Data Sheet, Form 60-R) be completed for entry 
into the Command’s Volunteer Registry Database for all individuals participating in research studies. This 
information includes the volunteer’s name, address, social security number, study identity, and dates of 
participation. The intent of this database is twofold: first, to readily answer questions about an 
individual’s participation in research sponsored by USAMRDC and second, to ensure that USAMRDC 
can exercise its obligation to ensure that all research study participants are adequately warned (duty to 
warn) of risks and to provide new information as it becomes available. This information will be stored at 
USAMRDC for a minimum of 75 years and is kept confidential. The Volunteer Registry Data Base is 
separate from and not linked to the study database. 
 
Will I Be Compensated for My Participation in the Study? 
 
You will be paid up to $2500.00 for your participation in this study. You will be paid for the visits that 
you complete based on the following: 
 
Study Timeline and Payment Breakdown 
Screening Visit 
$50.00 
Inpatient Stay (4 days/3 nights in the clinic) 
Day -1: Admission 
$300.00 
Day 1: Dosing 
$350.00 
Day 2: In-Clinic Day 
$300.00 
Day 3: Discharge 
$300.00 
Day 4: Follow-up Telephone Call 
$150.00 
Day 8: Outpatient Visit 
$300.00 
Day 30: Follow-up Telephone Call 
$150.00 
Study Completion 
$600.00 
TOTAL 
$2500.00 
 
You will not be paid for the screening visit if you test positive for drugs or alcohol. You will be 
withdrawn from the study if you test positive for drugs and/or alcohol at any other time during the study 
and paid only for your completed portion of the study. 
 
You will receive $50.00 for each unscheduled visit requested by a study physician (such as when lab tests 
need to be repeated). You will receive payment within 7 days of the completion of your participation in 
the study. If you are designated as an alternate (admitted on Day -1 but not dosed on Day 1), you will be 
paid $200.00. Alternates who remain eligible may be asked to return to the clinic on the next admission 
date. 


Protocol number S-16-14 
 
Paolo DePetrillo, M.D. 
Informed Consent 
 
 
Page 14 of 17 
APPROVED BY 
INTEGREVIEW IRB 
SEPTEMBER 4, 2020 
 
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In agreeing to participate in this study, you will be acting as an independent contractor, not as an 
employee of Pharmaron. Because payments made to you for participating in this study will be reported to 
the Internal Revenue Service as income as required by law, you are required to provide your social 
security number. No deductions for any state or federal withholding or any other similar taxes will be 
made. It is the responsibility of the participant to report this compensation (payment) on state and federal 
tax returns and for the payment of any taxes that are due on this compensation. 
 
What about My Confidentiality? 
 
Confidentiality:  
 
All data and medical information obtained about you as an individual will be considered privileged and 
held in confidence. We may need to request your medical or hospital records to monitor your safety. You 
will not be identified by name in any published report or in any presentation of the results. Information 
bearing on your health may be required to be reported to appropriate medical or military authorities. 
Representatives from other regulatory agencies, such as the FDA, USAMRDC and its subordinate 
commands, IntegReview IRB and study personnel are eligible to review research records as part of their 
responsibility to protect human participants in research and to carry out their obligations relating to the 
study. Representatives from the USAMRDC may review your research record. By signing this consent 
document, you agree to such inspection and disclosure. 
 
The Institutional Review Board (IRB), IntegReview, and accrediting agencies may inspect and copy your 
records, which may have your name on them.  Therefore, total confidentiality cannot be guaranteed.  If 
the study results are presented at meetings or printed in publications, your name will not be used. 
 
HIPAA Authorization:  
 
The Federal Health Insurance Portability and Accountability Act (HIPAA) requires that researchers 
obtain the participant’s permission (called an Authorization) to use and disclose protected health 
information (PHI) about the participant that is either created by or used in connection with this research. 
This Authorization has no expiration date. By signing this consent form, you are agreeing to the use 
and disclosure of your PHI by the PI and the research staff, including results of physical exams, blood 
tests, and other diagnostic and medical procedures as well as vaccination and medical history. Your PHI 
may also be viewed and used by other regulatory and medical representatives, including but not limited to 
representatives from FDA and USAMRDC and the study Medical Monitor and Research Monitor. 
 
Subject records will be maintained in accordance with applicable FDA guidelines and HIPAA 
requirements. Your PHI may also be used by others who do not necessarily work under HIPAA rules. De-
identified subject data will be maintained permanently in electronic format by the sponsor. 
 
If you choose not to authorize these uses and disclosure of your PHI by signing this form, you will not be 
eligible to participate in this study. However, your decision not to sign this consent form will not affect 
any other treatment, payment, or enrollment in health plans or eligibility for benefits. You may also 
change your mind and cancel this Authorization at any time by sending a written notice to the PI. 
Cancellation of this Authorization will not alter disclosure of PHI that has already been collected; 
however, no further PHI about you will be collected by or disclosed to the researcher for this study. 


Protocol number S-16-14 
 
Paolo DePetrillo, M.D. 
Informed Consent 
 
 
Page 15 of 17 
APPROVED BY 
INTEGREVIEW IRB 
SEPTEMBER 4, 2020 
 
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Consent for the Use of Your Samples/Information 
 
There is a chance that your pharmacokinetic blood samples collected during this study may be used in 
other future studies and may have some commercial value. Should your sample(s) lead to the 
development of a commercial drug, the US government will own it and may patent and license the drug. 
You will not receive compensation for any future value that the samples you have given may be found to 
have. You will not be contacted if your samples are used for the purposes defined in this study. However, 
you will be notified if your samples are used for research purposes that are not defined in this study, and 
your identity will not be associated with these samples. 
 
No genetic testing will be performed (now or in the future) on any samples collected during this 
study. 
 
Please indicate your willingness to permit the use of your samples for future research purposes that are 
not defined in this study by initialing beside the appropriate statement below: 
 
_____ Yes, my stored pharmacokinetic blood samples MAY be used for future research purposes that 
are not defined in this study. 
 
_____ No, my stored pharmacokinetic blood samples MAY NOT be used for future research purposes 
and may only be used for the research purposes defined in this study (protocol # S-16-14). 
 
Even if you initial “Yes” above, you may withdraw your consent at any time for the use of your 
blood samples in future research. To withdraw your consent, please contact a study team member. 
 
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 PI: 
 
Paolo DePetrillo, M.D.  
410-706-8801 daytime telephone number 
 301-961-5667 after hours number 
 
If you are unable to reach anyone at the number(s) listed above and you require immediate (life 
threatening) medical attention, please go to the nearest emergency room. 
 
If you seek emergency care or hospitalization is required, inform the treating physician that you 
are participating in this research study. 


Protocol number S-16-14 
 
Paolo DePetrillo, M.D. 
Informed Consent 
 
 
Page 16 of 17 
APPROVED BY 
INTEGREVIEW IRB 
SEPTEMBER 4, 2020 
 
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If you do not want to talk to the investigator or study staff if you have concerns or complaints about the 
research or want to ask questions about your rights as a study subject you may contact the IntegReview 
IRB. The IntegReview IRB is a group of people that has reviewed this study. The main goal of this 
review is to protect the rights and well-being of the human subjects participating in the study. 
IntegReview’s policy indicates that all concerns/complaints are to be submitted in writing for review at a 
convened IRB meeting to: 
 
Mailing Address 
E-mail Address 
Chairperson 
IntegReview IRB 
3815 S. Capital of Texas Highway 
Suite 320 
Austin, Texas 78704 
integreview@integreview.com 
 
If you are unable to provide your concerns/complaints in writing or if this is an emergency situation, you 
may contact IntegReview at:  
 
512-326-3001 
or toll free at 1-877-562-1589 
between 8 a.m. and 5 p.m. Central Time. 
 
IntegReview has approved the information in this consent form and has given approval for the 
investigator to do the study. This does not mean IntegReview has approved your being in the study.  You 
must consider the information in this consent form for yourself and decide if you want to be in this study. 
 


Protocol number S-16-14 
 
Paolo DePetrillo, M.D. 
Informed Consent 
 
 
Page 17 of 17 
APPROVED BY 
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SEPTEMBER 4, 2020 
 
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Consent for Participation in the Research Study 
 
Your signature on this form indicates that you have read this consent form, that the research study has 
been explained to you and your questions have been answered, and that you agree to take part in this 
study. You will receive a signed and dated copy of this form. 
 
SIGNATURES 
 
 
 
 
 
Printed Full Name of Study Participant 
 
 
 
 
 
 
 
Signature of Study Participant 
 
Date 
 
 
 
 
 
 
 
Printed Name of Person Conducting Informed Consent Discussion 
 
 
 
 
 
 
 
Signature of Person Conducting Informed Consent Discussion 
 
Date 
 

Prot_000.pdf: 
Scopolamine Hydrobromide Trihydrate Phase 1 
The Surgeon General 
IND 130620; Protocol S-16-14 
Department of the Army 
Version 4.0 (01Mar2021) 
1 
US Government Proprietary 
1. 
Title Page 
A PHASE 1, DOUBLE-BLIND, RANDOMIZED, 
PLACEBO-CONTROLLED, DOSE-ESCALATION 
STUDY TO EVALUATE THE SAFETY, TOLERABILITY, 
AND PHARMACOKINETICS OF INTRAMUSCULAR 
ADMINISTRATION OF SCOPOLAMINE 
HYDROBROMIDE TRIHYDRATE, INJECTION 
Sponsor 
The Surgeon General, Department of the Army 
Sponsor’s Representative 
 
 
 
 
 
 
 
 
Medical Monitor 
 
 
 
 
 
 
 
Research Monitor 
 
 
 
 
 
 
Principal Investigator 
Paolo DePetrillo, MD 
800 West Baltimore Street, 5th Floor 
Baltimore, MD 21201 
Telephone: 
 
Fax: 410-706-8963 
E-mail: paolo.depetrillo@pharmaron-us.com 


Scopolamine Hydrobromide Trihydrate Phase 1 
The Surgeon General 
IND 130620; Protocol S-16-14 
Department of the Army 
Version 4.0 (01Mar2021) 
2 
US Government Proprietary 
Subinvestigators 
 
 
 
 
 
   
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 


Scopolamine Hydrobromide Trihydrate Phase 1 
The Surgeon General 
IND 130620; Protocol S-16-14 
Department of the Army 
Version 4.0 (01Mar2021) 
3 
US Government Proprietary 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
Clinical Trial Site 
Pharmaron 
800 West Baltimore Street, 5th and 6th Floors 
Baltimore, MD 21201 
Telephone: 410-706-8895 
Fax: 410-706-8963 
Qualified Physician Responsible for 
All Trial-Site-Related Medical 
Decisions 
Paolo DePetrillo, MD 
800 West Baltimore Street, 5th Floor 
Baltimore, MD 21201 
Telephone: 
 
Fax: 410-706-8963 
E-mail: paolo.depetrillo@pharmaron-us.com 
Clinical Laboratories and Other Departments/Institutions Involved in the Trial 
Site Investigational Product 
Accountability 
 
800 West Baltimore Street, 6th Floor 
Baltimore, MD 21201 
Telephone: 
 
Fax: 410-706-8963 
E-mail: 
 


Scopolamine Hydrobromide Trihydrate Phase 1 
The Surgeon General 
IND 130620; Protocol S-16-14 
Department of the Army 
Version 4.0 (01Mar2021) 
4 
US Government Proprietary 
Clinical Laboratories 
Pharmaron 
800 West Baltimore Street, 6th Floor 
Baltimore, MD 21201 
Telephone: 
 
Fax: 410-706-8963 
E-mail: 
 
Quest Diagnostics, Inc. 
1901 Sulphur Spring Road 
Baltimore, MD 21227 
Research Laboratory 
Battelle Memorial Institute 
505 King Avenue 
Columbus, OH 43201-2696 
Telephone: 
 
Fax: 614-458-4361 
E-mail: 
 
Statistician 
 
Battelle Health Analytics 
505 King Ave 
Columbus, OH 43201 
Telephone: 
 
Fax: 614-458-3231 
Email: 
 
Data Management 
 
 
Parexel International 
1 Federal Street 
Billerica, MA 01821 
Telephone: 
 
Email: 
 
Sponsor’s Safety Office 
 
 
 
 
Please Contact the Following for 
Serious Adverse Events and Other 
Study-related Emergencies: 
 
 
 
 
 
 
 
 
 
 


Scopolamine Hydrobromide Trihydrate Phase 1 
The Surgeon General 
IND 130620; Protocol S-16-14 
Department of the Army 
Version 4.0 (01Mar2021) 
5 
US Government Proprietary 
Institutional Review Board 
 
IntegReview IRB 
3815 S. Capital of Texas Highway 
Suite 320 
Austin, TX 78704 
Telephone: 512-326-3001 
Fax: 512-697-0085 
E-mail: integreview@integreview.com 
AND 
 
 
 
 
 
 
 
 
 
 
 
 
Funding Source 
 
 
 
FOR OFFICIAL USE ONLY 
Information and data included in this document contain privileged and/or proprietary information, which is the 
property of the United States Army. No person is authorized to make it public without express written permission of 
the United States Army. These restrictions on disclosure will apply equally to all future information, which is 
indicated as privileged or proprietary. 




Scopolamine Hydrobromide Trihydrate Phase 1 
The Surgeon General 
IND 130620; Protocol S-16-14 
Department of the Army 
Version 4.0 (01Mar2021) 
7 
US Government Proprietary 
EMERGENCY CONTACT INFORMATION 
Table 1: 
Emergency Contact Information 
Role in Study 
Name 
Address and Telephone Number 
Principal Investigator 
Paolo DePetrillo, MD 
800 West Baltimore Street, 5th Floor 
Baltimore, MD 21201 
Office: 
 
Cell: 
 
 
Subinvestigators 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Project Manager 
 
 
 
 
 
Director of Clinical Operations 
 
 
 
 
 


Scopolamine Hydrobromide Trihydrate Phase 1 
The Surgeon General 
IND 130620; Protocol S-16-14 
Department of the Army 
Version 4.0 (01Mar2021) 
8 
US Government Proprietary 
Role in Study 
Name 
Address and Telephone Number 
Research Monitor 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Institutional Review Board 
 
IntegReview IRB 
3815 S. Capital of Texas Highway 
Suite 320 
Austin, TX 78704 
Telephone: 512-326-3001 or 
877-562-1589 (toll-free) 


Scopolamine Hydrobromide Trihydrate Phase 1 
The Surgeon General 
IND 130620; Protocol S-16-14 
Department of the Army 
Version 4.0 (01Mar2021) 
9 
US Government Proprietary 
2. 
SYNOPSIS 
Name of Sponsor: 
The Surgeon General, Department of the Army 
Name of Investigational Product: 
Scopolamine Hydrobromide Trihydrate, Injection 
Name of Active Ingredient: 
Scopolamine Hydrobromide Trihydrate, USP 
Title of Study:  
A Phase 1, Double-Blind, Randomized, Placebo-Controlled, Dose-Escalation Study to Evaluate the 
Safety, Tolerability, and Pharmacokinetics of Intramuscular Administration of Scopolamine 
Hydrobromide Trihydrate, Injection 
Study Center: 
Pharmaron 
Principal Investigator: 
Paolo DePetrillo, MD 
Study Period (years): 1 
Estimated date first subject enrolled: June 2020 
Estimated date last subject completed: June 2021 
Phase of Development: 1 
Objectives: 
The primary objectives of this study are: 
• To characterize the safety and tolerability profile of ascending doses of scopolamine 
hydrobromide trihydrate (Scopolamine HBT) administered by intramuscular (IM) injection 
• To characterize the pharmacokinetics (PK) of ascending doses of Scopolamine HBT 
administered by IM injection 
Methodology: 
This is a double-blinded, randomized, placebo-controlled, in-clinic, Phase 1, single-dose, 
IM, sequential dose-escalation study in healthy adults aged 18-55. Healthy volunteers will 
be assigned to 1 of 5 cohorts of Scopolamine HBT dosage groups: 0.005, 0.007, 0.011, 
0.014, or 0.021 mg/kg, or will receive the placebo administered by IM injection to the 
anterior thigh. In each cohort, 6 to 9 subjects will receive active drug and 2 to 3 subjects 
will receive placebo. Each cohort will have at least 3 male and 3 female subjects enrolled 
among the first 8 subjects in the dosing group to ensure that at least 1 male subject and 1 
female subject in each dosing group receive active drug. If nonextreme dose-limiting 
toxicities are observed in any of the cohorts, 4 additional subjects, 3 active and 1 placebo, 
may be added to each cohort. In addition, to assure study population diversity in an 8-
subject cohort, no more than 5 subjects may be enrolled from any one of these single racial 
and ethnic groups: American Indian or Alaska Native, Asian, Black or African American, 
Native Hawaiian or Other Pacific Islander, White, Hispanic/Latino, or Other. If the cohort is 
expanded to 12 subjects, no more than 8 subjects (2/3 of the subjects) may be enrolled from 
any one of the above racial and ethnic groups. 


Scopolamine Hydrobromide Trihydrate Phase 1 
The Surgeon General 
IND 130620; Protocol S-16-14 
Department of the Army 
Version 4.0 (01Mar2021) 
10 
US Government Proprietary 
On the first day of dosing for each cohort, 2 subjects will be dosed (1 active and 1 placebo). Upon 
review of the adverse event (AE) data for both subjects at 24 hours post dose (± 1 hour), the 
principal investigator (PI) and the medical monitor will determine if it is safe to proceed with dosing 
the remaining 6 of the first 8 subjects. 
New subjects will not be enrolled into the next higher dosage group until at least 8 subjects in the 
previous cohort have completed the Day 8 follow-up visit without the occurrence of dose-limiting 
toxicities, predefined as requiring termination of the study; the Data Safety Monitoring Board has 
reviewed data and made a dose-escalation recommendation to the sponsor; and the sponsor concurs 
with the recommendation. The sponsor must approve dose escalation. Dose escalation cannot occur 
until after sponsor approval of recommendations and notification of the investigator(s), not at the 
time of the recommendation. 
Estimated Number of Subjects Screened: 
240 
Maximum Number of Subjects Enrolled: 
60 (12 per group) 
Criteria for Inclusion/Exclusion: 
Inclusion Criteria: 
1. Male or female, 18 to 55 years of age, inclusive, at the time of drug administration 
2. Without clinically significant abnormities on physical examination at screening or prior to 
drug administration 
3. Generally healthy, as determined by medical history review, physical examination, and 
laboratory testing at screening and prior to drug administration 
4. Must have a body mass index (BMI) of ≥ 19.0 and ≤ 30.0, and weight range of 55.0 to 
85.0 kg at screening or prior to drug administration 
5. Must have adequate venous access and sufficient upper leg muscle tissue for drug 
administration 
6. If female, the subject must be nonpregnant and nonbreastfeeding, and have a negative serum 
pregnancy test at screening and prior to drug administration 
7. If female of childbearing potential, the subject must have been using adequate contraception 
(as defined in Section 5.3.1.5) for at least 3 months prior to drug administration and must 
agree to use an adequate method of contraception for at least 30 days following drug 
administration 
8. Females of nonchildbearing potential are also eligible, defined as a subject who is 
postmenopausal (continuous amenorrhea for 24 months) or surgically sterile (bilateral tubal 
ligation, bilateral oophorectomy, or total hysterectomy) 
9. A male with a female partner of childbearing potential must agree to use a barrier method of 
contraception (defined as condoms with spermicide) for at least 30 days following drug 
administration 
10. If male, must not have past diagnoses of benign prostatic hypertrophy or urinary tract 
obstruction and must not have on screening history/review of systems symptoms suggestive 
of urinary tract obstruction (eg, urinary hesitancy, urgency, frequency, or nocturia) 
11. Nonsmoker/tobacco/nicotine product (including e-cigarettes) user within 3 months of first 
dosing and must have a total lifetime exposure to cigarettes of < 15 pack-years 
12. No evidence of significant neuropsychiatric disorders based on the Brief Psychiatric Rating 
Scale (BPRS) at screening and prior to drug administration, which is defined as having a 
global score of ≤ 25 with no score higher than 2 on any one item, with the exception of a 
score of 1 (ie, Not Present) to disorientation, hallucinatory behavior, and suspiciousness 
(ie, paranoia) 


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13. No evidence of suicidal ideation or behavior at screening and prior to drug administration, 
which is defined as having a global score of 0 on the Columbia-Suicide Severity Rating 
Scale (C-SSRS) 
14. Ability to read, speak, and comprehend English and a willingness to sign informed consent 
 
Exclusion Criteria: 
A subject meeting any of the following criteria will be excluded from the study: 
1. Received any other investigational drug within 30 days prior to drug administration 
2. Known allergies to any component of the study drug, other belladonna alkaloids, or the 
recovery medications (physostigmine, atropine, or benzodiazepines [diazepam or 
lorazepam]) 
3. History of migraine headaches or seizures 
4. History of psychosis or psychotic episodes 
5. Clinically relevant abnormal physical findings (including vital signs) as determined by the 
investigator at screening or prior to drug administration that could interfere with the 
objectives of the study or the safety of the subject 
6. Has ongoing drug abuse/dependence (including alcohol), recent history (over the past 
5 years) of treatment for alcohol or drug abuse, or a current positive alcohol breathalyzer 
test or current positive urine test for drugs of abuse (as defined in Section 11.1.9.5) at 
screening or prior to drug administration 
7. Has consumed Seville orange (bitter orange), grapefruit, grapefruit juice, other grapefruit-
containing products, or starfruit within 7 days prior to dosing 
8. Has consumed caffeine or other xanthine-containing products within 7 days prior to dosing 
9. Has any specified laboratory values (eg, hematology, serum chemistry, and urinalysis) 
outside of the normal range for age and sex and deemed clinically significant by the 
investigator within 30 days before drug administration 
10. Has positive (reactive) test results for hepatitis B surface antigen, hepatitis C, syphilis, HIV-
1, or HIV-2 
11. Has narrow-angle glaucoma or high intraocular pressures in either or both eyes 
12. Has pyloric obstruction or urinary bladder neck obstruction 
13. Has impaired liver or kidney functions 
14. Clinically relevant electrocardiogram (ECG) abnormalities on any 12-lead ECG obtained at 
screening or prior to dosing 
15. ECG with a PR interval ≥ 200 msec at screening or prior to dosing 
16. ECG with QRS duration > 120 msec at screening or prior to dosing 
17. ECG RR interval > 1500 msec at screening or prior to dosing 
18. ECG with a QTc interval > 450 msec for males or 470 msec for females (QT interval 
corrected with Fridericia correction [QTcF]) at screening or prior to dosing 
19. Systolic blood pressure > 140 mm Hg and/or diastolic blood pressure > 90 mm Hg at 
screening or prior to dosing 
20. Systolic blood pressure < 90 mm Hg and/or diastolic blood pressure < 50 mm Hg at 
screening or prior to dosing 
21. Currently taking or has taken other antimuscarinic drugs such as phenothiazines, tricyclic 
antidepressants, antihistamines (including meclizine), meperidine, or other anticholinergics 
that have weak antimuscarinic activity or that cause drowsiness, including antidepressants, 
benzodiazepines, alcohol, sedatives (used to treat insomnia), pain relievers, anxiety 
medicines, and muscle relaxants within 72 hours prior to dosing 
22. Has taken, within 14 days of planned dosing, any prescription or nonprescription medication 
(including home remedies, herbal supplements, or nutritional supplements) unless the 
PI/subinvestigator, in consultation with the medical monitor, provides a statement justifying 


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that the medication taken will not impact the results of this study (with rare exceptions 
taking prescriptions drugs will be grounds for exclusion) 
23. History of major DSM-5 Axis I or II disorder, or evidence of such disorder at Day -1 as 
determined via the Structured Clinical Interview for DSM-5, customized Clinical Trials 
version (SCID-5-CT) 
24. Has any skin condition, scars, or tattoos that would interfere with injection of study drug 
25. Donated > 480 mL of blood within 8 weeks of drug administration 
26. Any other reason, in the opinion of the investigator, the subject should not participate in the 
study 
Investigational Product Dosage, Schedule, and Mode of Administration: 
Single dose, IM either 0.005, 0.007, 0.011, 0.014, or 0.021 mg/kg Scopolamine HBT or placebo 
Duration of Participation: 
Four-day and 3-night, in-clinic stay; telephone follow-up on Day 4; and follow-up visit on Day 8. 
Total duration of subject participation in the study, including the screening period and 30-day post-
dose telephone follow-up, may be up to 9 weeks. 
Criteria for Evaluation: 
Pharmacokinetics: 
Blood samples will be obtained for PK assessments prior to dosing and at 2, 5, 10, 15, 20, and 
30 minutes and 1, 2, 4, 8, 12, 24, 36, and 48 hours post dose. Scopolamine HBT PK assessments 
will include determination of the following parameters: observed maximum concentration (Cmax) 
and time to reach Cmax (Tmax), apparent volume of distribution (Vd_F), half-life or elimination time 
(t½), apparent clearance (Cl_F), AUClast, AUC∞, Cmax/Dose, MRT (mean residence time), and 
AUC∞/Dose. Plasma concentration time profiles for each subject tested will be evaluated using 
semi-log plots and characterized using noncompartmental analysis (WinNonlin). PK and safety 
endpoints will undergo pharmacodynamic analysis and evaluation. 
Safety: 
All subjects participating in the study will be monitored closely throughout the in-clinic phase of the 
study. The PI and/or physician designee will be in the treatment room during dosing and for 4 hours 
post dose. A crash cart will be in the immediate area where subjects are residents. A specific rescue 
medication to treat Scopolamine HBT effects (physostigmine) will be immediately accessible, as 
well as atropine and a benzodiazepine (diazepam or lorazepam). 
Continuous cardiovascular monitoring of ECG (3-lead) and vital signs (systolic and diastolic blood 
pressure (at 5-15 minute intervals), heart rate, respiration rate, and pulse oximetry) will be 
performed from 1 hour prior to and for 24 hours following Scopolamine HBT or placebo 
administration. During the first 24 hours and through 48 hours post dose, vital sign monitoring 
(including body temperature), 12-lead ECG, clinical assessment of neuropsychiatric status (using the 
BPRS, C-SSRS, and Richmond Agitation and Sedation Scale), and injection site reaction 
assessments will be performed and documented at specified times. The Digit Symbol Substitution 
Test will be administered prior to dosing and at 48 hours post dose and Day 8 to detect any 
persistent cognitive effects. Standard serum chemistry, hematology, and urinalysis testing will be 
performed at baseline (Day-1), at 24 and 48 hours post dose, and at Day 8. Subjects will be 
monitored for AEs continuously while in clinic, and AEs will be documented as they are reported. 
Follow-up for AEs will be conducted via telephone on Days 4 and 30, and via an in-clinic visit on 
Day 8 unless otherwise reported by the subject. In the event of a potential AE, additional 


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assessments/testing may be performed if, in the judgment of the investigator or designee, they are 
warranted for the safety of the subject. AEs will be followed until resolution/stabilization. 
 
Statistical Methods: 
Results of safety assessments will be summarized across dosing levels and compared to the placebo 
group. AEs will be listed by treatment group and body system using MedDRA terms. Confidence 
intervals for the probability of dose-limiting toxicities and severe adverse events will be estimated 
based on the number of observed events in each dosing cohort. Scores for injection site assessments, 
and changes in cognitive and neuropsychiatric scales will be compared for each dosage level relative 
to placebo. Plasma concentration curves will be fit using noncompartmental analysis to obtain PK 
parameters for each dosing cohort prior to dosage escalation. PK parameters will be summarized by 
dosage level, and the parameters Cmax and AUC∞ will be tested statistically for dose proportionality. 


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3. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF 
FIGURES 
1. 
TITLE PAGE .............................................................................................................1 
INVESTIGATOR’S AGREEMENT ...............................................................................................6 
EMERGENCY CONTACT INFORMATION ................................................................................7 
2. 
SYNOPSIS .................................................................................................................9 
3. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES ............14 
LIST OF TABLES .........................................................................................................................18 
LIST OF FIGURES .......................................................................................................................18 
4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..........................19 
5. 
INTRODUCTION ....................................................................................................22 
Military Relevance ...................................................................................................24 
Rationale for Study ...................................................................................................24 
5.1. 
Name and Description of the Investigational Product .................................24 
5.2. 
Summary of Nonclinical and Clinical Trials ................................................24 
5.2.1. Nonclinical Proof-of-Concept Studies .............................................24 
5.2.2. Nonclinical Studies to Support Safety .............................................25 
5.2.2.1. 
Bioequivalence of Vital and Phytex Scopolamine 
HBT ................................................................................28 
5.2.3. Clinical Studies ................................................................................28 
5.2.4. HMR 11-013 Clinical Study ............................................................28 
5.3. 
Known and Potential Risks and Benefits to Human Subjects ......................31 
5.3.1. Risks/Discomfort to Subjects and Precautions to Minimize 
Risk ...................................................................................................31 
5.3.1.1. 
Local Reactions ..............................................................31 
5.3.1.2. 
Systemic Reactions ........................................................32 
5.3.1.3. 
Pregnancy .......................................................................32 
5.3.1.4. 
Lactation .........................................................................32 
5.3.1.5. 
Reproductive Health .......................................................32 
5.3.1.6. 
Venipuncture ..................................................................33 
5.3.1.7. 
Allergic Reaction ............................................................33 
5.3.1.8. 
Unknown Risks ..............................................................33 
5.3.2. Alternatives to This IND Product or Study ......................................33 
5.3.3. Intended Benefit for Subjects ...........................................................33 
5.3.4. Risks to the Study Personnel and the Environment .........................34 
5.4. 
Route of Administration, Dosage Regimen, Treatment Period, and 
Justification ..................................................................................................34 
5.5. 
Compliance Statement ..................................................................................34 
5.6. 
Study Population ..........................................................................................34 
5.7. 
Study Site .....................................................................................................35 
6. 
TRIAL OBJECTIVES AND PURPOSE .................................................................35 
6.1. 
Primary Objective ........................................................................................35 


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7. 
TRIAL DESIGN ......................................................................................................36 
7.1. 
Study Endpoints ...........................................................................................36 
7.2. 
Overall Study Design ...................................................................................37 
7.3. 
Measures Taken to Minimize/Avoid Bias ....................................................43 
7.3.1. Randomization .................................................................................43 
7.3.2. Blinding ............................................................................................43 
7.3.3. Unblinding ........................................................................................43 
7.4. 
Investigational Product .................................................................................44 
7.4.1. Investigational Product Packaging and Labeling .............................45 
7.4.2. Investigational Product Storage .......................................................46 
7.4.3. Investigational Product Preparation .................................................46 
7.4.4. Investigational Product Accountability ............................................46 
7.5. 
Duration of Subject Participation .................................................................47 
7.6. 
Dose-adjustment Criteria ..............................................................................47 
7.6.1. Safety Criteria for Dose Adjustment or Stopping Doses .................47 
7.6.1.1. 
Extreme Dose-Limiting Toxicities .................................48 
7.6.1.2. 
Nonextreme Dose-Limiting Toxicities ...........................49 
7.6.1.3. 
Serious Adverse Events ..................................................50 
7.6.2. Pharmacokinetic Criteria for Dose Adjustment or Stopping 
Doses ................................................................................................51 
7.6.3. Study Termination Criteria ...............................................................52 
7.7. 
Trial Treatment Randomization Assignments ..............................................52 
7.8. 
Identification of Data to Be Recorded on the Case Report Forms ...............52 
8. 
SELECTION AND WITHDRAWAL OF SUBJECTS ...........................................52 
Recruitment of Subjects ...........................................................................................52 
Eligibility Screening .................................................................................................52 
8.1. 
Subject Inclusion Criteria .............................................................................54 
8.2. 
Subject Exclusion Criteria ............................................................................55 
8.3. 
Subject Withdrawal Criteria .........................................................................56 
8.3.1. When and How to Withdraw Subjects .............................................57 
8.3.2. Data Collected for Withdrawn Subjects ...........................................57 
8.3.3. Replacement of Subjects ..................................................................57 
8.3.4. Follow-up for Withdrawn Subjects ..................................................57 
9. 
TREATMENT OF SUBJECTS ...............................................................................57 
9.1. 
Dose Administration and Follow-up Periods/Study Visits ..........................57 
9.1.1. Treatment .........................................................................................57 
9.1.1.1. 
Informed Consent for Screening Procedures .................58 
9.1.1.2. 
Study Day -1 (One Day Prior to Dosing) .......................59 
9.1.1.3. 
Drug Administration (Study Day 1 at 0 Hour) ...............60 
9.1.2. Follow-up .........................................................................................65 
9.1.2.1. 
Study Day 2 (24 Hours ± 1 Hour) ..................................65 
9.1.2.2. 
Study Day 3 (48 Hours ± 1 Hour; Discharge) ................66 
9.1.2.3. 
Study Day 4 (+ 2 Days; Telephone Follow-up) .............66 
9.1.2.4. 
Study Day 8 (+ 2 Days; Follow-up Visit) ......................67 
9.1.2.5. 
Study Day 30 (+ 7 Days; Telephone Follow-up) ...........68 
9.1.3. Biological Samples ...........................................................................68 


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9.2. 
Rescue Medications and Concomitant Medications ....................................69 
9.2.1. Rescue Medications ..........................................................................69 
9.2.2. Concomitant Medications and Prohibitions .....................................70 
9.3. 
Procedures for Monitoring Subject Compliance ..........................................71 
10. 
PHARMACOKINETIC SAMPLE COLLECTION ................................................71 
10.1. Clinical Blood Sample Collection ................................................................71 
10.2. Urine Sample Collection ..............................................................................72 
10.3. Sample Analysis ...........................................................................................72 
11. 
SAFETY ASSESSMENT ........................................................................................73 
11.1. Specification of Safety Assessments ............................................................74 
11.1.1. Demographic/Medical History .........................................................74 
11.1.2. Continuous Cardiovascular Monitoring ...........................................74 
11.1.3. Vital Signs ........................................................................................75 
11.1.4. Weight and Height ...........................................................................75 
11.1.5. Physical Examination .......................................................................75 
11.1.6. Neuropsychiatric/Behavioral/Cognitive Assessments .....................76 
11.1.7. Injection Site Assessments ...............................................................77 
11.1.8. Electrocardiogram ............................................................................77 
11.1.9. Laboratory Assessments ...................................................................78 
11.1.9.1. Hematology and Coagulation .........................................78 
11.1.9.2. Serum Chemistry ............................................................79 
11.1.9.3. Urinalysis .......................................................................80 
11.1.9.4. Pregnancy Screen ...........................................................80 
11.1.9.5. Additional Tests .............................................................80 
11.2. IND Safety Reporting ...................................................................................81 
11.2.1. Adverse Event or Suspected Adverse Reaction ...............................81 
11.2.2. Serious Adverse Event or Serious Suspected Adverse 
Reaction ............................................................................................81 
11.2.3. Unexpected Adverse Event or Unexpected Suspected 
Adverse Reaction .............................................................................82 
11.2.4. Unanticipated Problems Involving Risks to Subjects or 
Others ...............................................................................................82 
11.3. Relationship to Investigational Product .......................................................83 
11.3.1. Severity Assessment .........................................................................83 
11.4. Recording Adverse Events ...........................................................................84 
11.4.1. Methods/Timing for Assessing, Recording, and Analyzing 
Safety Endpoints ..............................................................................85 
11.4.2. Duration of Follow-Up of Subjects after Serious Adverse 
Events ...............................................................................................85 
11.5. Reporting Adverse Events ............................................................................85 
11.5.1. Reporting Serious and Unexpected Adverse Events ........................85 
11.5.1.1. Reporting to the Sponsor ................................................86 
11.5.1.2. Reporting to the IRB ......................................................87 
11.5.2. Reporting Additional Immediately Reportable Events to the 
Sponsor’s Safety Office and Local IRB and/or the 
 .............................................................................88 


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11.5.2.1. Pregnancy .......................................................................88 
11.5.2.2. AE-related Withdrawal of Consent ................................88 
11.5.2.3. Pending Inspections/Issuance of Reports .......................88 
11.5.3. IND Annual Report to the FDA .......................................................88 
11.5.4. Final Report ......................................................................................89 
12. 
STATISTICS ............................................................................................................89 
12.1. Description of Statistical Methods ...............................................................89 
12.1.1. Pharmacokinetic Analysis ................................................................89 
12.1.2. Safety Analyses ................................................................................90 
12.1.3. Clinical Laboratory Data Analyses ..................................................91 
12.1.4. Subgroup Analysis ...........................................................................91 
12.2. Planned Enrollment and Reason for Sample Size ........................................91 
12.3. Interim Analysis and Stopping Rules ...........................................................92 
12.4. Procedures for Reporting Deviations from the Original Statistical 
Plan ...............................................................................................................92 
12.5. Key Assumptions .........................................................................................92 
12.6. Selection of Subjects to Be Included in Analyses ........................................92 
13. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS ......................................92 
13.1. Accounting for Missing, Unused, and Spurious Data ..................................93 
13.2. Study Monitoring .........................................................................................93 
13.3. Audits and Inspections .................................................................................93 
13.4. Institutional Review Board ...........................................................................94 
14. 
QUALITY CONTROL AND QUALITY ASSURANCE .......................................94 
15. 
ETHICS ....................................................................................................................94 
15.1. Ethics Review ...............................................................................................94 
15.1.1. Review/Approval of Study Protocol ................................................95 
15.1.2. Protocol Modifications .....................................................................95 
15.1.3. Protocol Deviation Procedures .........................................................95 
15.2. Ethical Conduct of the Study .......................................................................96 
15.2.1. Confidentiality ..................................................................................96 
15.2.2. Medical Care for Research-Related Injury .......................................96 
15.3. Written Informed Consent ............................................................................96 
16. 
DATA HANDLING AND RECORDKEEPING .....................................................97 
16.1. Inspection of Records ...................................................................................98 
16.2. Retention of Records ....................................................................................98 
17. 
PUBLICATION POLICY ........................................................................................99 
18. 
LIST OF REFERENCES .......................................................................................100 
18.1. Publications ................................................................................................100 
18.2. Study Reports .............................................................................................102 
19. 
APPENDICES ........................................................................................................103 
APPENDIX A. VISUAL ANALOG SCALES .........................................................................104 
APPENDIX B. TOXICITY GRADING SCALE FOR INJECTION SITE REACTIONS ......105 


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APPENDIX C. INJECTION SITE ASSESSMENT FORM .....................................................106 
APPENDIX D. RICHMOND AGITATION AND SEDATION SCALE (RASS) ..................107 
 
LIST OF TABLES 
Table 1: 
Emergency Contact Information ...................................................................................7 
Table 2: 
Abbreviations ..............................................................................................................19 
Table 3: 
Study Events Schedule ...............................................................................................38 
Table 4: 
Study Events Schedule – Pre Dose through 36 Hours Post Dose ...............................41 
Table 5: 
Investigational Products ..............................................................................................44 
Table 6: 
Progression of Dosing Related to Dose-Limiting Toxicity Events ............................51 
Table 7: 
Treatment Groups and Dose Levels ...........................................................................62 
Table 8: 
Pharmacokinetic Blood Sample Deviation Windows .................................................63 
Table 9: 
Pharmacokinetic Parameters .......................................................................................72 
Table 10: Study Contacts for Reporting Serious Adverse Events and Unanticipated 
Problems Involving Risks to Subjects or Others ........................................................86 
Table 11: SAE Information to Be Reported to the Sponsor’s Safety Office ..............................87 
Table 12: Study Objectives and Endpoints .................................................................................89 
 
LIST OF FIGURES 
Figure 1: 
Scopolamine HBT CNS Effects by Dosage (Ketchum et al, 1973) ...........................31 
Figure 2: 
Scopolamine HBT Injection 0.8 mg/mL and 2.0 mg/mL and Placebo Labels ...........45 
 


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4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
The following abbreviations are used in this study protocol. 
Table 2: 
Abbreviations 
Abbreviation 
Explanation 
μmol 
micromolar 
2-PAM 
pralidoxime chloride 
5x 
5 times 
ACh 
acetylcholine 
AChE 
acetylcholinesterase 
ACLS 
Advanced Cardiovascular Life Support 
AE 
adverse event 
ATNAA 
AUC 
antidote treatment nerve agent, auto-injector 
area under the curve 
BMI 
body mass index 
BPRS 
Brief Psychiatric Rating Scale 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CANA 
CFR 
Convulsant Antidote for Nerve Agent 
Code of Federal Regulations 
Cl_F 
apparent clearance 
CLIA 
Clinical Laboratory Improvement Amendments 
cm 
centimeter(s) 
Cmax 
maximum concentration 
CNS 
central nervous system 
CTCAE 
Common Terminology Criteria for Adverse Events 
DLT 
dose-limiting toxicity(ies) 
DoD 
Department of Defense 
DSMB 
Data Safety Monitoring Board 
DSST 
Digit Symbol Substitution Test 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
ED50 
effective dose for 50% of the population 
EENT 
eyes, ears, nose, and throat 
dL 
deciliter 
FDA 
US Food and Drug Administration 


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Abbreviation 
Explanation 
g 
gram 
GB 
sarin 
GD 
soman 
GCP 
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
human immunodeficiency virus 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IM 
intramuscular(ly) 
IND 
Investigational New Drug (application) 
IRB 
Institutional Review Board 
IV 
intravenous(ly) 
  
 
 
 
 
 
kg 
kilogram(s) 
L 
liter(s) 
LD50 
lethal dose of a compound resulting in 50% mortality 
mEq 
milliequivalent 
mg 
milligram(s) 
mL 
milliliter(s) 
mm 
millimeter(s) 
mm Hg 
millimeter of mercury 
mM 
millimolar 
MRT 
mean residence time 
msec 
millisecond(s) 
ng 
nanograms(s) 
NOAEL 
no-observed-adverse-effect level 
OP 
organophosphorus 
 
 
 
 
 
PB 
pyridostigmine bromide 


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Abbreviation 
Explanation 
PD 
pharmacodynamic(s) 
PI 
principal investigator 
PK 
pharmacokinetic(s) 
 
 
PVG 
pharmacovigilance 
qEEG 
quantitative electroencephalogram 
QTcF 
QT interval corrected with Fridericia correction 
RASS 
Richmond Agitation and Sedation Scale 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SCID-5-CT 
Structured Clinical Interview for DSM-5, Clinical Trials Version 
Scopolamine HBT 
scopolamine hydrobromide trihydrate 
SOP 
standard operating procedure 
t½ 
half-life or elimination time 
TK 
toxicokinetic 
Tmax 
time to reach Cmax 
TSG-DA 
The Surgeon General, Department of the Army 
US 
United States 
 
 
USP 
United States Pharmacopeia 
VAS 
visual analog scales 
Vd_F 
apparent volume of distribution 
 


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5. 
INTRODUCTION 
 
 
 is developing scopolamine hydrobromide trihydrate 
(Scopolamine HBT) as a centrally and peripherally acting injectable therapeutic that would be 
administered in conjunction with the ATNAA (antidote treatment nerve agent, auto-injector) upon 
exposure to nerve agents and also as an adjunctive therapy along with atropine. Scopolamine HBT is 
being developed as a liquid intramuscular (IM) injectable product in vials to treat muscarinic effects. 
Future plans are to develop the product in an autoinjector and file it (the final drug-device combination 
product) as an IM injectable therapeutic the post-exposure management of muscarinic effects in 
warfighters exposed to organophosphorus (OP) nerve agents. 
Chemical and biological threats are real, dynamic, and ever changing. The rapid advancement 
and global proliferation of chemical and biological capabilities greatly extend the spectrum of 
plausible actors, agents, concepts of use, and targets. Specific threats may include the use of 
traditional chemical weapons (eg, mustard, sarin [GB], or G-series nerve agents; VX or V series 
nerve agents; or other newly developed nerve agents) as well as the use of nontraditional 
chemical agents such as pharmaceutical-based OP agents, employed in either tactical/operational 
military settings or as terrorist attacks. The identity of threat agents may be initially uncertain; 
however, broadly based response capabilities must be rapidly available. 
As part of the Department of Defense’s (DoD) continued search for better and more readily 
available treatment options, 
 has identified Scopolamine HBT 
(formulated in 1 mM citrate buffer; 150 mM sodium chloride, pH 3.0 ± 0.1) as having the 
mechanism of action (anticholinergic properties) to prevent the effect of excess acetylcholine 
(ACh) by blocking its binding to muscarinic cholinergic receptors at neuroeffector sites on 
smooth muscle, cardiac muscle, and gland cells; in peripheral ganglia; and in the central nervous 
system (CNS). 
Nonclinical data generated support the utility of scopolamine in addition to the currently fielded 
standard-of-care treatment regimen (medical countermeasure), which consists of PB pretreatment 
followed by ATNAA and CANA (Convulsant Antidote for Nerve Agent) administrations by self 
or buddy aid, and in some cases may provide the warfighter with the best chance of survival in 
the event of chemical nerve agent exposure in combat or terrorist situations. 
The current, accepted understanding of the toxic effects of nerve agents in humans is primarily 
due to the inhibition of the acetylcholinesterase (AChE) enzyme within nerve synapses, resulting 
in uncontrolled accumulation of the neurotransmitter ACh. The cholinergic system is the only 
neurotransmitter system known in which the action of the neurotransmitter ACh is terminated by 
the enzyme, AChE. Although there are several types of choline esters, the neurotransmitter of the 
cholinergic portion of the nervous system is most relevant to nerve agent activity. This classic 
explanation of nerve agent poisoning holds that the intoxicating effects are due to inhibition of 
AChE leading to excess endogenous ACh, which produces cholinergic over-activity or 
cholinergic crisis (Sidell et al, 2008). Some early signs of exposure by sublethal quantities of 
nerve agent are miosis, rhinorrhea, and airway constriction. Without medical intervention, higher 
levels of exposure (experienced through greater concentrations or longer durations) to these 
nerve agents will cause loss of consciousness, seizures, convulsions, cessation of respiration and 
cardiac activity, and death. Effects occur within minutes of exposure via inhalation, and after a 


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high level of exposure, death occurs in 10 to 15 minutes (Schultheiss, 2013). Exposure is 
typically via inhalation, dermal, or ingestion. 
The anticholinergic drug, scopolamine, has been approved by the FDA as a transdermal 
therapeutic to relieve nausea, vomiting, and dizziness associated with motion sickness and 
recovery from anesthesia after surgical procedures since 1979 (Novartis NDA 17-874). 
Scopolamine is dermally delivered by a transdermal patch (containing 1.5 mg scopolamine base) 
worn behind the ear that delivers scopolamine over the course of 3 days. Scopolamine can 
rapidly cross the blood‒brain barrier and thus is centrally acting. In addition to peripheral effects, 
it is this antimuscarinic activity in the CNS that gives scopolamine its potential for use to treat 
muscarinic symptoms as part of nerve agent treatment options (Koplovitz and Schulz, 2010). 
As scopolamine base and scopolamine hydrobromide have been used in humans for various 
therapeutic indications for more than 100 years, the proposed use of Scopolamine HBT is as a 
stand-alone therapeutic to manage muscarinic symptoms or as an adjunct to the current and 
future OP nerve agent treatment regimen of PB pretreatment and atropine plus pralidoxime 
chloride (2-PAM) plus an anticonvulsant as post-exposure therapeutics. 
Like atropine, scopolamine prevents the effect of excess ACh levels by antagonizing or blocking 
its binding to cholinergic muscarinic receptors at neuroeffector sites. Scopolamine is more potent 
(approximately 8 times) in the CNS since it enters the brain more rapidly than atropine, but 
atropine is approximately 10 times more potent in the periphery than scopolamine (Ketchum et 
al, 1973). When scopolamine was administered with atropine (0.5 mg/kg), 2-PAM (25 mg/kg), 
and diazepam (0.72 mg/kg), guinea pig survival after challenge with 5 times (5x) or 10 times 
(10x) the lethal dose that kills 50% of those exposed (2x LD50) of GB or VX was significantly 
increased compared to medical countermeasure treatment without scopolamine (Koplovitz et al, 
2015). 
Exposure to toxic nerve agents or OP insecticides may cause severe reactions rapidly leading to 
significant morbidity or mortality. The underlying, primary mechanism in these pathological 
toxidromes is mediated by an inhibition of the ubiquitous enzyme AChE, which catalyzes the 
breakdown of the primary neurotransmitter ACh at neuromuscular junctions (Adeyinka and 
Kondamudi, 2018). Over-stimulation of the muscarinic receptors due to excess ACh results in 
cholinergic crisis characterized by the “SLUDGEM” Syndrome (salivation, lacrimation, 
urination, diarrhea, gastrointestinal upset, emesis, and miosis). The symptoms of this muscarinic 
syndrome may also be characterized by another mnemonic “DUMBELS” (diaphoresis and 
diarrhea; urination; miosis; bradycardia, bronchospasm, bronchorrhea; emesis; excess 
lacrimation; and salivation). There are 5 types of muscarinic receptors (M1 to M5) with 
differential tissue distributions that are involved in the cholinergic crisis toxidrome. 
Early management of cholinergic crisis is both supportive and through utilization of 
antimuscarinic agents. Treatment of the major symptoms of cholinergic crisis is initially targeted 
at the copious oral and nasal secretions, bronchorrhea, and bronchospasm as these can be life 
threatening (Wiercinski and Jackson, 2018). These issues can lead to airway compromise, loss of 
patency, and breathing difficulties. Excess cholinergic stimulation causes both glandular and 
mucus secretion in the airways (Rogers, 2001). Anticholinergics, such as atropine and 
scopolamine, are effective treatments for control of secretions (Hockstein et al, 2004; Wildiers et 
al, 2009). The parasympatholytic scopolamine, structurally very similar to atropine, is used in 


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conditions requiring decreased parasympathetic activity in salivary and bronchial secretory 
glands (Renner et al, 2005). 
Military Relevance 
Scopolamine exerts few effects on the actions of ACh at nicotinic receptor sites such as 
autonomic ganglia. Like atropine, scopolamine is a tertiary amine and a competitive antagonist 
to ACh, and nonselectively binds all muscarinic receptor types (M1-M5). However, scopolamine 
binds to muscarinic receptors with higher potency (~ 8 times more potent) than atropine in the 
CNS. Since scopolamine has a greater solubility in lipids and rapidly crosses the blood-brain 
barrier, the high receptor potency and lipid solubility of scopolamine in the CNS results in fast 
inhibition of ACh activity at centrally acting muscarinic receptors. Scopolamine’s high 
muscarinic receptor potency and ability to cross the blood-brain barrier makes it an ideal 
candidate for addition to the current treatment regimen by providing a centrally acting nerve 
agent medical countermeasure to improve the overall effectiveness for treatment of nerve agent 
intoxication. The symptoms elicited during the cholinergic crisis in OP nerve agent or pesticide 
exposure are receptor mediated via overstimulation of muscarinic receptors (M1-M5) within the 
parasympathetic nervous system. These muscarinic receptors, with differential distributions in 
central and peripheral tissues, are involved in the cholinergic crisis toxidrome. Early medical 
management of cholinergic crisis is both supportive and through utilization of anti-muscarinic 
agents. Treatment of the major symptoms of cholinergic crisis is initially targeted at the copious 
oral and nasal secretions, bronchorrhea, and bronchospasm, as these can be life threatening. 
Thus, an important therapeutic strategy is the targeted management of secretions. 
Rationale for Study 
The goal of the Phase 1 clinical investigation is to evaluate the safety, tolerability, and PK 
(including dose exposure proportionality) of Scopolamine HBT in 5 cohorts, with 8 to 12 
subjects in each cohort. The doses of Scopolamine HBT chosen for this study are: 0.005, 0.007, 
0.011, 0.014, and 0.021 mg/kg. These doses were chosen as they have been used previously in 
clinical studies (Kanto et al, 1989, Ketchum et al, 1973, Liem-Moolenaar et al, 2011), and the 
safety of the starting dose is supported by Good Laboratory Practice, single-dose, IM toxicology 
studies in rats (Battelle Study Numbers 0740002 and 0740098) and monkeys (Battelle Study 
Number 0740001). This Phase 1 clinical study will support development by providing a human 
safety and PK profile. 
5.1. 
Name and Description of the Investigational Product 
Scopolamine HBT injection is formulated in 1 mM citrate buffer; 150 mM sodium chloride at 2 
concentrations for use in the clinical study, 0.8 and 2.0 mg/mL, and is adjusted to pH 3.0 ± 0.1 
with hydrochloric acid and/or sodium hydroxide. Refer to Section 7.4 for additional information. 
5.2. 
Summary of Nonclinical and Clinical Trials 
5.2.1. 
Nonclinical Proof-of-Concept Studies 
Nonclinical proof-of-concept studies were conducted in guinea pigs to demonstrate the potential 
efficacy of scopolamine as an adjunct treatment after challenge with nerve agents. 


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Koplovitz and Schulz (2010) evaluated the effect of atropine dose, PB pretreatment, and oxime 
selection on the efficacy of scopolamine as an adjunct treatment to enhance survival following 
lethal nerve agent exposure in guinea pigs. Results showed that the use of an effective oxime 
and/or PB pretreatment was a critical factor in determining the efficacy of scopolamine. 
Scopolamine was also found to reduce the dose of atropine required for survival against lethal 
nerve agent intoxication. 
When scopolamine was administered with atropine (0.5 mg/kg), 2-PAM (25 mg/kg), and 
diazepam (0.72 mg/kg), guinea pig survival was increased compared to treatment without 
scopolamine after challenge with 5 times (5x) or 10 times the lethal dose that kills 50% of 
animals exposed (LD50) to GB or VX (Koplovitz et al, 2015). 
In a pilot study (Battelle Study Report 04600), guinea pigs pretreated with PB or saline were 
challenged with GB or soman (GD) and 1 minute later treated with atropine, 2-PAM, and 
midazolam. Scopolamine was administered at 1, 30, 60, or 120 minutes following challenge. For 
challenge at the 5x LD50 GB level, animals receiving scopolamine at any time point and 
pretreated with PB did not show increased survival at 8 or 24 hours post challenge compared to 
those that did not receive PB. For animals challenged with 3.5x LD50 GD, an increase in survival 
at 8 and 24 hours was observed in animals receiving both scopolamine and PB when 
administered with the current nerve agent treatment. This observed increase in survival was not 
dependent on the timing of scopolamine administration provided that it occurred ≤ 60 minutes 
post challenge. This highlights the potential benefit of rapid scopolamine administration in 
combination with PB pretreatment, specifically if the exposure is to a nerve agent that is more 
difficult to treat (ie, GD). 
JPM-CBRN Medical has tested the timing of scopolamine in conjunction with the current nerve 
agent treatment regimen (atropine + 2-PAM followed by an anticonvulsant) with and without PB 
pretreatment. The results of this guinea pig challenge study demonstrated scopolamine with PB 
increased survival and quality of life of animals when scopolamine was administered within 
1 hour of agent exposure (Battelle Study Report 08100). 
5.2.2. 
Nonclinical Studies to Support Safety 
The safety of Scopolamine HBT was examined in single-dose studies using Sprague-Dawley rats 
and rhesus macaques. In Battelle Study 100077148-0740001, Scopolamine HBT was 
administered as a single IM administration to adult male and female rhesus macaques at doses of 
0, 0.016, 0.128, and 1.02 mg/kg with a cohort humanely terminated on Day 2 to examine acute 
effects and the remaining animals observed for a 14-day recovery period before humane 
termination. There were no test-article-related effects or changes observed in body weights, 
instances of redness or swelling at the site of injection, and clinical pathology (ie, coagulation, 
hematology, serum chemistry, and urinalysis). In addition, there were no apparent test-article-
related organ weight differences or microscopic findings when high-dose-treated animals were 
compared to respective control animals. Lethargy was observed in 4 out of 10 high-dose (1.02 
mg/kg) animals on Day 1 following dosing; however, this was resolved by Day 2. High-dose 
administration of Scopolamine HBT also resulted in slight decreases in food consumption. 
Functional observational battery assessments revealed scopolamine-induced mydriasis and loss 
of pupillary constriction in response to a light stimulus observed in all animals dosed at 0.128 
and 1.02 mg/kg (mid and high doses, respectively). These findings were observed at 


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approximately 30 minutes post dose on Day 1 and persisted through Day 2. There was no 
evidence of continued pupil dilation during the recovery period beginning on Day 3. 
Evaluation of the toxicokinetic (TK) parameters and systemic exposure suggested that there was 
no sex effect on the TK parameters for Scopolamine HBT as all group mean values were within 
2-fold when comparing males and females with the exception of apparent clearance and apparent 
Vd_F for Group 2. However, these 2 parameters were artificially high due to the low 
concentrations at all time points for one animal. In addition, systemic exposure, as measured by 
both Cmax and AUC, increased in a dose-proportional manner as the dose increased and mean 
Tmax remained constant between the 3 dose groups (approximately 8 to 16 minutes). The mean (± 
SE) elimination half-life, Cl_F, and apparent Vd_F were similar for all animals with values of 
1.14 ± 0.05 hr, 2370 ± 510 mL/hr/kg, and 3640 ± 580 mL/kg, respectively. Based on data 
generated during this study, the IM administration of Scopolamine HBT at dose levels up to 1.02 
mg/kg to male and female monkeys is associated with expected pharmacological effects, such as 
pupillary dilation, but there were no obvious adverse effects. Under the conditions of this study, 
the no observed adverse effect level (NOAEL) was the highest dose evaluated, 1.02 mg/kg, as a 
single IM administration, which corresponds to a mean Cmax value of 413 ng/mL in males and 
476 ng/mL in females and AUC values of 551 hr*ng/mL in males and 669 hr*ng/mL in females. 
In Battelle Study 100077148-0740002, Scopolamine HBT was administered to adult male and 
female Sprague-Dawley rats via a single IM injection at doses of 0, 0.12, 1.2, and 12 mg/kg. This 
study was to determine the toxicity and TK of Scopolamine HBT when administered to male and 
female Sprague-Dawley rats via a single IM injection. A cohort of rats was humanely terminated 
on Day 2 to examine acute effects, and the remaining animals were observed for a 14-day 
recovery period before humane termination. There were no treatment-related effects noted for 
body weights, food consumption, clinical pathology, organ weights, or macroscopic or 
microscopic findings. Scopolamine HBT primarily induced mydriasis and loss of the pupillary 
constriction response after dosing at all levels tested. Pupil size and reactivity returned to normal 
by 24 hours post dose for animals at 0.12 and 1.2 mg/kg and returned to normal by Day 3 (Day 2 
of recovery) for animals at 12 mg/kg. At 12 mg/kg, all animals had normal pupil reactivity when 
examined in the recovery period, indicating a complete recovery of all treatment-related 
pupillary effects. Gasping and/or labored breathing was seen for 2 rats at 0.12 mg/kg, 2 rats at 
1.2 mg/kg, and 3 rats at 12 mg/kg during clinical observations or functional battery testing. This 
was considered treatment related. A single animal at 0.12 mg/kg was found dead after the motor 
activity test, and one TK animal each in the 1.2 and 12 mg/kg groups died following anesthesia 
and the second TK blood collection. Gasping was noted for each of these animals prior to death, 
and ultimately a potential effect of respiratory abnormalities could not be excluded. Scopolamine 
HBT treatment increased multiple measures of locomotor activity for both sexes at all dose 
levels on Day 1 only. This was considered to be a pharmacological effect and not adverse. No 
relevant findings were noted on Day 2 or when tested during the recovery period, indicating a 
complete reversal of the observed motor activity effects. Evaluation of the TK parameters and 
systemic exposure suggested that there was no sex effect on the TK parameters for scopolamine 
as group mean TK parameters were typically within 2-fold, for a given dose, when comparing 
males and females. When comparing the 3 dose groups, there were no apparent dose effects on 
the TK parameters. In addition, systemic exposure, as measured by both Cmax and AUC, 
increased in a dose-proportional manner as the dose increased, suggesting no dose effects on 
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for the 3 dose groups. The mean (± SE) elimination half-life, Cl_F, and apparent Vd_F for all 
groups were 0.599 ± 0.056 hr, 3770 ± 410 mL/hr/kg, and 3170 ± 350 mL/kg, respectively. In 
summary, a single IM administration of Scopolamine HBT resulted principally in 
pharmacological effects including mydriasis and loss of pupil constriction in response to light at 
all dose levels examined. These were completely resolved by Day 2 for animals at 0.12 and 1.2 
mg/kg and within a 14-day recovery period for animals at 12 mg/kg. Pupil diameter returned to 
normal by Day 3 (Day 2 of recovery) for animals at 12 mg/kg, and pupillary constriction was 
normal during the functional observational battery testing when examined within the 14-day 
recovery period for animals at 12 mg/kg. Gasping and/or labored breathing was noted post dose 
in a few animals from all treated groups. This was considered a serious adverse effect due to its 
likely contribution to morbidity for individual animals at all dose levels. Morbidity was observed 
at each dose level, characterized by gasping/respiratory distress and subsequent mortality, and 
these effects were considered test article related; therefore, a NOAEL could not be determined in 
this study.  
Since a NOAEL could not be established due to mortality, a follow-on repeat study was 
conducted using an increased number of animals (35 animals/sex/group) to provide adequate 
statistical power to determine whether the previously observed morbidity and mortality at 0.12 
mg/kg was incidental or test article related. In the repeat study, Battelle Study Number 
100077148-0740098, rats were administered 0, 0.10, 0.12, 1.2, and 12 mg/kg Scopolamine HBT 
via a single IM injection and observed for acute effects over 24 hours and recovery for 14 days. 
There were 3 unscheduled deaths, 1 at 1.2 mg/kg and 2 at 12 mg/kg. Two animals died after 
respiratory abnormalities and seizures were observed, and the third was euthanized for gasping 
sustained for several hours. Seizures and respiratory abnormalities were seen for a few animals at 
1.2 and 12 mg/kg only and most of the animals recovered completely. The majority of findings 
seen after Scopolamine HBT administration were pharmacological effects and were also seen in 
the previous study (Battelle Study Number: 0740002). Findings were primarily mydriasis and no 
pupil constriction in response to light after dosing at all levels tested (0.10, 0.12, 1.2, and 12 
mg/kg). This was observable from approximately 15 minutes until 1 hour post dose. Thereafter, 
pupil dilation and impaired constriction to light remained partially recovered at 3 hours post dose 
for animals at 0.10 and 0.12 mg/kg, and at 6 hours for animals at 1.2 mg/kg. Animals at 12 
mg/kg still showed full pupil dilation and impaired constriction at 6 hours post dose but 
recovered completely by 24 hours after treatment. In summary, a single IM administration of 
Scopolamine HBT principally resulted in mydriasis and loss of pupil constriction in response to 
light at all dose levels examined. Mortality/moribundity occurred at 1.2 and 12 mg/kg. Gasping 
and/or noisy/audible breathing and seizures were noted post dose in a few animals from 1.2 and 
12 mg/kg only, including for the animals with premature deaths. Based on the mortality, 
seizures, and respiratory abnormalities observed at 1.2 and 12 mg/kg, a NOAEL of 0.12 mg/kg 
was established in the study under the conditions of the study; however, due to inconsistencies 
observed at the 0.12 mg/kg dose level across several studies, the overall NOAEL for 
Scopolamine HBT was considered to be 0.10 mg/kg. 
The rat was determined to be the most sensitive species. Exposure parameters measured at the 
0.12 mg/kg dose level included maximum plasma concentrations of 87.1 and 52.9 ng/mL and 
AUCs of 45.8 and 47.4 ng·h/mL in males and females, respectively. Since the PK of 
scopolamine was linear in rats from 0.12 to 12 mg/kg; the extrapolated Cmax and AUC values for 
a 0.10 mg/kg dose (based on the 0.12 mg/kg TK data) are 72.6 and 44.1 ng/mL for Cmax and 38.2 


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and 39.5 h·ng/mL for AUC in males and females, respectively. Thus the two lowest exposure 
parameters are 44.1 ng/mL and 38.2 h·ng/mL. Based on clinical PK data from healthy volunteers 
across several studies, an IM dose of 0.005 mg/kg (0.35 mg in a 70 kg subject) is estimated to 
result in a mean Cmax of 0.68 ± 0.45 ng/mL and AUC of 0.94 ± 0.52 h·ng/mL based on 99% CI. 
Assuming exposures on the high end of the confidence interval (1.13 ng/mL and 1.46 h·ng/mL) 
the exposures estimates are 39.0-fold (44.1 ng/mL / 1.13 ng/mL) and 26.2-fold (38.2 h·ng/mL / 
1.46 h·ng/mL) lower than exposures supported based on the NOAEL in rats; both well in excess 
of a 10-fold safety margin. 
5.2.2.1. 
Bioequivalence of Vital and Phytex Scopolamine HBT 
For the initial development studies, the API, Scopolamine HBT USP, was obtained from Vital 
Laboratories Private Limited. However, on April 6, 2017, FDA investigators audited the Vital 
Vapi, India facility and manufacturing findings were noted. Inspectional observations (FDA 483) 
were issued and agency reservations conveyed on October 10, 2017. The Ology Bioservices 
Quality Review Board performed a risk assessment on November 2, 2017, recommending that 
the API procured from Vital not be used in upcoming current good manufacturing practice lots. 
As a direct consequence of this occurrence, a new API supplier was identified as Phytex 
Australia Pty Ltd of Peakhurst, Australia. Scopolamine HBT USP was obtained from Phytex for 
subsequent development. 
Side-by-side comparison of the physical characteristics and bioequivalence of the Phytex API 
with the reference Vital API was performed to determine comparability. Data from these studies 
showed that the two batches of API (1) were considered to be chemically equivalent, (2) were 
pharmacokinetically equivalent in rats, and (3) initiated comparable pharmacological responses 
in rats. Based on these data, it can be assumed there would be no differences in the resulting 
pathophysiology between the two formulations; thus, the safety studies conducted using the 
reference API from Vital do not need to be repeated using the new API from Phytex. A full 
report (K05193) of the study has been submitted with the IND. 
5.2.3. 
Clinical Studies 
Much is known about how scopolamine is metabolized and excreted as well as the drug’s effects 
in different CNS domains. Scopolamine pharmacodynamics (PD) include dilated pupils, flushed 
skin, tachycardia, hypertension, and ECG abnormalities, which are reversible and transient, 
decreasing with decreased exposure levels. The literature also reports a number of previous 
studies conducted with scopolamine in humans for neurological and PK assessments. 
Scopolamine is used for the prevention of motion sickness, in various gastrointestinal disorders, 
and as premedication before anesthesia. As previously mentioned, in the published literature 
from the 1940s to 1970s physicians routinely used scopolamine to treat patients at doses of 0.07-
0.7 mg/kg and, in some cases, went as high as 2.86 mg/kg (200 mg total) without causing death 
(Eger, 1962; Elkin et al, 1965; Wangeman and Hawk, 1942). 
5.2.4. 
HMR 11-013 Clinical Study 
The United Kingdom’s Defence Science & Technology Laboratory sponsored a randomized, 
double-blind, placebo-controlled, crossover, dose-escalation study to assess the safety, 
tolerability, PK, and PD of physostigmine salicylate and hyoscine (scopolamine) hydrobromide 
by continuous, IV infusion in healthy volunteers conducted by Hammersmith Medicines 


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Research (HMR, 2016). Data relevant to scopolamine safety from this study are described as 
follows. The clinical investigation demonstrated a tolerable safety profile of scopolamine in 
healthy volunteers up to a total dose of 797.5 μg given over 4 hours of continuous IV infusion. 
Doses of 1200 μg given over 10 hours were associated with psychiatric treatment emergent 
adverse effects in 2 subjects and lead to withdrawal (disorientation in 1 subject, and 
hallucinations and confusional state in the other). The 6 male volunteers administered 797.5 μg 
over 4 hours resulted in an average Cmax of 1.4373 ng/mL and an average AUC∞ of 
6.749 hr*ng/mL. All 6 volunteers (100%) displayed treatment emergent adverse effects of 
somnolence, dizziness, and dry mouth, 5/6 blurry vision, 4/6 headache, 3/6 mood, and 1/6 
coordination abnormality. 
Though not a perfect comparison, HMR IV infusion data were compared to the IM injection data 
presented in the report by Ketchum and colleagues (1973), patients tended to exhibit the same 
pattern of symptoms although the IM injections were more tolerable. In the HMR study, 50% of 
subjects in the group receiving 0.5945 mg over 4 hours had blurred vision, whereas the ED50 for 
blurred vision in the Ketchum study was a single IM dose of 0.7 mg. Also in the HMR study, 
reports of a confusional state were observed in 50% of the combined subjects who received 
either 1.0 mg or 1.2 mg over 10 hours, whereas the ED50 for general confusion in the Ketchum 
report was a single IM dose of 1.4 mg. In both cases, the dose in the HMR (IV) study is about 
85% of the dose in the Ketchum (IM) study. The PK of scopolamine when administered as a 
single IM injection of 6 μg/kg into the deltoids of 6 healthy volunteers was found to support this 
hypothesis. A 90% confidence interval for the Cmax and AUC was determined based on this dose 
and scaled proportionally to estimate the exposures in the Ketchum report. From this, similar 
exposure estimates can be correlated to similar symptoms as the IV groups. 
In HMR study, the frequency of dry mouth increased with dose: after 300 μg administered over 
10 hours and 232 μg administered over 4 hours, half of the subjects experienced dry mouth; after 
intermediate doses (600 μg over 10 hours), most subjects experienced dry mouth; and, after the 
highest doses (≥ 1000 μg over 10 hours and 797.5 μg over 4 hours), all subjects experienced dry 
mouth. All instances of dry mouth began during the infusion and most persisted for many hours. 
This report does not have a time to effect of dry mouth after starting scopolamine infusion. The 
effect also reversed once scopolamine infusion ended. Plasma concentrations lower than 0.4 
ng/mL (232 μg over 4 hours) reduced mean salivary weight from 1.40 g at pre dose to 0.52 g at 
2.5 hours. This study confirms the clinical literature on the antisialagogue property of 
scopolamine in humans. 
Liem-Moolenaar and colleagues (2011) evaluated the PK-PD relationships of CNS effects of 
0.5 mg scopolamine administered IV to 90 healthy male subjects. Results indicated that most PD 
responses following scopolamine administration in 85 subjects differed significantly from the 
placebo. As PD measures lagged behind the plasma PK profile, PK-PD relationships were 
modeled using an effect compartment and arbitrarily categorized according to their equilibration 
t1/2keo, hysteresis measure. The t1/2keo for heart rate was 17 minutes; saccadic eye movements and 
adaptive tracking were 1 to 1.5 hours; body sway, smooth pursuit, visual analog scales, alertness, 
and psychedelic effects were 2.5 to 3.5 hours; and pupil size, finger tapping, and visual analog 
scales for feeling high were more than 8 hours. It was concluded that scopolamine affected 
different CNS functions in a concentration-dependent manner, which based on their distinct 
PK-PD characteristics seemed to reflect multiple distinct functional pathways of the cholinergic 
system. 


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Ebert and colleagues (1998) evaluated effects of SC administered scopolamine on quantitative 
electroencephalogram (qEEG) and cognitive performance and correlated them with PK 
parameters in a randomized, double-blind, placebo-controlled, crossover study in 10 healthy 
male volunteers (72-88 kg). Subcutaneous administration of scopolamine produced time-
dependent impairments of attention and memory, a time-dependent increase in delta power 
(1.25-4.5 Hz), and a decrease in fast alpha power (9.75-4.5 Hz) on qEEG compared with 
placebo. Maximum serum concentration of scopolamine occurred 10 to 30 minutes after drug 
administration. Mean peak serum concentrations (free base) were 3.27, 8.99, and 18.81 ng/mL 
after administration of 0.4, 0.6, and 0.8 mg scopolamine, respectively. Elimination half-life was 
approximately 220 minutes. These findings indicate temporary changes in qEEG and 
psychometric tests, and support the possible use of this testing model for impaired cognitive 
functions such as age-related memory disturbances. 
Sannita and colleagues (1987) studied the effects of scopolamine (0.25-0.75 mg, IM) on qEEG 
and the neuropsychological status of healthy volunteers (63-80 kg). At a dose of 0.75 mg, 
subjects complained about subjective symptoms that were definitely unpleasant. The effects of 
this dose on the EEG and neuropsychological status did not differ significantly from those 
observed after a dose of 0.50 mg. Regarding dose and tolerance, 0.50 mg of scopolamine IM 
administered appears to be a tolerable dose for pharmaco-EEG studies. 
Ghoneim and Mewaldt (1975) administered 1 mg (0.014 mg/kg) of scopolamine IM to healthy 
volunteers resulting in marked disorientation, confusion, and motor incoordination in addition to 
physical incapacitation. In a follow-up study, 70 volunteers were administered diazepam 
(0.3 mg/kg) and scopolamine (0.008 mg/kg) IM followed 70 minutes later by another injection of 
physostigmine, physostigmine plus methscopolamine, or placebo (Ghoneim and Mewaldt, 1977). 
The investigators found that diazepam and scopolamine did not affect recall of information that 
had been learned prior to drug injection; however, both drugs impaired the learning or 
acquisition of new information. In addition, they found that high doses of physostigmine 
reversed the memory deficits produced by scopolamine but not by diazepam, suggesting that 
scopolamine acts centrally through an anticholinergic mechanism while diazepam may act 
through a different system, possibly through facilitation of GABA-ergic transmission. 
In a study conducted by Ketchum and colleagues (1973), healthy adult males were administered 
Scopolamine HBT IM from 0.005-0.024 mg/kg and evaluated for pharmacological effects and 
drug-drug interactions. At the highest dose, other than CNS-related pharmacological effects (ie, 
excitement, restlessness, irritability, hallucinations, and delirium), which are similar to the effects 
of other anticholinergic drugs such as atropine, no other scopolamine-related toxicities were 
reported. This study provided a unique dataset of the CNS effects of Scopolamine HBT, reported 
as effective dose for 50% of the population (ED50) for observer ratings and subjective 
assessments of adverse symptoms, in a relatively large number of patients (n = 36, IM; Figure 1). 


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Figure 1: 
Scopolamine HBT CNS Effects by Dosage (Ketchum et al, 1973) 
 
5.3. 
Known and Potential Risks and Benefits to Human Subjects 
5.3.1. 
Risks/Discomfort to Subjects and Precautions to Minimize Risk 
The following are anticipated and unexpected adverse reactions and a brief description of 
procedures to ameliorate risks and symptoms. All known risks and precautions described are 
explained in detail in the informed consent. 
5.3.1.1. 
Local Reactions 
Potential risks associated with the administration of Scopolamine HBT, Injection or placebo with 
a syringe may include the following local effects at the site of injection: 
• pain (possibly severe) and tenderness 
• pruritus 
• rashes 
• tingling or numbness 
• hematoma 
• induration 
• redness 
• muscle stiffness 
• swelling or feeling of burning 
• warmth or coldness 


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5.3.1.2. 
Systemic Reactions 
Scopolamine HBT is more potent than atropine and has a stronger action on the iris, ciliary body, 
and certain secretory glands such as salivary, bronchial, and sweat (APP Pharmaceuticals, 2012). 
Scopolamine HBT at 0.005-0.007 mg/kg normally causes drowsiness/fatigue, dizziness, 
euphoria, amnesia, impairment of memory and concentration, disorientation or mental confusion, 
and dreamless sleep with a reduction in rapid eye movement sleep. However, the same doses 
occasionally cause excitement, restlessness, insomnia, delirium, hallucinations, and/or paranoia, 
especially in the presence of severe pain. Headaches, loss of consciousness, psychosis, seizures, 
and neuroleptic malignant syndrome can also occur. 
Typically, dry mouth is the first notable reaction followed by dry skin. Thirst and difficulty in 
swallowing occur when the mouth and esophagus become sufficiently dry; chronic dry mouth 
also fosters dental caries. Suppression of sweating causes reflexive flushing and heat intolerance 
and can result in heat exhaustion or heat stroke in a hot environment; it also contributes to the 
hyperthermia seen in intoxication. Mydriasis frequently occurs with Scopolamine HBT, and 
photophobia and blurring of vision are consequences of mydriasis. Cycloplegia (which 
exacerbates blurred vision) occurs approximately concomitantly with mydriasis but usually 
higher doses are required. In susceptible persons, especially the elderly, cycloplegia may 
contribute to an elevation of intraocular pressure. Difficulty in urination and urinary retention 
may occur. Tachycardia is a common side effect. Bradycardia (at low doses), initial tachycardia 
followed by bradycardia (at higher doses), hypotension, and arrhythmia can occur. 
Constipation, bowel stasis, nausea and vomiting may occur. In higher doses (ie, 0.011 mg/kg and 
above), Scopolamine HBT may cause dizziness, restlessness, tremors, fatigue, and locomotor 
difficulties. 
Scopolamine HBT reduces salivary secretion, gastric secretion (both the volume and acid 
content), and also inhibits the motor activity of the stomach, duodenum, jejunum, ileum, and 
colon, characterized by a decrease in tone, amplitude, and frequency of peristaltic contractions. 
5.3.1.3. 
Pregnancy 
Scopolamine HBT is a Category C investigational product. Risks to unborn babies are unknown 
at this time; pregnant females will be excluded from this study. Female subjects should not 
become pregnant for at least 30 days after dose administration. 
5.3.1.4. 
Lactation 
Risks to nursing infants are unknown at this time; breastfeeding females will be excluded from 
this study. 
5.3.1.5. 
Reproductive Health 
The effects of Scopolamine HBT on the reproductive health of men and women are unknown. 
Appropriate contraceptive measures will be required for females of childbearing potential and 
men whose female partners are of childbearing potential. 
Females of childbearing potential must have been using adequate contraception for at least 
3 months prior to drug administration and must agree to use an adequate method of contraception 
for at least 30 days following drug administration. 


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For this study, adequate contraception for females of childbearing potential is defined as a male 
partner using condoms with spermicide or the use of one of the following methods: 
• Cervical cap or diaphragm with spermicidal gel, cream or foam, 
• Hormonal contraceptives (oral, implant, injection, patch, or vaginal ring), or 
• Intrauterine devices. 
Females of nonchildbearing potential are also eligible, defined as a subject who is 
postmenopausal (continuous amenorrhea for 24 months) or surgically sterile (bilateral tubal 
ligation, bilateral oophorectomy, or total hysterectomy). There are no contraceptive requirements 
for females of nonchildbearing potential. 
Males with female partners of childbearing potential must agree to use adequate contraception 
from screening, throughout the study period, and for 30 days after drug administration. Adequate 
male contraception is defined as male condoms with spermicide. 
5.3.1.6. 
Venipuncture 
Blood sampling carries a minimal risk of minor discomfort and the possibility of minor bruising 
at the site of the needle puncture, and the possibility of lightheadedness and fainting. Rarely, 
there is also the possibility of infection at the needle puncture site or inflammation of the vein. 
5.3.1.7. 
Allergic Reaction 
As with any investigational new drug (IND) product administration and no matter what 
precautions are taken, there is always the risk of a serious, or even life-threatening, allergic 
reaction. Medical emergency equipment will be available at the study site to handle emergencies, 
such as anaphylaxis, angioedema, bronchospasm, and laryngospasm. A crash cart will be located 
in close proximity to the treatment room where subjects are residents. 
5.3.1.8. 
Unknown Risks 
As with all research, there is the remote possibility of risks that are unknown or that cannot be 
foreseen based on current information. 
5.3.2. 
Alternatives to This IND Product or Study 
At this time, atropine and 2-PAM are the only approved nerve agent treatments. Scopolamine 
HBT is being evaluated as a potential therapeutic to treat muscarinic symptoms and as an adjunct 
therapeutic to increase survival from lethal exposure to chemical warfare nerve agents. 
An alternative is not to participate in this study. 
5.3.3. 
Intended Benefit for Subjects 
There is no benefit to subjects participating in this study. Payment for participation in this study 
is not a benefit and should not be presented as such. However, potential subjects can be told that 
study results may provide information required for the marketing of a new or improved product. 
Results of this clinical investigation will inform follow-on animal efficacy studies and a Phase 2 
human clinical study of Scopolamine HBT dosing by confirming the PK upon IM administration. 


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PK data are key to determining the efficacious dose of Scopolamine HBT for these future 
studies. 
5.3.4. 
Risks to the Study Personnel and the Environment 
The principal risk in the clinical setting is in the handling of needles that may be contaminated 
and the attendant risks including hepatitis, human immunodeficiency virus (HIV), and other 
human pathogens. Adherence to standard operating procedures (SOPs) for working with 
infectious agents and universal precautions will reduce the risk of exposure. 
There are no known risks to the environment other than those associated with the generation of 
biohazardous waste. All biohazardous waste will be disposed of as stipulated by local, state, and 
federal regulations and in accordance with study site SOPs. 
5.4. 
Route of Administration, Dosage Regimen, Treatment Period, and 
Justification 
Up to 240 subjects will be consented and screened for participation in the study. 
This is a double-blinded, randomized, placebo-controlled, in-clinic, Phase 1, single-dose, IM, 
sequential dose-escalation study in healthy adults aged 18-55. Healthy volunteers will be 
assigned to 1 of 5 cohorts of Scopolamine HBT dosage groups: 0.005, 0.007, 0.011, 0.014, or 
0.021 mg/kg, or receive the placebo, administered by IM injection to the anterior thigh. In each 
cohort, 6 to 9 subjects will receive active drug and 2 to 3 subjects will receive placebo. Each 
cohort will have at least 3 male and 3 female subjects enrolled among the first 8 subjects in the 
dosing group to ensure that at least 1 male subject and 1 female subject in each dosing group 
receive active drug. If nonextreme dose-limiting toxicities (DLTs) are observed in any of the 
cohorts, 4 additional subjects, 3 active and 1 placebo, may be added to each cohort. 
On the first day of dosing for each cohort, 2 subjects will be dosed (1 active and 1 placebo). 
Upon review of the adverse event (AE) data for both subjects at 24 hours post dose (± 1 hour), 
the principal investigator (PI) and the medical monitor will determine if it is safe to proceed with 
dosing the remaining 6 of the first 8 subjects. 
5.5. 
Compliance Statement 
The study will be conducted according to the protocol and in compliance with International 
Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use 
(ICH) Good Clinical Practice (GCP), Belmont Principles, and other applicable regulatory and 
DoD requirements. All identified study personnel will be trained to perform their roles and will 
carry out their responsibilities in accordance with ICH/GCP guidelines and clinic site SOPs. 
5.6. 
Study Population 
Up to 60 (30 to 45 active; 10 to 15 placebo) male and female volunteers, 18 to 55 years of age, 
will be enrolled in 5 dosing groups (cohorts) of 8 to 12 participants each. The actual number 
enrolled in the study will be determined by the safety responses noted during the study.  


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Each of the 5 cohorts will include at least 3 male and 3 female subjects enrolled among the first 8 
subjects in the cohort to ensure that at least 1 male and 1 female subject in each dosing group 
receive active drug.  
In addition, to assure study population diversity in an 8-subject cohort, no more than 5 subjects 
may be enrolled from any one of these single racial and ethnic groups: American Indian or 
Alaska Native, Asian, Black or African American, Native Hawaiian or Other Pacific Islander, 
White, Hispanic/Latino, or Other. If the cohort is expanded to 12 subjects, no more than 8 
subjects (2/3 of the subjects) may be enrolled from any one of the above racial and ethnic groups. 
A specific distribution of subject gender across racial and ethnic groups is not required. 
Refer to Section 12.2 for a statistical justification of the sample size. 
5.7. 
Study Site 
Pharmaron, a clinical pharmacology unit established in 2006, specializes in Phase 1/2a complex 
clinical pharmacology research. Pharmaron occupies the fifth and sixth floors of Building 1 in 
the University of Maryland BioPark. This location in downtown Baltimore, Maryland, is easily 
accessible by public transportation and/or personal vehicle, and volunteers will receive free 
parking in the nearby garage. 
Pharmaron has the necessary experience, personnel, and technical resources to effectively 
conduct the study. Resources include, but are not limited to, a dedicated recruitment department; 
an outpatient unit for screening and follow-up visits; 96 inpatient beds with various unit 
configurations; an on-site, CLIA (Clinical Laboratory Improvement Amendments)-certified 
clinical diagnostic laboratory; and a United States Pharmacopeia (USP) 797-compliant 
pharmacy. Staff includes full-time physicians, physician assistants, nurse practitioners, and 
nursing, regulatory, quality, laboratory, pharmacy, and clinical personnel. Physicians and nursing 
staff are ACLS (Advanced Cardiovascular Life Support) certified. 
Subjects will be recruited from the civilian population in the Baltimore, Maryland, metropolitan 
area and surrounding areas. Recruitment will include data mining of Pharmaron’s racially 
diverse database, study-specific advertising, and pre-screening of potential participants. 
6. 
TRIAL OBJECTIVES AND PURPOSE 
6.1. 
Primary Objective 
The primary objectives of this study are: 
• To characterize the safety and tolerability profile of ascending doses of Scopolamine 
HBT administered by IM injection, and 
• To characterize the PK of ascending doses of Scopolamine HBT administered by IM 
injection. 


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7. 
TRIAL DESIGN 
7.1. 
Study Endpoints 
The safety of Scopolamine HBT will be assessed from: 
• The occurrence, intensity, and relationship of AEs from Day 1 through Day 30 
• Results of clinical laboratory tests (hematology, coagulation, serum chemistry, and 
urinalysis) at Day -1 (baseline) and Days 2, 3, and 8 
• Clinically relevant changes or findings from physical examinations on Day -1 and 
Days 1, 3, and 8 
• Vital signs and ECGs on Day -1, Days 1-3, and Day 8 
• Injection site assessments: 
− Visual analog scales (VAS) for pain, pruritus, tingling, and numbness at pre dose, 
and 5, 10, 15, 30, and 45 minutes, at and 1, 1.5, 3, 5, 8, 12, 24, and 48 hours post 
dose, and at Day 8 (Appendix A) 
− Assessment of pain, tenderness, erythema, and induration at the injection site by a 
physician, physician assistant, or nurse to be performed immediately after the 
VAS (Appendix C) 
• Changes in neuropsychiatric and cognitive status assessments: 
− Brief Psychiatric Rating Scale (BPRS) expended version 4.0, 24-item scale at 
Day -1 (baseline), at 6 (+ 2) hours post dose (timing at the discretion of the 
investigator or designee), 48 hours post dose (prior to discharge), and Day 8 
− Columbia-Suicide Severity Rating Scale (C-SSRS) at Day -1 (baseline) and Day 8 
− Severity of agitation or sedation using the Richmond Agitation and Sedation 
Scale (RASS) if AEs of general agitation or sedation are reported (Appendix D) 
− Persistent cognitive effects using the Digit Symbol Substitution Test (DSST) at 
Day-1 (baseline), 48 hours post dose, and Day 8 (screening DSST will serve as a 
practice session) 
The PK of Scopolamine HBT will be determined from the following parameters calculated from 
plasma concentration using semi-log plots with noncompartmental analysis: 
• Peak plasma concentration, Cmax; 
• Time of peak concentration, Tmax; 
• Apparent volume of distribution, Vd_F; 
• Elimination half-life, t½; 
• Plasma clearance, Cl_F; 
• Area under the curve at last sampling point, AUClast, and at infinity, AUC∞; 
• Mean residence time (MRT); and 


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• Dose proportionality using Cmax/Dose and AUC∞/Dose 
7.2. 
Overall Study Design 
The study events schedule is shown in Table 3. This is a double-blinded, randomized, placebo-
controlled, in-clinic, Phase 1, single-dose, IM, sequential dose-escalation study in healthy adults 
aged 18-55. Healthy volunteers will be assigned to 1 of 5 cohorts of Scopolamine HBT dosage 
groups: 0.005, 0.007, 0.011, 0.014, or 0.021 mg/kg, or receive the placebo, administered by IM 
injection to the anterior thigh. In each cohort, 6 to 9 subjects will receive active drug and 2 to 3 
subjects will receive placebo. Each cohort will have at least 3 male and 3 female subjects 
enrolled among the first 8 subjects in the dosing group to ensure that at least 1 male subject and 1 
female subject in each dosing group receive active drug. If nonextreme DLTs are observed in 
any of the cohorts, 4 additional subjects, 3 active and 1 placebo, may be added to each cohort. 
On the first day of dosing for each cohort, 2 subjects will be dosed (1 active and 1 placebo). 
Upon review of AE data for both subjects at 24 hours post dose (± 1 hour), the PI and the 
medical monitor will determine if it is safe to proceed with dosing the remaining 6 of the first 8 
subjects. 
New subjects will not be enrolled into the next higher dosage group until at least 8 subjects in the 
previous cohort have completed the Day 8 follow-up visit without the occurrence of DLTs, 
predefined as requiring termination of the study; the Data Safety Monitoring Board (DSMB) has 
reviewed data and made a dose-escalation recommendation to the sponsor; and the sponsor 
concurs with the DSMB recommendation. The sponsor must approve dose escalation. Dose 
escalation cannot occur until after sponsor approval of the DSMB recommendation and 
notification of the investigator(s), not at the time of the DSMB recommendation. Table 4 shows 
study events for pre dose through 36 hours post dose. 
This Phase 1, GCP-compliant study is being performed to collect reliable PK data for 
Scopolamine HBT administered IM, as these are not found in the published literature, and to 
inform future studies. The goal of this study is to assess safety, tolerability, and PK, including the 
assessment of dose exposure proportionality, of Scopolamine HBT in the 5 cohorts. 
 


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Table 3: 
Study Events Schedule 
Study Phase 
Screening 
Baselinea 
Treatmenta 
Follow-upb 
Study Day 
-30 to -2 
-1 
1c 
2 
(24 ± 1 h) 
3 
(48 ± 1 h) 
4 
(+ 2 days) 
8 
(+2 days) 
30 
(+ 7 days) 
Procedures 
Informed Consent 
X 
 
 
 
 
 
 
 
Inclusion/Exclusion 
X 
X 
Xd 
 
 
 
 
 
Medical History including Demography 
X 
X 
 
 
 
 
 
 
Physical or Brief Neurological Examination 
X 
X 
Xe 
 
Xe 
 
X 
 
Serum Pregnancy Test 
X 
X 
 
 
 
 
X 
 
Laboratory Safety Testsf 
X 
X 
 
X 
X 
 
X 
 
Serologyg 
X 
 
 
 
 
 
 
 
Urine Drug Screenh 
X 
X 
 
 
 
 
X 
 
Alcohol Breathalyzer Test 
X 
X 
 
 
 
 
 
 
Body Weight and Height/Body Mass Index 
Xi 
Xi 
 
 
Xi 
 
Xi 
 
Vital Signsj 
X 
X 
X 
X 
X 
 
X 
 
Electrocardiogram (ECG), 12-lead (supine)k 
X 
X 
X 
X 
X 
 
X 
 
Dose Administration 
 
 
X 
 
 
 
 
 
Pharmacokinetic Assessment 
 
 
Xl 
X 
X 
 
 
 
Adverse Events 
 
 
Xm 
X 
X 
X 
X 
X 
Prior/Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
X 
Continuous Cardiovascular Monitoring 
 
 
Xn 
Xn 
 
 
 
 
Injection Site Assessmento 
 
 
X 
X 
X 
 
X 
 
Injection Site: VASo 
 
 
X 
X 
X 
 
X 
 
Reminder of Study Restrictions 
X 
 
 
 
X 
X 
X 
 


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Table 3: 
Study Events Schedule (Continued) 
Study Phase 
Screening 
Baselinea 
Treatmenta 
Follow-upb 
Study Day 
-30 to -2 
-1 
1c 
2 
(24 ± 1 h) 
3 
(48 ± 1 h) 
4 
(+ 2 days) 
8 
(+2 days) 
30 
(+ 7 days) 
Procedures 
Brief Psychiatric Rating Scale (BPRS)p 
X 
X 
X 
 
X 
 
X 
 
Columbia-Suicide Severity Rating Scale 
(C-SSRS)q 
X 
X 
 
 
 
 
X 
 
Richmond Agitation and Sedation Scale 
(RASS) 
 
 
Xr 
 
 
 
 
Structured Clinical Interview for DSM-5, 
Clinical Trial version (SCID-5-CT) 
 
Xs 
 
 
 
 
 
Digit Symbol Substitution Testt 
X 
X 
 
X 
 
X 
 
a Subjects will be in clinic for the baseline and treatment days. Days 2 and 3 procedures should be performed at 24 and 48 hours (± 1 hour) post dose, 
respectively, except for PK samples, which should be collected as close to the specified time points as possible. Refer to Table 4 for expansion of pre-dose 
through 36-hour post-dose activities. 
b Day 4 and Day 30 follow-up is conducted by telephone. Day 4 follow-up may be performed on Days 4-6. Day 30 follow-up may be performed on Days 30-37. 
Day 8 follow-up is an in-clinic visit and may be performed on Days 8-10. Note: Subjects who withdraw/are withdrawn after receiving study drug will undergo 
all Day 8 follow-up procedures, including pregnancy testing for females, if possible. 
c See Table 4 for study events occurring pre dose through 36 hours post dose. 
d Final eligibility criteria review and completion of eligibility checklist prior to dosing. 
e Abbreviated physical examinations with changes from Day -1 (baseline) noted; Day 1 exam is prior to dosing; brief neurological assessment at 1 hour post 
dosing (+30 min) to evaluate alertness/level of consciousness, orientation, ability to follow commands and coordination (refer to Section 11.1.5 and footnote r 
below). 
f Hematology (including coagulation), serum chemistry, and urinalysis (refer to Section 11.1.9.1, Section 11.1.9.2, and Section 11.1.9.3, respectively, for specific 
tests). Fasting ≥ 8 hours at screening. Adequacy of venous access will be assessed and documented at screening. 
g Hepatitis B surface antigen, hepatitis C, HIV-1/2, and syphilis testing at screening only. 
h Urine drug screen (refer to Section 11.1.9.5 for specific tests). 
i Body weight (kg) and height (cm; screening only) will be measured at screening and body mass index (BMI) calculated. Weight will be measured on Day -1 
with BMI calculation. Day-1 weight to be used for Day 1 dose determination. Weight will be measured at Day 3 and Day 8 with no BMI calculation. 
j Systolic and diastolic blood pressure, heart rate, respiration rate, body temperature, and pulse oximetry will be performed after subject has been supine for at 
least 5 minutes. See Table 4 for vital sign time points from pre dose through 24 hours post dose. 
k See Table 4 for time points to performing ECG (supine) from pre-dose through 24 hours post-dose. 


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l See Table 4 for PK sample collection time points from pre dose through 36 hours post dose. PK samples should be collected as close to the actual time point as 
possible (within the windows specified in Table 8); however, when multiple tests are scheduled at the same time, ECG and vital signs will be performed within 
5 minutes prior to the time point, and injection site and AE assessments will be performed immediately after the PK blood draw. AEs identified prior to dosing 
will be considered part of the medical history. Urine PK samples will be collected prior to dosing (no earlier than 2 hours pre dose) and for 24 hours after 
dosing. All urine specimens will be pooled into 1 of 3 collection interval containers by the subject. See Table 4 for collection intervals from pre dose through 
24 hours post dose. Refer to Section 9 for details. 
m See Table 4 for AE assessment time points from pre dose through 24 hours post dose. 
n Continuous cardiovascular monitoring of ECG (3-lead) and vital signs (blood pressure (at 5-15 min intervals), heart rate, respiration rate, and pulse oximetry) 
from 1 hour prior to dosing through 24 hours post dose (see Table 4 and Section 11.1.2 for details). 
o Injection site assessments: Subject will be asked to rate the maximum intensity of pain, pruritus, tingling, and numbness using the VAS. See Table 4 for 
assessment time points from pre dose through 24 hours post dose. Immediately following the subjective assessment, an assessment of pain, tenderness, 
erythema, and induration at the injection site will be performed by a physician, physician assistant, or nurse. 
p See Table 4 for assessment time points on Day 1. For items assessed over time (eg, items 1, 2, and 3), the period of assessment should be “over the prior week,” 
except for the assessments performed at 6-8 and 48 hours post dose, which should be assessed “since the prior assessment.” 
q C-SSRS will be assessed at screening, Day -1 (baseline), and Day 8. 
r  RASS will be used to assess alertness/level of consciousness at 1 hour post dosing (+30 min) (see footnote e above), and at other times for severity if AEs of 
general agitation or sedation occur. 
s SCID-5-CT will be administered at Day -1 to identify the presence of any major DSM-5 Axis I or II disorder. Note: Alternates who return for dosing on 
another day will not have the SCID repeated. 
t The DSST will be administered at screening, baseline, 48 hours post dose, and Day 8 to detect any persistent cognitive impairment. The DSST will not be used 
to determine eligibility. 
 


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Table 4: 
Study Events Schedule – Pre Dose through 36 Hours Post Dose 
Activity/Assessment 
Pre 
Dose 
Dosing = Time 0 
Minutes Post-dose 
Hours Post-dose 
2 
5 
10 
15 
20 
30 
45 
1 
1.5 
2 
3 
4 
5 
8 
12 
24 
36 
ECG 
X 
 
X 
X 
X 
 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
 
Vital Signs 
X 
 
X 
X 
X 
 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
 
Abbreviated Physical or 
Brief Neurological Exama 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
Injection Site: VASb 
X 
 
X 
X 
X 
 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
 
Injection Site: Physician, 
Physician Assistant or 
Nurse 
X 
 
X 
X 
X 
 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
 
BPRSc 
 
 
 
 
 
 
 
 
 
 
 
 
 
6 
 
 
 
C-SSRS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
RASSd 
 
At 1 hour post-dosing (+30 min) and as needed to assess severity only if adverse events of general agitation 
or sedation occur 
Final Eligibility 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility Checklist 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine PK Samplese 
X 
0-4 h 
4-12 h 
12-24 h 
 
Blood PK Samples 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
Safety Lab Tests 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Adverse Events 
X 
 
X 
X 
X 
 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
 
Concomitant Medications 
X 
 
X 
X 
X 
 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
 
Continuous Cardiovascular 
Monitoring 
Begin 
ECG (3-lead) and vital signs (blood pressure (5-15 min intervals), heart rate, respiration rate, 
and pulse oximetry)(see Section 11.1.2 for details) 
End 
 
Error! Reference source not found. 
Abbreviated physical exam at pre-dose; brief neurological assessment at 1 hour post dosing (+30 min) to assess 
alertness, orientation, ability to follow commands and coordination (refer to Section 11.1.5  and footnote d below). 


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b If the PI or designee determines a subject is incapable of providing valid responses on the VAS due to the neuropsychiatric effects of Scopolamine HBT, the 
reason(s) why the VAS assessment(s) could not be done will be documented by time point in the source. 
c BPRS will be performed at 6 (+ 2) hours post dose. The + 2-hour window is provided to allow the investigator some discretion should the assessment need to 
be delayed or cannot be performed. The timing may be dependent on the emergence and severity of neuropsychiatric symptoms. The reason(s) why the BPRS 
was delayed or could not be done will be documented in the source. 
d RASS will be employed as part of the brief neurological assessment at 1 hour post dosing (+30 min) to assess alertness/level of consciousness, and at other 
times if adverse events of agitation or sedation occur.  
e Record the time and estimated volume of individual voids from pre dose through 24 hours post dose. This information will assist in the assessment of urine 
output and hydration, and will subsequently be used to calculate the total volume of urine pooled for each PK collection interval. Refer to Section 9.1.1.3 for 
details. 


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7.3. 
Measures Taken to Minimize/Avoid Bias 
7.3.1. 
Randomization 
Subjects who are eligible for the study following the clinical assessments will be randomly 
assigned to receive Scopolamine HBT, Injection or placebo. The randomization will be balanced 
by using randomly permuted blocks. Randomization will be performed by coded list, provided 
by the study statistician, to which the pharmacist and pharmacy team will be unblinded. The 
pharmacist and/or pharmacy technician will prepare and document the blinded drug to be 
administered. The person administering the study drug will be blinded. In each cohort, 6 to 9 
subjects will receive active drug and 2 to 3 subjects will receive placebo. Each cohort will have 
at least 3 male and 3 female subjects enrolled among the first 8 subjects in the cohort to ensure 
that at least 1 male subject and 1 female subject in each dosing group receive active drug. 
7.3.2. 
Blinding 
This study is double blinded. The study drugs (active and placebo) are filled in amber vials with 
a 1.2-mL fill volume, are clear and colorless liquids, and labeling is identical. The pharmacist 
and/or pharmacy technician at the clinical site will fill syringes for each study subject on dosing 
days to maintain the blind of the study staff. However, once a subject has been dosed with 
Scopolamine HBT, Injection, the study staff, including the investigators, will likely become 
unblinded as the CNS effects of Scopolamine HBT will be evident in the subjects, especially at 
the higher concentrations. Nevertheless, every effort should be made to maintain the blind, even 
at the higher concentrations. Study participants who become unblinded will be encouraged to 
maintain the confidentiality of the blind from other study staff if possible, as well as other study 
participants. 
7.3.3. 
Unblinding 
Unblinding of a subject should be requested only in the case of medical emergency or in the 
event of a serious medical condition when, in the opinion of the PI, knowledge of the 
investigational product is essential for the clinical management or welfare of the subject. 
Whenever possible before the blind is broken, the pharmacovigilance (PVG) physician will be 
consulted to discuss the rationale for the request. When a request for unblinding cannot be made 
prior to providing emergency treatment, the PI may unblind the subject’s treatment. 
The clinical site pharmacist will have access to individual randomization codes and can perform 
emergency unblinding in the event of a medical emergency or serious medical condition upon 
approval of the PI. 


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Contact Information for Emergency Unblinding: 
Any emergency unblinding of individual treatment assignments and the reason for unblinding 
will be clearly specified by the PI in the source documentation and reported to the 
 
 
 immediately (within 24 hours) via the telephone 
number or safety e-mail address below: 
 
 
7.4. 
Investigational Product 
Table 5 shows a summary description of the investigational product, Scopolamine HBT, 
Injection and the comparator product, Scopolamine Hydrobromide Placebo. 
Table 5: 
Investigational Products 
Product Name 
Scopolamine Hydrobromide 
Trihydrate, Injection 
Scopolamine Hydrobromide 
Placebo 
Dosage Form 
Liquid 
Liquid 
Unit Dose 
0.8 or 2.0 mg/mL 
0 mg/mL 
Route of Administration 
IM 
IM 
Physical Description 
Amber vial with a clear, colorless 
liquid of 0.8 mg/mL and 2.0 mg/mL 
Scopolamine HBT in 1 mM citrate 
buffer; 150 mM sodium chloride; and 
adjusted to pH 3.0 ± 0.1 with 
hydrochloric acid and sodium 
hydroxide 
Amber vial with a clear, 
colorless liquid of citrate buffer 
Manufacturer 
Ology Bioservices, Inc 
Ology Bioservices, Inc 
Lot Number 
TBD 
TBD 
Product Indication 
Scopolamine is being developed as a 
muscarinic receptor antagonist 
(SCTID 734696004) indicated for 
cholinergic crisis (SCTID 8563000). 
Scopolamine is a muscarinic 
antagonist indicated for temporary 
relief or improvement of muscarinic 
effects 
Comparator product 
For this study, the treatments to be administered are 0.005, 0.007, 0.011, 0.014, and 0.021 mg/kg 
of Scopolamine HBT, depending on cohort assignment, or placebo as a one-time dose to study 
subjects via IM injection in the anterior thigh muscle. In each cohort, 6 to 9 subjects will receive 
active drug and 2 to 3 subjects will receive placebo. Each cohort will have at least 3 male and 3 
female subjects enrolled among the first 8 subjects in the cohort to ensure that at least 1 male 
subject and 1 female subject in each cohort receive active drug. 


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7.4.1. 
Investigational Product Packaging and Labeling 
The investigational product, Scopolamine HBT, Injection (0.8 mg/mL and 2.0 mg/mL, 
equivalent to 0.55 mg and 1.38 mg Scopolamine, respectively) and Scopolamine HBT placebo 
are packaged in amber, 2-mL Type I USP glass vials with 13-mm sterile serum stoppers and 
sealed with 13-mm blue, red, or white flip-off crimp seals, respectively. Each single-use vial 
contains 1.2 mL (± 0.2 mL). 
Scopolamine HBT, Injection product components are as follows: 
• Scopolamine HBT, USP 
• Sterile Water for Injection 
• Sodium Chloride 
• Citric Acid Anhydrous 
• Sodium Citrate Dihydrate 
• 0.1 N Hydrochloric Acid 
The Scopolamine HBT Placebo product components are as follows: 
• Sterile Water for Injection 
• Sodium Chloride 
• Citric Acid Anhydrous 
• Sodium Citrate Dihydrate 
• 0.1 N Hydrochloric Acid 
Examples of the investigational product vial and carton labels (0.8 mg/mL, 2.0 mg/mL, and 
placebo) are shown in Figure 2. Please note the label text has been enlarged for legibility 
purposes; the actual label dimensions and font will be smaller. 
Figure 2: 
Scopolamine HBT Injection 0.8 mg/mL and 2.0 mg/mL and Placebo Labels 
0.8 mg/mL Vial Label 
 
0.8 mg/mL Carton Label 
Scopolamine Hydrobromide Trihydrate, 
Injection, 0.8 mg/mL (0.55 mg of Scopolamine) 
Item Number: 10-0003825       Lot No.: XXXXX 
Contents: 1.2 mL ± 0.12 mL       Storage: 15-25°C            
Protect from light            DOM: DDMMMYYYY 
CAUTION:  New Drug-Limited by Federal (or United  
States) Law to Investigational Use 
Manufactured by Ology Bioservices for the 
Surgeon General – Department of the Army 
 
Scopolamine Hydrobromide Trihydrate, Injection, 0.8 mg/mL 
(0.55 mg of Scopolamine) 
Item Number: 10-0003825        Lot No.: XXXXX    
Storage: 15-25°C         __________ vials in Carton   
CAUTION:  New Drug-Limited by Federal (or United States) Law to 
Investigational Use 
Manufactured by Ology Bioservices, Alachua, FL for the Surgeon 
General – Department of the Army 
State of Florida Prescription Drug Manufacturing License. 20313 
 


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2.0 mg/mL Vial Label 
 
2.0 mg/mL Carton Label 
Scopolamine Hydrobromide Trihydrate, 
Injection, 2.0 mg/mL (1.38 mg of Scopolamine) 
Item Number: 10-0003826       Lot No.: XXXXX 
Contents: 1.2 mL ± 0.12 mL       Storage: 15-25°C            
Protect from light            DOM: DDMMMYYYY 
CAUTION:  New Drug-Limited by Federal (or United  
States) Law to Investigational Use 
Manufactured by Ology Bioservices for the 
Surgeon General – Department of the Army 
 
Scopolamine Hydrobromide Trihydrate, Injection, 2.0 mg/mL 
(1.38 mg of Scopolamine) 
Item Number: 10-0003826        Lot No.: XXXXX    
Storage: 15-25°C         __________ vials in Carton   
CAUTION:  New Drug-Limited by Federal (or United States) Law to 
Investigational Use 
Manufactured by Ology Bioservices, Alachua, FL for the Surgeon General 
– Department of the Army 
State of Florida Prescription Drug Manufacturing License. 20313 
 
Placebo Vial Label 
 
Placebo Carton Label 
 
Scopolamine Hydrobromide Trihydrate Placebo 
Item Number: 10-0003824       Lot No.: XXXXX 
Contents: 1.2 mL ± 0.12 mL       Storage: 15-25°C             
Protect from light            DOM: DDMMMYYYY 
CAUTION:  New Drug-Limited by Federal (or United States) 
Law to Investigational Use 
Manufactured by Ology Bioservices for the 
Surgeon General – Department of the Army 
 
Scopolamine Hydrobromide Trihydrate Placebo 
Item Number: 10-0003824        Lot No.: XXXXX    
Storage: 15-25°C         __________ vials in Carton   
CAUTION:  New Drug-Limited by Federal (or United States) Law to 
Investigational Use 
Manufactured by Ology Bioservices, Alachua, FL for the Surgeon General – 
Department of the Army 
State of Florida Prescription Drug Manufacturing License. 20313 
7.4.2. 
Investigational Product Storage 
All investigational products will be stored at 15°C-25°C and protected from light. 
7.4.3. 
Investigational Product Preparation 
No dilutions are required prior to administration of the investigational products. Dosing volumes 
are calculated by subject weight and drawn directly from the vial. For complete details of dose 
preparation and administration, refer to the pharmacy manual.  
Note: For determining the clinical dosing calculations, the concentration of Scopolamine HBT 
(Scopolamine Hydrobromide Trihydrate, Injection 0.8 mg/mL and Scopolamine Hydrobromide 
Trihydrate, Injection 2.0 mg/mL) should be used. 
7.4.4. 
Investigational Product Accountability 
The sponsor’s representative is responsible for distributing the investigational product to the 
study site. The sponsor’s representative has delegated drug accountability responsibility for this 
product to the PI at the study site; however, the sponsor’s representative has ultimate 
responsibility for product accountability. After the investigational product is distributed, the PI is 
responsible for and will maintain logs of investigational product receipt, storage, reconstitution, 
accountability by subject, and investigational product remaining before final disposition. The PI 
may delegate, in writing, this responsibility to another individual, but the PI is ultimately 
responsible for the investigational product and its proper storage upon receipt at the study site 
until it is transferred back to the sponsor’s representative or designee or is destroyed, as directed 


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by the sponsor’s representative. At the study site, the logs will be maintained in the product 
accountability files within the pharmacy. 
All unused or partially used investigational product and empty vials will be destroyed or returned 
to the responsible party, as directed by the sponsor’s representative at the end of the study, and as 
stipulated by local, state, and federal regulations. 
7.5. 
Duration of Subject Participation 
Study subject participation includes 4 days and 3 nights for the in-clinic phase. Subjects will be 
administered drug product on Day 1 and released on Day 3. Study staff will follow up with each 
subject via telephone on Day 4. Subjects will return for an in-clinic visit on Day 8, and study 
staff will follow up with each subject via telephone on Day 30. Total duration of subject 
participation in the study, including the screening period and the 30-day, post-dose telephone 
follow-up, may be up to 9 weeks. 
7.6. 
Dose-adjustment Criteria 
New subjects will not be enrolled into the next higher dosage group until at least 8 subjects in the 
previous cohort have completed the Day 8 follow-up visit without the occurrence of DLTs, and 
the DSMB has made a recommendation to the sponsor regarding dose escalation. The sponsor 
must approve the dose escalation and notify the investigator(s) before any new subjects can be 
enrolled. The occurrence of any DLT(s) would result in the immediate discontinuation of dosing 
and study enrollment, pending a review of study data by the PI, research monitor, PVG 
physician, the DSMB, and the sponsor. 
7.6.1. 
Safety Criteria for Dose Adjustment or Stopping Doses 
For the purposes of determining continued dosing within a cohort or dose escalation to a 
subsequent planned cohort, stopping rules are based on the emergence of DLTs. Nonextreme and 
extreme DLTs will be considered related AEs/serious adverse events (SAEs) and will be 
recorded/reported as such. 
Dosing of study drug and study enrollment will be halted (temporarily or permanently) as 
follows: 
• Occurrence of any extreme DLT (dosing and enrollment to be halted immediately; PI, 
research monitor, PVG physician, and DSMB will review and make a 
recommendation to the sponsor, which will determine if dosing and enrollment may 
continue); 
• Emergence of a specified number (see Table 6) of nonextreme DLTs among subjects 
in a particular dosage group (DSMB will review to determine whether dosing and 
enrollment may continue); 
• Occurrence of an SAE not already designated as an extreme or nonextreme DLT, 
determined to be possibly, probably, or definitely related to the investigational 
product; dosing and enrollment to be halted immediately until the DSMB has 
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• Sponsor, DSMB, or PI’s clinical judgment warrants stopping based on ongoing 
review of the safety profile. 
The maximum tolerated dose will be the highest dose at which none of the following has been 
observed: 
• An extreme DLT in any one subject; 
• A nonextreme DLT in 2 of the first 4 subjects or in 3 subjects at any time; and 
• Any SAE, not already categorized as a DLT that is considered to be possibly related, 
probably related, or definitely related to the study drug. 
7.6.1.1. 
Extreme Dose-Limiting Toxicities 
In the event that any one of the following extreme DLTs is evident, the PI is to discontinue 
dosing study drug and study enrollment immediately, pending review by the PI, research 
monitor, PVG physician, and DSMB. These extreme DLTs include: 
• Respiratory 
− Prolonged apnea or respiratory distress where intubation is required 
• Neuropsychiatric 
− Presence of convulsions or seizure-like activity 
− Neuropsychiatric symptoms (eg, delirium, paranoia, and/or hallucinations) 
requiring treatment with physostigmine or other medication(s) and, in the opinion 
of the investigator, did not adequately respond to treatment 
• Cardiovascular 
− Cardiac arrest 
− Clinically significant hypotension that requires IV fluids or vasopressors 
− Cardiac arrhythmias 
▪ 10 AV block (if the PR interval becomes ≥ 280 milliseconds) 
▪ If the QRS duration increases by more than 25% from the pre-dose 
measurement and is > 140 msec 
▪ QTc (Fridericia) is > 500 msec and increase of QTc of 60 msec from 
baseline 
▪ AV block (2nd degree, 3rd degree) 
▪ Bundle branch block 
▪ Bigeminy or trigeminy associated with hypotension 
▪ Atrial fibrillation or atrial flutter 


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7.6.1.2. 
Nonextreme Dose-Limiting Toxicities 
Nonextreme DLTs are AEs that do not meet the criteria for extreme DLTs but are serious 
conditions that require immediate medical attention and monitoring. The incidence and severity 
of these events will be used to determine whether (1) the total cohort size will be increased from 
8 to 12 and (2) the need to suspend dosing until the DSMB has completed a safety review and 
made a recommendation to the sponsor (Table 6). Nonextreme DLTs include: 
• Respiratory 
− Spontaneous respiratory rate < 8 or > 25 breaths per minute, with oxygen 
saturation less than 90%, which cannot be explained by agitation or other 
behavioral symptoms and that does not respond immediately to oxygen 
supplementation via nasal cannula or face mask but for which there is recovery 
without sequelae prior to the need for intubation 
− Dyspnea at rest 
− Symptomatic bronchospasm 
• Neuropsychiatric 
− Neuropsychiatric symptoms (eg, delirium, paranoia, and/or hallucinations) 
requiring treatment with physostigmine or other medication(s) and, in the opinion 
of the investigator, responded adequately to treatment 
− Persistent neuropsychiatric symptoms, defined as a score of 4 or higher on any 
one item or a total score of 40 or higher on the BPRS assessment at the 48-hour, 
post-dose evaluation 
− Paresthesia that interferes with any activity 
− Athetoid movement 
• Cardiac 
− Hypertension, which cannot be explained by agitation or other behavioral 
symptoms, requiring antihypertensive medication 
− Cardiac arrhythmias or changes that are deemed clinically significant but do not 
cause the subject to be hemodynamically unstable 
− QTc is > 450 msec for males or >470 msec for females and has increased 
> 60 msec from baseline 
− Supraventricular tachycardia alone without hemodynamic compromise 
− Bigeminy or trigeminy not associated with hypotension 
• Renal 
− Increase of serum creatinine by ≥ 0.3 mg/dL (≥ 26.4 µmol/L) or increase to 
≥ 150% from baseline or urine output < 0.5 mL/kg/hour for > 6 hours 
• Injection Site Reaction 


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− Any reaction determined to be severe, as defined by the FDA’s guidance for 
injection site reactions (Appendix B). 
7.6.1.3. 
Serious Adverse Events 
In the event of an SAE that has not already been designated as a DLT but has been determined 
by the PI, research monitor, and PVG physician to be possibly, probably, or definitely related to 
the study drug, the PI is to discontinue dosing study drug and study enrollment immediately until 
the DSMB has completed a safety review and made a recommendation to the sponsor. The 
sponsor must concur with the recommendation and notify the investigator(s) before enrollment 
can be resumed (see Section 11.2.2 for SAE criteria.) 


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Table 6: 
Progression of Dosing Related to Dose-Limiting Toxicity Events 
Dose-Limiting Toxicity 
Number of Subjects 
Action 
Follow-up 
Extreme DLT 
1 
Dosing and 
enrollment halted 
PI, research monitor, PVG 
physician, and DSMB 
review; sponsor determines 
whether trial should continue 
Nonextreme DLT 
1 of first 4 in a cohort 
(or 2 in the first 8) 
Dosing halted 
PI, research monitor, PVG 
physician, and DSMB 
review; sponsor determines 
whether to increase cohort 
size from 8 to 12 
 
2 of the first 4 in a 
cohort (or 3 total) 
Dosing and 
enrollment halted 
PI, research monitor, PVG 
physician, and DSMB 
review; sponsor determines 
whether trial should continue 
SAE Not Already 
Designated as a DLT 
(except unrelated) 
1 
Dosing and 
enrollment halted 
DSMB to make 
recommendation to sponsor 
whether trial should continue 
In summary, if any one subject has an extreme DLT, enrollment and dosing will be halted 
pending review by the PI, research monitor, PVG physician, and DSMB. In making its 
determination, the DSMB will review all relevant data and obtain additional input as needed. As 
a guideline to the DSMB, it is suggested that if a nonextreme DLT is observed that the DSMB 
consider an increase in the cohort sample size from 8 to 12 if one nonextreme DLT is observed 
in the first 4 subjects or 1 or 2 nonextreme DLTs are observed in the first 8 subjects and that 
enrollment be halted if nonextreme DLTs are observed in 2 of the first 4 subjects in a cohort or 
in a total of 3 subjects at any time. 
If an SAE occurs at any time that is not already designated as an extreme or nonextreme DLT, 
unless it is reported as unrelated to the study drug, enrollment and dosing will also be halted 
pending review by the DSMB. While the presence of any specific AE may not necessarily halt 
enrollment, careful reporting of these events is necessary. After thorough review by the DSMB 
and consultation with the investigators, a decision will be made by the sponsor whether to 
proceed with the dosing escalation. 
If any of the above events occurs, administration of investigational product will be discontinued 
until a thorough review of the events is undertaken by the investigators, local Institutional 
Review Board (IRB) and/or 
 
, research monitor, and/or sponsor’s safety office 
 
. The study may be resumed with the concurrence of the research monitor, PVG 
physician, sponsor’s representative, PI, and the FDA. 
7.6.2. 
Pharmacokinetic Criteria for Dose Adjustment or Stopping Doses 
A goal of this clinical study is to determine the PK parameters of Scopolamine HBT after IM 
administration. The predicted efficacious Cmax, based on limited nonclinical studies, is 


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16-18 ng/mL. At the end of each cohort, the PI, DSMB, and sponsor will evaluate the safety 
outcomes and PK data associated with the Scopolamine HBT dosing for that group.  
7.6.3. 
Study Termination Criteria 
The PI, research monitor, sponsor’s representative, the local IRB, and/or the 
, 
DSMB, or the FDA may stop or suspend the use of this product at any time. 
7.7. 
Trial Treatment Randomization Assignments 
Randomization tables, containing the dosing assignments (active or placebo) for up to 
12 subjects in each cohort, will be provided by the statistician to the unblinded pharmacist at the 
clinical site. The tables will be maintained in the secure, limited-access pharmacy and accessed 
by unblinded pharmacy staff only. Refer to Section 7.3.3 for unblinding procedures. 
7.8. 
Identification of Data to Be Recorded on the Case Report Forms 
The electronic case report form (eCRF) data will be transcribed from source documentation. No 
source data will be recorded directly in the eCRF (ie, without prior written or electronic record of 
data). The transcribed data will be consistent with the source documents or the discrepancies will 
be explained. 
For more information on data handling, refer to Section 16. 
8. 
SELECTION AND WITHDRAWAL OF SUBJECTS 
Recruitment of Subjects 
Refer to Section 5.6 for a detailed description of the subject population. 
Subjects will be recruited from the civilian population in the Baltimore, Maryland, metropolitan 
area and surrounding areas via advertisement, word-of-mouth, the Internet to include social 
media, and other media methods. Interested subjects who meet the prescreening criteria will be 
scheduled for an in-clinic visit. Any questions asked of subjects during the recruitment process 
(prior to informed consent) will respect the privacy of their protected health information and will 
have been reviewed and approved by the IRB.  
After reviewing the informed consent form, subjects will have the opportunity to ask any 
questions related to the study. All subjects who wish to enroll in the study must provide written 
informed consent. After providing written consent, subjects will be given an IRB-approved ICF 
assessment test to verify each subject has a clear understanding of the study and study 
procedures. Subjects will have three attempts to pass the test. Incorrect responses will be 
discussed with the subject between attempts.  
Eligibility Screening 
Each subject must meet all inclusion and no exclusion criteria. The PI or designee will make the 
final decision on eligibility. Only eligible subjects will be given the investigational product. 
Before any study-related procedures are conducted, a written, signed informed consent form 
(ICF) must be obtained and the subject assigned a subject number. Study material, including 


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ICFs, will be available only in English. AEs will be recorded from the time of investigational 
product administration on Day 1. AEs reported or observed after the screening visit but prior to 
administration should be added to the subject’s medical history. After informed consent is 
obtained, screening procedures can begin. Subjects who are prescreened on the telephone but 
who do not sign an ICF will not be assigned a subject number. The investigator or designee will 
maintain a subject master list of every subject who has signed an ICF. A copy of the list should 
be retained in the investigator’s study files. 
Informed consent must be obtained and an IRB-approved ICF signed and dated by the subject 
before any study-related procedures can be performed. After obtaining informed consent, the 
following will be completed: 
• A complete medical history with demography including date of birth, gender, race 
and/or ethnicity, any surgeries/hospitalizations (including childbirth), past or current 
treatments, past and current illnesses (including psychiatric history), and other 
information, as specified on the eCRF. Females of childbearing potential will be 
asked to list their current contraceptive method(s) for comparison with the 
requirements of this study (refer to Section 5.3.1.5). 
• Vital signs, including systolic and diastolic blood pressure, heart rate, respiration rate, 
body temperature, and pulse oximetry, will be measured after the subject has been 
supine for at least 5 minutes. 
• Weight (kg) and height (cm; screening only) will be recorded and body mass index 
(BMI) calculated. 
• A complete physical examination including the review of all major systems including 
general appearance; eyes, ears, nose, and throat (EENT); chest/respiratory; 
heart/cardiovascular; abdomen/gastrointestinal; lymph nodes/spleen; genitourinary 
(prostate exam is not required); musculoskeletal (including assessment of upper leg 
muscle tissue (ie, adequacy for IM injection); skin; neurological; and hepatic 
• Prior/concomitant medications review 
• ECG (12-lead) will be performed after the subject has been supine for at least 
5 minutes. 
• BPRS will be administered by a psychologist or trained clinician 
• C-SSRS (Baseline/Screening version) and DSST will be administered by study staff 
• Blood samples (fasting ≥ 8 hours) for hematology, coagulation, and serum chemistry 
(refer to Section 11.1.9.1 and Section 11.1.9.2 for specific tests) 
• Venous access assessment (performed during blood collection) 
• Serum pregnancy test (all females regardless of childbearing potential) 
• Blood sample for serology testing (hepatitis B surface antigen, hepatitis C, HIV-1/2, 
and syphilis) 
• Urine samples for urinalysis (refer to Section 11.1.9.3 for specific tests) 
• Urine drug screen (refer to Section 11.1.9.5 for specific tests) 


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• Alcohol breathalyzer test 
• Assessment of inclusion/exclusion criteria 
• Reminder of study restrictions 
Subjects will be notified at the time of the screening visit if any completed tests will exclude 
them from the study. However, because not all test results will be known by the end of the 
screening visit, subjects will be contacted by telephone a few days after their screening visit and 
told whether they qualify for the study and any reason for exclusion. Any subjects who have 
been found to be positive (reactive) for hepatitis B surface antigen, hepatitis C, HIV-1/2, or 
syphilis will be asked to come to the study site to discuss the results of the screening test, and 
results will be reported to the local health department. These subjects will be provided 
counseling and referrals to the appropriate healthcare providers. 
8.1. 
Subject Inclusion Criteria 
A subject must meet all of the following criteria to be included in the study: 
1. Male or female, 18 to 55 years of age, inclusive, at the time of drug administration 
2. Without clinically significant abnormities on physical examination at screening or prior 
to drug administration 
3. Generally healthy, as determined by medical history review, physical examination, and 
laboratory testing at screening and prior to drug administration 
4. Must have a BMI of ≥ 19.0 and ≤ 30.0, and weight range of 55.0 to 85.0 kg at screening 
or prior to drug administration 
5. Must have adequate venous access and sufficient upper leg muscle tissue for drug 
administration 
6. If female, the subject must be nonpregnant and nonbreastfeeding, and have a negative 
serum pregnancy test at screening and prior to drug administration 
7. If female of childbearing potential, the subject must have been using adequate 
contraception (as defined in Section 5.3.1.5), for at least 3 months prior to drug 
administration and must agree to use an adequate method of contraception for at least 
30 days following drug administration 
8. Females of nonchildbearing potential are also eligible, defined as a subject who is 
postmenopausal (continuous amenorrhea for 24 months) or surgically sterile (bilateral 
tubal ligation, bilateral oophorectomy, or total hysterectomy) 
9. A male with a female partner of childbearing potential must agree to use a barrier method 
of contraception (defined as condoms with spermicide) for at least 30 days following 
drug administration 
10. If male, must not have past diagnoses of benign prostatic hypertrophy or urinary tract 
obstruction and must not have on screening history/review of systems symptoms 
suggestive of urinary tract obstruction (eg, urinary hesitancy, urgency, frequency, or 
nocturia) 


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11. Nonsmoker/tobacco/nicotine product (including e-cigarettes) user within 3 months of 
first dosing and must have a total lifetime exposure to cigarettes of < 15 pack-years 
12. No evidence of significant neuropsychiatric disorders based on the BPRS at screening 
and prior to drug administration, which is defined as having a global score of ≤ 25 with 
no score higher than 2 on any one item, with the exception of a score of 1 (ie, Not 
Present) to disorientation, hallucinatory behavior, and suspiciousness (ie, paranoia) 
13. No evidence of suicidal ideation or behavior at screening and prior to drug 
administration, which is defined as having a global score of 0 on the C-SSRS 
14. Ability to read, speak, and comprehend English and a willingness to sign informed 
consent 
8.2. 
Subject Exclusion Criteria 
A subject meeting any of the following criteria will be excluded from the study: 
1. Received any other investigational drug within 30 days prior to drug administration 
2. Known allergies to any component of the study drug, other belladonna alkaloids, or the 
recovery medications (physostigmine, atropine, or benzodiazepines [diazepam or 
lorazepam]) 
3. History of migraine headaches or seizures 
4. History of psychosis or psychotic episodes 
5. Clinically relevant abnormal physical findings (including vital signs) as determined by 
the investigator at screening or prior to drug administration that could interfere with the 
objectives of the study or the safety of the subject 
6. Has ongoing drug abuse/dependence (including alcohol), recent history (over the past 5 
years) of treatment for alcohol or drug abuse, or a current positive alcohol breathalyzer 
test or current positive urine test for drugs of abuse (as defined in Section 11.1.9.5) at 
screening or prior to drug administration 
7. Has consumed Seville orange (bitter orange), grapefruit, grapefruit juice, other 
grapefruit-containing products, or starfruit within 7 days prior to dosing 
8. Has consumed caffeine or other xanthine-containing products within 7 days prior to 
dosing 
9. Has any specified laboratory values (eg, hematology, serum chemistry, and urinalysis) 
outside of the normal range for age and sex and deemed clinically significant by the 
investigator within 30 days before drug administration 
10. Has positive (reactive) test results for hepatitis B surface antigen, hepatitis C, syphilis, 
HIV-1, or HIV-2 
11. Has narrow-angle glaucoma or high intraocular pressures in either or both eyes 
12. Has pyloric obstruction or urinary bladder neck obstruction 
13. Has impaired liver or kidney functions 


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14. Clinically relevant ECG abnormalities on any 12-lead ECG obtained at screening or prior 
to dosing 
15. ECG with a PR interval ≥ 200 msec at screening or prior to dosing 
16. ECG with QRS duration > 120 msec at screening or prior to dosing 
17. ECG RR interval > 1500 msec at screening or prior to dosing 
18. ECG with a QTc interval > 450 msec for males or 470 msec for females (QT interval 
corrected with Fridericia correction (QTcF)) at screening or prior to dosing 
19. Systolic blood pressure > 140 mm Hg and/or diastolic blood pressure > 90 mm Hg at 
screening or prior to dosing 
20. Systolic blood pressure < 90 mm Hg and/or diastolic blood pressure < 50 mm Hg at 
screening or prior to dosing 
21. Currently taking or has taken other antimuscarinic drugs such as phenothiazines, tricyclic 
antidepressants, antihistamines (including meclizine), meperidine, or other 
anticholinergics that have weak antimuscarinic activity or that cause drowsiness, 
including antidepressants, benzodiazepines, alcohol, sedatives (used to treat insomnia), 
pain relievers, anxiety medicines, and muscle relaxants within 72 hours prior to dosing 
22. Has taken, within 14 days of planned dosing, any prescription or nonprescription 
medication (including home remedies, herbal supplements, or nutritional supplements) 
unless the PI/subinvestigator, in consultation with the medical monitor, provides a 
statement justifying that the medication taken will not impact the results of this study 
(with rare exceptions taking prescriptions drugs will be grounds for exclusion) 
23. History of major DSM-5 Axis I or II disorder, or evidence of such disorder at Day -1 as 
determined via the Structured Clinical Interview for DSM-5, customized Clinical Trials 
version (SCID-5-CT) 
24. Has any skin condition, scars, or tattoos that would interfere with injection of study drug 
25. Donated > 480 mL of blood within 8 weeks of drug administration 
26. Any other reason, in the opinion of the investigator, the subject should not participate in 
the study 
8.3. 
Subject Withdrawal Criteria 
Each subject may withdraw consent at any time during the study without penalty. If a subject 
wishes to withdraw after dosing, he or she will be encouraged to continue with the follow-up 
procedures (to the extent possible) for safety reasons. If the subject agrees to continue, he or she 
will not be considered withdrawn from the study. If the subject refuses all post-dosing follow-up, 
he or she will be considered withdrawn. 
Counseling about the subject’s health will be provided if he or she decides to discontinue 
participation in the study. Medical advice regarding the best interests of the subject will be 
provided. 


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The PI may discontinue a subject’s activity without the subject’s consent if any of these criteria 
is met: 
• A subject fails to comply with study procedures 
• A subject’s safety or health may be compromised by further participation 
8.3.1. 
When and How to Withdraw Subjects 
If a subject withdraws, the investigator or designee will make a reasonable effort to determine 
the reason for the withdrawal from the study and to complete termination procedures as 
described in Section 8.3.4. Telephone calls, registered letters, and e-mail correspondence are 
considered reasonable effort (ie, at least 3 attempts to contact the subject by phone and/or e-mail 
followed by a registered letter if there is no response to the phone/e-mail attempts). A subject 
may be withdrawn for an AE or SAE resulting in a safety concern or for noncompliance with 
protocol requirements. When a subject withdraws due to an AE or is withdrawn by the PI due to 
an AE, the sponsor’s safety office 
 must be notified within 24 hours of 
identification 
. Investigators 
must follow specific policy regarding the timely reporting of AEs and SAEs to the local IRB 
(Section 11.5.1.2). In all cases, the PI or designee will make a reasonable effort to complete 
study termination procedures. 
If a subject meets withdrawal conditions for a concomitant medication violation or 
noncompliance, this should clearly be stated in the source document and the study termination 
eCRF. 
8.3.2. 
Data Collected for Withdrawn Subjects 
All data collected up to the time of withdrawal will be reported. The end-of-study eCRF will be 
completed with the reason for withdrawal specified. 
8.3.3. 
Replacement of Subjects 
Subjects who withdraw from the study prior to receiving study drug will be replaced. 
Replacements can be of a different sex than the replaced subject as long as 3 females and 3 males 
are included in the cohort. Subject numbers should not be reused. 
8.3.4. 
Follow-up for Withdrawn Subjects 
Subjects who withdraw/are withdrawn after receiving study drug will undergo all Day 8 follow-
up procedures, if possible. 
9. 
TREATMENT OF SUBJECTS 
9.1. 
Dose Administration and Follow-up Periods/Study Visits 
9.1.1. 
Treatment 
Subjects will be assigned to 1 of 5 cohorts/dosage groups (Scopolamine HBT: 0.005, 0.007, 
0.011, 0.014, or 0.021 mg/kg or placebo). The investigational product will be administered by 


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IM injection to the anterior thigh. In each cohort, 6 to 9 subjects will receive active drug and 2 to 
3 subjects will receive placebo. Each cohort will have at least 3 male and 3 female subjects 
enrolled among the first 8 subjects in the dosing group to ensure that at least 1 male subject and 
1 female subject in each dosing group receive active drug. If nonextreme DLTs are observed in 
any of the cohorts, 4 additional subjects, 3 active and 1 placebo, may be added to each cohort. 
On the first day of dosing for each cohort, 2 subjects will be dosed (1 active and 1 placebo). 
Upon review of the AE data for both subjects at 24 hours post dose (± 1 hour), the PI and the 
medical monitor will determine if it is safe to proceed with dosing the remaining 6 of the first 8 
subjects. 
New subjects will not be enrolled into the next higher dosage group until at least 8 subjects in the 
previous cohort have completed the study Day 8 follow-up visit without the occurrence of DLTs, 
predefined as requiring termination of the study; the DSMB has made a recommendation to the 
sponsor; and the sponsor concurs with the DSMB recommendation regarding dose escalation 
following a review of study data. The sponsor must approve dose escalation. Dose escalation 
cannot occur until after sponsor approval of DSMB recommendations and notification of the 
investigator(s), not at the time of the DSMB recommendation. 
All subjects participating in the study will be monitored closely throughout the in-clinic phase of 
the study. Staff will be available with the appropriate expertise to assess and manage 
neuropsychiatric problems that may arise. The PI and/or physician designee will be in the 
treatment room during dosing and for 4 hours post dose. A psychiatrist will be available by 
phone to consult with the investigator throughout the study. At the investigator’s request, the 
psychiatrist will come to the clinic to evaluate a subject. A crash cart, which will include specific 
drugs to treat Scopolamine HBT effects (eg, physostigmine and diazepam), will be in the 
immediate area where subjects are residents. 
During the in-clinic phase, continuous cardiovascular monitoring of ECG (3-lead) and vital signs 
(blood pressure (at 5-15 minute intervals), heart rate, respiration rate, and pulse oximetry) will be 
performed starting at 1 hour prior to and for 24 hours following Scopolamine HBT or placebo 
administration (refer to Section 11.1.2 for details). In addition, 12-lead ECG and vital signs 
(including body temperature), clinical laboratory tests, neuropsychiatric status, and injection site 
assessments will be performed at specified times through 48 hours post dose. Subjects will be 
monitored for AEs continuously during the inpatient phase, and AEs will be documented as they 
are reported. A cardiologist will be available to consult with the investigator, as needed, 
throughout the study. 
9.1.1.1. 
Informed Consent for Screening Procedures 
All applicants will be given copies of the following before participating in any screening 
procedures: 
• The study ICF 
• Site-required informed consents and agreements for Health Insurance Portability and 
Accountability Act (HIPAA) Authorization, HIV testing, hepatitis testing, medical 
release authorization, database authorization, and subject conduct 


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• 
Form 60-R (Volunteer Registry Data Sheet) to be completed for each 
volunteer to document participation in a US Army research trial 
Regulatory agencies have issued regulations to provide protection for human subjects in clinical 
investigations and to describe the general requirements for informed consent. The ICF shall 
contain all of the elements of informed consent specified in the Code of Federal Regulations 
(21 CFR 50.25). Nothing in these regulations is intended to limit the authority of a physician to 
provide emergency medical care under applicable regulations. Regulations require that 
investigators permit the sponsor, sponsor’s representative, and appropriate regulatory agencies to 
conduct inspections and review records pertaining to clinical investigations. The delegation of 
investigator responsibilities including obtaining informed consent must be documented in the 
study records. 
Prior to giving a copy of the 
 Form 60-R (Volunteer Registry Data Sheet) to any 
volunteer, the clinical site will complete Part A, Investigator Information. The volunteer will be 
asked to complete Part B, Volunteer Information, during the screening visit. The form will then 
be filed in the subject binder, pending determination of eligibility. When a subject is enrolled 
into the study (dosed), the investigator/designee will complete Part C, Additional Information. At 
the end of the study, a copy of the completed form for each enrolled subject will be sent to the 
. 
9.1.1.2. 
Study Day -1 (One Day Prior to Dosing) 
If subjects qualify, they will be asked to return to the clinic on the day prior to dosing to check in 
for the in-clinic stay. Subjects will be given standardized meals during their in-clinic stay. 
Subjects with dietary restrictions will receive the appropriate food substitutes to ensure proper 
nutrition and to prevent potential biological material from interfering with the PK evaluation of 
the blood samples. 
All eligible subjects are considered alternates until they are dosed. Eligible subjects not dosed on 
Day 1 will be considered for the next dosing day. Subjects who are administered the study drug 
will remain at the study site for 48 hours after dosing (until the morning of Day 3). 
On the day prior to dosing (ie, Day -1), the following will be performed: 
• Physical examination of all major systems including general appearance, EENT, 
chest/respiratory, heart/cardiovascular, abdomen/gastrointestinal, lymph 
nodes/spleen, genitourinary, musculoskeletal, skin, neurological, and hepatic 
• Medical history update: AEs identified/reported prior to dosing will be added to the 
medical history 
• 12-lead ECG after the subject has been supine for at least 5 minutes 
• Vital signs (including systolic and diastolic blood pressure, heart rate, respiration rate, 
body temperature, and pulse oximetry) collected after the subject has been resting in a 
supine position for at least 5 minutes 
• Weight measurement and BMI confirmation; Day -1 weight will be used for dose 
determination on Day 1 


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• Clinical laboratory tests to include hematology and coagulation (Section 11.1.9.1) and 
serum chemistry (Section 11.1.9.2) 
• Urinalysis (Section 11.1.9.3) 
• Serum pregnancy test (Section 11.1.9.4) for all females regardless of childbearing 
potential 
• Urine drug screen (Section 11.1.9.5) 
• Alcohol breathalyzer test 
• SCID-5-CT (customized) will be administered by a psychologist to determine 
whether there is evidence of major DSM-5 Axis I or II disorder 
Note: Subjects who are designated alternates and readmitted on another day will not 
have the SCID repeated (see Section 11.1.6).   
• BPRS will be administered by a psychologist or trained clinician 
• C-SSRS (Since Last Visit version) and DSST will be administered by study staff 
• Prior/concomitant medications/treatments 
• Review of inclusion/exclusion criteria 
Starting the evening of Day -1, all subjects will be required to fast (water and clear liquids only) 
overnight (for at least 8 hours) prior to injection of the study drug; all liquids will be stopped 
1 hour prior to dosing. Subjects will be permitted to begin consuming liquids at 1 hour after 
dosing and to eat solid foods as long as they are clinically well. 
Adequate hydration should be ensured by having subjects drink at least 1000 mL of water within 
24 hours prior to administration of study drug and 1000 mL within 24 hours following the 
administration of study drug. The consumption of this (total) 2000 mL of water should be 
recorded in the source documentation. 
Note: Except for the SCID-5-CT (as noted above), the Day-1 assessments will be repeated on 
alternates who are readmitted on another day. Repeat testing includes the BPRS, C-SSRS, DSST, 
weight measurement and BMI calculation, and all other Day-1 assessments with the following 
possible exception. If an alternate does not leave the clinic, the serum pregnancy, urine drug 
screen, and alcohol breathalyzer tests do not have to be repeated. 
9.1.1.3. 
Drug Administration (Study Day 1 at 0 Hour) 
One hour prior to dosing, subjects will be placed on continuous cardiovascular monitoring that 
includes ECG (3-5 lead) and vital signs (blood pressure, heart rate, respiration rate, and pulse 
oximetry). Within 2 hours prior to IM injection, the following will be performed: 
• Physical examination (abbreviated) 
• 12-lead ECG will be obtained after the subject has been supine for at least 5 minutes 
• Vital signs ( blood pressure, heart rate, respiration rate, body temperature, and pulse 
oximetry) will be measured after the subject has been supine for at least 5 minutes 
• Blood sample for pre-dose PK 


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• Urine sample for urine PK assessment. The pre-dose urine PK specimen will be 
collected no earlier than 2 hours before dosing. If a second pre-dose specimen is 
collected, then it will become the pre-dose specimen, and the first pre-dose specimen 
will be disposed of. 
• Baseline injection site assessment for pain, pruritus, tingling, and numbness (subject 
rating using VAS) 
• Baseline injection site assessment for pain, tenderness, erythema, and induration by 
physician, physician assistant, or nurse 
• Concomitant medications and AEs: AEs identified/reported prior to dosing will be 
added to the medical history 
• Inclusion/exclusion criteria will be confirmed and eligibility checklist signed by a 
physician investigator 
• Randomization form will be signed by a physician investigator and sent to the 
pharmacy. Weight measurement from Day -1 will be used for dose determination. 
• The unblinded study pharmacist or pharmacy technician will remove a predetermined 
dosing volume from a single-use vial (refer to the Pharmacy Manual). 
• Subjects will be administered the drug product formulation at the assigned dosage of 
Scopolamine HBT, Injection or placebo IM to the anterior thigh using an appropriate 
size syringe. 
• Administration of individual injections will be performed by a blinded study staff 
member (licensed medical personnel). Injections should be completed within 20 
seconds. 
• The PI and/or physician designee must be in the treatment room during drug 
administration. 
• Regardless of the injection duration, blood sampling for PK analyses will begin with 
Time 0 at the completion of administration of the injection. Time 0 for the purpose of 
timing pre-injection procedures and post-dosing data collection is defined as the time 
the needle is removed at the completion of study drug injection. Both the injection 
start and end times should be recorded in the source documentation by hours, 
minutes, and seconds. 
Table 7 summarizes treatment groups and dose levels. 


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Table 7: 
Treatment Groups and Dose Levels 
Cohort 
Scopolamine HBT Target Dose (mg/kg) 
1 
0.005 
2 
0.007 
3 
0.011 
4 
0.014 
5 
0.021 
In addition to continuous cardiovascular monitoring during the 24 hours following 
administration of study drug, subjects will undergo the following procedures: 
• Subjective injection site assessments: a physician, physician assistant, or nurse will 
ask the subject to rate the intensity of pain, pruritus, tingling, and numbness using the 
VAS at 5, 10, 15, 30, and 45 minutes and 1, 1.5, 3, 5, 8, and 12 hours after dosing. 
• A physician, physician assistant, or nurse will assess the injection site for presence 
and severity of pain, tenderness, erythema, and induration at 5, 10, 15, 30, and 
45 minutes and 1, 1.5, 3, 5, 8, and 12 hours after dosing. This assessment will follow 
the subjective assessment at each time point. 
• 12-lead ECG (supine for at least 5 minutes) will be obtained at 5, 10, 15, 30, and 
45 minutes and 1, 1.5, 3, 5, 8, and 12 hours after dosing. 
• Vital signs (blood pressure, heart rate, respiration rate, body temperature, and pulse 
oximetry) will be recorded at 5, 10, 15, 30, and 45 minutes and 1, 1.5, 3, 5, 8, and 
12 hours after dosing after the subject has been supine for at least 5 minutes. 
• Brief neurological assessment will be performed at 1 hour post dosing (+30 min), 
after all of the other 1 hour post dosing activities have been completed. 
Alertness/level of consciousness, orientation, ability to follow commands and 
coordination will be documented (refer to Section 11.1.5).  
• Neuropsychiatric assessments: BPRS will be administered by a psychologist or 
trained clinician at 6 (+ 2) hours post dose. The + 2 hour window is provided to allow 
the investigator some discretion should he or she determine the assessment needs to 
be delayed. The timing may be dependent on the emergence and severity of 
neuropsychiatric symptoms. 
• The RASS will be performed as part of the brief neurological assessment (refer to 
Section 11.1.5) and at other times if needed to assess agitation and sedation (refer to 
Section 11.1.6). 
• AE assessment: The subject will be observed for any clinical adverse signs and asked 
“how are you feeling?” at 5, 10, 15, 30, and 45 minutes and 1, 1.5, 3, 5, 8, and 
12 hours after dosing. All AEs will be documented. 


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• Concomitant medication assessments will be performed at 5, 10, 15, 30, and 
45 minutes and 1, 1.5, 3, 5, 8, and 12 hours after dosing. All medications taken will 
be documented. 
• Urine for separation and identification of urinary Scopolamine HBT and its 
metabolites will be collected (“clean catch”) from each subject at intervals of 0-4, 
4-12, and 12-24 hours post dose. The pre-dose specimen will be collected no earlier 
than 2 hours before dosing. If a second pre-dose specimen is collected, then it will 
become the pre-dose specimen and the first pre-dose specimen will be disposed of. 
The post-dosing urine specimens for each subject will be collected as often as voiding 
occurs for 24 hours, and these specimens will be pooled into 1 of 3 collection interval 
containers by subject (ie, 0-4–hour interval, 4-12–hour interval, or 12-24–hour 
interval).  
Note: Prior to pooling the urine, the time and estimated volume of each individual 
void will be recorded to assist in the assessment of urine output and hydration. The 
time and volume information will also be used to calculate the total volume of the 
three collection intervals (see additional instructions following Table 8). 
• Blood samples will be obtained for PK assessments prior to dosing and at 2, 5, 10, 15, 
20, and 30 minutes and 1, 2, 4, 8, 12, 24, 36, and 48 hours post dose. For purposes of 
scheduling the post-dose blood collection target time point, the time of dosing will be 
the time immediately after administration of the injection for that subject. 
Approximately 10 mL of blood will be collected for each PK sample. 
The acceptable deviations before and after the target sample collection time are shown in 
Table 8. Time points from 2 minutes to, and including, 2 hours will be collected within ± 5% of 
the target time point. Time points greater than 2 hours through, and including, 48 hours will be 
collected within ± 15 minutes of the target time point. 
Table 8: 
Pharmacokinetic Blood Sample Deviation Windows 
Target Time Point 
Acceptable Sample Collection Time Point Range 
Low-End Range 
High-End Range 
2 min 
1 min 50 s 
2 min 10 s 
5 min 
4 min 40 s 
5 min 20 s 
10 min 
9 min 30 s 
10 min 30 s 
15 min 
14 min 15 s 
15 min 45 s 
20 min 
19 min 
21 min 
30 min 
28 min 30 s 
31 min 30 s 
1 h (60 min) 
57 min 
63 min 
2 h (120 min) 
114 min 
126 min 
4 h (240 min) 
228 min 
252 min 
8 h (480 min) 
465 min 
495 min 


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Target Time Point 
Acceptable Sample Collection Time Point Range 
Low-End Range 
High-End Range 
12 h (720 min) 
705 min 
735 min 
24 h (1440 min) 
1425 min 
1455 min 
36 h (2160 min) 
2145 min 
2175 min 
48 h (2880 min) 
2865 min 
2895 min 
The value recorded as the actual time after dosing that a given blood sample is collected will be 
based on when blood first appears in the tube (as opposed to the time after the mid or entire 
blood sample is collected). By using the “first appearance” of blood as the guideline for 
determining the actual collection time, the documented sample collection time points will be 
more consistent among technicians. In addition, good agreement between target and actual 
collection time points will be achieved since the time needed to collect the full sample will not 
need to be taken into consideration prior to the collection. 
Approximately 10 mL of whole blood per collection time point per subject will be collected into 
individual lithium heparin, vacutainer-type tubes that are appropriately and uniquely labeled. 
Immediately upon collection, the tubes will be mixed well (eg, hand rocked or rocker table) to 
ensure the whole blood and anticoagulant are sufficiently mixed to prevent clotting. After 
mixing, the blood samples will be placed in wet ice until centrifuged for separation and 
collection of plasma, which will occur within 1 hour after the blood sample collection time. Each 
plasma sample will be split into 2 aliquots, a primary aliquot “A” of approximately 3 mL of 
plasma and a backup aliquot “B” containing all remaining plasma. The plasma will be stored in 
wet ice until transferred to a freezer (< -20C) where it will remain until removed for shipment. 
The samples must remain frozen during storage and shipment. 
For urine samples for separation and measurement of metabolites, “clean catch” urine specimens 
will be collected. For each subject, the date and time of collection, as well as the estimated 
volume of each void, will be recorded from pre-dose through 24 hours post dose. Note: The time 
and volume of each void will be used for the assessment of urine output and hydration and do not 
need to be entered into the CRF. However, the time and volume of each individual void will also 
be used to calculate the total volume for each of the urine PK collection intervals, and the pre-
dose and collection interval volumes will be entered into the CRF for use in the analysis of 
metabolites.   
The urine specimens will be stored in a polyethylene, screw-cap container by interval and subject 
and, immediately upon collection, will be stored refrigerated. The urine will be mixed well 
before transferring two 10-mL aliquots into 2 separate 15-mL screw-cap, polypropylene conical-
shaped vials, a primary aliquot “A” and a backup aliquot “B.” The urine specimen container caps 
will be taped in place to prevent leakage and stored upright in a freezer at approximately < -20C 
until shipped for analysis. The specimens must remain frozen during storage and shipment. 
Samples will be shipped by traceable carrier for analysis to: 
Battelle Memorial Institute 
 
 


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9.1.2. 
Follow-up 
After receiving the study drug or placebo on Day 1, subjects will be monitored in clinic for 
48 hours (until the morning of Day 3). Follow-up for AEs will be made via telephone on Days 4 
and 30, and via an in-clinic visit on Day 8. Additional monitoring and assessments may be 
performed if, in the judgment of the investigator, they are warranted for the safety of the subject. 
AEs will be followed until resolution/stabilization. 
The following is the schedule of post-dose events. 
9.1.2.1. 
Study Day 2 (24 Hours ± 1 Hour) 
Continuous cardiovascular monitoring of ECGs (3-5 lead) and vital signs will continue until 
24 hours post dose on Day 2. At 24 hours post dose (± 1 hour for all assessments except PK 
sample collection), the following will be performed: 
• 12-lead ECG will be obtained after the subject has been supine for at least 5 minutes. 
• Vital signs (blood pressure, heart rate, respiration rate, body temperature, and pulse 
oximetry) will be measured after the subject has been supine for at least 5 minutes. 
• Blood samples will be obtained for PK assessments at 24 and 36 hours post dose 
(± 15 minutes) using a 10-mL, lithium heparin vacutainer-type tube; mixed well; and 
immediately placed on wet ice. 
• Blood samples will be obtained for serum chemistry, hematology, and coagulation 
(approximately 16 mL). 
• Urine sample will be obtained for urinalysis. 
• End of urine PK sample collection for the 12-24–hour interval. 
• RASS (if needed) 
• Medications taken since dosing will be recorded. 
• AEs experienced by the subject will be recorded. 
• Pain, pruritus, tingling, and numbness at injection site will be rated by the subject 
using the VAS. 
• Pain, tenderness, erythema, and induration at injection site will be assessed by a 
physician, physician assistant, or nurse. 


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9.1.2.2. 
Study Day 3 (48 Hours ± 1 Hour; Discharge) 
Subjects will be asked to remain at the study site until the 48-hour assessment on Day 3. At 
48 hours post dose (± 1 hour for all assessments except PK sample collection), the following will 
be performed before subjects are released from the in-clinic portion of the study: 
• Physical examination (abbreviated) 
• Body weight will be measured. 
• 12-lead ECG will be obtained after the subject has been supine for at least 5 minutes. 
• Vital signs (blood pressure, heart rate, respiration rate, body temperature, and pulse 
oximetry) will be measured after the subject has been supine for at least 5 minutes. 
• Blood sample will be obtained for PK assessment at 48 hours post dose 
(± 15 minutes) using a 10-mL, lithium-heparin vacutainer-type tube; mixed well; and 
immediately placed on wet ice. 
• Blood samples will be obtained for serum chemistry, hematology, and coagulation 
(approximately 16 mL). 
• Urine sample will be obtained for urinalysis. 
• Medications taken since the 24-hour assessment will be recorded. 
• AEs experienced by the subject since the 24-hour assessment or present at the 
physical examination will be recorded. 
• Pain, pruritus, tingling, and numbness at injection site will be rated by the subject 
using the VAS. 
• Pain, tenderness, erythema, and induration at injection site will be assessed by a 
physician, physician assistant, or nurse. 
• BPRS will be performed by a psychologist or trained clinician 
• DSST will be administered by study staff. 
• Male subjects with a female partner of childbearing potential will be reminded that 
they must use a barrier form of birth control (defined as condoms with spermicide) 
for 30 days after receipt of study drug. 
• Female subjects of childbearing potential will be reminded to continue their current 
form of birth control for 30 days after receipt of study drug. 
• Subjects will be reminded of all study restrictions, including to refrain from donating 
blood or other blood components for 8 weeks after completion of the study. 
• Days 4, 8, and 30 follow-up appointments will be scheduled. 
9.1.2.3. 
Study Day 4 (+ 2 Days; Telephone Follow-up) 
Subjects will be contacted via telephone on Day 4. During this call, the following will be 
performed: 
• Medications taken since the Day 3 assessment will be recorded. 


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• AEs experienced by subject since Day 3 will be recorded, and subjects will be 
queried regarding AEs that were persisting at discharge (Day 3). 
• Male subjects with a female partner of childbearing potential will be reminded that 
they must use a barrier form of birth control (defined as condoms with spermicide) 
for 30 days after receipt of study drug. 
• Female subjects of childbearing potential will be reminded to continue their current 
form of birth control for 30 days after receipt of study drug. 
• Subjects will be reminded of all study restrictions, including to refrain from donating 
blood or other blood components for 8 weeks after completion of the study. 
• Subjects will be reminded of the Day 8 follow-up visit. 
9.1.2.4. 
Study Day 8 (+ 2 Days; Follow-up Visit) 
Subjects will be required to return to the study site on Day 8. At this visit the following will be 
performed: 
• Complete physical examination including general appearance, EENT, 
chest/respiratory, heart/cardiovascular, abdomen/gastrointestinal, lymph 
nodes/spleen, genitourinary, musculoskeletal, skin, neurological and hepatic. 
• Body weight will be measured. 
• 12-lead ECG will be obtained after the subject has been supine for at least 5 minutes. 
• Vital signs (blood pressure, heart rate, respiration rate, body temperature, and pulse 
oximetry) will be measured after the subject has been supine for at least 5 minutes. 
• BPRS will be administered by a psychologist or trained clinician. 
• C-SSRS (Since Last Visit) and DSST will be administered by study staff. 
• Blood samples will be obtained for serum chemistry, hematology, and coagulation 
(approximately 16 mL). 
• Serum pregnancy test for all females regardless of childbearing potential. 
• Urine samples will be obtained for drug screening and urinalysis. 
• Medications taken since the Day 4 assessment will be recorded. 
• AEs experienced by the subject since Day 4 or present at the physical examination 
will be recorded; subjects will be queried regarding any AEs that were persisting at 
Day 4. 
• Pain, pruritus, tingling, and numbness at injection site will be rated by the subject 
using the VAS. 
• Pain, tenderness, erythema, and induration at injection site will be assessed by a 
physician, physician assistant, or nurse. 


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• Male subjects with a female partner of childbearing potential will be reminded again 
that they must use a barrier form of birth control (defined as condoms with 
spermicide) for 30 days after receipt of study drug. 
• Female subjects of childbearing potential will be reminded to continue their current 
form of birth control for 30 days after receipt of study drug. 
• Subjects will be reminded of all study restrictions, including to refrain from donating 
blood or other blood components for 8 weeks after completion of the study. 
• Subjects will be reminded of the study Day 30 telephone follow-up. 
If a subject does not return for his or her Day 8 assessment, a reasonable effort will be made to 
contact this subject and schedule another visit (ie, at least 3 attempts to contact the subject by 
telephone and/or e-mail, followed by a registered letter if there is no response to the 
telephone/e-mail attempts). 
9.1.2.5. 
Study Day 30 (+ 7 Days; Telephone Follow-up) 
Subjects will be contacted via telephone on Day 30 (+ 7 days). During this call, the following 
will be performed: 
• Medications taken since the Day 8 assessment will be recorded. 
• AEs experienced by the subject since the Day 8 visit will be recorded; subjects will 
be queried regarding any AEs that were persisting at the Day 8 visit. 
• Subjects will asked whether they have donated blood or other blood components 
since the Day 8 visit and will be reminded to refrain from donating blood or other 
blood components for 8 weeks after completion of the study. 
• Male subjects with a female partner of childbearing potential and female subjects of 
childbearing potential will be asked whether they continued to use birth control 
through 30 days after receipt of study drug. 
• Females will be asked if they have become pregnant since the Day 8 visit and to 
notify the PI if they later discover that they have become pregnant within the previous 
30-day period. 
9.1.3. 
Biological Samples 
Samples collected under this protocol will be used to conduct protocol-related safety and PK 
evaluations. No genetic testing will be performed on these samples. 
Plasma for PK evaluations will be stored at Battelle Memorial Institute in a quality-controlled 
environment. Transport and storage of these biological samples will be handled according to 
institute SOPs. Any study for the future use of these biological samples will have IRB/Human 
Use Committee approval. In addition, a subject may decide at any point to withdraw consent for 
the future use of his or her samples. Should a subject withdraw consent for the use of his or her 
samples, the samples will be destroyed according to institute SOPs. 


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9.2. 
Rescue Medications and Concomitant Medications 
This protocol places restrictions on all medication use during the study including the use of 
rescue medications. The PI will recommend medication for symptomatic relief, if necessary. 
9.2.1. 
Rescue Medications 
Physostigmine should be used as needed to reverse the effects of scopolamine in any instance 
where there is a concern that the symptoms may result in harm (self-induced or otherwise) to the 
subject or a concern that the subject may pose a risk to others. The following circumstances 
would indicate a need for physostigmine treatment: 
• A rating of severe (ie, score of 5 or greater) on any of the following 5 items on the 
BPRS: 
− #4 Suicidality 
− #5 Hostility 
− #10 Hallucinations 
− #11 Unusual Thought Content Item 
− #12 Bizarre Behavior 
• Severe agitation (score of 3 or greater) on the RASS 
A physician investigator must make the determination to administer physostigmine. 
Administration may be performed by a physician, physician assistant, or nurse; however, a 
physician must be present to evaluate the response and determine the need for additional 
treatment. 
If used, a physician, physician assistant, or nurse will administer 0.5 mg physostigmine IV over 
1 minute, which may be repeated every 5 minutes until a total dose of 2 mg has been given (ie, a 
total of 4 doses). Atropine and a benzodiazepine (eg, diazepam or lorazepam) should be at the 
bedside in case of bradycardia or seizures. If the subject is not already on continuous 
cardiovascular monitoring when physostigmine is administered, the subject will be placed on 
continuous monitoring of ECG (3-lead) and vital signs (refer to Section 11.1.2 for details). The 
effects of physostigmine last only 1-2 hours; therefore, a repeat dose may be necessary. 
If there is an adequate response to treatment with physostigmine, the event should be considered 
a nonextreme DLT; however, if there is not an adequate response to treatment, the event should 
be considered an extreme DLT (refer to Section 7.6.1 for further detail regarding procedures 
related to DLTs). 
When a physician investigator determines that physostigmine administration is necessary, the 
following will be recorded in the subject’s record to ensure adequate information is available for 
evaluation of the associated DLTs by the PI, research monitor, DSMB members, and the 
sponsor’s PVG physician: 
• Study day and date (to be recorded by study staff) 
• Circumstance(s) indicating the need for treatment (see above) and physician 
investigator’s authorization to administer physostigmine 


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• For each dose given, the following will be recorded: 
− Dose number (eg, 1-4), dose administered (mg; see above), and start and stop 
times of administration (to be recorded by staff member administering the dose) 
− Response to treatment, and reason(s) for administering an additional 
physostigmine dose, if needed 
• Total number of physostigmine doses (1-4) and total dose (mg) administered 
• Whether the overall response to physostigmine was adequate or inadequate (refer to 
Section 7.6.1 for further detail regarding procedures related to DLTs) 
• Any other information deemed relevant by the physician investigator authorizing the 
treatment and by the physician(s) providing follow up care 
• If any other treatment (eg, atropine and/or benzodiazepine) is provided, the drug 
name, reason(s) for administration, dose and time given, and route of administration 
will be recorded for each. 
9.2.2. 
Concomitant Medications and Prohibitions 
Concomitant medications should be collected from the screening visit through 30 days after the 
investigational product is administered. 
All prescription drugs and nonprescription medication (excluding hormonal contraceptives) are 
prohibited within 14 days of planned dosing unless the PI/subinvestigator, in consultation with 
the medical monitor, provides a statement justifying that the medication taken will not impact the 
results of this study (with rare exceptions taking prescriptions drugs will be grounds for 
exclusion). 
Smoking and tobacco and nicotine-containing (including e-cigarettes) products are prohibited 
within 3 months of dosing and throughout the study period; subjects must also have a total 
lifetime exposure to cigarettes of < 15 pack-years. 
Consumption of foods and beverages containing the following substances will be prohibited as 
indicated: 
• Alcohol: 72 hours before dosing and throughout the period of sample collection 
• Seville orange (bitter orange), grapefruit, grapefruit juice, grapefruit-containing 
products, or starfruit: 7 days before dosing and through 48 hours post dose 
• Any prescription or nonprescription medication (including home remedies, herbal 
supplements, or nutritional supplements) 14 days before dosing (see above for rare 
exceptions) 
• Any food 8 hours prior to dosing (water and clear liquids only up to 1 hour pre dose) 
and 1 hour post injection 
• Liquids 1 hour before and 1 hour after dosing 
• Caffeine or other xanthine-containing products: 7 days before dosing and throughout 
the period of PK sample collection 


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• Strenuous physical activity of any kind is prohibited starting 48 hours prior to 
admission on Day -1 and until after the Day 8 visit is completed. 
9.3. 
Procedures for Monitoring Subject Compliance 
Subject compliance for investigational product administration is not an issue because the study 
materials will be administered by study staff. Subjects will be reminded to return to the clinic for 
the Day 8 follow-up. In addition, attempts to reschedule missed appointments, within allowable 
day ranges, will be made. 
10. 
PHARMACOKINETIC SAMPLE COLLECTION 
Blood samples (approximately 10 mL each draw) will be obtained for PK assessments within 
2 hours prior to dosing and at 2, 5, 10, 15, 20, and 30 minutes and 1, 2, 4, 8, 12, 24, 36, and 
48 hours post dose. These sampling points should allow for adequate and full characterization of 
the Scopolamine HBT PK profile.  
Scopolamine HBT PK assessments will include determination of the following parameters: 
observed Cmax and Tmax, Vd_F, t½, Cl_F, AUClast, AUC∞, Cmax/Dose, MRT, and AUC∞/Dose. 
Samples will be analyzed for Scopolamine HBT at Battelle in Columbus, Ohio, using a high-
performance liquid chromatography-tandem mass spectrometry method validated with respect to 
accuracy, precision, linearity, sensitivity, and specificity. Samples will be shipped as agreed 
upon by the site and Battelle. It is expected that plasma samples will be analyzed and 
concentration time profiles constructed for each cohort to assist the DSMB in making dose-
escalation recommendations. After analysis, samples will be stored until study report approval 
and permission from the sponsor has been received to dispose or ship the samples to a sponsor-
designated location. 
The backup (“B”) PK samples will be stored at the investigator site at -20°C or lower until 
directed to ship by Battelle. These samples will be shipped to Battelle’s Chemistry Technical 
Center in Columbus, Ohio, for confirmatory testing, if applicable. Approximately 2 mL of 
plasma for each PK assessment will be transferred to a long-term storage facility where samples 
will be stored at -20°C or lower for at least 2 years after FDA approval of the last indication for 
this product. These backup samples may be used for additional or repeat PK testing, as required. 
10.1. 
Clinical Blood Sample Collection 
Blood samples (approximately 24 mL at screening and 16 mL on subsequent days) will be 
obtained for clinical laboratory testing. Serum chemistry and hematology (including coagulation) 
tests will be performed at screening, baseline (Day-1), at 24 and 48 hours post dose, and at Day 8 
(refer to Section 11.1.9.1 and Section 11.1.9.2 for specific tests). Serum pregnancy testing will 
be performed at screening, Day-1, and at Day 8 (refer to Section 11.1.9.4). Serology will be 
performed at screening only (refer to Section 11.1.9.5 for specific tests). 
The total blood volume to be collected in this study is approximately 250 mL. This includes 
blood collection for PK assessments and clinical laboratory testing but does not include 
additional clinical testing deemed necessary by the investigator or designee for subject safety. 


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10.2. 
Urine Sample Collection 
Urine samples will be obtained for urinalysis at screening, baseline (Day-1), at 24 and 48 hours 
post dose, and at Day 8 (refer to Section 11.1.9.3 for specific tests). Urine drug screening will be 
performed on an aliquot of the urine sample at screening, baseline (Day-1), and at Day 8 (refer to 
Section 11.1.8 for specific tests). 
Urine will also be obtained for separation and identification of urinary Scopolamine HBT and its 
metabolites. For urine samples for separation and measurement of metabolites, a “clean catch” 
urine specimen will be collected. For each subject, the date and time of collection, as well as the 
estimated volume of each void, will be recorded from pre-dose through 24 hours post dose. The 
urine specimens will be stored in a polyethylene, screw-cap container by interval and subject 
and, immediately upon collection, will be stored refrigerated. The urine will be mixed well 
before transferring two 10-mL aliquots into 2 separate 15-mL screw-cap, polypropylene, conical-
shaped vials. Refer to Section 9.1.1.3 and the PK Sample Instruction Manual for collection and 
processing details. 
10.3. 
Sample Analysis 
The plasma concentration time profiles for Scopolamine HBT will be subject to a model-
independent PK analysis (noncompartmental analysis) using WinNonlin software by a Battelle 
Memorial Institute pharmacokineticist to estimate the PK parameters shown in Table 9. PK and 
safety ± will undergo PD analysis and evaluation. 
Table 9: 
Pharmacokinetic Parameters 
Parameter 
Description 
Cmax 
Maximum measured plasma time concentration over the time span 
specified 
Tmax 
Time of the maximum measured plasma concentration. If the maximum 
value occurs at more than one time point, Tmax is defined as the first time 
point with this value. 
Apparent Volume of 
Distribution (Vz/F) 
Volume of distribution during terminal phase calculated as 
Dose/AUC∞/z 
t½ 
Apparent first-order terminal elimination half-life will be calculated as 
0.693/ke. 
Apparent Clearance (Cl_F) 
Volume of blood or plasma cleared of drug per unit time 
MRT 
Mean residence time calculated as AUMC/AUC 
AUClast 
The area under the plasma concentration versus time curve, from time 0 
to the last measurable concentration, as calculated by the linear 
trapezoidal method 
AUC∞ 
The area under the plasma concentration versus time curve from time 0 
to infinity. AUC∞ is calculated as the sum of AUClast plus the ratio of the 
last measurable plasma concentration to the elimination rate constant 
(ke). The elimination rate constant will be determined from the terminal 
linear phase of the plasma concentration time profile. 


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Parameter 
Description 
Cmax/Dose and AUC∞/Dose 
Dose normalization of Cmax and AUC∞ for evaluation of dose 
proportionality. 
No value for Vd_F, Cl_F, AUC∞, t½, or MRT will be reported for profiles that do not exhibit a 
terminal log-linear phase in the concentration versus time profile. 
11. 
SAFETY ASSESSMENT 
Safety monitoring will be conducted throughout the study; therefore, safety concerns will be 
identified by continuous review of data by the PI, clinic staff, clinical trial monitor, research 
monitor, and 
. 
Study Safety Management: The PI, research monitor, 
 PVG physician, 
and IRB will review any safety concern. 
An independent DSMB is required for this study. The DSMB will be convened to review safety 
data and provide recommendations to the sponsor’s representative. Prior to any data being 
provided to the DSMB, it must be reviewed and approved for release by a study biostatistician in 
collaboration with the 
 biostatistician. The DSMB will review cumulative study data during 
scheduled in-process and ad hoc reviews to evaluate safety, study conduct, and the scientific 
validity and integrity of the trial. After each review of study data, the DSMB will make a 
recommendation to the sponsor’s representative. DSMB recommendations will be documented 
and provided in writing (via the DSMB Chair Recommendation Form) to the 
 
. The sponsor’s representative will then decide whether to continue, modify, or suspend the 
study. The 
 will communicate the final decision to the investigator, who 
in turn will notify the IRB as appropriate. The 
 regulatory affairs scientist will communicate 
the final decision to the FDA, as appropriate. A description of the DSMB’s roles and 
responsibilities, functions, reporting requirements, meeting frequency, and the study 
stopping/continuation criteria is included in the DSMB charter. 
Research Monitor: The DoD research monitor is responsible for overseeing the safety of the 
research and reporting observations/findings to the IRB or a designated institutional official. The 
research monitor will review all unanticipated problems involving risks to subjects or others 
associated with the protocol and provide an independent report of the event to the IRB. The 
research monitor may discuss the research protocol with the investigators; shall have authority to 
stop a research protocol in progress, remove individual human subjects from a research protocol, 
and take whatever steps are necessary to protect the safety and well-being of human subjects 
until the IRB can assess the research monitor’s report; and shall have the responsibility to 
promptly report his or her observations and findings to the IRB or other designated official and 
the 
. 
In addition to the responsibilities above, the research monitor is required to review and provide 
an unbiased written report for all SAEs and subject deaths to the 
 within 
24 hours of his or her awareness of the event. The report provided must include, at a minimum, a 
brief summary of the research monitor’s review of the event and event outcome, relationship of 
the event to the investigational product, and whether the research monitor concurs with the 
details of the study investigator’s SAE report. 


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The PI (or designee) will report SAEs to the DoD research monitor. Upon receipt of an SAE 
report (initial or follow-up), the DoD research monitor will provide the unbiased written report 
using the 
 Research Monitor Report Form for each assessment. The DoD Research 
Monitor’s report may be submitted to the 
 by the Research Monitor or the PI. 
Multiple follow-up reports may be necessary for a single event, depending on when additional 
information becomes available. The PI (or designee) will also report all events that meet extreme 
and non-extreme DLT criteria, unanticipated problems, and other events with the potential to 
impact a subject’s clinical care to the research monitor. The occurrence of any DLT(s) would 
result in the immediate discontinuation of dosing and study enrollment, pending a review of 
study data by the PI, research monitor, PVG physician, the DSMB, and the sponsor. 
Medical Monitor: The medical monitor’s role is separate and distinct from that of the research 
monitor. The medical monitor is available to serve as a resource to the clinical site and may 
provide consultations relating to issues such as general conduct of the study, subject eligibility, 
or potential protocol exceptions. The medical monitor may discuss with on-site medical staff any 
clinical situations that arise and provide recommendations. After the first day of dosing for each 
cohort, the medical monitor will review safety data with the PI to determine if it is safe to 
proceed with dosing the remaining subjects. The medical monitor may also perform additional 
tasks such as reviewing safety data listings for identification of data trends. 
: The 
 is responsible for the review of safety 
data regarding The Surgeon General, Department of the Army (TSG-DA)-sponsored products. 
The 
 reviews all safety events and follows them until resolution. 
 PVG Physician: The 
 PVG physician, as 
delegated by the sponsor, evaluates all safety cases and provides the final determination on 
relatedness and expectedness to the product, and whether expedited reporting is warranted per 
current FDA regulation and guidance. 
11.1. 
Specification of Safety Assessments 
PK samples should be collected as close to the actual time point as possible (within the windows 
specified in Table 8); however, when multiple tests are scheduled at the same time, ECG and 
vital signs will be performed within 5 minutes prior to the nominal time point, and injection site 
and AE assessments will be performed immediately after the PK blood draw. 
11.1.1. 
Demographic/Medical History 
A complete medical history including demography will be collected at the screening visit after 
informed consent is obtained but before any other procedures are performed. A review of 
systems will be conducted by the PI or designee to ensure that subjects meet eligibility criteria. 
Females of childbearing potential will be asked to list their current method(s) of birth control for 
comparison with the requirements of this study. 
11.1.2. 
Continuous Cardiovascular Monitoring 
A DRE Waveline EZ Portable Patient Monitor (Avante Medical Surgical, Louisville KY) will be 
employed for continuous measurement of 3-lead ECG and vital signs (SpO2, blood pressure, 
heart rate, and respiratory rate). Each subject will have the Patient Monitor placed at the bedside, 
and monitoring will be performed from pre-dose until 24 hours post dose. Subjects may be 


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monitored for a longer period of time at the discretion of the investigator, based on clinical 
indication.   
• SpO2 is the saturation of arterial blood with oxygen as measured by pulse oximetry, 
and reported as a percentage. The SpO2 sensor will be placed on the index finger of 
the non-dominant arm using a clip device.  
• Blood pressure will be monitored via a standard size-appropriate cuff placed on the 
non-dominant arm, and measurements will be obtained every 5 minutes until 1 hour 
post dose, and every 15 minutes thereafter. The frequency of blood pressure sampling 
may be increased up to every 5 minutes at any time after 1 hour post dose at the 
discretion of the investigator, based on clinical indication.  
• Heart rate and ECG will be obtained using 3 standard chest leads. 
• Respiratory rate will be measured by thoracic impedance, via an electrode placed at 
approximately the right lateral 8th intercostal space. 
Note: the measurements obtained during continuous monitoring will not be recorded unless an 
AE occurs. Safety assessments will be recorded according to the time points below (also refer to 
Table 3 and Table 4, Study Events Schedules).  
11.1.3. 
Vital Signs 
Vital signs will include systolic and diastolic blood pressure, heart rate, respiration rate, body 
temperature, and pulse oximetry, and will be measured after the subject has been resting in a 
supine position for at least 5 minutes. Vital signs will be performed at screening, Day -1, Day 1 
(prior to dosing, at 5, 10, 15, 30, and 45 minutes, and at 1, 1.5, 3, 5, 8, and 12 hours after dosing), 
Day 2 (24 hours post-dose ± 1 hour), Day 3 (48 hours post dose ± 1 hour), and Day 8. Vital signs 
may be taken at other times if deemed necessary by the investigator or site SOPs. 
In addition, starting at 1 hour prior to dosing on Day 1, vital signs (excluding body temperature) 
will be continuously monitored for 24 hours post dose (refer to Section 11.1.2 for details). 
Where the time of vital signs monitoring coincides with a blood draw, vital signs will be 
performed within 5 minutes prior to the nominal time point (refer to Section 11.1 for details).  
11.1.4. 
Weight and Height 
Subjects will have a height (cm; screening only) and weight (kg) measurement during screening 
with BMI calculation, a weight measurement on Day -1 with BMI calculation, and a weight 
measurement only on Days 3 and 8. The Day -1 weight will be used for dose determination. 
11.1.5. 
Physical Examination 
Each subject will have a complete physical examination at screening, Day -1, and Day 8. 
Abbreviated (targeted) physical examinations will be performed as needed prior to dosing on 
Day 1 and prior to discharge on Day 3. A complete physical examination includes all major 
systems, including general appearance, EENT, chest/respiratory, heart/cardiovascular, 
abdomen/gastrointestinal, lymph nodes/spleen, genitourinary, musculoskeletal, skin, 
neurological, and hepatic. The screening physical exam includes an assessment of upper leg 


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muscle tissue (ie, adequacy of tissue for IM injection). Targeted physical examinations may be 
performed at other times as deemed necessary by the investigator. 
In addition, at the request of the DSMB for Cohorts 3-5, a brief neurological assessment will be 
performed at 1 hour post dosing (+30 min) on Day 1 to assess alertness/level of consciousness, 
orientation, ability to follow commands and coordination. The assessment will be documented in 
the subject’s medical record. At the end of each cohort, the PI will provide narratives (per cohort 
and subject) for inclusion in the DSMB data reviews.  
The brief neurological assessment will be performed as follows in this sequence: 
1) To assess alertness and level of consciousness, the RASS (Appendix D) will be employed 
and the completed scale will be added to the subject’s medical record.  
The RASS score will be entered into the eCRF; however, the scores for orientation and 
ability to follow commands (see below) will not be entered into the eCRF.  
2) Orientation will be assessed using questions 1 and 2 of the Folstein Mini-Mental Status 
Examination (Rovner and Folstein, 1987), as shown below. The answers to each question 
will be noted in the subject’s medical record, along with the combined score for the two 
questions. Scoring will be performed according to Rovner and Folstein (1987). 
• “What is the year? Season? Date? Day of the week? Month?” 
• “Where are we now: State? County? Town/city? Hospital? Floor?” 
3) Ability to follow commands and coordination (to the extent possible) will be assessed 
using a modified question 8 of the Folstein Mini-Mental Status Examination as shown 
below. The total score will be noted in the subject’s medical record. Scoring will be 
performed according to Rovner and Folstein (1987). 
• “Take the paper in your right hand, fold it in half, and hand it back to me.” 
(The examiner gives the patient a piece of blank paper). 
11.1.6. 
Neuropsychiatric/Behavioral/Cognitive Assessments 
The SCID-5-CT (customized) (First et al-2015) will be administered by a psychologist at Day-1 
as a screening tool to exclude any subjects with major DSM-5 Axis I or II disorders. Due to the 
nature of the assessment, the SCID should not be repeated during this study. Therefore, for any 
subject who receives the SCID on Day -1, but is subsequently designated an alternate and 
readmitted on another day, the initial SCID will serve as their assessment of record.   
Other assessments of neuropsychiatric/behavioral symptoms will be performed by appropriately 
experienced and trained study staff using the C-SSRS (Posner et al-2011), BPRS (expanded 
version 4.0, 24 items) (Ventura et al-1993), and RASS (Sessler et al-2002, Ely et al-2003). A 
psychiatrist will be available by phone to consult with the investigator throughout the study. At 
the investigator’s request, the psychiatrist will come to the clinic to evaluate a subject. 
The C-SSRS Baseline/Screening version will be administered by study staff at screening, and the 
C-SSRS Since Last Visit version will be administered at Day -1 and at follow-up on Day 8. 
Scoring and analysis will be performed according to the Columbia-Suicide Severity Rating Scale 
Scoring and Data Analysis Guide. Study staff administering the C-SSRS will complete C-SSRS 
training. 


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The BPRS will be performed by a psychologist or trained clinician at screening, Day -1 
(baseline), at 6 (+ 2) hours post dose (timing at the discretion of the investigator), 48 hours post 
dose (prior to discharge), and on Day 8. For BPRS items assessed over time (eg, items 1, 2, and 
3), the period of assessment should be over the prior week, except for assessments performed at 
6 and 48 hours post dose, which will be assessed since the prior assessment. The + 2-hour 
window for the 6-hour post-dose BPRS is intended to allow the investigator some discretion 
should the assessment need to be delayed. The timing may be dependent on the emergence and 
severity of neuropsychiatric symptoms. If the investigator determines a subject is incapable of 
providing valid responses during the + 2-hour window, the reason(s) why the BPRS was delayed 
or could not be done will be documented in the source documentation. 
Mental health/behavioral symptoms, judged to be clinically significant, should be reported as 
AEs at whatever time point they may be observed. As part of the reporting process, if the AE 
corresponds to an item on the BPRS, the relevant item on the BPRS scale should be used for 
assessing the severity of the event. In addition, if AEs of general agitation or sedation are 
reported, since these do not correspond to a specific item on the BPRS, the RASS should be used 
by a physician, physician assistant, or nurse to assess severity (see Appendix D). 
The DSST (Strauss et al-2006) will be administered by appropriately trained study staff at 
screening, baseline (Day -1), 48 hours post dose (Day 3), and Day 8 to detect any persistent 
cognitive effects. The screening time point is included to reduce practice effects between 
baseline and re-administrations thereafter. The DSST will not be used to determine eligibility. 
Note: Alternates who are readmitted on another day will have the BPRS, C-SSRS, and DSST 
repeated. 
11.1.7. 
Injection Site Assessments 
At approximately 5 minutes after injection, the subject will be asked by the study staff to rate the 
maximum intensity of pain, pruritus, tingling, and numbness at the injection site using the VAS 
(Appendix A). The VAS will also be completed at pre dose and at 10, 15, 30, and 45 minutes and 
1, 1.5, 3, 5, 8, 12, 24, and 48 hours post dose, and at Day 8. In addition, an injection site 
assessment for presence and severity of pain, tenderness, erythema, and induration/swelling will 
be performed by a physician, physician assistant, or nurse approximately 5 minutes after 
injection and for all subsequent time points (as stated above; Appendix C). Refer to Appendix B 
for the Toxicity Grading Scale for Injection Site Reactions. 
The anticipated neuropsychiatric effects of Scopolamine HBT may hinder obtaining reasonable 
subjective data on the VAS, especially at the earlier post-dose time points. If the PI or designee 
determines a subject is incapable of providing valid responses at one or more time point(s), the 
reason(s) why the VAS assessment(s) could not be done will be documented by time point in the 
source documentation. 
Note: All mild (grade 1) events, including all nonzero VAS scores, will be recorded as an AE, 
(refer to Section 11.3.1 and Appendix B).   
11.1.8. 
Electrocardiogram 
A 12-lead ECG will be performed supine at screening, Day-1, Days 1-3, and Day 8 (prior to the 
blood draws, if applicable). On Day 1, 12-lead ECG will be performed prior to dosing and at 5, 


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10, 15, 30, and 45 minutes and 1, 1.5, 3, 5, 8, and 12 hours after dosing. The 12-lead ECG 
tracings will be reviewed and signed and dated by the investigator or designee on the same study 
day. ECGs may be performed at other times if deemed necessary by the investigator.  
When the time of an ECG coincides with a blood draw, the ECG will be performed within 5 
minutes prior to the nominal time point (refer to Section 11.1for details).   
A cardiologist will be available to consult with the investigator, as needed, throughout the study.  
P-R intervals will be determined for each of these ECGs from single reading (invalid 
measurements will be repeated). QTc will be calculated using both Bazett’s and Fridericia’s 
corrections as follows: 
• Fridericia correction: QTc = QT/RR0.33 
• Bazett’s correction: QTc = QT/RR0.5 
The 3-lead ECG will be utilized for continuous monitoring starting at 1 hour prior to dosing and 
ending at 24 hours post dose. 
Due to the continuous monitoring and large number of 12-lead ECGs during the first 24 hours, 
the ECG electrodes may be left in place from pre dose through 24 hours post dose (and replaced 
as necessary). 
Note: Subjects will not be allowed to shower from pre dose until after all 24-hour, post dose 
procedures have been completed and the electrodes removed. 
11.1.9. 
Laboratory Assessments 
Clinical laboratory tests will primarily be performed by Pharmaron with the remaining tests to be 
performed by Quest Diagnostics (refer to the Clinical Laboratory Manual for details). 
11.1.9.1. Hematology and Coagulation 
The following hematological tests will be performed: 
• Red Blood Count 
• White Blood Count Total 
• Hematocrit 
• Hemoglobin 
• Platelet Count 
• Absolute Eosinophil Count 
• Absolute Basophil Count 
• Absolute Monocyte Count 
• Absolute Neutrophil Count 
• Mean Corpuscular Volume 
• Mean Corpuscular Hemoglobin Concentration 


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• Mean Corpuscular Hemoglobin 
• Absolute Lymphocyte Count 
• Red (cell) Distribution Width 
The following coagulation tests will be performed: 
• Prothrombin Time 
• Partial Thromboplastin Time 
• Fibrinogen 
11.1.9.2. Serum Chemistry 
The following serum chemistry tests will be performed: 
• Glucose 
• Uric Acid 
• Blood Urea Nitrogen 
• Creatinine 
• Creatine kinase 
• Sodium 
• Potassium 
• Chloride 
• Calcium 
• Phosphorous 
• Protein, Total 
• Albumin 
• Globulin 
• Albumin/Globulin Ratio 
• Bilirubin, Total 
• Bilirubin, Direct 
• Alkaline Phosphatase 
• Lactic Dehydrogenase 
• Aspartate Aminotransferase 
• Alanine Aminotransferase 
• Gamma Glutamyl Transferase 
• Iron 


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• Total Cholesterol 
• Triglycerides 
• Magnesium 
• Carbon Dioxide 
11.1.9.3. Urinalysis 
The following urinalysis tests will be performed: 
• Color 
• Appearance 
• Specific Gravity 
• pH 
• Protein 
• Glucose 
• Ketones 
• Occult Blood 
• Leukocyte Esterase 
• Nitrite 
• Bilirubin 
• Urobilinogen 
• Magnesium (with calculation of fractional excretion) 
• Creatinine 
• Potassium (with calculation of fractional excretion) 
11.1.9.4. Pregnancy Screen 
All female subjects, regardless of childbearing potential, will undergo 2 pregnancy tests prior to 
receiving the study drug. A serum pregnancy test to measure human β-chorionic gonadotropin 
will be administered during screening and also within 24 hours prior to dosing in a controlled 
environment. A pregnancy test will also be conducted on Day 8, or at study termination, if it 
occurs before Day 8. 
11.1.9.5. Additional Tests 
The following tests will be performed: 
• Serology (screening only) 
− HIV Test (1 and 2) 
− FTA-ABS Test for Syphilis 


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− Hepatitis B Virus Surface Antigen 
− Hepatitis C Virus 
• Alcohol Breathalyzer 
• Urine Drug Screen (screening, Day -1, Day 8) 
− Barbiturates 
− Benzodiazepines 
− Cannabinoids 
− Cocaine 
− Opiates 
− Methadone 
− Phencyclidine 
− Propoxyphene 
− Oxycodone 
− Tricyclic Antidepressants 
− Amphetamines 
− Methylenedioxymethamphetamine 
11.2. 
IND Safety Reporting 
All AEs regardless of group (treatment or placebo) or suspected causal relationship to the 
investigational product will be reported as described in the following sections. 
The following terms, as defined by 21 CFR 312.32, apply to IND safety reporting. 
11.2.1. 
Adverse Event or Suspected Adverse Reaction 
Adverse event means any untoward medical occurrence associated with the use of a drug in 
humans whether or not considered drug related. This includes any unfavorable and unintended 
sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) 
temporally associated with the use of a medicinal (investigational) product. 
Suspected adverse reaction means any AE for which there is a reasonable possibility that the 
drug caused the AE. For the purposes of IND safety reporting, “reasonable possibility” means 
there is evidence to suggest a causal relationship between the drug and the AE. Suspected 
adverse reaction implies a lesser degree of certainty about causality than adverse reaction, which 
means any AE caused by a drug. 
11.2.2. 
Serious Adverse Event or Serious Suspected Adverse Reaction 
An AE or suspected adverse reaction is considered “serious” if, in the view of either the 
investigator or sponsor, it results in any of the following outcomes: 


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• Death 
• Life-threatening AE ‒ An AE or suspected adverse reaction is considered “life 
threatening” if, in the view of either the investigator or sponsor, its occurrence places 
the patient or subject at immediate risk of death. It does not include an AE or 
suspected adverse reaction that, had it occurred in a more severe form, might have 
caused death. 
• Inpatient hospitalization or prolongation of existing hospitalization 
• Persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions 
• Congenital anomaly/birth defect 
• Important medical events that may not result in death, be life threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical 
judgment, they may jeopardize the patient or subject and may require medical or 
surgical intervention to prevent one of the outcomes listed in this definition. 
Examples of such medical events include allergic bronchospasm requiring intensive 
treatment in an emergency room or at home, blood dyscrasias or convulsions that do 
not result in inpatient hospitalization, or the development of drug dependency or drug 
abuse. 
11.2.3. 
Unexpected Adverse Event or Unexpected Suspected Adverse Reaction 
An AE or suspected adverse reaction is considered “unexpected” if it is not listed in the 
investigator’s brochure or is not listed at the specificity or severity that has been observed or, if 
an investigator’s brochure is not required or available, is not consistent with the risk information 
described in the general investigational plan or elsewhere in the current application, as amended. 
For example, under this definition, hepatic necrosis would be unexpected (by virtue of greater 
severity) if the investigator’s brochure referred only to elevated hepatic enzymes or hepatitis. 
Similarly, cerebral thromboembolism and cerebral vasculitis would be unexpected (by virtue of 
greater specificity) if the investigator’s brochure listed only cerebral vascular accidents. 
“Unexpected,” as used in this definition, also refers to AEs or suspected adverse reactions that 
are mentioned in the investigator’s brochure as occurring with a class of drugs or as anticipated 
from the pharmacological properties of the drug but are not specifically mentioned as occurring 
with the particular drug under investigation. 
11.2.4. 
Unanticipated Problems Involving Risks to Subjects or Others 
Federal regulations (45 CFR Part 46/32 CFR 219) require that unanticipated problems involving 
risks to subjects or others be promptly reported to the IRB. These events encompass a broader 
category of events than SAEs and may include issues such as problems with loss of control of 
subject data or the investigational product, adverse psychological reactions, or breach of 
confidentiality. Risks to others (eg, program personnel) must also be reported. 
Unanticipated problems involving risks to subjects or others are any incident, experience, or 
outcome that meets all of the following criteria: 


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• Unexpected (in terms of nature, severity, or frequency) given (a) the procedures that 
are described in the protocol, investigator’s brochure, or ICF and (b) the 
characteristics of the subject population; 
• Related or possibly related to a subject’s participation in the study; and 
• Suggests that the study places subjects or others at a greater risk of harm than was 
previously known or recognized. 
The IRB and/or the ORP will evaluate the PI’s and research monitor’s reports to determine 
whether a given incident, experience, or outcome constitutes an unanticipated problem involving 
risks to subjects or others and, in coordination with the sponsor, ensure upward reporting of the 
unanticipated problems involving risks to subjects or others to the appropriate investigative sites 
and regulatory offices, as applicable. 
11.3. 
Relationship to Investigational Product 
The investigator must assign a relationship of each AE to the receipt of the investigational 
product. The investigator will use clinical judgment in conjunction with the assessment of a 
plausible biologic mechanism, a temporal relationship between the onset of the event in relation 
to receipt of the investigational product, and identification of possible alternate etiologies 
including underlying disease, concurrent illness, or concomitant medications. The following 
guidelines should be used by investigators to assess the relationship of an AE to study product 
administration. ONLY A PHYSICIAN CAN MAKE THIS DETERMINATION. 
Not related: No relationship to investigational product. Applies to those events for which 
evidence exists that there is an alternate etiology. 
Unlikely: Likely unrelated to the investigational product. Likely to be related to factors 
other than investigational product but cannot be ruled out with certainty. 
Possible: An association between the event and the administration of investigational 
product cannot be ruled out. There is a reasonable temporal association, but there may also 
be an alternative etiology such as the subject’s clinical status or underlying factors including 
other therapy. 
Probable: There is a high degree of certainty that a relationship to the investigational 
product exists. There is a reasonable temporal association, and the event cannot be explained 
by known characteristics of the subject’s clinical state or factors including other therapy. 
Definite: An association exists between the receipt of investigational product and the event. 
An association to other factors has been ruled out. 
11.3.1. 
Severity Assessment 
All AEs will be assessed for severity by an investigator. Inherent in this assessment is the 
medical and clinical consideration of all information surrounding the event including any 
medical intervention required. The Common Terminology Criteria for Adverse Events (CTCAE), 
version 5.0 (November 27, 2017) is a descriptive terminology that will be utilized for grading all 
AEs, with the exception of injection site reactions, which will be graded using the Local 
Reaction to Injectable Product table from the FDA’s Guidance for Industry: Toxicity Grading 


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Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical 
Trials (see Appendix B). 
Both guidance documents provide a grading (severity) scale for each AE term. Each event will 
be assigned one of the following categories: mild (grade 1), moderate (grade 2), severe (grade 3), 
or potentially life threatening (grade 4).  
All events (Grade 1 or higher) must be recorded, regardless of group assignment (treatment or 
placebo), suspected causal relationship or clinical significance (e.g., including those determined 
by the Investigator as non-clinically significant). 
Refer to Appendix A for assessing the severity of pain, pruritus, tingling, and numbness at the 
injection site (subject rating using the VAS); Appendix C for severity of pain, tenderness, 
erythema, and induration at the injection site (assessed by a physician, physician assistant, or 
nurse); and Appendix D for assessing the severity of agitation and sedation (using the RASS). 
The following criteria may be used for any symptom not included in the grading scale. 
Any Grade 4 (potentially life-threatening) or Grade 5 (fatal) AE must be reported as an 
SAE. 
The eCRF for AEs will reflect only the highest severity for continuous days an event occurred. 
Mild 
 
Grade 1 
Does not interfere with routine activities 
Minimal level of discomfort 
Moderate 
 
Grade 2 
Interferes with routine activities 
Moderate level of discomfort 
Severe 
 
Grade 3 
Unable to perform routine activities 
Significant level of discomfort 
Potentially Life Threatening 
Grade 4 
Hospitalization or ER visit for 
potentially life-threatening event 
Fatal 
 
Grade 5 
Death 
If a subject is evaluated in an emergency room for non-life-threatening illness or symptoms 
(ie, visits the emergency department over the weekend for mild problems because the physician’s 
office is closed), the information from that visit will be reviewed and the severity of the AE will 
be assessed by the PI according to the subject’s clinical signs and symptoms. 
As defined by the ICH guideline for GCP, the term “severe” is often used to describe intensity 
(severity) of a specific event (as in mild, moderate, or severe myocardial infarction); the event 
itself, however, may be of relatively minor medical significance (such as severe headache). This 
is not the same as “serious,” which is based on subject/event outcome or action criteria usually 
associated with events that pose a threat to a subject’s life or functioning. Seriousness (not 
severity) serves as a guide for defining regulatory reporting obligations. 
11.4. 
Recording Adverse Events 
Section 7.3.3 presents procedures to request unblinding of a subject’s randomization code due to 
a medical emergency or serious medical condition. 


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11.4.1. 
Methods/Timing for Assessing, Recording, and Analyzing Safety Endpoints 
AEs and SAEs will be documented in the source records, and recorded on the eCRFs and the 
sponsor-approved Serious Adverse Event Reporting Form, using accepted medical terms and/or 
the diagnoses that accurately characterize the event. It should be noted that the form for 
collection of SAE information is not the same as the AE case report form. If the same data are 
collected on both forms, the forms must be completed in a consistent manner (ie, the same event 
term should be used on both forms. When a diagnosis is known, the AE term recorded on the 
eCRF will be the diagnosis rather than a constellation of symptoms. The investigator will assess 
all AEs for seriousness, relationship to investigational product, severity, and other possible 
etiologies. When an event has not resolved by study closure, it will be documented on the AE 
eCRF as “not recovered/not resolved.” 
The time frame for the collection of AEs and SAEs begins at the administration of 
investigational product through 30 days after the investigational product is administered.  
Any condition recorded on the medical history should not be reported as an AE unless it worsens 
in frequency, intensity, or severity, or there are clinically significant changes in laboratory values 
after administration of study drug. 
11.4.2. 
Duration of Follow-Up of Subjects after Serious Adverse Events 
Investigators are required to follow SAEs to resolution, even if this extends beyond the 
prescribed reporting period. Resolution is the return to baseline status or stabilization of the 
condition; determined to have become chronic. The SAE outcomes will be reported to the 
 using 
the Serious Adverse Event Report Form. The investigator will submit any updated SAE data to 
the sponsor within 24 hours of receipt of the updated information. 
Investigators are not obligated to actively seek SAEs in former subjects; however, if an SAE, 
considered to be related to the investigational product is brought to the attention of the 
investigator at any time following completion of the study, the event will be reported to the 
sponsor’s safety office as defined in Section 11.5.1.1. 
11.5. 
Reporting Adverse Events 
The PI or designee will report all AEs to the local IRB and/or the 
 in the 
appropriate safety, annual, and/or final reports. The sponsor’s safety office 
 
 only receives SAEs, not all AEs. After appropriate data cleaning and query resolution 
between the clinical site, sponsor’s clinical monitor, and clinical data manager, SAEs from the 
clinical database will be reconciled with the sponsor’s SAE database. SAEs and AEs for 
inclusion in annual and final reports to the FDA will be provided from the clinical database by 
the clinical data manager in 
. 
11.5.1. 
Reporting Serious and Unexpected Adverse Events 
Contact information for reporting SAEs is provided in Table 10. 


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11.5.1.1. Reporting to the Sponsor 
All SAEs must be reported promptly (within 24 hours) to the sponsor’s safety office 
 per 21 CFR 312.64 whether or not the event is considered related to 
study product. Further, the investigator should comply with relevant study site SOPs on reporting 
SAEs. 
The minimum information that the investigator will provide to the 
 is 
specified in Table 11. The sponsor’s representative may request additional information for 
purposes of the study. 
Table 10: 
Study Contacts for Reporting Serious Adverse Events and Unanticipated 
Problems Involving Risks to Subjects or Others 
Sponsor’s Safety Office 
 
 
 
 
 
 
 
 
Institutional Review Board 
 
 
 
 
 
 
 
 
IntegReview IRB 
3815 S. Capital of Texas Highway 
Suite 320 
Austin, TX 78704 
Fax: 512-697-0085 
Telephone: 512-326-3001 
E-mail: integreview@integreview.com 
AND 
 
 
 
 
 
 
 
 
Research Monitor 
 
 
 
 
 
 
 


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Table 11: 
SAE Information to Be Reported to the Sponsor’s Safety Office 
Notification Method 
Information to Be Provided 
E-mail or Telephone 
(within 24 hours) 
IND number, sponsor study number, name of the investigational 
product, and investigator name and contact number 
 
Subject identification number 
 
SAE event term and description, onset date, date(s) of investigational product 
administration, severity, relationship to investigational product, and subject’s 
current status 
AND 
 
E-mail or Fax 
Cover sheet or letter 
 
Sponsor-approved serious adverse event report form 
 
Admission/discharge summary or medical record progress notes including 
pertinent laboratory/diagnostic test results 
NOTE: When submitting SAE reports via e-mail, the subject line of each email notification will read as 
follows: 
SAFETY REPORT – IND # 130620, Sponsor Study # S-16-14, Subject # ____, Event Term: ____ 
To comply with regulations mandating sponsor notification of specified SAEs to the FDA within 
7 calendar days, investigators must submit additional information as soon as it is available on the 
SAE report form. The sponsor’s representative will report unexpected SAEs associated with the 
use of the drug to the FDA as specified in 21 CFR 312.32 (c). 
Investigators must follow all relevant regulatory requirements as well as specific policy 
regarding the timely reporting of SAEs to the research monitor and the local IRB and/or the 
. 
Reporting to the sponsor’s safety office does not fulfill the investigator’s duty to report all 
unanticipated problems involving risks to subjects or others to the IRB. The PI will notify the 
local IRB and/or the 
 and the research monitor. 
11.5.1.2. Reporting to the IRB 
Unanticipated problems involving risks to subjects or others, SAEs related to participation in the 
study, and all subject deaths related to participation in the study should be promptly reported by 
telephone, e-mail, or fax to the local IRB and/or the 
. A complete written report 
should follow the initial notification. 
Investigators are required to forward safety information provided by the sponsor’s representative 
to the IRB. 


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11.5.2. 
Reporting Additional Immediately Reportable Events to the Sponsor’s Safety 
Office and Local IRB and/or the 
 
11.5.2.1. Pregnancy 
Each pregnancy must be reported immediately (within 24 hours of identification) by 
completing and submitting the initial sponsor-approved Pregnancy Report Form by e-mail or fax 
to the sponsor’s safety office 
. In addition, each pregnancy must be 
reported to the local IRB and/or the 
 in accordance with IRB policy. 
Subjects who become pregnant after dose administration on Day 1 will not receive any additional 
investigational product. The subject will be followed for safety to term, and the following 
information will be documented on the Pregnancy Report form: type and date of delivery, Apgar 
scores, and health status of the mother and child including the child’s sex, head circumference, 
gestational age at delivery, length, and weight. Complications and or abnormalities should be 
reported including any premature terminations. A pregnancy is reported as an AE or SAE only 
when there is suspicion that the investigational product may have interfered with the 
effectiveness of contraception or there was a serious complication in the pregnancy including a 
spontaneous abortion or an elective termination for medical rationale. Otherwise, pregnancy will 
not be categorized as an AE. It may be necessary to obtain authorization to access a subject’s 
medical records for details pertaining to the pregnancy and/or pregnancy outcome. 
11.5.2.2. AE-related Withdrawal of Consent 
Any AE-related withdrawal of consent during the study must be reported immediately (within 
24 hours of identification) to the sponsor’s safety office 
 
. The PI should report the 
withdrawal to the local IRB and the 
 in accordance with local policies. 
11.5.2.3. Pending Inspections/Issuance of Reports 
The knowledge of any pending compliance inspection/visit by the FDA, 
 
, Department of Health and Human Services, or other government agency 
concerning clinical investigation or research, the issuance of Inspection Reports, FDA Form 483, 
warning letters, or actions taken by any regulatory agency including legal or medical actions and 
any instances of serious or continuing noncompliance with the regulations or requirements will 
be reported immediately to the local IRB and/or the 
 and the sponsor’s 
representative. 
11.5.3. 
IND Annual Report to the FDA 
The PI will be responsible for the preparation of a detailed annual synopsis of clinical activity, 
including AEs, for submission to the sponsor’s representative 
. Each annual report 
will summarize IND activity for 1 year beginning approximately 3 months before the IND FDA 
anniversary date. The sponsor’s representative will notify the PI of the due date with sufficient 
time for the PI to assemble the required information. 


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11.5.4. 
Final Report 
A final study report will be prepared in accordance with FDA’s Guidance for Industry: 
Submission of Abbreviated Reports and Synopses in Support of Marketing Applications and ICH 
E3 Guideline Structure and Content of Clinical Study Reports and provided to the sponsor’s 
representative for review and approval. The sponsor’s representative will use this report to 
prepare the final clinical study report for submission to the FDA. 
12. 
STATISTICS 
12.1. 
Description of Statistical Methods 
Detailed statistical procedures, listings, table shells, and figures will be provided in a separate 
statistical analysis plan (SAP).  
This Phase 1 trial has two objectives: 
• To characterize the safety and tolerability profile of ascending doses of Scopolamine 
HBT administered by IM injection (0.005mg/kg to 0.021mg/kg) and set upper limits 
on the probability of extreme and non-extreme DLTs across dosage levels 
• To characterize the PK of ascending doses of Scopolamine HBT administered by IM 
injection and assess dose proportionality for Cmax and AUC∞ over the dosing range 
Table 12 shows the study objectives and endpoints. 
Table 12: 
Study Objectives and Endpoints 
Study Objective 
Study Endpoints 
Safety 
Extreme and nonextreme DLTs 
SAEs related to drug 
All AEs that are not SAEs 
Vitals signs, ECG, and clinical laboratory values and their 
changes from baseline 
Injection site assessments 
Clinically relevant physical exam findings 
Neuropsychiatric measures (BPRS, C-SSRS, and RASS) 
Cognitive measures (DSST) 
Pharmacokinetics 
Cmax, Tmax, t1/2, Vd_F, Cl_F, MRT, Cmax/Dose, AUC∞/Dose 
Detailed descriptions of the endpoints and their measurements can be found in Section 10 and 
Section 11. Additional discussion of the statistical methodology and assumptions can be found in 
the SAP. 
12.1.1. 
Pharmacokinetic Analysis 
The PK analysis will be performed on the pharmacokinetics analysis set. Blood samples will be 
obtained for PK assessments prior to dosing and at 2, 5, 10, 15, 20, and 30 minutes and 1, 2, 4, 8, 
12, 24, 36, and 48 hours post dose. Scopolamine HBT PK assessments will include 


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determination of the following parameters: observed Cmax, Tmax, Vd_F, t½, Cl_F, AUClast, AUC∞, 
Cmax/Dose, MRT, and AUC∞/Dose. Plasma concentration time profiles for each subject tested 
will be evaluated using semi-log plots and characterized using noncompartmental analysis 
(WinNonlin). PK data will also be summarized graphically by dose group. PK and safety 
endpoints will undergo PD analysis and evaluation. 
Data for PK parameters will be summarized by group using descriptive statistics including mean, 
standard deviation, minimum, maximum, and may include median and quartiles. All PK data for 
individual participants will be provided in listings. 
Dose proportionality will be tested for Cmax/Dose and AUC∞/Dose using ANOVA models. 
Likelihood ratio tests will be used to test the joint hypothesis of equivalence across dose levels. 
Equivalence will be tested for each dose level against the next higher dose level. Equivalence of 
parameters across doses (dose equivalence) will be tested for Tmax, t1/2, Vd_F, and MRT. All 
ANOVA models of PK parameters will adjust for sex. 
12.1.2. 
Safety Analyses 
Safety analysis will include data collected from the safety analysis set. DLT and AE data will be 
coded using the current MedDRA version at the time of study setup, listed individually 
(including intervention and outcome), and summarized by system organ class and preferred 
terms within a body system for each treatment group. Data will be summarized by both event 
(counting each event regardless of subject) and by subject (counting only one event within each 
system organ class or preferred term). Serious and/or unexpected AEs will also be discussed on a 
case-by-case basis. 
Changes in pulse rate, systolic and diastolic blood pressure, weight, and respiratory rate will be 
summarized (mean, median, minimum, maximum, standard deviation) by dose level and time 
point. Clinical laboratory assessment results will be presented. 
Upper bounds of 80% confidence intervals of the true probability of events (extreme DLTs, non-
extreme DLTs, and severe AEs) will be estimated from the number of events in each cohort 
using the Pearson-Clopper method. 
Descriptive statistics of BPRS, C-SSRS, DSST, RASS (if conducted), and injection site VAS 
scores (mean, median, standard deviation, minimum, and maximum) will be presented for each 
dose level and time point. 
Changes in the BPRS score (6 hours, 48 hours, and 8 days) from baseline will be compared 
between placebo and active dose levels using ANOVA models for each time point. The null 
hypothesis of no difference between placebo and the active dose will be tested for each dose 
level using a one-sided alternative hypothesis of higher increases among the participants 
receiving the active drug than among the placebo group. 
Participants have C-SSRS scores of zero at baseline. The proportion of individuals having any 
increase in their C-SSRS score from zero will be compared for each drug dosage level to the 
placebo group using Fisher’s exact test. 
The DSST will be conducted at screening, Day -1, Day 3, and Day 8. Changes from baseline 
(Day -1) will be compared between placebo and active dose levels using ANOVA models for 
each time point. Placebo control will help to exclude any remaining practice effects or changes 


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unrelated to the study drug. The null hypothesis of no difference in DSST scores between active 
Scopolamine and placebo will be tested for each dose level using a one-sided alternative 
hypothesis of more negative changes in DSST scores among participants receiving the active 
drug than among the placebo group. A pooled analysis will compare all Scopolamine dosage 
levels to placebo. Individual participants’ DSST scores will be presented by study day, and 
persistent declines in scores at Day 3 or Day 8 will be noted. 
Frequencies of severity (None, Mild, Moderate, Severe, Potentially Life Threatening) from 
injection site assessments performed by clinicians will be summarized by type (pain, tenderness, 
erythema/redness, induration/swelling) and time point by dosage group. Semi-log graphs of 
mean VAS scores will be plotted (VAS score vs. log-time since injection). Differences between 
placebo and active drug injection site VAS scores will be compared statistically by dosage level 
using 3 different ANOVA models corresponding to the first hour, next 4 hours, and 8-48 hours 
after injection. A Wald test with a one-sided alternative will be used. 
12.1.3. 
Clinical Laboratory Data Analyses 
For hematology and serum chemistry tests, the median, mean, standard deviation, minimum, and 
maximum of all values for each test within each treatment group at baseline and for all raw 
values and change for baseline for subsequent time points will be provided in a summary table. 
A second table (a “shift table”) will be made, showing for each laboratory variable the 
percentage of subjects in each treatment group whose values decreased, stayed the same, or 
increased between the baseline or pretreatment period and the subsequent visits. A third table 
will be prepared displaying the numbers of subjects in each treatment group who had values 
below, within, and above the normal range at baseline and at subsequent time points. 
These tables will be reviewed by the PI or research monitor to evaluate whether any significant 
trends in laboratory values occurred. The PI or research monitor will also review urinalysis data 
by inspecting the laboratory data tabulations, but no summary tables of these will be prepared. 
12.1.4. 
Subgroup Analysis 
The small sample size of this study limits meaningful subgroup analyses; however, descriptive 
statistics by sex will be provided as appropriate. Sex will be included as a covariate in the 
analysis of PK parameters. Any subgroup analyses specified after data unblinding will be labeled 
as post hoc. 
12.2. 
Planned Enrollment and Reason for Sample Size 
The sample size calculation of 40-60 healthy subjects has been chosen to provide adequate 
numbers of subjects for characterization of the safety and tolerability of Scopolamine HBT 
administered in 1 to 5 dose-escalating cohorts in normal, healthy volunteers as well as a placebo 
group. No formal statistical sample size computation was performed; however, the 6 to 9 active 
subject and 2 to 3 control subject design is commonly employed in Phase 1 clinical trials because 
it provides adequate power to detect non-rare events (true probability, P > 0.20-0.25) events 
within each cohort. Enrollment may be stopped at any dosing level if stopping criteria are met; 
therefore, the total sample size may be substantially smaller than 40-60. 


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12.3. 
Interim Analysis and Stopping Rules 
Criteria for halting enrollment and recruitment have been outlined in Section 7 of the protocol. 
These criteria are pre-specified and not related to the statistical analysis. No interim statistical 
analysis is planned, and there are no statistical criteria for study termination in this Phase 1 
clinical trial. Summary tables and listings for safety and PK parameters will be provided to the 
DSMB for review prior to dose adjustment. Prior to any data being provided to the DSMB, it 
must be reviewed and approved for release by a study biostatistician in collaboration with the 
 biostatistician. The DSMB will not use statistical tests in making determinations about 
whether to halt or terminate the study. 
12.4. 
Procedures for Reporting Deviations from the Original Statistical 
Plan 
Any deviation(s) from the original SAP as indicated in the protocol will be described in an 
amendment to the protocol and the SAP. If the amendment is approved prior to unblinding, the 
outcome will be presented in the main statistical report. Any additional analyses proposed after 
data lock and unblinding will be noted as “post hoc” in the final statistical report. Deviations 
from the SAP will be documented in accordance with study site SOPs. 
12.5. 
Key Assumptions 
Some of the hypothesis testing planned for this study relies on ANOVA, which requires 
normality and equal variance across dosing levels (homoskedasticity). If the normality 
assumption for ANOVA does not hold, link functions will be assessed for use in generalized 
linear models. In the event that no appropriate link function can be identified to attain normality, 
non-parametric bootstrap replication will be used to generate standard errors for coefficients. The 
Koenker-Bassett/generalized Breusch-Pagan Test will be used to test the assumption of 
homoskedasticity. If homoskedasticity is rejected, unequal variance ANOVA will be used with 
robust (Huber-White) standard errors. 
12.6. 
Selection of Subjects to Be Included in Analyses 
12.6.1. 
Safety Analysis Set 
The safety analysis set is defined as those subjects who meet eligibility requirements and 
received at least one dose of study drug or placebo. Subjects will be analyzed according to the 
dose they received. 
12.6.2. 
Pharmacokinetics Analysis Set 
The pharmacokinetics analysis set is defined as those subjects who meet eligibility requirements, 
received at least one dose of study drug, and have at least one PK data point. Subjects will be 
analyzed according to the dose they received. 
13. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
Subjects will be identified on eCRFs by a unique subject identification number and on source 
documents by the unique subject identification number and subject initials. The unique 


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identification number will be assigned to each subject at screening, and this number will be used 
to identify the subject throughout the study. 
No personal identifier will be used in any publication or communication used to support this 
research study. The subject identification number will be used if it becomes necessary to identify 
data specific to a single subject. Representatives of 
, the sponsor’s representative, the 
local IRB and/or the 
, and the FDA are eligible to review medical and research 
records related to this study as a part of their responsibility to protect human subjects in clinical 
research. Personal identifiers will be removed from photocopied medical and research records. 
13.1. 
Accounting for Missing, Unused, and Spurious Data 
Instances of missing data will be reported along with a reason that data is missing. If multiple 
measurements are collected, a reason for repeat measurement will be recorded, and the data point 
corresponding to erroneous or incomplete data collection will be censored. Otherwise, all data 
will be included in the analysis as specified in the SAP. Data collected following administration 
of rescue medication will be censored in the analysis of endpoints that are likely to be affected 
by the rescue medications (BPRS, RASS, DSST, C-SSRS). However, injection site VAS scores 
will not be censored following administration of rescue medications. 
13.2. 
Study Monitoring 
Study monitoring will be the responsibility of the 
, as designated by the 
sponsor. Upon successful approval of the protocol and establishment of the regulatory file, the 
clinical trial monitor will draft a clinical monitoring plan. To ensure that the investigator and the 
study staff understand and accept their defined responsibilities, the clinical monitor will maintain 
regular correspondence with the site and may be present during the course of the study to verify 
the acceptability of the facilities, compliance with the investigational plan and relevant 
regulations, and the maintenance of complete records. As needed, the clinical monitor may 
witness the informed consent process or other applicable study procedures to ensure the safety of 
subjects and the investigators’ compliance with the protocol and GCPs. 
Monitoring visits by the 
 clinical trial monitor will be scheduled to take place 
at pre-study (for site qualification), the initiation of the study, during the study at appropriate 
intervals, and after the last subject has completed the study. A report of monitoring observations 
will be provided to the PI (for corrective actions), 
, and the product manager. 
The clinical trial monitor will perform complete investigational product accountability at the end 
of the study. If it is deemed necessary by the Sponsor, an unblinded clinical trial monitor (or 
product compliance scientist) will visit the site pharmacy during the study to monitor 
accountability and/or follow up on concerns.  
13.3. 
Audits and Inspections 
Authorized representatives of the sponsor, the FDA, the independent ethics committee, or IRB 
may visit the site to perform audits or inspections, including source data verification. The 
purpose of the audit or inspection is to systematically and independently examine all 
study-related activities and documents to determine whether these activities were conducted, and 
data were recorded, analyzed, and accurately reported according to the protocol, GCP guideline 
of the ICH, and any applicable regulatory requirements. 


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The investigator should contact the sponsor’s representative and 
 
immediately if contacted by a regulatory agency about an inspection. 
13.4. 
Institutional Review Board 
As the IRB of record, the local IRB will serve as the responsible IRB and will review the 
protocol, informed consent, and progress reports on a continuing basis in accordance with all 
applicable regulations, including 21 CFR Parts 50 and 56. The 
 will 
provide a second review. 
The PI must obtain IRB approval for the study. Initial IRB approval and all materials approved 
by the IRB for this protocol, including the patient consent form and recruitment materials, must 
be maintained by the protocol physician and made available for inspection. 
The PI will be responsible for preparing and submitting continuing review reports per institution 
and IRB requirements. The PI or a designee will submit the approved continuing review reports 
and the local IRB approval notifications to 
 as soon as the documents 
are available. 
14. 
QUALITY CONTROL AND QUALITY ASSURANCE 
To ensure compliance with GCP and all applicable regulatory requirements, the sponsor’s 
representative may conduct quality assurance audits. Refer to Section 13.3 for more details 
regarding the audit process. 
Auditing of the clinical trial may be conducted at any time during the study to ensure continued 
compliance with regulations, policies, and procedures. Auditing will be undertaken, as needed, 
by independent personnel designated by the 
. Audit findings will be documented in a 
formal audit report that will detail the conduct of the audit and summarize the observations 
noted. 
15. 
ETHICS 
15.1. 
Ethics Review 
The study is based on adequately performed laboratory and animal experimentation and will be 
conducted under a protocol reviewed by the local IRB and/or 
. The 
study is to be conducted by scientifically and medically qualified persons. The IRB will 
determine whether the benefits of the study are in proportion to the risks. The rights and welfare 
of the subjects will be respected, the physicians conducting the study will ensure that the hazards 
do not outweigh the potential benefits, the results to be reported will be accurate, subjects will 
give their informed consent and will be competent to do so and not under duress, and all study 
staff will comply with the ethical principles in 21 CFR Part 50 and the Belmont Principles. 


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15.1.1. 
Review/Approval of Study Protocol 
Before a clinical study can be initiated, the study protocol and other required documents will be 
submitted to the following departments in the order listed for review and/or approval, with the 
final review by the FDA: 
• Integrated Product Team 
• Scientific Review Committee 
• Sponsor’s Representative Team (Senior Regulatory Affairs Advisor; 
 
) 
• Protocol Review Board, 
 
• Local IRB and the 
 
• Sponsor’s Representative (acting for TSG-DA) 
• 
 Commanding General, if applicable 
Enrollment in this protocol may not begin until all approvals have been obtained and the formal 
authorization letter is received by the PI from the sponsor’s representative. 
15.1.2. 
Protocol Modifications 
All modifications to the protocol and supporting documents (informed consent, study-specific 
procedures, SOPs, recruitment materials, etc.) must be reviewed and approved prior to 
implementation. Any protocol amendment will be agreed upon and approved by the sponsor’s 
representative prior to submission to the local IRB and/or the 
 and prior to implementation 
of any change or modification. Any modification that could potentially increase risk to patients 
must be submitted to the FDA prior to implementation. The ICF must be revised to concur with 
any amendment as appropriate and must be reviewed and approved with the amendment. Any 
patient already enrolled in the program will be informed about the revision and asked to sign the 
revised ICF if the modification directly affects the individual’s participation in the program. A 
copy of the revised, signed, and dated ICF will be given to the patient. All original versions of 
the ICF will be retained in the protocol regulatory file, and a copy will be retained in the protocol 
regulatory file. 
15.1.3. 
Protocol Deviation Procedures 
All subject-specific deviations from the protocol (eg, failure to return for follow-up visits or 
blood collection within the time indicated in the protocol) are to be documented. The PI or 
designee will be responsible for identifying and reporting all deviations, which are defined as 
isolated occurrences involving a procedure that did not follow the study protocol or study-
specific procedure. Deviations will be reported annually in the continuing review report to the 
local IRB and/or the 
 and, if appropriate, in the final study report. Action taken in response 
to the deviation and the impact of the deviation will be assessed by the PI or subinvestigator and 
recorded as significant or nonsignificant. 
Any protocol deviation that adversely affects the safety or rights of a subject or the scientific 
integrity of the study will be reported immediately to the sponsor’s representative, local IRB, 
and/or the 
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15.2. 
Ethical Conduct of the Study 
This study will be conducted in accordance with all applicable federal and DoD human research 
protections requirements and the Belmont Principles of respect for persons, beneficence, and 
justice. 
The procedures set out in this study are designed to ensure that the sponsor’s representative and 
all study personnel abide by the principles of the ICH GCP Guidelines and the CFR. The PI 
confirms this by signing this study protocol and FDA Form 1572. 
15.2.1. 
Confidentiality 
HIPAA requires that researchers obtain the subject’s permission (HIPAA Authorization) to use 
and disclose health information about the subject that is either created by or used in connection 
with this research. The information includes the entire research record and supporting 
information from the subject’s medical records, results of laboratory tests, and both clinical and 
research observations made during the individual’s participation in the research. 
In this research, the subject’s health information will be collected and used to conduct the study; 
to monitor the subject’s health status; to measure effects of the investigational product; to 
determine research results, and possibly to develop new tests, procedures, and commercial 
products. Health information is used to report results of research to the sponsor’s representative 
and federal regulators and may be reviewed during study audits for compliance with study plans, 
regulations, and research policies. After the study ends, each subject has the right to see and 
receive a copy of his or her information. 
Representatives of the TSG-DA as the IND sponsor, the sponsor’s representative, the local IRB 
and/or the 
, the DoD, and the FDA are eligible to photocopy and review 
records related to this protocol as a part of their responsibility to protect the participants of this 
protocol. In addition, these representatives are eligible to witness the applicable study procedures 
to ensure the safety of subjects. 
No personal identifier will be used in any publication or communication used to support this 
research study. The subject’s identification number will be used in the event it becomes 
necessary to identify data specific to a single subject. 
15.2.2. 
Medical Care for Research-Related Injury 
All nonexempt research involving human subjects shall, at a minimum, meet the requirement of 
32 CFR 219.116(a)(6). 
If a subject is injured because of participation in this research, s/he may choose to seek care 
under their personal health insurance, and their workers’ compensation/disability coverage may 
also apply. No reimbursement is available for medical expenses to treat research-related injuries. 
No compensation is available for research-related injuries. This does not constitute a waiver or 
release of legal rights.  
15.3. 
Written Informed Consent 
The informed consent process and document will be reviewed and approved by the local IRB 
and/or the 
 and sponsor’s representative prior to initiation of the study. The consent form 


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contains a full explanation of the possible risks, advantages, and alternate treatment options, and 
availability of treatment in the case of injury, in accordance with 21 CFR 50. The consent form 
indicates that by signature, the subject, or where appropriate, legal guardian, permits witnessing 
of applicable study procedures by the sponsor’s representative, as well as access to relevant 
medical records by the sponsor’s representative and by representatives of the FDA. The 
sponsor’s representative will submit a copy of the initial IRB- and sponsor’s representative-
approved consent form to the FDA and will maintain copies of revised consent forms that have 
been reviewed and approved by the local IRB and/or the 
. 
A written ICF, in compliance with 21 CFR Part 50, 32 CFR Part 219, the Belmont Principles, 
and HIPAA Authorization will be signed by the subject before any study-related procedures are 
initiated for that subject. This consent form must be retained by the investigator as part of the 
study records. Each subject will receive a copy of the signed ICF. The investigators or their 
designees will present the protocol in lay terms to individual subjects. Questions on the purpose 
of the protocol, protocol procedures, and risks to the subjects will then be solicited. Any question 
that cannot be answered will be referred to the PI. No subject should grant consent until 
questions have been answered to his or her satisfaction. The subject should understand that the 
study product is an investigational drug and is not licensed by the FDA for commercial use but is 
permitted to be used in this clinical research. Informed consent includes the principle that it is 
critical the subject be informed about the principal potential risks and benefits. This information 
will allow the subject to make a personal risk versus benefit decision and understand the 
following: 
• Participation is entirely voluntary, 
• Subjects may withdraw from participation at any time, 
• Refusal to participate involves no penalty, and 
• The individual is free to ask any questions that will allow him or her to understand the 
nature of the protocol. 
Should the protocol be modified, the subject consent form must be revised to reflect the changes 
to the protocol. If a previously enrolled subject is directly affected by the change, the subject will 
receive a copy of the revised ICF. The approved revision will be read, signed, and dated by the 
subject. 
The subject will be informed that a description of this clinical trial will be available on 
http://www.ClinicalTrials.gov, as required by US law. 
16. 
DATA HANDLING AND RECORDKEEPING 
The primary source document for this study will be the subject’s medical record. Source 
documents will be retained at the site. 
Paper source documents will be used for this study and source data will be entered into an 
electronic database system. The eCRF layouts and specifications will define and identify the 
applicable source data that will be collected and entered into the system. Applicable source data 
will be electronically transcribed by the site designee onto the eCRF (data entry screens). The 
investigator is ultimately responsible for the accuracy of data transcribed onto the eCRF. Data 


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monitoring and management will be performed in the database system by the 
 
clinical trial monitor and the designated clinical data management contract research organization. 
All individuals who will be expected to transcribe data into the eCRF will be given the training 
necessary to perform their assigned tasks as described in 21 CFR 11.10(i)). Training will be 
conducted by qualified individuals from the designated clinical data management contract 
research organization, both initially and on a continuing, as-needed basis. The training 
documentation will be maintained at the trial site. The sponsor will also keep a record of the 
training files. 
A detailed data management plan will be written prior to study start, with approval by the 
sponsor’s data manager in the 
 Clinical Data Management Branch. All updates 
to the data management plan must be approved before study closeout and database lock. 
16.1. 
Inspection of Records 
The sponsor’s representative or designee will be allowed to conduct site visits at the 
investigation facilities for the purpose of monitoring any aspect of the study. The investigator 
agrees to allow the monitor to inspect the drug storage area, investigational product stocks, drug 
accountability records, subject charts, study source documents, and other records relative to 
study conduct. 
Subjects’ health information is used to report results of research to the sponsor’s representative 
and federal regulators and may be reviewed during study audits for compliance with study plans, 
regulations, and research policies. The consent form indicates that by signature, the subject 
permits access to relevant medical records by the sponsor’s representative and by representatives 
of the FDA. 
Upon a subject’s termination from the trial, completed eCRFs will be ready and available for on-
site review by the sponsor’s representative or the designated representative within 14 days after 
receipt of the subject’s data. 
16.2. 
Retention of Records 
The PI must maintain all documentation relating to the study for a period of 2 years after the last 
marketing application approval, or if not approved for 2 years following the discontinuance of 
the investigational product for investigation. If it becomes necessary for the sponsor’s 
representative or designee or the FDA to review any documentation relating to the study, the 
investigator must permit access to such records. 
Completed, monitored eCRFs will be stored in a secure location by the sponsor’s representative 
or designee. A copy of each completed eCRF will be retained by the investigator. 
The PI will be responsible for retaining sufficient information about each subject (ie, name, 
address, telephone number, Social Security number, and subject identifier in the study) so that 
the sponsor’s representative, the local IRB, the FDA, employees of 
, or other 
regulatory authorities may have access to this information should the need arise. 
It is the policy of the 
 that data sheets are to be completed for all subjects 
participating in research (Form 60-R, Volunteer Registry Data Sheet). The data sheets will be 
entered into this Command’s Volunteer Registry Database. The information to be entered into 


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this confidential data base includes the subject’s name, address, and Social Security Number; 
study title; and dates of participation. The intent of this database is twofold: first, to readily 
answer questions concerning an individual’s participation in research sponsored by 
 
and second, to ensure that 
 can exercise its obligation to ensure research subjects are 
adequately warned (duty to warn) of risks and to provide new information as it becomes 
available. The information will be stored at 
 for a minimum of 75 years. The 
Volunteer Registry Database is a separate entity and is not linked to the study database. 
17. 
PUBLICATION POLICY 
All data collected during this study will be used to support this IND. All data may be published 
in the open medical or military literature with the identity of the subjects protected. Anyone 
desiring to publish or present data obtained during the conduct of the study will conform to local 
site policies and then forward the publication for review to the Director, 
 
. 


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18. 
LIST OF REFERENCES 
18.1. 
Publications 
Adeyinka A, Kondamudi NP. Cholinergic crisis. StatPearls Jan-.2018 Oct 27. 
APP Pharmaceuticals, LLC. Scopolamine Hydrobromide Injection USP. Schaumburg, IL: APP 
Pharmaceuticals. 2012(unapproved label, NDC 63323-268-01). 
Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0, Department of Health 
and Human Services, November 27, 2017. 
Ebert U, Siepmann M, Oertel R, Wesnes KA, Kirch W. Pharmacokinetics and 
pharmacodynamics of scopolamine after subcutaneous administration. J Clin Pharmacol. 
1998;38(8):720-726. 
Eger E. Atropine, scopolamine, and related compounds. Anesthesiology. 1962;23(3):365-383. 
Elkin EH, Freedle RO, Van Cott HP, Fleishman EA. Effects of Drugs on Human Performance: 
The Effects of Scopolamine on Representative Human Performance Tests: Technical Report I, 
American Institutes for Research, Silver Spring, MD. 1965. 
Ely EW, Truman B, Shintani A, et al. Monitoring sedation status over time in ICU patients: the 
reliability and validity of the Richmond Agitation-Sedation Scale (RASS). JAMA. 
2003;289(22):2983-2991. 
First MB, Williams JBW, Karg RS, and Spitzer, Structured Clinical Interview for DSM-5 Clinical 
Trials (SCID-5-CT). 2015; American Psychological Association. 
Ghoneim MM, Mewaldt SP. Effects of diazepam and scopolamine on storage, retrieval and 
organizational processes in memory. Psychopharmacologia. 1975;44(3):257-62. 
Ghoneim MM, Mewaldt SP. Studies on human memory: the interactions of diazepam, 
scopolamine, and physostigmine. Psychopharmacology (Berl). 1977;52(1):1-6. 
Hammersmith Medicines Research Clinical Trial Report. Effects, Side Effects & Blood Levels 
of Hyoscine & Physostigmine. Trial Codes: 11-013 and PHiv101, Version 1, 20 January 2016. 
Hockstein NG, Samadi DS, Gendron K, Handler SD. Sialorrhea: a management challenge. Am 
Fam Physician. 2004 Jun 1;69(11):2628-2634. 
Kanto J, Kentala E, Kaila T, Pihlajamaki K. Pharmacokinetics of scopolamine during caesarean 
section: relationship between serum concentration and effect. Acta Anaesthesiologica 
Scandinavica. 1989;33(6):482-486. 
Kentala E, Scheinin H, Kaila T, Seppälä T, Kanto J. Pharmacokinetics and clinical effects of 
intramuscular scopolamine plus morphine. Acta Anaesthesiol Scand. 1998;42:323-328. 
Ketchum J, Sidell F, Crowell E Jr, Aghajanian G, Hayes A Jr. Atropine, scopolamine, and ditran: 
comparative pharmacology and antagonists in man. Psychopharmacologia. 1973;28(2):121-145. 
Koplovitz I, Schulz S. Perspectives on the use of scopolamine as an adjunct treatment to enhance 
survival following organophosphorus nerve agent poisoning. Military Medicine. 
2010;175(11):878-882. 


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Koplovitz I, McDonough JH Jr, Capacio B. Efficacy of Scopolamine as an Adjunct Post-
exposure Treatment for GA, GB, GD, GF, and VX in Guinea Pigs. Edgewood: Booz Allen 
Hamilton; 2015. 
Liem-Moolenaar M, de Boer P, Timmers M, et al. Pharmacokinetic-pharmacodynamic 
relationships of central nervous system effects of scopolamine in healthy subjects. British 
Journal of Clinical Pharmacology. 2011;71(6):886-898. 
Overall JE, Gorham DR (1962). The brief psychiatric rating scale. Psychological Reports 
1962;10:799-812.  
Posner K, Brown GK, Stanley B, Brent DA, Yershova KV, Oquendo MA, Currier GW, Melvin 
GA, Greenhill L, Shen S, Mann JJ. The Columbia–Suicide Severity Rating Scale: Initial Validity 
and Internal Consistency Findings From Three Multisite Studies With Adolescents and Adults. 
American Journal of Psychiatry. 2011;1681266–77.  
Renner U, Oertel R, Kirch W. Pharmacokinetics and pharmacodynamics in clinical use of 
scopolamine. Ther Drug Monit. 2005;27(5):655-665. 
Rogers DF. Motor control of airway goblet cells and glands. Respir Physiol. 2001;125:129-144. 
Rovner BW, Folstein MF. Mini-mental state exam in clinical practice. Hosp Pract (Off Ed) 
1987;22:99,103,106,110. 
Sannita WG, Maggi L, Rosadini G. Effects of scopolamine (0.25-0.75 mg i.m.) on the 
quantitative EEG and the neuropsychological status of healthy volunteers. Neuropsychobiology. 
1987;17(4):199-205. 
Schultheiss P. Centrally Acting Nerve Agent Treatment System Analysis of Alternatives 
(CANATS AoA) Study Report; March 12, 2013. 
Scopolamine hydrobromide injection USP: For intramuscular, intravenous, or subcutaneous use. 
(n.d.). Accessed November 30, 2014, from http://www.drugs.com/pro/scopolamine-
injection.html. 
Sessler CN, Gosnell M, Grap MJ, et al. The Richmond Agitation-Sedation Scale: validity and 
reliability in adult intensive care patients. Am J Respir Crit Care Med. 2002;166:1338-1344. 
Sidell F, Newmark J, McDonough J. Chapter 5: Nerve Agents. In Medical Aspects of Chemical 
Warfare. Aberdeen Proving Ground, MD: US Army Medical Research Institute of Chemical 
Defense; 2008. 
Strauss E, Sherman EMS, Spreen O. A compendium of neuropsychological tests: administration, 
norms, and commentary. 2006. 3rd Edition, p.301. Oxford University Press, New York, NY. 
Ventura J, Lukoff D, Nuechterlein KH, Liberman RP, Green M, Shaner A. Appendix 1: Brief 
Psychiatric Rating Scale (BPRS) Expanded version (4.0) scales, anchor points and 
administration manual. International Journal of Methods in Psychiatric. 1993;3:227–244. 
Wangeman C, Hawk M. The effects of morphine, atropine and scopolamine on human subjects. 
Anesthesiology. 1942;3:24-36. 
Wiercinski A, Jackson JP. Nerve Agents. StatPearls Publishing; Oct 27 2018. 


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Wildiers H, Dhaenekint C, Demeulenaere P, Clement PM, Desmet M, Van Nuffelen R, et al. 
Atropine, hyoscine butylbromide, or scopolamine are equally effective for the treatment of death 
rattle in terminal care. J Pain Symptom Manage. 2009 Jul;38(1):124-133. 
18.2. 
Study Reports 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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19. 
APPENDICES 
 


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APPENDIX A. VISUAL ANALOG SCALES 
Note: This example is for illustration purposes and may not be to scale. The horizontal line 
should be exactly 10 cm in length after the form is printed, with a vertical line in the exact center 
of the horizontal line. After completion, the distance (cm) from the “zero” point to the subject’s 
mark is measured and recorded in the source. 
VISUAL ANALOG SCALES (VAS): INJECTION SITE ASSESSMENT 
PAIN 
Place a vertical mark on the line below to indicate how PAINFUL the injection site feels currently. 
 
 
ITCHING 
Place a vertical mark on the line below to indicate how ITCHY the injection site feels currently. 
 
 
TINGLING 
Place a vertical mark on the line below to indicate level of TINGLING at the injection site currently. 
 
 
NUMBNESS 
Place a vertical mark on the line below to indicate how NUMB the injection site feels currently. 
 
 
 
Subject Signature: 
Staff Signature: 
0 
NO PAIN 
10 
SEVERE PAIN 
0 
NO ITCHING 
10 
SEVERE ITCHING 
0 
NO TINGLING 
10 
SEVERE TINGLING 
0 
NO NUMBNESS 
10 
SEVERE NUMBNESS 


Scopolamine Hydrobromide Trihydrate Phase 1 
The Surgeon General 
IND 130620; Protocol S-16-14 
Department of the Army 
Version 4.0 (01Mar2021) 
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US Government Proprietary 
APPENDIX B. TOXICITY GRADING SCALE FOR INJECTION SITE 
REACTIONS 
Local Reaction to 
Injectable Product 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Potentially Life 
Threatening 
(Grade 4) 
Pain 
Does not 
interfere with 
activity 
Repeated use of 
non-narcotic pain 
reliever > 24 
hours or 
interferes with 
activity 
Any use of 
narcotic pain 
reliever or 
prevents daily 
activity 
Emergency room 
(ER) visit or 
hospitalization 
Tenderness 
Mild discomfort 
to touch 
Discomfort with 
movement 
Significant 
discomfort at rest 
ER visit or 
hospitalization 
Erythema/ 
Rednessa 
2.5-5 cm 
5.1-10 cm 
> 10 cm 
Necrosis or 
exfoliative 
dermatitis 
Induration/ 
Swellingb 
2.5-5 cm and 
does not interfere 
with activity 
5.1-10 cm or 
interferes with 
activity 
> 10 cm or 
prevents daily 
activity 
Necrosis 
a In addition to grading the measured local reaction at the greatest single diameter, the measurement should be 
recorded as a continuous variable. 
b Induration/swelling should be evaluated and graded using the functional scale as well as the actual measurement. 


Scopolamine Hydrobromide Trihydrate Phase 1 
The Surgeon General 
IND 130620; Protocol S-16-14 
Department of the Army 
Version 4.0 (01Mar2021) 
106 
US Government Proprietary 
APPENDIX C. INJECTION SITE ASSESSMENT FORM 
Injection Site Assessment  
Nominal Time Point: _____________________ 
Time of Assessment:    __ __: __ __ 
Injection Site Location (circle one):    Right Thigh        Left Thigh 
Local 
Reaction 
Severity 
(circle one) 
Comments 
Staff 
Initials 
Injection Site 
Pain 
         None                        Mild 
 
         Moderate                Severe 
 
         Potentially Life Threatening 
________________________________ 
________________________________ 
________________________________ 
________________________________ 
________________________________ 
 
Tenderness 
         None                         Mild 
 
         Moderate                Severe 
 
         Potentially Life Threatening 
________________________________ 
________________________________ 
________________________________ 
________________________________ 
________________________________ 
 
Erythema/ 
Redness 
         None                         Mild 
 
         Moderate                Severe 
 
         Potentially Life Threatening 
________________________________ 
________________________________ 
________________________________ 
________________________________ 
________________________________ 
 
Induration/ 
Swelling 
         None                        Mild 
 
         Moderate                Severe 
 
         Potentially Life Threatening 
________________________________ 
________________________________ 
________________________________ 
________________________________ 
________________________________ 
 
SEE APPENDIX B: Toxicity Grading Scale for Injection Site Reactions 
Mild = Grade 1, Moderate = Grade 2, Severe = Grade 3, Potentially Life Threatening = Grade 4 


Scopolamine Hydrobromide Trihydrate Phase 1 
The Surgeon General 
IND 130620; Protocol S-16-14 
Department of the Army 
Version 4.0 (01Mar2021) 
107 
US Government Proprietary 
APPENDIX D. RICHMOND AGITATION AND SEDATION SCALE 
(RASS) 
Score 
Term 
Description 
 
+4 
Combative 
Overtly combative, violent, immediate danger to staff 
 
+3 
Very agitated 
Has aggressive behavior toward staff 
+2 
Agitated 
Frequent non-purposeful movement 
+1 
Restless 
Anxious but movements not aggressive vigorous 
0 
Alert and calm 
 
-1 
Drowsy 
Not fully alert, but has sustained awakening (eye-
opening/eye contact) to voice (>10 seconds) 
Verbal 
Stimulation 
-2 
Light sedation 
Briefly awakens with eye contact to voice (<10 seconds) 
-3 
Moderate sedation 
Movement or eye opening to voice (but no eye contact) 
-4 
Deep sedation 
No response to voice, but movement or eye opening to 
physical stimulation 
Physical 
Stimulation 
-5 
Unarousable 
No response to voice or physical stimulation 
Procedure for RASS Assessment 
 
1. Observe patient 
 
a. 
Patient is alert, restless, or agitated 
Score 0 to +4 
2. If not alert, state patient’s name and say to open eyes and look at speaker. 
 
b. Patient awakens with sustained eye opening and eye contact. 
Score -1 
c. 
Patient awakens with eye opening and eye contact, but not sustained. 
Score -2 
d. Patient has any movement in response to voice but no eye contact 
Score -3 
3. When no response to verbal stimulation, physically stimulate patient by shaking shoulder 
and/or rubbing sternum 
 
e. 
Patient has any movement in response to voice but no eye contact. 
Score -4 
f. 
Patient has no response to any stimulation 
Score -5 
 
 
 
 
 
 
 

SAP_001.pdf: 
1 
 
 
 
 
 
 
IND 130620; Protocol S-16-14 
 
A Phase 1, Double-Blind, Randomized, Placebo-Controlled, Dose-Escalation 
Study to Evaluate the Safety, Tolerability, And Pharmacokinetics Of 
Intramuscular Administration Of Scopolamine Hydrobromide Trihydrate, 
Injection 
 
Statistical Analysis Plan 
 
Original Issue Date: March 25, 2020 
 
Final SAP Version 2.0 (based on Protocol Version 4.0 dated March 1, 2021) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


2 
SAP Prepared by: 
Author: 
 
Battelle Health Analytics 
505 King Ave 
Columbus, OH 43201-2696 
 
Battelle Memorial Institute 
6115 Falls Rd. 
Baltimore, MD 21209 
 
Battelle Health Analytics 
505 King Ave 
Columbus, OH 43201-2696 
 
Battelle Health Analytics 
505 King Ave 
Columbus, OH 43201-2696 
 
Battelle Advanced Analytics 
505 King Ave 
Columbus, OH 43201-2696 
Telephone: 
  
E-mail: 


Signature Page 
By signing, I attest I have reviewed this document and that it meets my approval. 
Prepared by: 
Date 
Approved by: 
Approved by: 
Reviewed by: 
Reviewed by: 
Battelle 
Dr. DePetrillo, Principal Investigator 
Pharmaron 
 
 
Battelle 
Date 
Date 
Date 
3 
6 OCT 21
Signature on next page




4 
 
List of Abbreviations and Definitions 
Abbreviation Explanation 
AEs 
Adverse Events 
ANOVA 
Analysis of Variance (also known as multivariate regression) 
ATC 
Anatomical Therapeutic Chemical 
AUC∞ 
Area under the Curve at Infinity 
AUClast 
Area under the curve at last measurement 
AV 
Atrioventricular 
BLQ 
Below Limit of Quantification 
BMI 
Body Mass Index 
BP 
Blood Pressure 
BPRS 
Brief Psychiatric Rating Scale 
Cmax 
Maximum concentration 
CNS 
Central Nervous System 
CRF 
Case Report form 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CV 
Coefficient of Variation 
DLTs 
Dose-limiting toxicity 
DSMB 
Data and Safety Monitoring Board 
DSST 
Digit Symbol Substitution Test 
ECG 
Electrocardiogram 
FDA 
Food and Drug Administration 
FDR 
False Discovery Rate 
HIV 
Human Immunodeficiency Virus 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use 
IM 
Intramuscular  
IND 
Investigational New Drug 
IV 
Intravenous 
Kg 
Kilogram 
L 
Liter 
MedDRA 
Medical Dictionary for Regulatory Activities 
Min 
Minute 
mL 
milliliter 
MRT 
Mean Residence Time 
PD 
Pharmacodynamics 
PI 
Principal Investigator 
PK 
Pharmacokinetics 
PR interval 
Time between P and R waves 
 
 
QRS interval 
Time between Q, R, and S waves  
QTc 
QT interval adjusted for heart rate 
QTcF 
QTC (Fridericia) 


5 
 
RASS 
Richmond Agitation Sedation Scale 
SAE 
Sever Adverse Event 
SAP 
Statistical Analysis Plan 
Scop HBT 
Scopolamine Hydrobromide Trihydrate 
SD 
Study Day 
Sec 
Second 
SEM 
Standard Error of the Mean 
Ng 
Nanogram 
t1/2 
Half life 
TEAEs 
Treatment-emergent Adverse Events 
Tmax 
Time to maximum concentration 
VAS 
Visual Analog Scale 
Vd/F 
Apparent Volume of Distribution 
WHO 
World Health Organization 
 
 
 


6 
 
Summary of Changes 
Version 
Change 
Sections 
Made By 
Approved by  
2.0 
 
 
 
 
 
Updated personnel  
Page 1-2 
 
 
Corrected typographical error 
3.1 
 
 
Clarified references to protocol appendices 
5.1.3.1 
5.1.10 
 
 
Corrected references to other parts of the SAP 
6.3 
 
 
Updated to clarify PK analysis will be 
presented in separate PK report 
6.6.2 
 
 
Revised statistical modeling for PK parameters 
to better reflect the Protocol specified 
analyses. 
6.3, 6.15 
 
 
Updated to add imputation rules for missing 
or partial dates for AEs and concomitant 
medications 
6.6.3 
 
 
Updated to remove figures based on 
discussion and agreement from client 
Biostatistician.  No figure shells will be 
provided. 
5.1.9, 6.2 
6.14.2, 6.14.3, 
6.14.4, 6.14.6, 
6.14.8, 6.18 
 
 
 
Add Table and Listing shells. 
 
Table and 
Listing Shells 
 
 
 
 


7 
 
1. INTRODUCTION/BACKGROUND 
This statistical analysis plan (SAP) describes the data analysis specifications for IND 130620; 
Protocol S-16-14 entitled “A Phase 1, Double-Blind, Randomized, Placebo-Controlled, Dose-
Escalation Study to Evaluate the Safety, Tolerability, And Pharmacokinetics Of Intramuscular 
Administration Of Scopolamine Hydrobromide Trihydrate, Injection.” The preparation of this 
SAP adheres to the IRB-approved protocol S-16-14 version 2.0 dated March 12, 2020.  
This SAP follows the International Conference on Harmonisation (ICH) Guidelines E3 and E9.  
In cases in which the analyses in this SAP differ from those in the study protocol, the analyses in 
the SAP supersede those in the protocol. Should differences exist, these will be described in 
Section 6.2 of this document.  
This initial Phase 1 trial is a single, ascending dose study in healthy volunteers with single doses 
of Scopolamine Hydrobromide Trihydrate (Scop HBT) ranging from 0.005 to 0.021 mg/kg 
administered in a single intramuscular (IM) injection.  The dosing regimen to be evaluated in 
future trials will be determined in part on the basis of the pharmacokinetic (PK) and safety data 
obtained in this Phase 1 study. All statistical analyses will be performed using SAS®, Version 9.4 
or higher.   
2. STUDY OBJECTIVES 
The objectives of this study are: 
• To characterize the safety and tolerability profile of ascending doses of Scop HBT 
administered by IM injection (0.005mg/kg to 0.021mg/kg), and set upper limits on 
the probability of extreme dose limiting toxicities and non-extreme DLTs across 
dosage levels; 
• To characterize the PK of ascending doses of Scop HBT administered by IM 
injection, and assess dose-proportionality for Cmax and AUC∞, over the dosing range; 
3. STUDY DESIGN 
3.1 
OVERVIEW AND LENGTH OF STUDY 
This is a double blinded, placebo-controlled, Phase 1 sequential dose escalation study to evaluate 
the safety, tolerability, and PK of Scop HBT in healthy participants. Healthy volunteers will be 
assigned to one of five target dosage groups to receive Scop HBT or placebo, administered by 
IM injection. In each dosing cohort, the ratio of participants receiving placebo vs. active drug 
will be 1 placebo subject for every 3 active participants. Up to 60 participants will be enrolled. 
Participants will be assigned, sequentially, to one of five escalating target dosage groups or to the 
placebo group beginning with the lowest dose first. New participants will not be enrolled into the 
next higher dose until at least eight participants in the previous dosing cohort have completed 8-
day follow-up visits without the occurrence of DLTs, pre-defined as requiring termination of the 
study, and until approval by the data safety monitoring board (DSMB) following its review of 
the study data. Four additional participants, three active and one placebo, may be added to each 
cohort, depending upon AEs exhibited in the first eight participants.  
The study drug or placebo will be administered IM into the anterior thigh using a consistent 
procedure. The dose will be based on the subject’s weight. Treatment will begin at the lowest of 


8 
 
five Scop HBT target doses (0.005, 0.007, 0.011, 0.014, and 0.021 mg/kg) and progress to the 
next higher dosage escalating by multiples that range between 1.25 and 1.6 for each cohort. 
Escalation to the next dose level will only occur after safety has been determined by the DSMB 
in at least eight and up to twelve participants (of whom 6-9 will receive study drug), based on the 
clinical responses of the participants to each dosage level. Escalation will occur no sooner than 
six weeks after the first subject in each cohort has been dosed.  
Participants will report to the study site on the day prior to scheduled dosing. On the day of 
dosing, ECG (3-5 lead) and vital signs (excluding body temperature) will be monitored 
continuously for 24 hours. Blood pressure (BP) will be evaluated and documented at specified 
times through the 48-hours post administration. Echocardiograms will be conducted at screening, 
baseline (Day -1), and at Study Days (SD) 1,2,3 & 8. Blood and urine samples for safety 
monitoring will be collected prior to dosing and according to a specified schedule through 48 
hours post-dosing, as well as during the subject’s return visit on SD 8. Blood and urine samples 
for PK analyses will be collected prior to dosing and according to a specified schedule through 
24 hours post-dosing. 
All participants will be observed as in-patients at the research center for the first 48 hours (post-
dose) for AEs. Participants will also return for a study visit on SD 8 and receive a follow-up 
telephone call on SD 4 and SD 30. The study schedule of visits (time and events table) is 
presented in Section 3.2. 
3.2 
STUDY SCHEDULE (TIME AND EVENTS TABLE) 
Table 1:  Timeline of Key Events 
Study Phase 
Screening 
Baselinea 
Treatmenta 
Follow-upb 
Study Day 
-30 to -2 
-1 
1c 
2 
(24 ± 1 
h) 
3 
(48 ± 1 
h) 
4 
(+ 2 
days) 
8 
(+2 
days) 
30 
(+ 7 
days) 
Procedures 
Informed Consent 
X 
 
 
 
 
 
 
 
Inclusion/Exclusion 
X 
X 
Xd 
 
 
 
 
 
Medical History 
X 
X 
 
 
 
 
 
 
Physical Examination 
X 
X 
Xe 
 
Xe 
 
X 
 
Serum Pregnancy Test 
X 
X 
 
 
 
 
X 
 
Laboratory Safety Testsf 
X 
X 
 
X 
X 
 
X 
 
Serologyg 
X 
 
 
 
 
 
 
 
Urine Drug Screenh 
X 
X 
 
 
 
 
X 
 
Alcohol Breathalyzer Test 
X 
X 
 
 
 
 
 
 
Body Weight and 
Height/Body Mass Index 
Xi 
Xi 
 
 
Xi 
 
Xi 
 
Vital Signsj 
X 
X 
X 
X 
X 
 
X 
 
Electrocardiogram 
(ECG), 12-lead (supine)k 
X 
X 
X 
X 
X 
 
X 
 


9 
 
Study Phase 
Screening 
Baselinea 
Treatmenta 
Follow-upb 
Study Day 
-30 to -2 
-1 
1c 
2 
(24 ± 1 
h) 
3 
(48 ± 1 
h) 
4 
(+ 2 
days) 
8 
(+2 
days) 
30 
(+ 7 
days) 
Procedures 
Dose Administration 
 
 
X 
 
 
 
 
 
Pharmacokinetic 
Assessment 
 
 
Xl 
X 
X 
 
 
 
Adverse Events 
 
 
Xm 
X 
X 
X 
X 
X 
Prior/Concomitant 
Medications 
X 
X 
X 
X 
X 
X 
X 
X 
Continuous 
Cardiovascular 
Monitoring 
 
 
Xn 
Xn 
 
 
 
 
Injection Site 
Assessmento 
 
 
X 
X 
X 
 
X 
 
Injection Site: VASo 
 
 
X 
X 
X 
 
X 
 
Reminder of Study 
Restrictions 
X 
 
 
 
X 
X 
X 
 
Brief Psychiatric Rating 
Scale (BPRS)p 
X 
X 
X 
 
X 
 
X 
 
Columbia-Suicide 
Severity Rating Scale 
(C-SSRS)q 
X 
X 
 
 
 
 
X 
 
Richmond Agitation and 
Sedation Scale (RASS) 
 
 
Xr 
 
 
 
 
Structured Clinical 
Interview for DSM-5, 
Clinical Trial version 
(SCID-5-CT) 
 
Xs 
 
 
 
 
 
 
Digit Symbol Substitution 
Testt (DSST) 
X 
X 
 
X 
 
 
X 
 
a Participants will be in clinic for the baseline and treatment days. Days 2 and 3 procedures should be performed at 
24 and 48 hours (± 1 hour) post dose, respectively, except for PK samples, which should be collected as close to 
the specified time points as possible. Refer to Table 2 for expansion of pre-dose through 36-hour post-dose 
activities. 
b Day 4 and Day 30 follow-up is conducted by telephone. Day 4 follow-up may be performed on Days 4-6. Day 30 
follow-up may be performed on Days 30-37. Day 8 follow-up is an in-clinic visit and may be performed on Days 
8-10. 
c See Table 2 for study events occurring pre dose through 36 hours post dose. 
d Final eligibility criteria review and completion of eligibility checklist prior to dosing. 
e Abbreviated physical examinations with changes from Day -1 (baseline) noted; Day 1 exam is prior to dosing. 
f Hematology (including coagulation), serum chemistry, and urinalysis (refer to Section 5.1.6 for specific tests). 
Fasting ≥ 8 hours at screening. Adequacy of venous access will be assessed and documented at screening. 
g Hepatitis B surface antigen, hepatitis C, HIV-1/2, and syphilis testing at screening only. 
h Urine drug screen (refer to protocol Section 5.1.6 for specific tests). 


10 
 
i Body weight (kg) and height (cm; screening only) will be measured at screening and body mass index (BMI) 
calculated. Weight will be measured on Day -1 with BMI calculation. Day-1 weight to be used for Day 1 dose 
determination. Weight will be measured at Day 3 and Day 8 with no BMI calculation. 
j Systolic and diastolic blood pressure, heart rate, respiration rate, body temperature, and pulse oximetry will be 
performed after subject has been supine for at least 5 minutes. See Table 2 for vital sign time points from pre dose 
through 24 hours post dose. 
k See Table 2 for time points to performing ECG (supine) from pre-dose through 24 hours post-dose. 
l See Table 2 for PK sample collection time points from pre dose through 36 hours post dose. PK samples should be 
collected as close to the actual time point as possible (within the windows specified in ); however, when multiple 
tests are scheduled at the same time, ECG and vital signs will be performed within 5 minutes prior to the time 
point, and injection site and AE assessments will be performed immediately after the PK blood draw. AEs 
identified prior to dosing will be considered part of the medical history. Urine PK samples will be collected prior 
to dosing (no earlier than 2 hours pre-dose) and for 24 hours after dosing. All urine specimens will be pooled into 
1 of 3 collection interval containers by the subject. See Table 2 for collection intervals from pre-dose through 24 
hours post dose. 
m See Table 2 for AE assessment time points from pre dose through 24 hours post dose. 
n Continuous cardiovascular monitoring of ECG (3-5 lead) and vital signs (blood pressure, heart rate, respiration 
rate, and pulse oximetry) from 1 hour prior to dosing through 24 hours post dose (see Table 2) 
o Injection site assessments: Subject will be asked to rate the maximum intensity of pain, pruritus, tingling, and 
numbness using the VAS. See Table 2 for assessment time points from pre dose through 24 hours post-dose. 
Immediately following the subjective assessment, an assessment of pain, tenderness, erythema, and induration at 
the injection site will be performed by a physician, physician assistant, or nurse. 
p See Table 2 for assessment time points on Day 1. For items assessed over time (e.g., items 1, 2, and 3), the period 
of assessment should be “over the prior week,” except for the assessments performed at 6-8 and 48 hours post 
dose, which should be assessed “since the prior assessment.” 
q C-SSRS will be assessed at screening, Day -1 (baseline), and Day 8. 
r  RASS will be used to assess severity only if AEs of general agitation or sedation occur. 
s  SCID-5-CT will be administered at Day -1 to identify the presence of any major DSM-5 Axis I or II disorder. 
t  The DSST will be administered at screening, baseline, 48 hours post dose, and Day 8 to detect any persistent 
cognitive impairment. The DSST will not be used to determine eligibility. 


11 
 
Table 2:  Study Events Schedule – Pre-Dose through 36 Hours Post Dose 
Activity/Assessment 
Pre- 
Dose 
Dosing = Time 0 
Minutes Post-dose 
Hours Post-dose 
2 
5 
10 
15 
20 
30 
45 
1 
1.5 
2 
3 
4 
5 
8 
12 
24 
36 
ECG 
X 
 
X 
X 
X 
 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
 
Vital Signs 
X 
 
X 
X 
X 
 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
 
Abbrev Physical 
Exam 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Injection Site: VASa 
X 
 
X 
X 
X 
 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
 
Injection Site: 
Physician, Physician 
Assistant or Nurse 
X 
 
X 
X 
X 
 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
 
BPRSb 
 
 
 
 
 
 
 
 
 
 
 
 
 
6 
 
 
 
C-SSRS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
RASS 
 
As needed to assess severity only if adverse events of general agitation or sedation occur 
Final Eligibility  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility Checklist 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine PK Samples 
X 
0-4 h 
4-12 h 
12-24 h 
 
Blood PK Samples 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
Safety Lab Tests 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Adverse Events 
X 
 
X 
X 
X 
 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
 
Concomitant 
Medications 
X 
 
X 
X 
X 
 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
 
Continuous 
Cardiovascular 
Monitoring 
Begin 
ECG (3-5 lead) & vital signs (blood pressure, heart rate, respiration rate, & pulse oximetry) 
End 
 
 
a If the PI or designee determines a subject is incapable of providing valid responses on the VAS or DSST due to the neuropsychiatric effects of Scop 
HBT, the reason(s) why the VAS assessment(s) could not be done will be documented by time point, and VAS or DSST assessments will be 
conducted once deemed subject is capable of providing responses. 
b BPRS will be performed at 6 (+ 2) hours post dose. The + 2-hour window is provided to allow the investigator some discretion, should he or she 
determine the assessment needs to be delayed. The timing may be dependent on the emergence and severity of neuropsychiatric symptoms. 


12 
 
 
3.3 
STUDY DRUG ADMINISTRATION AND EXTENT OF EXPOSURE 
3.3.1 Dose Limiting Toxicity and Progression of Groups 
New participants will not be enrolled into the next higher dosage group until at least 8 
participants in the previous cohort have completed the SD 8 follow-up visit without the 
occurrence of DLTs and the DSMB has made a recommendation to the sponsor regarding dose 
escalation. The sponsor must approve the dose escalation and notify the investigator(s) before 
any new participants can be enrolled. The occurrence of any extreme DLT(s) or serious adverse 
events (SAEs), except unrelated, would result in the immediate discontinuation of dosing and 
study enrollment, pending a review of study data by the PI, the DSMB, and the sponsor. 
Nonextreme DLTs can result in halting of dosage pending review. Enrollment will also be halted 
if two nonextreme DLTs occur in the first four participants in a cohort or 3 participants in total. 
Table 3:  Progression of Dosing Related to Dose-Limiting Toxicity Events 
Dose-Limiting 
Toxicity 
Number of 
Participants 
Action 
Follow-up 
Extreme DLT 
1 
Dosing and 
enrollment halted 
PI and DSMB to make 
recommendation to sponsor whether 
trial should continue 
Nonextreme DLT 
1 of first 4 in a cohort 
(or 2 in the first 8) 
Dosing halted 
PI and DSMB to make 
recommendation to sponsor whether to 
increase cohort size from 8 to 12 
 
2 of the first 4 in a 
cohort (or 3 total) 
Dosing and 
enrollment halted 
PI and DSMB to make 
recommendation to sponsor whether 
trial should continue 
SAE not already 
designated as a 
DLT (except 
unrelated) 
1 
Dosing and 
enrollment halted 
DSMB to make recommendation to 
sponsor whether trial should continue 
 
3.4 
STUDY POPULATION 
The study will include up to 60 male and female volunteers, 18 to 55 years of age, who will be 
enrolled in 5 dosing groups (cohorts) of 8 to 12 participants each. The actual number enrolled in 
the study will be determined by the safety responses noted during the study. Each of the 5 
cohorts will include at least 3 male and 3 female participants enrolled among the first 8 
participants in the cohort to ensure that at least 1 male and 1 female subject in each dosing group 
receive active drug. Each cohort will include 6 to 9 individuals receiving active and 2-3 receiving 
placebo doses (total of 30-45 active and 10-15 placebo). 
 
3.5 
SAMPLE SIZE CALCULATION/JUSTIFICATION 
The planned sample of 40-60 healthy participants was chosen to provide a cohort size of 8–12 
per dose (6-9 active, 2-3 placebo). This cohort size is customary in Phase 1 clinical trials with 
safety and tolerability as primary endpoints as it allows detection of common dose-limiting 


13 
 
toxicities or SAEs. In a cohort of N individuals dosed with the active drugs, the probability that 
one non-extreme DLT or SAEs with a true probability of occurrence, 𝑝𝑝, will be observed is 1 −
(1 −𝑝𝑝)𝑁𝑁. There is 80% chance that at least one event with true probability of occurrence of 
23.5% will occur within a cohort of 6 active participants. In a cohort of 8 participants, there is 
80% probability of an event occurring if its true probability of occurrence is 18.2%. The addition 
of placebo controls is intended to help distinguish drug-related and unrelated events and for 
comparison of injection site reactions, cognitive, and neuropsychiatric responses.  
  
 
 


14 
 
Figure 1:  Power to Detect an Adverse Event with Probability of Occurrence, P, in an 
Active Drug Cohort of Size N 
 
3.6 
RANDOMIZATION SCHEME 
Participants will be randomized to receive either active Scop HBT or placebo injections using a 
blocked randomization design. In each cohort, 6 to 9 participants will receive active drug and 2 
to 3 participants will receive placebo. Each cohort will have at least at least 3 male and 3 female 
participants enrolled among the first 8 participants in the cohort to ensure that at least 1 male 
subject and 1 female subject in each dosing group receive active drug. The study PI will create 
cohorts of 8 to 12 participants. If a participant withdraws or is excluded, the participant will be 
replaced by a participant of the same or opposite sex so long as the sex of all participants in the 
block conforms to the requirements. 
Randomization will assign cohort members to active Scop HBT or Placebo at a ratio of 3 active 
to 1 placebo. Randomization will be conducted using blocking with three different block sizes 
per cohort. A block of 2 (1 active and 1 placebo) will be used for the first two participants in 
each cohort (Table 4A). A block of 6 (5 active and 1 placebo) will be used to assign the next 6 
participants in each cohort (Table 4B). A block of 4 (3 active and 1 placebo) will be used to 
randomized participants in a possible expansion cohort. The blocks will be randomly permuted 
using a randomization program for each dosage level to yield a randomization plan. 
 
 


15 
 
Table 4:  Blocks with Sample Randomization Assignment 
A. Block of Two for the First Two Participants in a Cohort 
Participant 
Order 
Randomization Assignment 
(Only visible to unblinded individuals) 
1 
Placebo 
2 
Active Scop HBT 
 
B. Block of Six for Third to Eighth Participants in a Cohort 
Participant 
Order 
Randomization Assignment 
(Only visible to unblinded individuals) 
3 
Active Scop HBT 
4 
Active Scop HBT 
5 
Active Scop HBT 
6 
Active Scop HBT 
7 
Placebo 
8 
Active Scop HBT 
 
C. Block of Four for Cohort Expansion Participants 
Participant 
Order 
Randomization Assignment 
(Only visible to unblinded individuals) 
9 
Active Scop HBT 
10 
Placebo 
11 
Active Scop HBT 
12 
Active Scop HBT 
 
For cohorts of 8 participants, only the first two blocks will be used. The third block will be used 
only if the cohort is expanded from 8 to 12. A sample randomization assignment for a dosing 
cohort is included in Table 5. 
 
Table 5:  Sample Randomization Scheme for a Dosing Cohort  
Cohort 
Block 
Participant 
Sex 
Randomization Assignment 
(Only visible to unblinded individuals) 
Primary 
(N=8) 
1 
1 
F 
Placebo 
2 
M 
Active Scop HBT 
2 
3 
M 
Active Scop HBT 
4 
F 
Active Scop HBT 
5 
F 
Active Scop HBT 
6 
M 
Active Scop HBT 
7 
M 
Placebo 
8 
M 
Active Scop HBT 


16 
 
Expansion 
(N=4) 
3 
9 
F 
Active Scop HBT 
10 
F 
Placebo 
11 
F 
Active Scop HBT 
12 
M 
Active Scop HBT 
 
4. ANALYSIS SETS 
4.1 
INTENT-TO-TREAT POPULATION 
The Intent-To-Treat Population is defined as all participants who are enrolled and randomized into 
the trial. 
4.2 
SAFETY POPULATION 
The Safety Population consists of all participants who received any amount of study medication, 
regardless of disposition.  All safety analyses will be performed on this population. 
4.3 
PHARMACOKINETICS POPULATION 
The PK Population will include any subject who receives a dose of active Scop HBT and has at 
least one blood draw to determine the concentration of scopolamine in plasma or one urine 
sample to determine concentration in urine. All PK analyses will be performed on this 
population. Please note, the calculation of PK parameters will not be described or performed 
within this SAP. A separate PK manual and the report will detail the procedures, results, and 
limitations for the PK parameters.  
4.4 
OTHER ANALYSIS POPULATIONS (INCLUDING SUBGROUPS) 
No subgroup analyses are proposed. PK analyses will include adjustment for sex of the 
participant. Although no additional analyses of sub-populations are planned at this time, 
additional populations and analyses may be conducted at the discretion of the Sponsor to 
supplement the results or for research purposes. Analysis of subgroups conducted after the final 
SAP is approved will be labeled as “post hoc” in the final statistical report/and or CSR. 
4.5 
TREATMENT MISALLOCATIONS 
Should any treatment misallocations occur, all participants will be analyzed in the Safety and PK 
populations “As Treated” instead of “As Randomized”. Due to the nature of this study whereby 
the biological effect of the study medication is being examined without respect to efficacy 
assessment, analyzing the participants “As Treated” is sufficient. A listing will be provided to 
display any participants with treatment misallocations, should they occur. 
 
5. ENDPOINTS AND COVARIATES 
5.1 
SAFETY ENDPOINTS 
The first objective of this study is to characterize the safety of Scop HBT at varying dosages. The 
study specifically defines three types of safety endpoints in the protocol:  extreme dose-limiting 
toxicities (DLTs), nonextreme DLTs, and serious adverse events (SAEs) related to the drug. Any 
events or issues not defined as extreme/nonextreme DLTs or SAEs will be considered as 
Adverse Events (AEs). In addition to AEs, data will be collected and analyzed on injection site 


17 
 
assessments and changes in cognitive function, neuropsychiatric status, vital signs, clinical 
laboratory results, heart rhythm, and physical health status. 
5.1.1 Extreme Dose-Limiting Toxicities 
Extreme DLTs include specific respiratory, neuropsychiatric, cardiac, renal, and severe injection 
site reaction events as outlined below and in the protocol section 7.6.1.1. These events are 
defined in the protocol and will be determined by the study PI, Pharmacovigilance physician, and 
DSMB. These extreme DLTs include: 
• Respiratory 
− Prolonged apnea or respiratory distress where intubation is required 
• Neuropsychiatric 
− Presence of convulsions or seizure-like activity 
− Neuropsychiatric symptoms (e.g., delirium, paranoia, and/or hallucinations) 
requiring treatment with physostigmine or other medication(s) and, in the opinion 
of the investigator, did not adequately respond to treatment 
• Cardiovascular 
− Cardiac arrest 
− Clinically significant hypotension that requires IV fluids or vasopressors 
− Cardiac arrhythmias 
 10 AV block (if the PR interval becomes ≥ 280 milliseconds) 
 If the QRS duration increases by more than 25% from the pre-dose 
measurement and is > 140 msec 
 QTc (Fridericia) is > 500 msec and increase of QTc of 60 msec from 
baseline 
 AV block (2nd degree, 3rd degree) 
 Bundle branch block 
 Bigeminy or trigeminy associated with hypotension 
 Atrial fibrillation or atrial flutter 
5.1.2 Nonextreme Dose-Limiting Toxicities 
Nonextreme DLTs are AEs that do not meet the criteria for extreme DLTs but are serious 
conditions that require immediate medical attention and monitoring. Nonextreme DLTs include: 
• Respiratory 
− Spontaneous respiratory rate < 8 or > 25 breaths per minute, with oxygen 
saturation less than 90%, which cannot be explained by agitation or other 
behavioral symptoms and that does not respond immediately to oxygen 
supplementation via nasal cannula or face mask but for which there is recovery 
without sequelae prior to the need for intubation 


18 
 
− Dyspnea at rest 
− Symptomatic bronchospasm 
• Neuropsychiatric 
− Neuropsychiatric symptoms (e.g., delirium, paranoia, and/or hallucinations) 
requiring treatment with physostigmine or other medication(s) and, in the opinion 
of the investigator, responded adequately to treatment 
− Persistent neuropsychiatric symptoms, defined as a score of 4 or higher on any 
one item or a total score of 40 or higher on the BPRS assessment at the 48-hour, 
post-dose evaluation 
− Paresthesia that interferes with any activity 
− Athetoid movement 
• Cardiac 
− Hypertension, which cannot be explained by agitation or other behavioral 
symptoms, requiring antihypertensive medication 
− Cardiac arrhythmias or changes that are deemed clinically significant but do not 
cause the subject to be hemodynamically unstable 
− QTc is > 450 msec for males or >470 msec for females and has increased 
> 60 msec from baseline; 
− Supraventricular tachycardia alone without hemodynamic compromise 
− Bigeminy or trigeminy not associated with hypotension 
• Renal 
− Increase of serum creatinine by ≥ 0.3 mg/dL (≥ 26.4 µmol/L) or increase to 
≥ 150% from baseline or urine output < 0.5 mL/kg/hour for > 6 hours 
• Injection Site Reaction 
− Any reaction determined to be severe, as defined by the FDA’s guidance1 for 
injection site reactions (See protocol Appendix B). 
5.1.3 Adverse Events (AEs) 
The term “AE,” as used by the Sponsor, is synonymous with the term “adverse experience,” 
which is used by the FDA. Any condition recorded on the medical history should not be reported 
as an AE unless it worsens in frequency, intensity, or severity, or there are clinically significant 
changes in laboratory values after administration of study drug. An AE or suspected adverse 
reaction is considered “unexpected” if it is not listed in the investigator’s brochure or is not listed 
at the specificity or severity that has been observed or, if an investigator’s brochure is not 
required or available, is not consistent with the risk information described in the general 
investigational plan or elsewhere in the current application, as amended. “Unexpected,” as used 
 
1 https://www.fda.gov/regulatory-information/search-fda-guidance-documents/toxicity-grading-scale-healthy-adult-
and-adolescent-volunteers-enrolled-preventive-vaccine-clinical 


19 
 
in this definition, also refers to AEs or suspected adverse reactions that are mentioned in the 
investigator’s brochure as occurring with a class of drugs or as anticipated from the 
pharmacological properties of the drug but are not specifically mentioned as occurring with the 
particular drug under investigation. 
Note: A procedure is not an AE, but the reason for a procedure may be an AE. 
The time frame for the collection of AEs and SAEs begins at the administration of 
investigational product through 30 days after the investigational product is administered.  
 
5.1.3.1 Severity 
All AEs will be assessed for severity by an investigator. Inherent in this assessment is the 
medical and clinical consideration of all information surrounding the event including any 
medical intervention required. The Common Terminology Criteria for Adverse Events (CTCAE), 
version 5.0 (November 27, 2017) is a descriptive terminology that will be utilized for grading all 
AEs, with the exception of injection site reactions, which will be graded using the Local 
Reaction to Injectable Product table from the FDA’s Guidance for Industry: Toxicity Grading 
Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical 
Trials (see protocol Appendix B). 
Both guidance documents provide a grading (severity) scale for each AE term. Each event will 
be assigned one of the following categories: mild (grade 1), moderate (grade 2), severe (grade 3), 
or potentially life threatening (grade 4). 
Note that use of rescue medications may be appropriate in response to the SAEs. 
5.1.3.2 Relationship 
The investigator must assign a relationship of each AE to the receipt of the investigational 
product. The investigator will use clinical judgment in conjunction with the assessment of a 
plausible biologic mechanism, a temporal relationship between the onset of the event in relation 
to receipt of the investigational product, and identification of possible alternate etiologies 
including underlying disease, concurrent illness, or concomitant medications. The following 
guidelines should be used by investigators to assess the relationship of an AE to study product 
administration. ONLY A PHYSICIAN CAN MAKE THIS DETERMINATION. 
Not related: 
No relationship to investigational product. Applies to those events for 
which evidence exists that there is an alternate etiology. 
Unlikely: Likely unrelated to the investigational product. Likely to be related to factors 
other than investigational product but cannot be ruled out with certainty. 
Possible: An association between the event and the administration of investigational 
product cannot be ruled out. There is a reasonable temporal association, but there may also 
be an alternative etiology such as the subject’s clinical status or underlying factors including 
other therapy. 
Probable: There is a high degree of certainty that a relationship to the investigational 
product exists. There is a reasonable temporal association, and the event cannot be explained 
by known characteristics of the subject’s clinical state or factors including other therapy. 


20 
 
Definite: An association exists between the receipt of investigational product and the event. 
An association to other factors has been ruled out. 
5.1.4 Serious Adverse Events 
An AE or suspected adverse reaction is considered “serious” if, in the view of either the 
investigator or sponsor, it results in any of the following outcomes: 
• Death 
• Life-threatening AE. An AE or suspected adverse reaction is considered “life 
threatening” if, in the view of either the investigator or sponsor, its occurrence places 
the patient or subject at immediate risk of death. It does not include an AE or 
suspected adverse reaction that, had it occurred in a more severe form, might have 
caused death. 
• Inpatient hospitalization or prolongation of existing hospitalization 
• Persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions 
• Congenital anomaly/birth defect 
• Important medical events that may not result in death, be life threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical 
judgment, they may jeopardize the patient or subject and may require medical or 
surgical intervention to prevent one of the outcomes listed in this definition. 
Examples of such medical events include allergic bronchospasm requiring intensive 
treatment in an emergency room or at home, blood dyscrasias or convulsions that do 
not result in inpatient hospitalization, or the development of drug dependency or drug 
abuse. 
Hospitalization is to be considered only as an overnight admission. Hospitalization or prolongation 
of a hospitalization is a criterion for considering an AE to be serious. In the absence of an AE, the 
participating Investigator should not report hospitalization or prolongation of hospitalization on a 
form. This is the case for Hospitalization for survey visits or annual physicals. 
In addition, a hospitalization planned before the start of the study for a preexisting condition that 
has not worsened does not constitute an SAE (e.g., elective hospitalization for a total knee 
replacement due to a preexisting condition of osteoarthritis of the knee that has not worsened 
during the study). 
If there is any doubt whether the information constitutes an AE or SAE, the information is treated 
as an AE or SAE. 
5.1.5 Vital Signs 
Vital signs, (minus body temperature), will be continuously monitored for 24 hours post-dosing.  
For reporting purposes, observations at specific time points as defined in Section 3.2 will be used. 
Where the time of vital signs monitoring coincides with a blood draw, vital signs will be taken 
prior to the scheduled blood draw. Vital signs may be taken at other times, if deemed necessary.      
 


21 
 
5.1.6 Clinical Laboratory Tests 
5.1.6.1 Hematology and Coagulation 
The following hematological tests will be performed: 
• Red Blood Count 
• White Blood Count Total 
• Hematocrit 
• Hemoglobin 
• Platelet Count 
• Absolute Eosinophil Count 
• Absolute Basophil Count 
• Absolute Monocyte Count 
• Absolute Neutrophil Count 
• Mean Corpuscular Volume 
• Mean Corpuscular Hemoglobin Concentration 
• Mean Corpuscular Hemoglobin 
• Absolute Lymphocyte Count 
• Red (cell) Distribution Width 
The following coagulation tests will be performed: 
• Prothrombin Time 
• Partial Thromboplastin Time 
• Fibrinogen 
5.1.6.2 The following serum chemistry tests will be performed: 
• Glucose 
• Uric Acid 
• Blood Urea Nitrogen 
• Creatinine 
• Creatine kinase 
• Sodium 
• Potassium 
• Chloride 
• Calcium 


22 
 
• Phosphorous 
• Protein, Total 
• Albumin 
• Globulin 
• Albumin/Globulin Ratio 
• Bilirubin, Total 
• Bilirubin, Direct 
• Alkaline Phosphatase 
• Lactic Dehydrogenase 
• Aspartate Aminotransferase 
• Alanine Aminotransferase 
• Gamma Glutamyl Transferase 
• Iron 
• Total Cholesterol 
• Triglycerides 
• Magnesium 
• Carbon Dioxide 
5.1.6.3 The following urinalysis tests will be performed: 
• Color 
• Appearance 
• Specific Gravity 
• pH 
• Protein 
• Glucose 
• Ketones 
• Occult Blood 
• Leukocyte Esterase 
• Nitrite 
• Bilirubin 
• Urobilinogen 
• Magnesium (with calculation of fractional excretion) 


23 
 
• Creatinine 
• Potassium (with calculation of fractional excretion) 
5.1.6.4 Pregnancy Screen 
All female participants, regardless of childbearing potential, will undergo 2 pregnancy 
tests prior to receiving the study drug. A serum pregnancy test to measure human β-
chorionic gonadotropin will be administered during screening and also within 24 hours 
prior to dosing in a controlled environment. A pregnancy test will also be conducted on 
SD 8, or at study termination, if it occurs before SD 8. 
5.1.6.5 Additional Tests 
The following tests will be performed: 
• Serology (screening only) 
− HIV Test (1 and 2) 
− FTA-ABS Test for Syphilis 
− Hepatitis B Virus Surface Antigen 
− Hepatitis C Virus 
• Alcohol Breathalyzer 
• Urine Drug Screen (screening, Day -1, Day 8) 
− Barbiturates 
− Benzodiazepines 
− Cannabinoids 
− Cocaine 
− Opiates 
− Methadone 
− Phencyclidine 
− Propoxyphene 
− Oxycodone 
− Tricyclic Antidepressants 
− Amphetamines 
− Methylenedioxymethamphetamine 
 
 


24 
 
5.1.7 Electrocardiograms 
The 3-5-lead ECG will be utilized for continuous monitoring starting at 1 hour prior to dosing 
and ending at 24 hours post dose.  
Due to the continuous monitoring with 3-lead and large number of 12-lead ECGs during the first 
24 hours, the ECG electrodes may be left in place from pre dose through 24 hours post dose (and 
replaced as necessary). 
Note: Participants will not be allowed to shower from pre dose until after all 24-hour, post-dose 
procedures have been completed and the electrodes removed. 
5.1.8 Neuropsychiatric/Behavioral Assessments 
Assessments of neuropsychiatric/behavioral symptoms will be performed by study staff using the 
C-SSRS, BPRS (expanded version 4.0, 24 items), and RASS (if general agitation or sedation are 
reported). A psychiatrist will be available on-site to consult with the investigator throughout the 
study. At the investigator’s request, the psychiatrist will come to the clinic to evaluate a subject. 
The C-SSRS Baseline/Screening version will be administered by a physician, physician assistant, 
or nurse at screening, and the C-SSRS Since Last Visit version will be administered at SD -1 and 
at follow-up on SD 8. Scoring and analysis will be performed according to the Columbia-Suicide 
Severity Rating Scale Scoring and Data Analysis Guide. Study staff administering the C-SSRS 
will complete C-SSRS training. The C-SSRS has excellent inter-rater reliability2. 
The BPRS will be performed by a psychologist or trained clinician. The BPRS will be assessed 
at screening, SD -1 (baseline), at 6 (+ 2) hours post dose (timing at the discretion of the 
investigator or designee), 48 hours post dose (prior to discharge), and on SD 8. In order to 
improve reliability between administrations, a structured interview guide will be used and the 
same clinician will administer the BPRS to each participant. For BPRS items assessed over time 
(e.g., items #1, 2, and 3), the reference period of assessment should be over the prior week, 
except for assessments performed at 6 and 48 hours post dose, which will be assessed since the 
prior assessment. The BPRS has low inter-rated reliability, and measures will be taken to ensure 
that it is captured consistently over time. 
5.1.9 Cognitive Assessment 
The digit symbol substitution test (DSST) will be used to measure cognitive impairment 
associated with Scop HBT. Study staff are experienced at performing the test, which typically 
takes 8 minutes to complete. The DSST will be administered at screening, at SD -1 (baseline), 48 
hours after injection (SD 3), and at the SD 8 follow-up visit. The DSST conducted at screening is 
intended to reduce practice effects. If the PI or designee determines a subject is incapable of 
engaging in the DSST at one or more time point(s), the reason(s) why the DSST assessment(s) 
could not be done will be documented by time point in the source documentation. 
 
The DSST will be used test for persistent cognitive impairment associated with Scop HBT at the 
individual and population levels. Differences in raw scores (number of correct pairings in 120 
seconds) between baseline and SD 3 and SD 8 will be presented individually in listings. The 
 
2 Posner K, Brown GK, Stanley B, Brent DA, Yershova KV, Oquendo MA, Currier GW, Melvin GA, Greenhill L, Shen S, Mann 
JJ (2011). The Columbia‐Suicide Severity Rating Scale: Initial Validity and Internal Consistency Findings from Three Multisite 
Studies with Adolescents and Adults. American Journal of Psychiatry 168(12): 1266‐77. 


25 
 
persistent effects of Scop HBT on cognition will also be assessed through comparison of within-
person changes in scores from baseline between active and placebo groups 
5.1.10 Injection Site Assessments 
At approximately 5 minutes after injection, the subject will be asked by the study staff to rate the 
maximum intensity of pain, pruritus, tingling, and numbness at the injection site using the VAS 
(see protocol Appendix A). The VAS will also be completed at pre dose and at 10, 15, 30, and 
45 minutes and 1, 1.5, 3, 5, 8, 12, 24, and 48 hours post dose, and at Day 8. In addition, an 
injection site assessment for presence and severity of pain, tenderness, erythema, and 
induration/swelling will be performed by a physician, physician assistant, or nurse approximately 
5 minutes after injection and for all subsequent time points (as stated above; see protocol 
Appendix C). Refer to protocol Appendix B for the Toxicity Grading Scale for Injection Site 
Reactions. 
The anticipated neuropsychiatric effects of Scop HBT may hinder obtaining reasonable 
subjective data on the VAS, especially at the earlier post-dose time points. If the PI or designee 
determines a subject is incapable of providing valid responses at one or more time point(s), the 
reason(s) why the VAS assessment(s) could not be done will be documented by time point in the 
source documentation. 
5.1.11 Physical Examinations 
Each subject will have a complete physical examination at screening, Day -1, pre-injection 
(abbreviated) and at 48 hours (abbreviated) and SD 8 post-injection. A complete physical 
examination will include the assessment of the following body systems: general appearance, eyes, 
ears, nose and throat, chest/abdominal, heart/cardiovascular, abdomen/gastrointestinal, lymph 
nodes/spleen, genitourinary, musculoskeletal, skin, neurological, hepatic and other.  The results of 
the physical examination will be recorded in the subject’s medical record and clinically significant 
findings will be recorded in the case report form (CRF).  The abbreviated physical examination 
will include documentation of any changes from the screening assessment. 
5.2 
PHARMACOKINETICS ENDPOINTS 
Determination of PK parameters at varying dose levels is an objective of this study, as is 
investigation of dose proportionality for Cmax and AUC∞. The PK measures, their definitions, 
methods of calculation, and methods for their statistical interpretation are described further. 
5.2.1 Plasma Pharmacokinetics 
The PK parameters will not be calculated as part of this SAP, but they will undergo statistical 
analysis according to this SAP. The PK parameters will be calculated by the Battelle Chemistry 
Technical Center according to their Standard Operating Procedures and conventions, using 
WinNonlin Phoenix v8.1). Plasma concentration time profiles for each subject tested will be 
evaluated using semi-log plots and characterized using noncompartmental analysis. 
Descriptive statistics for the concentration of Scopolamine in plasma and for the PK parameters 
will be calculated at each scheduled time point.  The summary of descriptive statistics at each 
time point will be displayed by cohort and dose level.  The statistics will include sample size, 
mean, median, standard deviation (SD), standard error of the mean (SEM), percent coefficient of 
variance (CV), minimum, and maximum for continuous variables, and 95% confidence intervals.  
Additionally, geometric means will be calculated for AUC∞ and Cmax.   


26 
 
Analysis of plasma concentrations will be performed for each subject on samples collected prior 
to dosing and at the following post-dose target time points: 2, 5, 10, 15, 20, and 30 minutes and 
1, 2, 4, 8, 12, 24, 36, and 48 hours post dose. Table 6 describes the time windows for blood draw. 
PK parameters will be calculated using the time points of the actual blood draw, rather than the 
target time. The serum PK parameters that will be analyzed are listed below and are outlined and 
defined as in the protocol:   
• Cmax:  Maximum measured plasma concentration over the time span specified. 
• Tmax: Time of maximum measured plasma concentration. If the maximum value occurs at more 
than one time point, Tmax is defined as the first time point with this value. 
• t1/2:  Apparent first-order terminal elimination half-life will be calculated as 0.693/ke. 
• Vd/F: Apparent Volume of distribution. 
• Cl/F: Apparent Volume of blood or plasma cleared of drug per unit time. 
• MRT (Mean Residence Time): Mean time the drug spends in the body before being 
eliminated. 
• AUClast: The area under the plasma concentration versus time curve, from time 0 to the last 
measurable concentration, as calculated by the linear trapezoidal method. 
• AUC∞: The area under the plasma concentration versus time curve from time 0 to infinity.  
AUC∞ is calculated as the sum of AUClast plus the ratio of the last measurable plasma 
concentration to the elimination rate constant (ke).  The elimination rate constant will be 
determined from the terminal linear phase of the plasma concentration time profile. 
• Cmax/Dose: Dose normalization of Cmax for evaluation of dose proportionality. 
• AUC∞/Dose: Dose normalization of AUC∞ for evaluation of dose proportionality. 
The terminal elimination phase is used to estimate a number of PK parameters. No value for 
Vd/F, Cl/F, AUC∞, or t1/2 will be reported for cases that do not exhibit a terminal log-linear phase 
in the concentration versus time profile. The PK analyses will not include the placebo group. 
Outlier screens will first be carried out.  For each PK parameter a one-way, heterogeneous 
variance analysis will be carried out across dose groups.  Studentized residuals (i.e. residuals 
divided by their standard errors) will be calculated within each group and combined across 
groups.  Studentized residuals in excess of three in absolute value will be considered “tentative 
outliers”.  The tentative outliers will be examined by Battelle to determine if they are due to 
testing errors or data entry errors.  If so, they will be reported and omitted from subsequent 
analyses.  If the tentative outliers are correctly determined they will be treated as outliers and 
subsequent analyses will be carried out both including and excluding the outlying values. 
 
 


27 
 
Table 6: 
Pharmacokinetic Blood Sample Deviation Windows 
Target Time Point 
Acceptable Sample Collection Time Point Range 
Low-End Range 
High-End Range 
Window 
2 min 
1 min 50 s 
2 min 10 s 
20 seconds 
5 min 
4 min 40 s 
5 min 20 s 
40 seconds 
10 min 
9 min 30 s 
10 min 30 s 
60 seconds 
15 min 
14 min 15 s 
15 min 45 s 
60 seconds 
20 min 
19 min 
21 min 
2 minutes 
30 min 
28.5 min 
31.5 min  
3 minutes 
1 h (60 min) 
57 min 
63 min 
6 minutes 
2 h (120 min) 
114 min 
126 min 
12 minutes 
4 h (240 min) 
228 min 
252 min 
24 minutes 
8 h (480 min) 
465 min 
495 min 
30 minutes 
12 h (720 min) 
705 min 
735 min 
30 minutes 
24 h (1440 min) 
1425 min 
1455 min 
30 minutes 
36 h (2160 min) 
2145 min 
2175 min 
30 minutes 
48 h (2880 min) 
2865 min 
2895 min 
30 minutes 
5.2.2 Urine Pharmacokinetics 
Urine will be collected continuously for 24 hours post dosing. A sample of urine will also be 
collected within 2 hours prior to dosing. Urine samples for PK will be pooled into four periods:  
pre-dose, 0-4 hours post dose, 4-12 hours, and 12-24 hours. Urine samples will be analyzed for 
concentrations of Scopolamine. Urine samples may also be analyzed for metabolites of 
Scopolamine. 
5.3 
COVARIATES 
In general, covariates are not applicable for this study, with the exception of PK analysis. The 
influence of the dose of Scopolamine will be evaluated in various analyses including the PK 
dose-response relationship, with sex included as a covariate. Sex is valid as a covariate in 
models of PK parameters based on plasma concentrations, as males typically have higher 
plasma volumes per unit body mass than females. 
6. STATISTICAL METHODOLOGY AND ANALYSES 
6.1 
GENERAL CONSIDERATIONS 
The first and second objective of this study will primarily be addressed through descriptive 
statistics of safety and PK data. Hypothesis testing and interval estimation will be limited. 
Specific hypotheses are detailed in 6.3 and interval estimation in 6.4. All data analyses and 
statistical testing will be conducted using SAS Version 9.4 or Stata version 15 or higher.  
 


28 
 
6.2 
CHANGES FROM PROTOCOL SPECIFIED ANALYSES 
Changes to the protocol specified analyses that are made prior to unblinding the data will 
be noted in a revised protocol and be approved by study sponsor, statistician, and ethical 
review committee. Upon approval, such analyses will be incorporated into the final SAP. 
The results of analyses not specified in the protocol but specified in the SAP prior to 
unblinding will be included in the final statistical report/and or CSR as “additional 
analyses”. 
Changes to the protocol-specified analyses made after unblinding of the data will be 
considered as “post-hoc”. Post hoc analyses will not be included in the protocol 
amendments or the final SAP. In the final statistical report/and or CSR, post hoc analyses 
will be presented separately and subsequent to all analyses specified in the final protocol. 
No interim analyses are planned. DSMB and 
 safety reviews are planned and do not 
constitute an interim analysis or changes from protocol-specified analyses.  
No graphs/figures will be produced for final analysis based on discussion and agreement 
from client Biostatistician. 
6.3 
HYPOTHESES AND DECISION RULES 
As the objective of this study is to characterize the safety and tolerability of escalating 
doses of Scop HBT, three sets of safety endpoints will be compared statistically between 
placebo and active dosing groups. Some PK parameters will also be compared statistically 
across dose levels. Table 7 describes the hypothesis testing pre-specified in the statistical 
analysis. 
The null hypothesis of no worse scores for Injection Site VAS (pain, itching, tingling, 
numbness); change in BPRS Score (6 hours, 48 hours, 8 days); change in DSST (48 hours, 
8 days); and C-SSRS (SD 8) between dose levels of active Scop HBT and placebo will be 
tested statistically using a one-sided alternative of worse (higher for C-SSRS, VAS, and 
BPRS, lower for DSST scores for Scop HBT vs. placebo. Each dose level will be tested 
against the same placebo group (all participants receiving placebo). Methods for analysis 
of neuropsychiatric scales and injection site reactions are described in Sections 6.13.4 
6.14.6 and  6.14.8, respectively. 
For PK parameters, variation across doses will be tested for Tmax, t1/2, Vd/F, Cl_F, and 
MRT against the null hypothesis of no difference across doses. A joint significance test (1 
test per parameter) will be used. 
Dose-proportionality will be tested using the dose-normalized parameters Cmax/Dose and  
AUC∞/Dose. A likelihood ratio test will be used for testing the joint null hypothesis of 
equivalence across all doses using a two-sided alternative. Each dose level will also be 
tested against the next dose level using a two-sided test. The methods for analysis and 
hypothesis testing are described in Section   6.15. A total of 110 hypothesis tests will be 
performed. Procedures for multiple comparisons are detailed in Section 6.8. 
 
 


29 
 
Table 7:  Pre-Specified Hypothesis Tests 
Drug 
Characteristic 
Null 
Hypothesis 
Relevant Endpoints 
[Count] 
Number of 
Comparisons 
Per Parameter 
Total Number 
of Hypothesis 
Tests 
Safety 
Equivalence 
with Placebo 
Injection site VAS (pain, 
itching, tingling, 
numbness) x (10-45 
minutes, 1-5 hours, 8-48 
hours) [12] 
 
Change in BPRS score 
from baseline (6 hours, 48 
hours, SD 8) [3] 
 
Change in DSST scores 
from baseline (48 hours, 
SD 8) [2] 
5 (Each dose 
level vs. 
Placebo) 
 
 
 
90 
Safety 
Equivalence 
with Placebo 
C-SSRS (SD 8) [1] 
 
Change in DSST scores 
from baseline (48 hours, 
SD 8) [2] 
 
Proportion with  
lower raw DSST scores 
compared to baseline (48 
hours, SD 8) [2] 
1 (All dose 
levels vs. 
Placebo) 
5 
PK Dose-
Equivalence 
Equivalence 
across doses 
Tmax, t1/2, Vd/F, MRT, Cl_F 
1 Joint Test 
5 
PK Dose-
Proportionality 
Equivalence 
across doses 
Cmax/Dose 
AUC∞/Dose 
1 (joint test) 
4 (each dose vs. 
next higher dose) 
10 
Total 
110 
 
6.4 
UPPER-BOUND ESTIMATION FOR DLTS & SAES 
As part of the first objective, to characterize the safety and tolerability of Scop HBT IM injection 
at varying dosages, upper limits for the probability of an event at each dosage will be estimated 
using data on the occurrence of extreme DLTs, non-extreme DLTs, and SAE. 
Dose progression follows rules that require dosing be halted if an extreme DLT or a SAE related 
to the drug occurs within any cohort. Therefore, the maximum number of extreme DLTs that can 
occur in a cohort prior to stopping is one. Should one nonextreme DLT occur in the first four 
participants or two in the first 8 participants, dosing will be halted. If dosing is resumed (upon 
determination of the PI, DSMB, and sponsor) and a second nonextreme DLT occurs among the 
first 4 in cohort or 3 total DLTs occur, dosing and enrollment will be halted.  
Confidence intervals will be determined using 80% confidence interval, such that there is a 10% 
probability that the true value exceeds the upper-bound. The Pearson-Clopper interval is the most 
conservative among the binomial intervals, resulting in the highest upper confidence bounds.  
Should no events of any type occur within a cohort, with 6 participants dosed, the 80% 
confidence interval upper bound for the probability of any event is 0.32. Should one extreme 


30 
 
DLT or SAE occur in any cohort, the upper bound for the SAE/extreme DLT will depend on the 
number dosed prior to the event occurring. Table 8 shows the upper bounds of confidence 
intervals based on the number of participants receiving active Scop HBT.  
 
Table 8:  Upper-bound estimates of Risk Inferred from Events in Cohort 
 
Number Receiving Active Scop HBT 
2 
4 
6 
91 
Event Type 
Number of Participants 
with Event 
80% C.I. Upper Bound 
(Pearson-Clopper Method) 
No Events 
0 
N/A 
N/A 
0.32 
N/A 
Extreme DLT 
1 
0.95 
0.68 
0.51 
0.37 
Nonextreme 
DLT 
1 of first 4 in a cohort, 
none thereafter  
0.95 
0.68 
0.51 
0.37 
2 in the first 8 in a cohort 
1.0 
0.86 
0.67 
N/A 
2 of the first 4 in a cohort 
1.0 
0.86 
N/A 
N/A 
3 in any cohort 
N/A 
0.97 
0.80 
0.60 
SAE not already 
designated as a 
DLT (except 
unrelated) 
1 
1.0 
0.68 
0.51 
0.37 
1If nonextreme DLT occurs in a given cohort, the cohort may be expanded to 12 participants, a maximum of 
9 of whom will receive active Scop HBT.  
6.5 
BLINDING AND UNBLINDING 
This study is double-blinded. Study drugs and placebo are filled in amber vials with a 1.2-mL fill 
volume, are clear and colorless liquids, and labeling is identical. The pharmacist and/or 
pharmacy technician at the clinical site will fill syringes for each study subject on dosing days to 
maintain the blind of the study staff. However, once a subject has been dosed with Scop HBT, 
Injection, the study staff will likely become unblinded as the CNS effects of Scop HBT will be 
evident in the participants, especially at the higher concentrations. Nevertheless, every effort 
should be made to maintain the blind, even at the higher concentrations.  
In addition to the study pharmacist, another Pharmaron team member is unblinded in order to 
verify the dosing calculations at the time of subject treatment. One (1) Battelle statistician, one 
(1) pharmacokineticist, and PK sample analysts will be unblinded. The unblinded statistician will 
prepare the study data for the DSMB closed session meetings, including the PK data received 
from the pharmacokineticist.   
Battelle will have a blinded statistician. The blinded statistician and all other Battelle staff 
responsible for cleaning the data and creating and validation of the tables, listings, and figures 
(TLFs), specifically the data management, statistics and programming staff, will be blinded 
throughout the study. Unblinding of the treatment levels will occur after all analysis populations 
are finalized and the final database is locked.   
 


31 
 
6.6 
HANDLING OF MISSING VALUES, PARTICIPANT WITHDRAWAL, AND STUDY 
TERMINATION 
Missing data can occur due to protocol deviations and withdrawal of participants from the study. 
All data documented in the CRFs will be presented in data listings. This means that missing 
values are listed as missing values. Repeated and additional measurements are listed as well. 
6.6.1 Assessment of Missing 
All missing datapoints will be identified from review of data listings. A table and listing of all 
missing data points will be generated for each endpoint with any missing. For each missing 
observation, the cause of missing will be identified from protocol deviations and participant 
disposition. Endpoints censored due to administration of rescue medication (as detailed in 6.11) 
will be presented separately. All protocol deviations will be listed by participant. The number of 
protocol deviations and the number of participants with protocol deviations will also be 
summarized by deviation category and by deviation classification (major/minor). If missing data 
is identified without a protocol-related reason or a protocol deviation, the missing measure will 
be added as protocol deviation. 
6.6.2 Handling of Missing PK Data 
For PK, a subject will be included in the calculation of the PK endpoints even if the subject has 
missing data at certain time points, as long as the subject has post-baseline data to define the PK 
plasma profile, i.e. a well-defined Cmax, Tmax, and at least three concentration time points to 
characterize the terminal linear phase. 
Plasma concentration below the level of quantification (BLQ) will be censored. For the intended 
assay for Scopolamine, the limit of quantification is 0.010ng/mL. The upper limit of 
quantification is 10.0ng/mL. For samples that exceed the upper limit of quantification, dilution 
will be used to obtain quantifiable samples. 
6.6.3 Handling of Other Missing Data 
Other than AE data, for which missing will be imputed as the most severe, missing values will not 
be imputed for statistical summaries or analysis. All planned analyses of non-AE data will be 
conducted using all available data, including for participants who withdraw, with the exception of 
data to be censored following administration of rescue medications (as detailed in 6.11). In the 
event of study termination, all available data will be used for analysis of cohorts with at least one 
participant receiving the study drug.   
Unless indicated otherwise, summary statistics will be reported for observed data only, with the 
exception of the cases described below.  
Partial or incomplete start/end dates of the AEs or concomitant medications will be imputed to 
help determine treatment-emergent adverse events and prior or concomitant medications. 
For incomplete start dates, following imputation rules will be implemented: 
• Missing day - Impute as the 1st of the month unless month is same as month of first dose 
of study drug then impute using the day of first dose date.  
• Missing day and month – impute as 1st January unless year is the same as first dose date 
then impute using the day and month of first dose date.  


32 
 
• Completely missing – impute using the first dose date unless the end date suggests it could 
have started prior to this in which case impute as 1st January of the same year as the end 
date.  
When imputing a start date, ensure that the new imputed date is sensible i.e. is prior or equal to 
the end date of the AE or medication. 
For incomplete end dates following imputation rules will be implemented:  
• Missing day - Impute as the last day of the month unless month and year are the same as 
the month and year of the end of study, then impute as the end of study date.  
• Missing day and month – Impute as 31st December unless year is the same as the year of 
the end of study date then impute as the end of study date.  
Completely Missing – need to look at whether the AE/medication is still ongoing before imputing 
a date and also when it started in relation to study drug. If the ongoing flag is not missing then 
assume that AE is still present / medication is still being taken (i.e. do not impute a date). If the 
AE/medication has stopped and start date is prior to first dose date then impute as the 1st dose 
date, if it started on or after first dose date then impute as the end of study date. 
For partial or completely missing datetime (s), impute 00:00 if both minutes and seconds are 
missing. If minutes or seconds are missing, impute 00 accordingly. Make sure the new imputed 
datetime are sensible and does not affect the assignment of the AEs or Concomitant medication as 
treatment-emergent or ongoing respectively.   
6.7 
INTERIM ANALYSES 
No interim analyses are planned. DSMB review will review data from each cohort. Dosing or 
enrollment may be halted if escalation criteria are not met. The DSMB may also recommend 
halting the trial at any point. 
6.7.1 Dose Progression Criteria 
Dosing may be halted prior to study completion. The criteria that require halting enrollment are 
specified in Table 3. Once halted the PI and DSMB will make recommendations to the sponsor 
on whether to resume enrollment.  
6.7.2 Independent Data Safety Monitoring Board (DSMB) Analyses 
An independent data safety monitoring board (DSMB) is required for this study. The DSMB will 
review safety and PK data for each cohort prior to cohort escalation. The DSMB will not conduct 
any statistical analyses or use a statistical test to determine whether to halt or terminate the trial. 
6.8 
ADJUSTMENT FOR MULTIPLE COMPARISONS 
Section 6.3 specifies the hypotheses to be tested in this Phase 1 trial of the safety and 
pharmacokinetics of IM injection of Scop HBT. Given the large number of hypothesis tests, the 
Benjamini-Hochberg method will be used to determine statistical significance. As this trial is 
exploratory, a relatively high false discovery rate (FDR), the proportion of significant findings  
that are spurious, will be used. For this study, the FDR will be set at 0.20. The choice of a high 
FDR prevents rejecting marginally significant findings, which may provide important 
information about the drug’s safety and pharmacokinetic properties. With 110 tests and an FDR 
of 0.20, the threshold for statistical significance for the five lowest p-values will be 0.0018, 


33 
 
0.0036, 0.0055, 0.0073, and 0.0091. Statistical significance of tests will be noted using at the 
alpha = 0.05 level as well as through the Benjamini-Hochberg method. Study sponsors should 
note that one-in-five significant findings obtained through this process are expected to be 
spurious. 
6.9 
POOLING OF SITES 
Not applicable for the study since only 1 investigative site is being utilized. 
6.10 DISTRIBUTIONAL ASSUMPTIONS  
The residuals of ANOVA models will be assessed for normality using a Shapiro-Wilk test in 
conjunction with visual inspection of quantile-quantile plots. Lognormality is commonly 
assumed for PK parameters. If the normality assumption is not met, logarithmic (natural or base-
10) transformation will be assessed. If lognormality is rejected, non-parametric bootstrap 
replication with a minimum of 10,000 replications will be used to calculate confidence intervals 
and perform hypothesis testing.  
With small samples, the normality of parameters, such as the sample mean, cannot be assured. 
Therefore, quantile-based confidence intervals will be obtained, and hypothesis testing will be 
conducted using comparisons of observed test statistics to test statistics obtained under the null 
hypothesis. For hypotheses of equivalence between two populations (e.g. placebo and dosage 
groups, 𝛽𝛽1 = 0, 𝜇𝜇1 = 𝜇𝜇2), an unequal sample unequal variance T-statistic will be used: 
𝑇𝑇=
𝜇𝜇1
ෞ−𝜇𝜇2
ෞ
𝑠𝑠𝑝𝑝ට1
𝑛𝑛1+ 1
𝑛𝑛2
  
 
 
 
 
(1) 
where, 𝜇𝜇1
ෞ and  𝜇𝜇2
ෞ are the observed sample means, and 
𝑠𝑠𝑝𝑝= ට
(𝑛𝑛1−1)𝑠𝑠12+(𝑛𝑛2−1)𝑠𝑠22
𝑛𝑛1+𝑛𝑛2−2
 
 
 
 
(2) 
Where 𝑠𝑠1
2 and 𝑠𝑠2
2 are the sample variances. The null distribution will be generated by resampling 
from the values at their two groups shifted to their pooled sample mean. 
For joint significance tests (e.g. 𝐻𝐻0:  𝛽𝛽1 = 𝛽𝛽2 = 𝛽𝛽3 = 𝛽𝛽4 = 0), the F-statistic will be used with 
the formula, 
𝐹𝐹𝑏𝑏=
ቀ𝑅𝑅𝑅𝑅𝑅𝑅1−𝑅𝑅𝑅𝑅𝑅𝑅2
𝑝𝑝2−𝑝𝑝1
ቁ
ቀ𝑅𝑅𝑅𝑅𝑅𝑅2
𝑛𝑛−𝑝𝑝2ቁ
 
 
 
 
 
(3) 
where 𝑅𝑅𝑅𝑅𝑅𝑅1 is the residual sum of squares for an ANOVA model fit under the null with 𝑝𝑝1 
parameters and 𝑅𝑅𝑅𝑅𝑅𝑅2 a model fit with all parameters 𝑝𝑝2 included. The null distribution will be 
generated through resampling from the distributions of each dosage cohort shifted to their 
common mean. With bootstrap resampling, p-values will be calculated by comparing observed 
values of the test statistic to the null distribution: 
𝑝𝑝=
1
𝐵𝐵∑
𝐼𝐼(𝐹𝐹𝑏𝑏≥𝐹𝐹𝑜𝑜𝑜𝑜𝑜𝑜 𝑜𝑜𝑜𝑜 |𝑇𝑇𝑏𝑏| ≥|𝑇𝑇𝑜𝑜𝑜𝑜𝑜𝑜|)
𝐵𝐵
𝑏𝑏=1
 
 
 
(4) 
where B is the number of bootstrap samples taken.  
ANOVA also assumes homogeneity of variance (i.e. homoskedasticity). Homogeneity of 
variance will be assessed. If variances are equal, homogenous variance ANOVA will be 


34 
 
performed, otherwise heterogeneous variance ANOVA will be performed, unless bootstrapping 
is used. 
6.11 EXTENT OF EXPOSURE AND TREATMENT COMPLIANCE 
This is a single dose study where the treatment is given in a single IM injection. The study 
medication (active or placebo) will be prepared by the pharmacist in accordance with the Drug 
Preparation Manual. Therefore, exposure will be closely monitored, and treatment compliance is 
not a major risk.  
In the event that rescue medications (physostigmine, atropine, diazepam or lorazepam) are 
administered, data for the participant will be analyzed according to the dosage of Scop HBT 
received for measures taken up to the administration of the rescue medication. Thereafter, 
participant data will be treated differently by endpoint. Data collected after administration of the 
rescue medication for the BPRS, DSST, and/or RASS will be censored in analyses, though 
presented descriptively. Adverse events, injection site VAS, and PK data will not be censored. 
6.12 SUBJECT DISPOSITION 
Subject disposition will be summarized in terms of the number of participants who were 
screened, failed screening (by criteria), consented, randomized, treated, completed all follow-up 
assessments, or discontinued early from the study. Frequency counts and percentages of 
participants by disposition status will be presented for each cohort and dose level with all data 
from Placebo participants pooled and summarized as a single group. Disposition will be 
summarized for the Safety population. 
6.12.1 Discontinuations/Early Terminations 
All participants who discontinue from the study will be identified, and the extent of their 
participation in the study will be reported. If known, a reason for their discontinuation will be 
summarized. Participants who withdraw or are excluded from participation in the study prior to 
receiving study drug will be replaced; however, withdrawing or terminating participants who 
have received study drug or placebo will not be replaced.  
6.13 DEMOGRAPHIC AND BASELINE CHARACTERISTICS 
Demographic characteristics, including age, gender, weight, BMI, race, and ethnicity will be 
summarized. The subject’s age is calculated as the number of years from the subject’s date of 
birth to the date the Informed Consent signed, rounded down to the nearest integer: 
Age = Integer ([Date Informed Consent Signed - Date of Birth] / 365.25) 
Demographics will be summarized for the Safety and PK populations, should these populations 
be different.  Demographic and baseline data will be listed for all participants to supplement 
summary results.  Results will be presented for each cohort and dose level with all data from 
Placebo participants pooled and summarized as a single group.  
 
6.14 SAFETY ANALYSES 
6.14.1 Physical Examination 
For the complete physical examination performed at Screening, the proportion of participants 
reporting results of “Normal”, “Abnormal, Not Clinically Significant”, and “Abnormal, 


35 
 
Clinically Significant” will be calculated and presented for each body system and cohort/dose 
level.  Any changes between the Screening and SD -1 physical examinations will be captured as 
part of medical history and any changes between the serial post-dose examinations and the SD -1 
physical examination will be captured as an AE and will be presented in those tabulations and/or 
listings.  The proportion of participants that report changes in physical examination between SD 
-1 and SD 8 will be calculated and presented for each body system and cohort and dose level 
with all data from Placebo participants pooled and summarized as a single group. The physical 
examination data will be summarized for the Safety population. A listing of all physical 
examination results will be provided to supplement the tabulated results. 
6.14.2 ECG Data 
Descriptive statistics of ECG results (ventricular HR, PR interval, QRS interval, QT interval, 
QTcF interval) will be calculated at each scheduled time point and will include the change from 
baseline.  The summary of descriptive statistics at each time point will be displayed by cohort 
and dose level, with all data from Placebo participants pooled and summarized as a single group.  
In addition, the frequency and percentage of participants classified as “Normal”, “Abnormal, Not 
Clinically Significant” or “Abnormal, Clinically Significant” will be summarized at each time 
point. The frequency and percentage of participants with ECGs that are classified as “Normal” at 
baseline but change to “Abnormal, Clinically Significant” or “Abnormal, Not Clinically 
Significant” after dosing, or that are classified as “Abnormal, Not Clinically Significant” at 
Baseline but change to “Abnormal, Clinically Significant” after dosing will also be summarized.   
ECG results and changes from baseline in ECG results will be categorized with the number and 
proportion of participants reporting changes presented as categorical variables.  
The ECG data will be summarized for the Safety population and a listing of all ECG data will be 
provided to supplement the tabulated results. 
6.14.3 Vital Signs 
Descriptive statistics of vital signs (pulse rate, BP, temperature, respiratory rate, pulse oximetry) 
will be calculated at each scheduled time point and will include the change from baseline. The 
summary of descriptive statistics at each time point will be displayed by cohort and dose level, 
with all data from Placebo participants pooled and summarized as a single group. The vital signs 
data will be summarized for the Safety population and a listing of all vital signs data will be 
provided to supplement the tabulated results. 
 
6.14.4 Clinical Laboratory Tests 
Descriptive statistics of clinical laboratory tests (serum chemistry, hematology, and urinalysis) 
will be calculated at each scheduled time point and will include the change from baseline for 
each analyte.  The summary of descriptive statistics at each time point will be displayed by 
cohort and dose level, with all data from Placebo participants pooled and summarized as a single 
group for each analyte.  
In addition, shift tables summarizing changes from normal to out-of-normal range will be 
provided.  - 


36 
 
The laboratory data will be summarized for the Safety population and a listing of all laboratory 
data will be provided to supplement the tabulated results. 
6.14.5 Adverse Events 
Treatment-emergent AEs (TEAEs) are defined as those AEs with onset date and time equal to or 
after start of study medication or those events in which the onset date and time are before the 
start of study medication but worsened after the start of study medication. To be conservative, in 
the case of a missing onset time for an AE, an AE with a start date equal to or after the dosing 
date will be considered treatment-emergent. All AEs will be coded using the MedDRA 
dictionary, version as noted in the Data Management Plan, using System Organ Class and 
Preferred Terms. 
All TEAEs will be summarized by cohort and dose level, with all data from Placebo participants 
pooled and summarized as a single group. The number of TEAEs as well as the number and 
percentage of participants who experienced at least one TEAE will be summarized for each 
system organ class and each preferred term. The percentage will be based on the number of 
safety participants in a particular treatment group. Each subject will contribute at most one count 
per summarization category. All TEAEs will be sorted in descending order of the incidence rate 
of system organ classes in the highest dosing group and then within each system organ class by 
descending order of incidence rate of preferred terms in the same group. TEAEs potentially 
related to study medication, serious TEAEs, and TEAEs leading to withdrawal will be 
summarized in a similar manner. A separate table will present all TEAEs that are coded as 
unexpected and possibly,probably, or definitely related to treatment. 
 
If a subject has more than one AE that codes to the same preferred term, the subject will be 
counted only once for that preferred term. Similarly, if a subject has more than one AE within a 
system organ class category, the subject will be counted only once in that system organ class 
category.  
 
TEAEs will also be summarized by maximum severity and by strongest relationship to treatment 
within each cohort and dose level. SAEs will be tabulated and listed in a manner similar to 
TEAEs. The AE data will be summarized for the Safety population and a listing of all AE data 
will be provided to supplement the tabulated results. 
6.14.6 Neuropsychiatric Scales 
Descriptive statistics (mean, standard deviation, minimum, maximum, median) of scores on the 
neuropsychiatric status assessments (BPRS and C-SSRS) will be presented for each timepoint by 
dosing group (placebo, 0.005, 0.007, 0.011, 0.014, 0.021mg/kg).  
As the RASS will only be used if general agitation or sedation are reported, the number of 
participants with RASS performed, the reason for performance of the RASS, the time since 
injection when the RASS was administered, the RASS score, the resulting action taken (e.g., 
rescue drug administered, resolved or unresolved) will be presented by dose group and overall.  
Signal neuropsychiatric events defined as DLTs (BPRS ≥40 or item score ≥4 at 48-hour post-
dose evaluation) or symptoms (e.g., delirium, paranoia, and/or hallucinations) defined as adverse 
events will be noted and the affected participants’ BPRS, C-SSRS, and RASS (if applicable) 
scores will be presented at each time point in relation to the determination of the event.  


37 
 
Change in BPRS scores from baseline (when BPRS≤25) will be compared for each dose level to 
placebo. Each time-point will be modeled separately. Changes in BPRS scores will be compared 
between each dose and the placebo group using a Wald test of coefficients from ANOVA. 
Change in C-SSRS scores at SD 8 (from a baseline of zero) will be assessed. The proportion of 
individuals having a change in score from zero will be compared for each drug dosage level to 
the placebo group using Fisher’s exact test. Scores for all participants receiving active Scop HBT 
will be compared to those receiving placebo.  
6.14.7 Assessment of Cognitive Impairment 
The DSST will be used to measure cognitive impairment due to Scop HBT. The raw score will 
be calculated from the difference in total number of trials attempted and the number of trials 
incorrect. Summary statistics for raw DSST scores (mean, median, min, max, standard deviation, 
95% confidence intervals) will be presented over time by dose level. The proportion of 
individuals with declines in raw scores between baseline and 48 hours and baseline and Day 8 
will be compared between active placebo and active Scop HBT using a Fisher’s Exact Test. This 
test will be conducted once for all participants receiving active Scop HBT and all participants 
receiving placebo. 
 
In addition, individual changes in DSST scores between baseline and 48 hours and SD 8 will be 
compared between each dosage cohort and placebo and for all active dosages and placebo. 
Equation 5 presents the model that will be used to compare DSST scores by cohort, 
 
       (5) 
 
where Yi,, is the change in DSST scores at 48 hours or SD 8, Di is the dosage level for 
participant  
i (1=0.005, 2=0.007, 3=0.011, 4=0.014, 5=0.021 mg/kg), β0 is the change in DSST scores for 
placebo participants, and εi is the error term for each participant i. Wald tests will be used for the 
null hypotheses of no differences between active Scop HBT and placebo: β1 = 0, β2 = 0, β3 =  
0, β4= 0, β5 = 0. 
 
Equation 6 shows the model that will be used to test the null hypothesis of no differences 
between all levels of active Scop HBT compared to placebo  
 
 
(6) 
 
A Wald test will be used to test the null hypothesis that there are no significant differences in the 
change in DSST scores between active and placebo Scop HBT (β1 = 0) in Eq. 6. 


38 
 
6.14.8 Assessment of Injection Sites 
Descriptive statistics of injection site assessments will be reported. Mean, median, standard 
deviation, minimum, and maximum VAS scores will be presented for each time-point by dosing 
group (placebo, 0.005, 0.007, 0.011, 0.014, 0.021mg/kg).  
Frequencies of severity (None, Mild, Moderate, Severe, Potentially Life Threatening) from 
injection site assessments performed by clinicians will be summarized by type (pain, tenderness, 
Erythema/Redness, Induration/Swelling) and timepoint, by dosage group.  
Differences between placebo and active Scop HBT injection site VAS scores will be compared 
statistically by dosage level using three different ANOVA models corresponding to the first 
hour, next 4 hours, and 8 – 48 hours after injection. In the first model, VAS scores will be 
averaged over 10, 15, 30, & 45 minutes. In the second model, VAS scores will be averaged over 
1, 1.5, 3, and 5-hour timepoints. The third model will include VAS scores averaged over 8, 12, 
24, and 48-hour timepoints. VAS scores for active Scop HBT doses will be tested against scores 
for placebo using a one-sided alternative of higher scores for Scop HBT than placebo. 
6.14.9 Medical History 
Medical History data will not be tabulated but will be provided in a listing by cohort, dose level, 
and subject.  
6.14.10 Concomitant Medications 
Concomitant Medications will be coded using the World Health Organization (WHO) Drug 
dictionary, using Anatomical Therapeutic Chemical (ATC) classifications and WHO preferred 
terms. Concomitant Medications will not be tabulated but will be provided in a listing by cohort, 
dose level, and subject.  
6.15 PHARMACOKINETIC ANALYSES 
6.15.1 Plasma Pharmacokinetics 
The estimation of pharmacokinetic parameters of interest is not described within this SAP.  A 
separate PK report will detail methods and limitations of the estimation of PK parameters. 
However, PK parameters will be analyzed as part of this SAP.  
PK parameters will be assessed for homoskedasticity prior to modeling using ANOVA. For 
parameters that vary by orders of magnitude across dose groups, a logarithmic transformation 
will be carried out prior to testing for homogeneity of variance.  Otherwise a likelihood ratio test 
for homogeneity of variance will be carried out on the untransformed PK values or on 
transformed values, as appropriate. The tests for homogeneity of variance will exclude outlying 
values. If there are significant differences (p<0.05) in variances across dose groups, comparison 
of PK means across dose groups will be carried out based on a heterogeneous variance analysis 
of variance.  Otherwise it will be carried out based on a homogeneous variance analysis of 
variance. 
Dose-equivalency of five PK parameters (Tmax, t1/2, Vd/F, CL_F, MRT) will be tested using 
ANOVA. Models will adjust for sex of the subject. Equation 3 presents the model to be used for 
all ANOVA of PK parameters, 


39 
 
 
, where G is a link function (or identity), 𝑌𝑌𝑖𝑖 is the PK parameter of interest i, 𝛽𝛽0 is the change in 
PK parameter for the placebo group, 𝐷𝐷𝑖𝑖 is the dosage level (1=0.005, 2=0.007, 3=0.011, 
4=0.014, 5=0.021 mg/kg), and 𝜀𝜀𝑖𝑖 is an error term each for participant i. Models will control for 
the sex of the participantThe significance of the difference in parameters by dose level will be 
tested using a likelihood ratio test for the joint null hypothesis:  𝐻𝐻0:  𝛽𝛽1 = 𝛽𝛽2 = 𝛽𝛽3 = 𝛽𝛽4 = 0. If 
bootstrapping is used, a null distribution will be generated using an F-statistic, as described 
previously. For parameters where dose-proportionality is assessed, the equivalency of each 
parameter with the next higher dose level will be tested, using the null hypotheses:    
 
 
Two PK parameters, Cmax and AUC∞, will also be used to test dose-proportionality. ANOVA 
models will compare Cmax/Dose and AUC∞/Dose across active dose levels. Joint significance 
will be tested using likelihood ratio tests. Individual doses will be compared to the next higher 
dose using Wald Tests of model parameters.  
 
6.15.2 Urine Pharmacokinetics 
The analysis of urine PK is exploratory and descriptive only. If available, urine concentrations 
and total quantities of Scopolamine in urine will be summarized by collection time window for 
each cohort. If metabolites of Scopolamine are analyzed, their concentrations and the ratio of 
Scopolamine to its metabolites will be calculated and presented descriptively as a function of 
collection window and dosing group. No hypothesis testing will be performed based on urine 
PK. 
REFERENCES 
None at this time. 
Tables, Listings, and Figures 
See separate shell document. 
6.16 LIST OF TABLES 
 See separate shell document. 


40 
 
6.17 LIST OF LISTINGS 
See separate shell document. 
7. APPENDICES 
None at this time.