Clinical trial NCT04290039
Conditions: Toxic Effect of Organophosphate and Carbamate Insecticides
Sponsor: Biomedical Advanced Research and Development Authority
Start date: 2020-01-04; Completion date: 2020-02-08
Enrollment: 15 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
This randomized, three-sequence, three-period, phase 1 study is designed to assess the bioavailability and pharmacokinetics (PK) of sublingually administered atropine sulfate ophthalmic solution 1% USP (at 0.5 mg and 1.0 mg; test) compared to atropine sulfate injection administered IV (1.0 mg; reference).

Detailed description:
This is a randomized, three-sequence, three-period crossover study to assess the bioavailability and PK of a single dose of atropine administered sublingually in healthy adult volunteers. At least 15 healthy male and female volunteers will be enrolled to obtain approximately 12 evaluable subjects in the per protocol population. Eligible subjects will be randomized at a 1:1:1 ratio to receive one of three treatment dosing sequences (A, B, or C).

Subjects assigned to treatment dosing sequence A will receive a low dose sublingually at Visit 1; Day 1 (Period 1), a high dose sublingually at Visit 2; Day 8 (Period 2) and an IV dose at Visit 3; Day 15 (Period 3).

Subjects assigned to treatment dosing sequence B will receive a high dose sublingually at Visit 1; Day 1 (Period 1), an IV dose at Visit 2; Day 8 (Period 2) and a low dose sublingually at Visit 3; Day 15 (Period 3).

Subjects assigned to treatment dosing sequence C will receive an IV dose at Visit 1; Day 1 (Period 1), a low dose sublingually at Visit 2; Day 8 (Period 2), and a high dose sublingually at Visit 3; Day 15 (Period 3).

Arms: arm 1: Atropine sulfate ophthalmic solution, USP 1% is a sterile topical anti-muscarinic indicated for cyclopegia, mydriasis, and penalization of the healthy eye in the treatment of amblyopia. Each mL of Atropine Sulfate Ophthalmic Solution USP, 1% contains active ingredient: atropine sulfate 10 mg equivalent to 8.3 mg of atropine. Inactive ingredients include benzalkonium chloride 0.1 mg (0.01%), dibasic sodium phosphate, edetate disodium, hypromellose (2910), monobasic sodium phosphate, hydrochloric acid and/or sodium hydroxide may be added to adjust pH (3.5 to 6.0), and water for injection, USP. Atropine Sulfate Ophthalmic Solution, USP 1% will be supplied in dropper bottles containing 2 mL.

Each bottle will only be used to administer a single dose, to a single subject. arm 2: Atropine sulfate ophthalmic solution, USP 1% is a sterile topical anti-muscarinic indicated for cyclopegia, mydriasis, and penalization of the healthy eye in the treatment of amblyopia. Each mL of Atropine Sulfate Ophthalmic Solution USP, 1% contains active ingredient: atropine sulfate 10 mg equivalent to 8.3 mg of atropine. Inactive ingredients include benzalkonium chloride 0.1 mg (0.01%), dibasic sodium phosphate, edetate disodium, hypromellose (2910), monobasic sodium phosphate, hydrochloric acid and/or sodium hydroxide may be added to adjust pH (3.5 to 6.0), and water for injection, USP. Atropine Sulfate Ophthalmic Solution, USP 1% will be supplied in dropper bottles containing 2 mL.

Each bottle will only be used to administer a single dose, to a single subject. arm 3: Atropine sulfate injection is indicated for temporary blockade of severe or life-threatening muscarinic effects, e.g., as an antisialagogue, an antivagal agent, an antidote for organophosphorus, carbamate, or muscarinic mushroom poisoning, and to treat symptomatic bradycardia.

Atropine sulfate injection, USP,8mg/20mL (0.4 mg per mL) is a sterile, nonpyrogenic, isotonic, clear solution of atropine sulfate in water for injection with sodium chloride sufficient to render the solution isotonic. Each mL contains atropine sulfate, 0.4 mg; benzyl alcohol, 9 mg; sodium chloride 9 mg; and may contain sulfuric acid for pH adjustment, pH 3.5 (3.0 to 3.8).

Atropine sulfate injection will be supplied in multidose vials containing 20 mL.

Each vial will only be used to administer a single dose, to a single subject.
Interventions: intervention 1: Atropine Sulfate Ophthalmic Solution intervention 2: Atropine Sulphate Injection
Intervention descriptions: intervention 1: Atropine sulfate ophthalmic solution, USP 1% is a sterile topical anti-muscarinic indicated for cyclopegia, mydriasis, and penalization of the healthy eye in the treatment of amblyopia. Each mL of Atropine Sulfate Ophthalmic Solution USP, 1% contains active ingredient: atropine sulfate 10 mg equivalent to 8.3 mg of atropine. Inactive ingredients include benzalkonium chloride 0.1 mg (0.01%), dibasic sodium phosphate, edetate disodium, hypromellose (2910), monobasic sodium phosphate, hydrochloric acid and/or sodium hydroxide may be added to adjust pH (3.5 to 6.0), and water for injection, USP. intervention 2: Atropine sulfate injection, USP, 8mg/20mL (0.4 mg per mL) is a sterile, nonpyrogenic, isotonic, clear solution of atropine sulfate in water for injection with sodium chloride sufficient to render the solution isotonic. Each mL contains atropine sulfate, 0.4 mg; benzyl alcohol, 9 mg; sodium chloride 9 mg; and may contain sulfuric acid for pH adjustment, pH 3.5 (3.0 to 3.8).

Protocol documents:
Prot_SAP_000.pdf: 
BARDA 
Atropine 
Protocol: BP-C-19010  Version 3.0 
 
21 November 2019 
 
1 
BARDA CLINICAL STUDY PROTOCOL  
A Randomized, Three-Sequence, Three-Period Crossover Study to Assess the 
Bioavailability and Pharmacokinetics of a Single Dose of Atropine Administered 
Sublingually in Healthy Adult Volunteers 
BP-C-19010 
Sponsor: 
Biomedical Advanced Research and Development Authority 
(BARDA) 
 
 
Sponsor Contact: 
  
 
 
 
  
  
  
 
  
 
 
 
 
 
Medical Monitor: 
  
  
 
  
 
 
Version of Protocol:  
 
3.0 
Date of Protocol:  
 
 
November 21, 2019 
CONFIDENTIAL 
All financial and nonfinancial support for this study will be provided by BARDA. The concepts 
and information contained in this document or generated during the study are considered 
proprietary and may not be disclosed in whole or in part without the expressed, written consent 
of BARDA. The study will be conducted according to the Integrated Addendum to International 
Conference on Harmonisation (ICH) E6 (R1): Guideline for Good Clinical Practice (GCP) E6 
(R2). 
 


BARDA 
Atropine 
Protocol: BP-C-19010  Version 3.0 
 
21 November 2019 
 
2 
 
Protocol Approval - Sponsor Signatory 
 
Study Title 
A Randomized, Three-Sequence, Three-Period Crossover Study to 
Assess the Bioavailability and Pharmacokinetics of a Single Dose of 
Atropine Administered Sublingually in Healthy Adult Volunteers 
Short Title 
Sublingual Atropine PK Study 
Protocol Number 
BP-C-19010 
Protocol Version 
Version 3.0 
Protocol Date 
November 21, 2019 
 
 
Protocol accepted and approved by: 
 
 
 
 
Signature  
 
Date 
 
 
 


BARDA 
Atropine 
Protocol: BP-C-19010  Version 3.0 
 
21 November 2019 
 
3 
Investigator’s Agreement 
 
Study Title 
A Randomized, Three-Sequence, Three-Period Crossover Study to 
Assess the Bioavailability and Pharmacokinetics of a Single Dose of 
Atropine Administered Sublingually in Healthy Adult Volunteers 
Short Title  
Sublingual Atropine PK Study 
Protocol Number 
BP-C-19010 
Protocol Version 
Version 3.0 
Protocol Date 
November 21, 2019 
 
I have read and understood all sections of the above referenced protocol, and the provided 
package inserts for atropine sulfate ophthalmic solution, United States Pharmacopeia (USP) 1% 
and atropine sulfate injection for intravenous administration. 
I agree to supervise all aspects of the protocol at my clinical research site and to conduct the 
clinical investigation in accordance with the protocol and the International Conference on 
Harmonisation (ICH) regulations and US Investigational New Drug (IND) regulations in 21 CFR 
312. I will not make changes to the protocol before consulting with BARDA or implement 
protocol changes without institutional review board approval except to eliminate an immediate 
risk to subjects. I agree to administer study treatment only to subjects under my personal 
supervision or the supervision of a subinvestigator. 
I will not supply the study drug to any person not authorized to receive it. Confidentiality will be 
protected. Subject identity will not be disclosed to third parties or appear in any study reports or 
publications. 
I will not disclose information regarding this clinical investigation or publish results of the 
investigation without authorization from BARDA. 
 
 
 
 
 
 
 
 
 
 
 
 
 
Printed Name of Investigator 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Investigator  
 
 
 
 
 
 
 
 
 
 
 
 
Date 
 


BARDA 
Atropine 
Protocol: BP-C-19010  Version 3.0 
 
21 November 2019 
 
4 
Emergency Contact Information 
Table 1: 
Emergency Contact Information 
Role in Study 
Name 
Address and Telephone Number 
Sponsor Contact 
 
 
 
 
 
 
Medical Monitor 
 
 
  
 
 
Principal Investigator 
 
 
 
 
 
 


BARDA 
Atropine 
Protocol: BP-C-19010  Version 3.0 
 
21 November 2019 
 
5 
1. 
SYNOPSIS 
Name of Sponsor/Company: Biomedical Advanced Research and Development Authority 
(BARDA) 
Name of Study Drug:   
Test Drug: Atropine sulfate ophthalmic solution, USP 1% (NDA 206289) for sublingual 
administration  
Reference Drug: Atropine sulfate injection for intravenous (IV) administration (NDA 209260) 
Name of Active Ingredient:  
Atropine sulfate 
Title of Study: A Randomized, Three-Sequence, Three-Period Crossover Study to Assess the 
Bioavailability and Pharmacokinetics of a Single Dose of Atropine Administered Sublingually in 
Healthy Adult Volunteers 
Short Title: Sublingual Atropine PK Study 
Protocol Number: BP-C-19010 
Version Number: 3.0 
Study center(s): 1 (one) 
Study period (years):  
Estimated date first subject enrolled: December 2019 
Estimated date last subject completed: January 2020 
Phase of development: 1 
 
Study Objectives:  
Primary Objective 
• 
To evaluate the bioavailability and pharmacokinetics (PK) of atropine administered 
sublingually against the reference IV route of administration 
Secondary Objectives 
• 
To evaluate the safety of atropine administered sublingually 
• 
To evaluate the tolerability of atropine administered sublingually, as assessed by changes in 
xerostomia 
Methodology:  
This is a randomized, three-sequence, three-period crossover study to assess the bioavailability and 
PK of a single dose of atropine administered sublingually in healthy adult volunteers. At least 
15 healthy male and female volunteers will be enrolled to obtain approximately 12 evaluable subjects 
in the per protocol population. Eligible subjects will be randomized at a 1:1:1 ratio to receive one of 
three treatment dosing sequences (A, B, or C) as depicted in the table below: 
 
 
 
 


BARDA 
Atropine 
Protocol: BP-C-19010  Version 3.0 
 
21 November 2019 
 
6 
Study Design Scheme by Dosing Sequence 
Dosing 
Sequence 
Expected 
Number of 
Evaluable 
Subjects (N) 
Period 1 
(Visit 1; Day 1) 
Period 2 
(Visit 2; Day 8) 
Period 3 
(Visit 3; Day 15) 
A 
4 
Low Dose sublingual 
High Dose sublingual 
IV 
B 
4 
High Dose sublingual IV 
Low Dose sublingual 
C 
4 
IV 
Low Dose sublingual 
High Dose sublingual 
Low Dose sublingual = 0.5 mg (50 µL) of atropine sulfate 1% ophthalmic solution, administered via sublingual 
route; High Dose sublingual = 1.0 mg (100 µL) of atropine sulfate 1% ophthalmic solution, administered via 
sublingual route; IV = 1.0 mg (2.5 mL) of atropine sulfate (0.4 mg/mL) administered via intravenous route  
 
Subjects will be screened for study participation from Days -14 to -1 and enrolled into the study on 
Day 1. On the morning of each treatment day (Visits 1, 2, and 3), subjects will receive a Low Dose 
sublingual, High Dose sublingual, or IV atropine sulfate administration, according to the randomly 
assigned treatment sequence. Blood samples for PK will be collected at time 0 (predose) and at 
13 time points postdose at 2, 4, 6, 10, 15, 20, 30, 45, and 60 minutes, and 2, 4, 6, and 8 hours after 
dosing. Site staff will record subjects’ reports of their subjective xerostomia predose and every 
10 minutes up to the first hour after dosing. Subjects will be discharged from the clinic after the 
8 hour blood sample collection. 
Meal timing, activity levels, and general conditions in the clinical research unit will be as similar as 
possible for all study subjects irrespective of dose and day. 
On the day of atropine administration, each subject:  
1. Will not be allowed food or drink 1 hour prior to drug administration and continuing through 
1 hour after drug administration or until the subject reports a 10 (maximum) on the xerostomia 
assessment or expresses the xerostomia is intolerable, whichever occurs first. After 1 hour or if either 
of these conditions are met, water will be provided ad libitum. 
2. Will be provided a meal/snack no less than 4 hours after drug administration. 
3. Will abstain from alcohol 24 hours before each dosing visit and until the last blood sample from 
each dosing visit is collected. 
4. Will report to site staff their subjective sense of xerostomia predose and every 10 minutes up to the 
first hour after dosing or until maximum/intolerable xerostomia is reached, whichever occurs first, 
based on the questions in Appendix 3.  
5. Will have automated blood pressure and heart rate measurements on the opposite arm from blood 
collection every 10 minutes for the first hour, every 20 minutes for the second hour, and every 
30 minutes for the third and fourth hours and thereafter as deemed clinically necessary by the 
investigator until the end of each visit.   
Blood Sampling  
An indwelling venous catheter will be placed before dose administration for blood sample collection 
for serial determinations at times: 0 (predose) and postdose at 2, 4, 6, 10, 15, 20, 30, 45, and 
60 minutes, and 2, 4, 6, and 8 hours. Ten (10) mL of whole blood will be collected into a sterile 
vacutainer containing ethylenediaminetetraacetic acid (EDTA) as a preservative for each sampling.  
Plasma will be stored frozen for future analysis. For IV atropine administration, serial blood sampling 
will be performed via indwelling catheter on the opposite arm from the one used for dosing; blood 


BARDA 
Atropine 
Protocol: BP-C-19010  Version 3.0 
 
21 November 2019 
 
7 
pressure and heart rate readings will be performed on the arm used for dosing after the IV has been 
removed. 
Number of subjects (planned): Approximately 15 healthy volunteers, with the option to enroll 
additional healthy volunteers, to obtain approximately 12 evaluable subjects (approximately 4 per 
dosing sequence) in the per protocol population. 
Inclusion and Exclusion Criteria 
Subjects will be randomized to study treatment only if they meet all of the applicable inclusion 
criteria and none of the exclusion criteria. In addition, eligibility criteria must be reviewed just prior 
to each dose of atropine unless specified below; if the subject no longer meets applicable eligibility 
criteria, the investigator, in consultation with the Rho medical monitor in cases of uncertainty, must 
determine whether the subject should receive the atropine dose or be terminated early from the study 
drug.  
Deviations from the inclusion and exclusion criteria are not allowed because they can potentially 
jeopardize the scientific integrity of the study or subject safety. Therefore, adherence to the criteria 
specified in the protocol is essential.   
Subject Inclusion Criteria: 
1. Healthy male and nonpregnant female volunteers between the ages of 18 and 55 years at time 
of randomization 
2. Willing and able to provide written informed consent 
3. Females who are of childbearing potential and are sexually active with a male partner must 
have used an acceptable method of birth control for at least 2 months prior to Screening, and 
must agree to continue using an acceptable method of birth control from Screening through 
Follow-up (Day 21) 
a. A female of childbearing potential is defined as a postonset menarche and 
premenopausal female capable of becoming pregnant. This does not include females 
who meet any of the following conditions: menopausal > 2 years, tubal ligation 
> 1 year, bilateral salpingo-oophorectomy, or hysterectomy. 
b. Adequate contraception is defined as a contraceptive method with a failure rate of 
less than 1% per year when used consistently and correctly and when applicable, in 
accordance with the product label. Examples include oral contraceptives, injectable 
progestogen, implants of etonogestrel or levonorgestrel, estrogenic vaginal ring, 
percutaneous contraceptive patches, intrauterine device or intrauterine system, or 
male partner sterilization at least 6 months prior to the female subject’s Screening 
Visit. 
4. In the judgment of the investigator, the subject is in good health, based on review of medical 
history and the results of screening evaluation (including vital signs, physical examination, 
12-lead electrocardiogram [ECG], and routine clinical laboratory testing, performed no more 
than 14 days prior to randomization into the study).  
5. Able to comply with the dosing instructions and available to complete the study Schedule of 
Events (Appendix 2) 
Subject Exclusion Criteria: 
1. Females who have a positive pregnancy test or who are breastfeeding 
2. Subjects with thyroid disease as evidenced by a thyroid-stimulating hormone (TSH) < 0.9 × 
lower limit of normal (LLN) or > 1.2 × upper limit of normal (ULN) at screening. (This test 
will not be repeated prior to subsequent dosing.) 


BARDA 
Atropine 
Protocol: BP-C-19010  Version 3.0 
 
21 November 2019 
 
8 
3. Subjects with aspartate aminotransferase (AST), alanine aminotransferase (ALT), or serum 
creatinine > 1.5 × ULN at screening. (These tests will not be repeated prior to subsequent 
dosing.) 
4. Have known human immunodeficiency virus (HIV), or acute or chronic hepatitis B or 
hepatitis C infection based on medical history; or test positive for any of these at Screening. 
Subjects who have been effectively treated for hepatitis C, as evidenced by a negative 
hepatitis C ribonucleic acid (RNA) confirmation test and who no longer require antiviral 
therapy, are eligible for participation. (Screening tests will not be repeated prior to subsequent 
dosing.)  
5. Subjects who took any prescription medications (with the exception of oral contraceptives or 
hormone replacement therapy) within 30 days of screening. Prior to each dose, the 
investigator will review prohibited medication use and determine whether the subject should 
be terminated from further dosing.  
6. Subjects who took any over-the-counter medication/vitamins/herbal supplements in the last 
72 hours prior to screening. Prior to each dose, the investigator will review prohibited 
medication use and determine whether the subject should be terminated from further dosing.  
7. Subjects with glaucoma and/or history of ocular surgery (including LasikTM), ocular trauma, 
or congenital ocular disorder 
8. Subjects with any history of heart disease, including but not limited to coronary artery 
disease, arrhythmia (treated or untreated), congestive heart failure, pacemaker, history of 
vasovagal syncope, peripheral vascular disease, or claudication 
9. Subjects with clinically significant arrhythmias or abnormal conduction; abnormal 
conduction is defined as a prolonged PR or QRS, or a QTc ≥ 450 msec for males or ≥ 470 
msec for females 
10. Subjects with a history of partial organic pyloric stenosis, chronic constipation, or other 
gastrointestinal motility issues 
11. Subjects with a history of xerostomia due to an underlying disease or previous radiation 
therapy to the head and neck  
12. Males with history of symptomatic prostatic hypertrophy; males or females with a history of 
urinary hesitancy or retention 
13. Subjects with a blood pressure > 140/90 mm Hg taken after the subject has been seated and 
resting for at least five minutes 
14. Subjects with a history or current diagnosis of myasthenia gravis 
15. Subjects with a history of drug or alcohol abuse in the last two years or evidence of a positive 
urine drug test at screening. (This screening test will not be repeated prior to subsequent 
dosing.)  
16. Subjects with a known sensitivity or prior adverse reaction to atropine   
Subjects cannot be rescreened for exclusionary laboratory test results. Potentially exclusionary vital 
sign results may be repeated once. If a subject’s repeat vitals remain exclusionary or the investigator 
determines that the repeat vital signs could pose a risk to the subject participating in the study, then 
the subject will be excluded.  


BARDA 
Atropine 
Protocol: BP-C-19010  Version 3.0 
 
21 November 2019 
 
9 
Concomitant medications: 
Contraceptive medications and estrogen or estrogen/progesterone hormone replacement therapy are 
permitted for female subjects. Nonsteroidal anti-inflammatory drugs and acetaminophen are permitted 
for all subjects. No other concomitant medications are allowed. 
Test drug, dosage and mode of administration:  
Each subject will receive a single dose of 0.5 mg (50 μL) of atropine sulfate 1% ophthalmic solution 
administered via the sublingual route and, on a separate day, a single dose of 1.0 mg (100 μL) of 
atropine sulfate 1% ophthalmic solution administered via the sublingual route. The order of 
administration will be based on the dosing sequence to which the subject is assigned.  
Reference drug, dosage and mode of administration: 
Each subject will receive a single dose of 1.0 mg (2.5 mL) of atropine sulfate (0.4 mg/mL) 
administered via an indwelling IV cannula. The order of administration of this dose relative to the 
sublingual doses will be based on the dosing sequence to which the subject is assigned. 
Duration of treatment: After a Screening period of up to 14 days, each subject will receive 3 doses 
of atropine, each dose separated by a washout period of 6 ± 1 days, and will be followed for 
approximately 6 days after their last dose. The expected study duration is approximately 35 days per 
subject.  
Criteria for evaluation: 
Primary Endpoint 
• 
The relative bioavailability of atropine administered sublingually versus intravenously as 
measured by the following key PK parameters: 
− Area under the analyte concentration versus time curve to infinity (AUC∞) 
− Area under the analyte concentration versus time curve to time of last quantifiable 
data point (AUCt) 
− Maximum measured plasma concentration (Cmax) 
− Time to Cmax (tmax) 
− Apparent terminal elimination half-life (t½) 
− Apparent total body clearance after extravascular administration (CL/F) 
− Apparent total volume of distribution after extravascular administration (Vd/F) 
Secondary Endpoints 
• 
All treatment-emergent adverse events (AEs) and serious adverse events (SAEs) occurring 
during study participation 
• 
Xerostomia assessment (Appendix 3), completed during screening and each day of dosing 
starting at predose, and every 10 minutes postdose up to 1 hour postdose 
Statistical methods: 
This study is descriptive in nature. Bioavailability of the sublingual administration of atropine relative 
to that of IV atropine will be assessed based on ratios of least-squares means of key plasma PK 
parameters and associated 90% confidence intervals (CIs). The PK parameters and baseline subject 
characteristics will be summarized using descriptive statistics. Key PK parameters (e.g., Cmax, AUCt, 
AUC∞, tmax, t½, CL/F, and Vd/F) for plasma concentrations will be compared between the study 
dosages by analysis of variance (ANOVA) including terms for sequence, dose, and period as fixed 


BARDA 
Atropine 
Protocol: BP-C-19010  Version 3.0 
 
21 November 2019 
 
10 
effects, and subject nested within sequence as a random effect in the model. The comparisons of 
interest are: 
        Low Dose sublingual vs IV 
        High Dose sublingual vs IV 
        Low Dose sublingual vs High Dose sublingual 
Safety data will be presented as tabular summaries of AEs and SAEs, and descriptive statistics for 
vital signs. Xerostomia scores will be analyzed descriptively for each of the 3 questions on the 
xerostomia assessment at each timepoint. Additional information on statistical methods will be 
described in the statistical analysis plan for the study.  


BARDA 
Atropine 
Protocol: BP-C-19010  Version 3.0 
 
21 November 2019 
 
11 
TABLE OF CONTENTS  
BARDA CLINICAL STUDY PROTOCOL ...................................................................................1 
Protocol Approval - Sponsor Signatory ...........................................................................................2 
Investigator’s Agreement .................................................................................................................3 
Emergency Contact Information ......................................................................................................4 
1. 
SYNOPSIS ...................................................................................................................5 
TABLE OF CONTENTS ...............................................................................................................11 
LIST OF TABLES .........................................................................................................................14 
LIST OF FIGURES .......................................................................................................................14 
LIST OF ABBREVIATIONS ........................................................................................................15 
2. 
INTRODUCTION ......................................................................................................17 
2.1. 
Background .................................................................................................................17 
2.2. 
Study Rationale ...........................................................................................................17 
2.3. 
Previous Studies..........................................................................................................18 
3. 
STUDY OBJECTIVES ..............................................................................................19 
3.1. 
Primary Objective .......................................................................................................19 
3.2. 
Secondary Objectives .................................................................................................19 
4. 
INVESTIGATIONAL PLAN .....................................................................................20 
4.1. 
Overall Study Design ..................................................................................................20 
4.2. 
Number of Subjects ....................................................................................................21 
4.3. 
Treatment Assignment ................................................................................................21 
4.4. 
Individual Subject Dosing and Study Stopping Rules ................................................22 
4.4.1. 
Early Termination of Dosing for an Individual Subject .............................................22 
4.4.2. 
Study Pausing Rules ...................................................................................................22 
4.5. 
Independent Medical Monitor Review .......................................................................23 
5. 
SELECTION AND WITHDRAWAL OF SUBJECTS ..............................................24 
5.1. 
Selection of Study Population ....................................................................................24 
5.1.1. 
Subject Inclusion Criteria ...........................................................................................24 
5.1.2. 
Subject Exclusion Criteria ..........................................................................................24 
5.2. 
Subject Withdrawal Criteria .......................................................................................26 
5.3. 
Replacements ..............................................................................................................26 
6. 
TREATMENT OF SUBJECTS ..................................................................................27 


BARDA 
Atropine 
Protocol: BP-C-19010  Version 3.0 
 
21 November 2019 
 
12 
6.1. 
Description of Study Drugs ........................................................................................27 
6.1.1. 
Atropine Sulfate Ophthalmic Solution, USP 1% ........................................................27 
6.1.2. 
Atropine Sulfate Injection ...........................................................................................27 
6.2. 
Concomitant Medications ...........................................................................................27 
6.2.1. 
Permitted and Prohibited Concomitant Medications ..................................................28 
6.3. 
Treatment Compliance ................................................................................................28 
7. 
STUDY DRUG MATERIALS AND MANAGEMENT ...........................................29 
7.1. 
Study Drug ..................................................................................................................29 
7.2. 
Study Drug Packaging and Labeling ..........................................................................29 
7.3. 
Study Drug Storage .....................................................................................................29 
7.4. 
Study Drug Preparation and Administration ..............................................................29 
7.5. 
Study Drug Accountability .........................................................................................29 
7.6. 
Study Drug Handling and Disposal ............................................................................30 
7.7. 
Randomization ............................................................................................................30 
7.7.1. 
Randomization ............................................................................................................30 
7.7.2. 
Blinding ......................................................................................................................30 
8. 
STUDY ASSESSMENTS ..........................................................................................31 
8.1. 
Pharmacokinetic Assessments ....................................................................................31 
8.2. 
Xerostomia Assessment ..............................................................................................31 
8.3. 
Safety Assessments .....................................................................................................31 
8.3.1. 
Demographic/Medical History ...................................................................................31 
8.3.2. 
Tobacco/Vaping History .............................................................................................31 
8.3.3. 
Vital Signs ..................................................................................................................32 
8.3.4. 
Height and Weight ......................................................................................................32 
8.3.5. 
Physical Examination .................................................................................................32 
8.3.6. 
Electrocardiogram .......................................................................................................32 
8.3.7. 
Clinical Laboratory Assessments ...............................................................................33 
8.3.7.1. 
Chemistry ....................................................................................................................33 
8.3.7.2. 
Hematology .................................................................................................................33 
8.3.7.3. 
Urine Drug Screen ......................................................................................................33 
8.3.8. 
Pregnancy Screen ........................................................................................................34 
8.3.9. 
Adverse Event Assessment .........................................................................................34 
8.3.10. 
Concomitant Medication Assessment .........................................................................34 


BARDA 
Atropine 
Protocol: BP-C-19010  Version 3.0 
 
21 November 2019 
 
13 
8.4. 
Adverse and Serious Adverse Events .........................................................................34 
8.4.1. 
Definition of Adverse Events .....................................................................................34 
8.4.1.1. 
Adverse Events ...........................................................................................................34 
8.4.1.2. 
Serious Adverse Events ..............................................................................................34 
8.5. 
Collection, Recording, and Grading Severity of Adverse Events ..............................35 
8.5.1. 
Collection of Adverse Events .....................................................................................35 
8.5.2. 
Recording of Adverse Events .....................................................................................35 
8.5.3. 
Grading Severity of Adverse Events ..........................................................................36 
8.6. 
Relationship and Attribution to Study Drug ...............................................................36 
8.7. 
Reporting Safety Events to IRB .................................................................................36 
8.8. 
Reporting of Serious Adverse Events .........................................................................36 
8.9. 
Pregnancy Reporting ..................................................................................................37 
8.10. 
Reporting Other Safety Information ...........................................................................37 
9. 
STATISTICS ..............................................................................................................38 
9.1. 
Endpoints ....................................................................................................................38 
9.1.1. 
Primary Endpoints ......................................................................................................38 
9.1.2. 
Secondary Endpoints ..................................................................................................38 
9.1.3. 
Measures to Minimize Bias ........................................................................................38 
9.1.4. 
Analysis Plan ..............................................................................................................38 
9.1.4.1. 
Analysis Populations ..................................................................................................39 
9.1.4.2. 
Primary Analyses ........................................................................................................39 
9.1.4.3. 
Secondary Analyses ....................................................................................................39 
9.1.4.4. 
Interim Analysis ..........................................................................................................40 
9.1.4.5. 
Final Analysis .............................................................................................................40 
9.1.4.6. 
Exploratory Analyses ..................................................................................................40 
9.2. 
Sample Size Considerations .......................................................................................40 
9.3. 
Statistical Considerations ............................................................................................40 
9.3.1. 
Covariates ...................................................................................................................40 
9.3.2. 
Subgroup Analyses .....................................................................................................40 
9.3.3. 
Missing Data ...............................................................................................................40 
9.4. 
Procedure for Documenting Deviations from the Planned Analyses .........................40 
10. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS.........................................41 
10.1. 
Inspection of Records .................................................................................................41 


BARDA 
Atropine 
Protocol: BP-C-19010  Version 3.0 
 
21 November 2019 
 
14 
10.2. 
Institutional Review Board .........................................................................................41 
11. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................42 
11.1. 
Data Quality Assurance ..............................................................................................42 
11.2. 
Study Monitoring ........................................................................................................43 
11.3. 
Protocol Deviations ....................................................................................................43 
11.3.1. 
Protocol Deviation Definition .....................................................................................43 
11.3.2. 
Reporting and Managing Deviations ..........................................................................43 
12. 
ETHICS ......................................................................................................................44 
12.1. 
Ethics Review .............................................................................................................44 
12.2. 
Ethical Conduct of the Study ......................................................................................44 
12.3. 
Written Informed Consent ..........................................................................................44 
13. 
DATA HANDLING AND RECORDKEEPING .......................................................45 
13.1. 
Confidentiality ............................................................................................................45 
13.2. 
Retention of Records ..................................................................................................45 
14. 
PUBLICATION POLICY ..........................................................................................46 
15. 
REFERENCES ...........................................................................................................47 
APPENDIX 1. PUBLICATION REVIEW OF SUBLINGUAL ADMINISTRATION 
OF ATROPINE ..........................................................................................................48 
APPENDIX 2. SCHEDULE OF EVENTS .................................................................................56 
APPENDIX 3. XEROSTOMIA ASSESSMENT .......................................................................59 
 
LIST OF TABLES 
Table 1: 
Emergency Contact Information ...................................................................................4 
Table 2: 
Study Design Scheme by Dosing Sequence ...............................................................20 
Table 3: 
Complete Blood Count with Differential ...................................................................33 
Table 4: 
Attribution of Adverse Events ....................................................................................36 
 
LIST OF FIGURES 
Figure 1: 
Overall Study Design ..................................................................................................21 
 
  


BARDA 
Atropine 
Protocol: BP-C-19010  Version 3.0 
 
21 November 2019 
 
15 
LIST OF ABBREVIATIONS 
Abbreviation or Specialist 
Term 
Explanation 
AE 
adverse event 
ALT 
alanine aminotransferase 
ASPR 
Assistant Secretary for Preparedness and Response 
AST 
aspartate aminotransferase 
AUC 
area under the analyte concentration versus time curve 
AUC∞  
AUC to infinity 
AUCt 
AUC to time of last quantifiable data point 
BARDA 
Biomedical Advanced Research and Development 
Authority 
BMI 
body mass index 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
CL/F 
apparent total body clearance after extravascular 
administration 
Cmax  
maximum measured plasma concentration 
CNS 
central nervous system 
CTCAE 
Common Terminology Criteria for Adverse Events 
DMP 
Data Management Plan 
eCRF 
electronic case report form 
ECG 
electrocardiogram 
EDTA 
ethylenediaminetetraacetic acid 
ET 
early termination 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HHS 
Department of Health and Human Services 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IRB 
institutional review board 
IV 
intravenous 


BARDA 
Atropine 
Protocol: BP-C-19010  Version 3.0 
 
21 November 2019 
 
16 
Abbreviation or Specialist 
Term 
Explanation 
LLN 
lower limit of normal 
MCM 
medical countermeasure 
MedDRA 
Medical Dictionary for Regulatory Activities 
NA 
nerve agent 
OTC 
over-the-counter 
PK 
pharmacokinetics 
QA 
quality assurance 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SAR 
suspected adverse reaction 
t½  
apparent terminal elimination half-life 
tmax 
time to Cmax 
TSH 
thyroid-stimulating hormone 
ULN 
upper limit of normal 
US 
United States 
USP 
United States Pharmacopeia 
UV 
unscheduled visit 
Vd/F 
apparent total volume of distribution after extravascular 
administration 


BARDA 
Atropine 
Protocol: BP-C-19010  Version 3.0 
 
21 November 2019 
 
17 
2. 
INTRODUCTION 
2.1. 
Background 
The Biomedical Advanced Research and Development Authority (BARDA) is tasked with, 
among other things, promoting and supporting the development of strategic medical 
countermeasures (MCMs) for the United States. Typically, this effort involves supporting novel 
drug development up to FDA approval and inclusion into the Strategic National Stockpile. 
However, in the event of widespread nerve agent (NA) poisoning, predeployed MCMs are likely 
to be inadequate due to limited availability of community caches (Chempack), logistical 
challenges in bringing the resource to the site of treatment, depletion of the resources before all 
patients needing treatment receive it, and expiration or unavailability of approved MCMs and/or 
preferred delivery devices (auto-injectors)1.  
In response to this challenge, the Department of Health and Human Services (HHS) is 
investigating the bioavailability and PK of an alternative (sublingual) route of administration of 
atropine sulfate ophthalmic solution 1% USP, compared to the reference, atropine sulfate 
injection, administered intravenously (IV)2.  
Atropine is an approved drug indicated for temporary blockade of severe or life-threatening 
muscarinic effects, symptomatic bradycardia, and to dilate the pupils to facilitate eye exams. 
Atropine is an antidote for organophosphorus or carbamate chemical warfare agent or pesticide 
poisoning, as well as the treatment of some (muscarinic) mushroom toxicity. Atropine, available 
in multiple dosing forms, is commonly administered by intramuscular injection, IV injection, and 
as ocular drops. The ocular drop formulation is also given off-label sublingually for excessive 
drooling in multiple contexts including: maintenance of perioral hygiene in hospice patients, to 
alleviate hypersalivation caused by certain antipsychotic medications, to manage oral 
secretions/reduce ventilator-associated pneumonia risk in mechanically ventilated patients, and 
for excessive drooling in developmentally disabled children3-6. 
This randomized, three-sequence, three-period, phase 1 study is designed to assess the 
bioavailability and pharmacokinetics (PK) of sublingually administered atropine sulfate 
ophthalmic solution 1% USP (at 0.5 mg and 1.0 mg; test) compared to atropine sulfate injection 
administered IV (1.0 mg; reference). 
2.2. 
Study Rationale 
Nerve agent toxicity requires the rapid administration of antimuscarinic MCMs to mitigate 
life-threatening bronchorrhea and seizures. Rapid administration of centrally acting doses of 
atropine and anticholinergic medications are most effective within 10 minutes of administration. 
Following IV administration of atropine, the heart rate increases within seconds, and the 
antisialagogue and central nervous system (CNS) effects may take a few minutes to achieve 
maximum effect. In contrast, the intramuscular route of atropine administration requires a very 
high dose before central antimuscarinic effects are seen, and the onset of action is delayed. 
Further, stockpiled NA MCM configurations (Chempack), containing drugs administered by 
auto-injector, are insufficient to treat large numbers of NA-poisoned patients in a timely manner. 
Ophthalmic atropine solution is generally available in the community and may provide a rapid, 
available source of effective medication in the event of an emergency. 


BARDA 
Atropine 
Protocol: BP-C-19010  Version 3.0 
 
21 November 2019 
 
18 
Administration of 1% ophthalmic atropine via the sublingual route may be an alternative means 
of delivering a rapid therapeutic dose of atropine to individuals exposed to NA, and in addition 
overcome the stockpile supply deficits identified above.  
The purpose of the current study is to evaluate the bioavailability and PK of atropine sulfate 1% 
ophthalmic solution when administered via the sublingual route at two different dose levels. 
2.3. 
Previous Studies 
BARDA conducted an extensive literature review and identified 110 published English language 
articles involving the administration of atropine by sublingual, nasal, and oral routes. Eighteen 
studies were selected based on their relevance to the proposed clinical study and are summarized 
in Appendix 1. Included among these reports are 6 wherein hyoscyamine, the levo-enantiomer of 
atropine, was the active agent. A total of 470 subjects were exposed to varying doses and 
regimens of sublingual atropine, including the ophthalmic formulation, or hyoscyamine in these 
reports. In several reports, atropine was administered sublingually on a regular regimen versus 
the single dose per timepoint as proposed in this study. No severe adverse reactions were 
reported, and the side effects observed were consistent with known anticholinergic effects 
previously observed with oral or parenteral administration, e.g., dry mouth. In one study of 
children in Brazil with cerebral palsy and drooling, side effects occurred in 4 of 33 (12%) 
patients.  These side effects and their respective frequency were as follows: fever and flush (1), 
irritability (1), flush and irritability (1) and flush and angioedema(1)5. Further characterization of 
these events was not provided.  Norderyd et al. prospectively studied the effect of sublingual 
atropine in children and adolescents 5 through 18 years old with disabilities and excessive 
salivation (n=23). During the course of the study, 1064 person-doses of atropine were 
administered to children without any reported adverse events (AEs)3.   
A study of sublingual injection of atropine is included here since it is a useful evaluation of 
atropine PK, and the atropine dose used was two-fold greater than the 1 mg dose to be used in 
the current study. Rajpal et al. 7 evaluated 9 healthy male volunteers (mean age 20.8 ± 4.7 years, 
mean weight 59.67 ± 4.76 kg) administered a single sublingual injection of 2 mg atropine sulfate 
(in 0.1 mL). Three of the subjects had 99mTc-labeled diethylene triamine pentaacetic acid 
(DTPA) added to their injection to monitor the release rate of atropine sulfate. Within 
10 minutes, 85% of the injected dose was released from the sublingual site of injection. This 
compared to only 24% released at 10 minutes from one subject who received intramuscular 
atropine. The remaining six subjects underwent blood sampling for PK and clinical monitoring 
for signs of atropinization (heart rate, pupil diameter, and mouth dryness). The peak serum 
concentration of sublingual atropine was 20 ng/mL at 15 minutes compared to peak serum 
concentrations of 6 to 8 ng/mL at 30 minutes following intramuscular administration. All 
volunteers who received atropine by sublingual injection showed signs of atropinization by 
10 minutes with peak intensity at 30 minutes, and persistence of symptoms for nearly 
60 minutes. The authors concluded that atropine administered by sublingual injection achieves 
clinically important serum levels more rapidly than by intramuscular administration. Adverse 
events were not reported in this trial. 
Based on the reported experience to date, the administration of atropine via the sublingual route 
appears to have an acceptable safety profile and does not significantly increase the risk 
associated with the use of the drug product as proposed. 


BARDA 
Atropine 
Protocol: BP-C-19010  Version 3.0 
 
21 November 2019 
 
19 
3. 
STUDY OBJECTIVES  
3.1. 
Primary Objective 
• To evaluate the bioavailability and PK of atropine administered sublingually against 
the reference intravenous route of administration 
3.2. 
Secondary Objectives 
• To evaluate the safety of atropine administered sublingually 
• To evaluate the tolerability of atropine administered sublingually, as assessed by 
changes in xerostomia 
 
 


BARDA 
Atropine 
Protocol: BP-C-19010  Version 3.0 
 
21 November 2019 
 
20 
4. 
INVESTIGATIONAL PLAN 
4.1. 
Overall Study Design 
This is a randomized, three-sequence, three-period crossover study to assess the bioavailability 
and PK of a single dose of atropine administered sublingually in healthy adult volunteers. At 
least 15 healthy male and female volunteers will be enrolled to obtain approximately 
12 evaluable subjects in the per protocol population. Eligible subjects will be randomized at a 
1:1:1 ratio to receive one of three dosing sequences (A, B, or C) as depicted in Table 2. 
Table 2: 
Study Design Scheme by Dosing Sequence 
Dosing 
Sequence 
Expected 
Number of 
Evaluable 
Subjects (N) 
Period 1 
(Visit 1; Day 1) 
Period 2 
(Visit 2; Day 8) 
Period 3 
(Visit 3; Day 15) 
A 
4 
Low Dose sublingual 
High Dose sublingual 
IV 
B 
4 
High Dose sublingual 
IV 
Low Dose sublingual 
C 
4 
IV 
Low Dose sublingual 
High Dose sublingual 
Low Dose sublingual = 0.5 mg (50 µL) of atropine sulfate 1% ophthalmic solution, administered via sublingual 
route; High Dose sublingual = 1.0 mg (100 µL) of atropine sulfate 1% ophthalmic solution, administered via 
sublingual route; IV = 1.0 mg (2.5 mL) of atropine sulfate (0.4 mg/mL) administered via intravenous route 
Figure 1 presents a diagram of the overall study design. After screening, subjects meeting all of 
the inclusion criteria and none of the exclusion criteria will be randomized to one of three dosing 
sequences as presented in Table 2. Once randomized, each subject will receive 3 doses of 
atropine according to their assigned dosing sequence. Each dose will be separated by a washout 
period of 6 ± 1 days. Blood samples for measurement of atropine plasma concentrations and to 
determine PK parameters will be collected during each dosing visit at the following time points: 
time 0 (predose), and postdose at 2, 4, 6, 10, 15, 20, 30, 45, and 60 minutes, and 2, 4, 6, and 
8 hours. Site staff will record subjects’ reports of their subjective xerostomia predose and every 
10 minutes up to the first hour after dosing. Subjects will be discharged from the clinic after the 
8 hour blood sample collection. Subjects will be followed for approximately 6 days after their 
last dose.  
On the day of atropine administration, each subject:  
1. Will not be allowed food or drink 1 hour prior to drug administration and continuing 
through 1 hour after drug administration or until the subject reports a 10 (maximum) on 
the xerostomia assessment or expresses the xerostomia is intolerable, whichever occurs 
first. After 1 hour or if either of these conditions are met, water will be provided ad 
libitum. 
2. Will be provided a meal/snack no less than 4 hours after drug administration. 
3. Will abstain from alcohol 24 hours before each dosing visit and until the last blood 
sample from each dosing visit is collected.  


BARDA 
Atropine 
Protocol: BP-C-19010  Version 3.0 
 
21 November 2019 
 
21 
4. Will report to site staff their subjective sense of xerostomia  every 10 minutes up to the 
first hour after dosing or until maximum/intolerable xerostomia is reached, whichever 
occurs first, based on the questions in Appendix 3. 
5. Will have automated blood pressure and heart rate measurements recorded on the 
opposite arm from blood collection every 10 minutes for the first hour, every 20 minutes 
for the second hour, and every 30 minutes for the third and fourth hours and thereafter as 
deemed clinically necessary by the investigator until the end of each visit. 
Meal timing, activity levels, and general conditions in the clinical research unit will be as similar 
as possible for all study subjects irrespective of dose and day. 
Safety will be assessed by interval medical history and physical examinations, vital signs, and 
standard 12-lead electrocardiograms (ECGs) as outlined in the Schedule of Events (Appendix 2).   
The expected study duration is approximately 35 days per subject.  
Figure 1: 
Overall Study Design 
 
Low Dose sublingual = 0.5 mg (50 µL) of atropine sulfate 1% ophthalmic solution, administered via sublingual 
route; High Dose sublingual = 1.0 mg (100 µL) of atropine sulfate 1% ophthalmic solution, administered via 
sublingual route; IV = 1.0 mg (2.5 mL) of atropine sulfate (0.4 mg/mL) administered via intravenous route 
4.2. 
Number of Subjects 
The proposed enrollment for this study is approximately 15 subjects in stable health, aged 
18 through 55 years, inclusive (Section 5.1). Additional subjects may be enrolled to obtain 
approximately 12 evaluable subjects (approximately 4 per dosing sequence) in the per protocol 
population.  
4.3. 
Treatment Assignment 
Each subject will receive 3 doses of atropine according to their assigned dosing sequence: one 
low dose sublingually, one high dose sublingually, and one dose IV. Each dose will be separated 
by 7 ± 1 days. Subjects will be randomized 1:1:1 across 3 dosing sequences (approximately 


BARDA 
Atropine 
Protocol: BP-C-19010  Version 3.0 
 
21 November 2019 
 
22 
5 subjects per dosing sequence) to achieve approximately the expected number of evaluable 
subjects (12) in the per protocol population as specified in Table 2. 
4.4. 
Individual Subject Dosing and Study Stopping Rules 
4.4.1. 
Early Termination of Dosing for an Individual Subject  
If a subject is confirmed pregnant, she will not receive further dosing of the study drug. 
If a subject meets one or more of the criteria below, then the subject’s dosing will be paused until 
the investigator has discussed the subject with the Rho medical monitor and the BARDA 
Pharmacovigilance Subject Matter Expert:  
• Subject experiences any Grade 3 or higher AE (Common Terminology Criteria for 
Adverse Events [CTCAE] v 5.0) 8 that, in the opinion of the investigator, is at least 
possibly related to the study drug.  
• Subject experiences an AE that, in the opinion of the investigator, makes further 
dosing inadvisable because the AE causes functional impairment or because the AE 
requires a medical intervention or observation for safety.  
• Subject no longer meets eligibility criteria in such a way that, in the judgment of the 
investigator, the safety of the subject may be compromised by continued participation 
or interpretation of the subject’s subsequent study data are likely to be significantly 
compromised. 
Once a subject has been reviewed by the Rho medical monitor and the BARDA 
Pharmacovigilance Subject Matter Expert, they will recommend to either (1) continue dosing per 
the protocol or (2) discontinue further dosing of the subject.  In cases of uncertainty, Rho and 
BARDA can also request the input of the independent medical monitor.   
Subjects who do not complete all study drug doses for any reason will continue to be followed 
for safety for six days following the last dose.   
The reason for early discontinuation of dosing will be captured in the electronic case report form 
(eCRF).   
4.4.2. 
Study Pausing Rules 
If the following criterion is met, further dosing of all subjects will be paused.  
• Two or more subjects experience a grade 3 AE in the same Medical Dictionary for 
Regulatory Activities (MedDRA) system organ class deemed at least possibly related to 
the study drug by the investigator, BARDA, or Rho medical monitor. 
At that time, the Rho medical monitor, the independent medical monitor, and the BARDA 
Pharmacovigilance Subject Matter Expert will convene to discuss and review these cases. After 
this review, it may be decided to either continue to pause dosing pending review of additional 
data, resume dosing as specified in the protocol, modify the study, or terminate the study. If the 
individuals designated above cannot come to agreement, the independent medical monitor will 
make the final decision. The clinical principal investigator may be present at these meetings to 
provide additional information but will not vote on the final decision. 


BARDA 
Atropine 
Protocol: BP-C-19010  Version 3.0 
 
21 November 2019 
 
23 
BARDA retains the right to suspend, modify, or end the study at any time. In case of premature 
termination or suspension and safety review of the study, Rho will promptly inform the 
investigator of the termination or suspension of the study and the reason for termination or 
suspension, and the clinical site will inform the institutional review board (IRB).  
4.5. 
Independent Medical Monitor Review 
An independent medical monitor will review the protocol, adjudicate individual stopping and 
study pausing rules if they occur, and provide guidance regarding subject safety, trial conduct, 
and data integrity as requested by Rho and/or BARDA. The independent medical monitor will 
perform these functions while protecting the integrity and confidentiality of the trial data. 


BARDA 
Atropine 
Protocol: BP-C-19010  Version 3.0 
 
21 November 2019 
 
24 
5. 
SELECTION AND WITHDRAWAL OF SUBJECTS 
5.1. 
Selection of Study Population 
Subjects will be randomized to study treatment only if they meet all of the applicable inclusion 
criteria and none of the exclusion criteria. In addition, eligibility criteria must be reviewed just 
prior to each dose of atropine unless specified below; if the subject no longer meets applicable 
eligibility criteria, the investigator, in consultation with the Rho medical monitor in cases of 
uncertainty, must determine whether the subject should receive the atropine dose or be 
terminated early from study drug.  
Deviations from the inclusion and exclusion criteria are not allowed because they can potentially 
jeopardize the scientific integrity of the study or subject safety. Therefore, adherence to the 
criteria specified in the protocol is essential.   
5.1.1. 
Subject Inclusion Criteria 
1. Healthy male and nonpregnant female volunteers between the ages of 18 and 55 years at 
time of randomization 
2. Willing and able to provide written informed consent 
3. Females who are of childbearing potential and are sexually active with a male partner 
must have used an acceptable method of birth control for at least 2 months prior to 
Screening, and must agree to continue using an acceptable method of birth control from 
Screening to Follow-up (Day 21) 
A female of childbearing potential is defined as postonset menarche and premenopausal 
female capable of becoming pregnant. This does not include females who meet any of 
the following conditions: menopausal > 2 years, tubal ligation > 1 year, bilateral 
salpingo-oophorectomy, or hysterectomy 
Adequate contraception is defined as a contraceptive method with a failure rate of less 
than 1% per year when used consistently and correctly and when applicable, in 
accordance with the product label. Examples include oral contraceptives, injectable 
progestogen, implants of etonogestrel or levonorgestrel, estrogenic vaginal ring, 
percutaneous contraceptive patches, intrauterine device or intrauterine system, or 
male partner sterilization at least 6 months prior to the female subject’s Screening 
Visit 
4. In the judgment of the investigator, the subject is in good health, based on review of 
medical history and the results of screening evaluation (including vital signs, physical 
examination, 12-lead ECG, and routine clinical laboratory testing, performed no more 
than 14 days prior to randomization into the study) 
5. Able to comply with the dosing instructions and available to complete the study Schedule 
of Events (Appendix 2) 
5.1.2. 
Subject Exclusion Criteria 
1. Females who have a positive pregnancy test or who are breastfeeding 


BARDA 
Atropine 
Protocol: BP-C-19010  Version 3.0 
 
21 November 2019 
 
25 
2. Subjects with thyroid disease as evidenced by a thyroid-stimulating hormone (TSH) 
< 0.9 × lower limit of normal (LLN) or > 1.2 × upper limit of normal (ULN) at screening. 
(This test will not be repeated prior to subsequent dosing.) 
3. Subjects with aspartate aminotransferase (AST), alanine aminotransferase (ALT), or 
serum creatinine > 1.5 × ULN at screening. (These tests will not be repeated prior to 
subsequent dosing.) 
4. Have known human immunodeficiency virus (HIV), or acute or chronic hepatitis B or 
hepatitis C infection based on medical history; or test positive for any of these at 
Screening. Subjects who have been effectively treated for hepatitis C, as evidenced by a 
negative hepatitis C ribonucleic acid (RNA) confirmation test and who no longer require 
antiviral therapy, are eligible for participation. (Screening tests will not be repeated prior 
to subsequent dosing.)  
5. Subjects who took any prescription medications (with the exception of oral 
contraceptives or hormone replacement therapy) within 30 days of screening. Prior to 
each dose, the investigator will review prohibited medication use and determine whether 
the subject should be terminated from further dosing.  
6. Subjects who took any over-the-counter medication/vitamins/herbal supplements in the 
last 72 hours prior to screening. Prior to each dose, the investigator will review prohibited 
medication use and determine whether the subject should be terminated from further 
dosing.  
7. Subjects with glaucoma and/or history of ocular surgery (including LasikTM), ocular 
trauma, or congenital ocular disorder 
8. Subjects with any history of heart disease including but not limited to coronary artery 
disease, arrhythmia (treated or untreated), congestive heart failure, pacemaker, history of 
vasovagal syncope, peripheral vascular disease, or claudication 
9. Subjects with clinically significant arrhythmias or abnormal conduction; abnormal 
conduction is defined as a prolonged PR or QRS, or a QTc ≥ 450 msec for males or 
≥ 470 msec for females 
10. Subjects with a history of partial organic pyloric stenosis, chronic constipation, or other 
gastrointestinal motility issue 
11. Subjects with a history of xerostomia due to an underlying disease or previous radiation 
therapy to the head and neck  
12. Males with history of symptomatic prostatic hypertrophy; males or females with a history 
of hesitancy or retention 
13. Subjects with a blood pressure > 140/90 mm Hg taken after the subject has been seated 
and resting for at least five minutes  
14. Subjects with a history or current diagnosis of myasthenia gravis  
15. Subjects with a history of drug or alcohol abuse in the last two years or evidence of a 
positive urine drug test at screening.  (This screening test will not be repeated prior to 
subsequent dosing.) 


BARDA 
Atropine 
Protocol: BP-C-19010  Version 3.0 
 
21 November 2019 
 
26 
16. Subjects with a known sensitivity or prior adverse reaction to atropine   
Subjects cannot be rescreened for exclusionary laboratory test results. Potentially exclusionary 
vital sign results may be repeated once. If a subject’s repeat vitals remain exclusionary or the 
investigator determines that the repeat vital signs could pose a risk to the subject participating in 
the study, then the subject will be excluded.  
5.2. 
Subject Withdrawal Criteria 
Every subject has the right to refuse participation in the study (i.e., withdraw consent) at any 
time without providing any reason for withdrawal. A subject’s participation must be 
discontinued immediately upon his/her request, and the reason(s) for discontinuation will be 
documented accordingly in the corresponding eCRF.  
Any subject who meets 1 or more of the following criteria will be removed from the study: 
• Subject request 
• Subject noncompliance, defined as refusal or inability to adhere to the study protocol 
or any other instances determined by the investigator or BARDA 
• Subject lost to follow-up 
• Investigator no longer believes participation is in the best interest of the subject 
• At request of BARDA  
• At request of the IRB. 
For any subject who is withdrawn prior to completion of the Follow-up (Day 21) Visit, the Early 
Termination (ET) Visit assessments will be performed as outlined in the Schedule of Events 
(Appendix 2), when possible. The ET Visit may be conducted in clinic or by phone as 
determined by the investigator. Applicable eCRFs will be completed for each ET. 
5.3. 
Replacements 
If a subject is randomized but does not receive the first dose of study drug, the subject will be 
withdrawn and will not be counted toward the total enrollment goal. Subjects who withdraw 
before receipt of the first dose of study drug will be replaced.  
If a subject is withdrawn from the clinical study after receipt of the first dose of study drug and 
prior to completing the third dose of study drug, the subject will be removed from the per 
protocol population. Additional subjects may be randomized to achieve the target number of 
evaluable subjects within the per protocol analysis population. 


BARDA 
Atropine 
Protocol: BP-C-19010  Version 3.0 
 
21 November 2019 
 
27 
6. 
TREATMENT OF SUBJECTS 
6.1. 
Description of Study Drugs 
6.1.1. 
Atropine Sulfate Ophthalmic Solution, USP 1% 
Atropine sulfate ophthalmic solution, USP 1% manufactured by AKORN LABORATORIES, 
INC, is a sterile topical anti-muscarinic indicated for cyclopegia, mydriasis, and penalization of 
the healthy eye in the treatment of amblyopia.  Each mL of Atropine Sulfate Ophthalmic 
Solution USP, 1% contains active ingredient: atropine sulfate 10 mg equivalent to 8.3 mg of 
atropine.  Inactive ingredients include benzalkonium chloride 0.1 mg (0.01%), dibasic sodium 
phosphate, edetate disodium, hypromellose (2910), monobasic sodium phosphate, hydrochloric 
acid and/or sodium hydroxide may be added to adjust pH (3.5 to 6.0), and water for injection, 
USP. 
Atropine Sulfate Ophthalmic Solution, USP 1% will be supplied in dropper bottles containing 2 
mL. Each bottle will only be used to administer a single dose, to a single subject.   
6.1.2. 
Atropine Sulfate Injection  
Atropine sulfate injection is indicated for temporary blockade of severe or life-threatening 
muscarinic effects, e.g., as an antisialagogue, an antivagal agent, an antidote for 
organophosphorus, carbamate, or muscarinic mushroom poisoning, and to treat symptomatic 
bradycardia.  
Atropine sulfate injection, USP,8mg/20mL (0.4 mg per mL) manufactured by Fresenius Kabi 
USA, LLC is a sterile, nonpyrogenic, isotonic, clear solution of atropine sulfate in water for 
injection with sodium chloride sufficient to render the solution isotonic. Each mL contains 
atropine sulfate, 0.4 mg; benzyl alcohol, 9 mg; sodium chloride 9 mg; and may contain sulfuric 
acid for pH adjustment, pH 3.5 (3.0 to 3.8). 
Atropine sulfate injection will be supplied in multidose vials containing 20 mL. Each vial will 
only be used to administer a single dose, to a single subject. 
6.2. 
Concomitant Medications 
Any treatment, including all prescription drugs, herbal products, vitamins, minerals, and 
over-the-counter (OTC) medications, administered from the time of consent through the end of 
study participation is considered a concomitant medication. Concomitant medication use will be 
recorded in the eCRF and will include the medication name, dose, frequency, route of 
administration, and the dates of administration. All concomitant medications used by the subject 
from the time of consent until the Follow-up (Day 21) Visit will be recorded in the subject’s 
eCRF. Any changes or additions to concomitant medications throughout the course of the 
subject’s participation in the study will be recorded in the subject’s eCRF.  
If a subject is discovered to be using a prohibited concomitant medication after he or she is 
enrolled in the study, the investigator, in consultation with the Rho medical monitor in cases of 
uncertainty, should determine the impact on the subject’s participation. All instances of use of 
prohibited concomitant medications must be documented on the appropriate eCRFs. 


BARDA 
Atropine 
Protocol: BP-C-19010  Version 3.0 
 
21 November 2019 
 
28 
6.2.1. 
Permitted and Prohibited Concomitant Medications 
Contraceptive medications and estrogen or estrogen/progesterone hormone replacement therapy 
are permitted for female subjects. Nonsteroidal anti-inflammatory drugs and acetaminophen are 
permitted for all subjects. No other concomitant medications are allowed. 
6.3. 
Treatment Compliance 
The study drug will be administered by an unblinded study staff member and thus is an observed 
compliance. Subject compliance will be determined by the number and percentage of subjects 
who receive study drug at Visits 1, 2, and 3 by dosing sequence. Any deviations from the dosing 
schedule outside the defined visit windows (Appendix 2) must be approved by BARDA and will 
be recorded on the appropriate eCRF.  


BARDA 
Atropine 
Protocol: BP-C-19010  Version 3.0 
 
21 November 2019 
 
29 
7. 
STUDY DRUG MATERIALS AND MANAGEMENT 
7.1. 
Study Drug 
Refer to Section 6.1 for detailed information regarding the atropine sulfate ophthalmic, USP 1% 
and the atropine sulfate injection. 
7.2. 
Study Drug Packaging and Labeling 
Study drug will be packaged and labeled according to applicable local and regulatory 
requirements.   
7.3. 
Study Drug Storage 
Study drug must be stored in a secure area (e.g., a locked room or locked cabinet), and protected 
from light and moisture. Atropine sulfate ophthalmic, USP 1% and atropine sulfate injection 
should be kept at controlled room temperature between 20° to 25°C (68° to 77°F), inclusive. The 
temperature of the storage unit must be monitored and documentation of proper storage must be 
maintained.   
7.4. 
Study Drug Preparation and Administration 
Because atropine sulfate ophthalmic, USP 1% and atropine sulfate injection are distinguishable 
visually and by route of administration, unblinded study staff will be responsible for preparing 
and administering study drug.   
Study drug will be visually inspected for particulate matter and discoloration prior to 
administration, whenever solution and container permit; it should not be administered if either 
condition exists. Study drug will not be administered if the seal is not intact immediately prior to 
dosing. Each bottle/vial of atropine will only be used to administer a single dose. After initial 
use, the used bottles/vials should be maintained in a separate location from the unused 
bottles/vials until drug accountability has been reconciled. Study drug will not be destroyed until 
authorized in writing by BARDA. 
Atropine sulfate ophthalmic, USP 1% will be administered sublingually. For low dose (0.5 mg) 
sublingual treatment, 50 µL of atropine sulfate ophthalmic, USP 1% will be administered via the 
sublingual route. For high dose (1.0 mg) sublingual treatment, 100 µL of atropine sulfate 
ophthalmic, USP 1% will be administered via the sublingual route. Before administration of 
sublingual atropine, subjects will be asked to swallow. Following administration, subjects will be 
instructed to attempt not to swallow for 30 seconds and thereafter swallow as they normally 
would. 
For intravenous administration (1.0 mg), 2.5 mL of atropine sulfate injection (0.4 mg/mL) will 
be administered via an indwelling IV cannula. 
7.5. 
Study Drug Accountability 
The investigator is required to maintain adequate records of the disposition of the study drug, 
including the date and quantity of drug received, to whom the drug was dispensed (subject-by-
subject accounting), and a detailed accounting of any drug accidentally or deliberately destroyed. 


BARDA 
Atropine 
Protocol: BP-C-19010  Version 3.0 
 
21 November 2019 
 
30 
Records for receipt, storage, use, and disposition will be maintained by the study site. A study 
drug dispensing log will be kept current and will include identification of each subject and the 
date and quantity of study drug dispensed. All records regarding the disposition of the study 
product will be available for inspection by the study monitor and BARDA. 
7.6. 
Study Drug Handling and Disposal 
After dosing has been completed, to satisfy regulatory requirements regarding accountability, all 
study drug will be reconciled and destroyed according to applicable regulations. Study drug will 
not be destroyed until authorized in writing by BARDA. 
7.7. 
Randomization 
7.7.1. 
Randomization 
Subjects 18 through 55 years of age will be randomized 1:1:1 to receive one of three dosing 
sequences (A, B, or C) as specified in Table 2. The randomization schedule will be generated by 
the statistical team at Rho using SAS. Due to the low randomization counts, randomization will 
not be stratified. 
7.7.2. 
Blinding 
This study is not blinded.  


BARDA 
Atropine 
Protocol: BP-C-19010  Version 3.0 
 
21 November 2019 
 
31 
8. 
STUDY ASSESSMENTS 
8.1. 
Pharmacokinetic Assessments 
Blood samples will be collected from each subject for PK assessments by a designated, qualified 
individual from the study research team. An indwelling venous catheter will be placed before 
dose administration for blood sample collection for serial determinations at the following times: 
0 (predose) and postdose at 2, 4, 6, 10, 15, 20, 30, 45, and 60 minutes, and 2, 4, 6, and 8 hours. 
For IV atropine administration, serial blood sampling will be performed via indwelling catheter 
on the opposite arm from the one used for dosing. Ten (10) mL of whole blood will be collected 
into a sterile vacutainer containing ethylenediaminetetraacetic acid (EDTA) as a preservative for 
each sampling. Plasma will be stored frozen until analysis.  
Pharmacokinetic samples will be analyzed by a bioanalytical facility approved by BARDA.   
8.2. 
Xerostomia Assessment 
Subjects will be assessed for xerostomia as described in Appendix 3. Subjects will be asked 3 
xerostomia assessment questions predose and after each dose of atropine. Subjects will be asked 
to rate xerostomia postdose every 10 minutes until one hour has passed, or the subject scores a 
10 on one or more of the xerostomia questions, or reports intolerable xerostomia, whichever 
occurs first. 
8.3. 
Safety Assessments 
Safety will be evaluated utilizing the assessments defined in this section. Subjects may 
experience AEs that necessitate an Unscheduled Visit (UV). There may also be situations in 
which the investigator asks a subject to report for a UV following the report of an AE. Additional 
assessments may be conducted at these visits as necessary to ensure the safety and well-being of 
subjects during the study (Appendix 2). If deemed clinically necessary, additional safety 
assessments not currently specified in the protocol may be performed at the discretion of the 
investigator in consultation with the Rho medical monitor and BARDA. Applicable eCRFs will 
be completed for each UV.   
8.3.1. 
Demographic/Medical History 
In order to define a baseline for potential AEs, the demographics and medical history of each 
subject will be collected at the Screening Visit and recorded on the appropriate eCRFs. Updated 
medical history will be collected at Visit 1 (Day 1 Predose), Visit 2 (Day 8 Predose), Visit 3 
(Day 15 Predose), UV, and ET Visits. 
8.3.2. 
Tobacco/Vaping History 
In order to qualify responses to the xerostomia questionnaire, it will be important to know 
whether subjects have ever used tobacco products or vaped. At Screening, Visit 1 (Day 1 
Predose), Visit 2 (Day 8 Predose), Visit 3 (Day 15 Predose), UV, and ET Visits, subjects will be 
asked whether they currently use or have ever used tobacco and whether they currently vape or 
have ever vaped. Subjects currently using tobacco or vaping will be asked when they last used 
tobacco or vaped. Subjects will also be asked additional questions regarding the type, frequency, 


BARDA 
Atropine 
Protocol: BP-C-19010  Version 3.0 
 
21 November 2019 
 
32 
and duration of tobacco use well as the frequency and duration of vaping. Responses will be 
recorded in the eCRF.    
8.3.3. 
Vital Signs 
Vital sign measurements, including oral temperature, heart rate, respiratory rate, and diastolic 
and systolic blood pressure (after the subject is seated for at least 5 minutes), will be collected at 
Screening, Visit 1 (Day 1 Predose), Visit 2 (Day 8 Predose), and Visit 3 (Day 15 Predose) prior 
to any blood draws. Postdose automated blood pressure and heart rate measurements will be 
recorded on the opposite arm from blood collection every 10 minutes for the first hour, every 20 
minutes for the second hour, and every 30 minutes for the third and fourth hours and thereafter as 
deemed clinically necessary by the investigator until the end of each visit. Vital signs may be 
repeated at UV or ET Visits per the investigator’s discretion. Vital signs will be recorded on the 
appropriate eCRF. 
Respiratory rate, if regular, may be assessed over 30 seconds and doubled, but in no case will it 
be assessed over a period of less than 30 seconds. If the respiratory rate is irregular, it will be 
assessed over 60 seconds.  
8.3.4. 
Height and Weight 
Subject’s height and weight will be taken and body mass index (BMI) calculated at the 
Screening Visit and recorded on the appropriate eCRF. Subject’s weight will be taken again at 
Visit 1 (Day 1 Predose), Visit 2 (Day 8 Predose), and Visit 3 (Day 15 Predose). Weight may be 
measured at UV and ET Visits per the investigator’s discretion. Measurements will be recorded 
on the appropriate eCRF.  
8.3.5. 
Physical Examination 
A physical examination will be performed at the Screening Visit to assess and confirm 
eligibility. The examination will include a general assessment of the skin, head, ears, eyes, nose, 
throat, neck, thyroid, lungs, heart, abdomen, lymph nodes, and musculoskeletal 
system/extremities, and a neurological (cranial nerve examination, including pupillary diameter, 
eye movements, and deep tendon reflexes) examination; the results will be recorded on the 
appropriate eCRF. A symptom-based physical examination may be performed at dosing visits, 
UV, or ET Visits per the investigator’s discretion.  
8.3.6. 
Electrocardiogram  
A standard 12-lead ECG will be recorded and assessed at the Screening Visit and results 
recorded on the appropriate eCRF. Additionally, an ECG will be performed within 5 minutes 
after IV atropine administration has been completed and repeated as needed at the investigator’s 
discretion during that visit. ECGs may also be performed at UV or ET Visits per the 
investigator’s discretion. ECGs will be reviewed by a medically qualified individual to verify 
whether any abnormalities are clinically significant. In general, clinically significant abnormal 
ECGs are expected to be associated with an item recorded in the subject’s medical history (when 
detected at Screening) or as an AE (when detected after Screening).    


BARDA 
Atropine 
Protocol: BP-C-19010  Version 3.0 
 
21 November 2019 
 
33 
8.3.7. 
Clinical Laboratory Assessments 
Venous blood will be collected for routine clinical laboratory safety evaluations at Screening. 
Clinical laboratory assessments may be repeated at UV and ET Visits as clinically indicated per 
the investigator’s discretion. Urine will be collected at the Screening Visit for a drug screen. 
Sample collection information will be entered on the appropriate eCRFs. Samples will be 
shipped to the central laboratory for analysis. The details for sample handling, processing, and 
shipping will be provided in the Laboratory Manual. 
Individual results will be sent to the clinical site, and the investigator will perform a clinical 
assessment of all laboratory safety data to assess eligibility and identify and document AEs as 
applicable. All results will be transferred electronically directly from the central laboratory to the 
clinical site and Rho using standard secure data transfer procedures. 
The clinical laboratory assessments planned for this study include chemistry, hematology, and a 
urine drug screen as follows: 
8.3.7.1. 
Chemistry 
• ALT 
• AST 
• blood urea nitrogen 
• alkaline phosphatase 
• total carbon dioxide 
• creatinine 
• glucose, random, serum 
• direct bilirubin 
• total bilirubin (fractionated for 
values for total bilirubin > ULN) 
• sodium 
• potassium 
• chloride 
8.3.7.2. 
Hematology  
Table 3 lists the parameters of the complete blood count with differential. 
Table 3: 
Complete Blood Count with Differential 
Red blood cells 
White blood cells 
 
Hematocrit 
 
Basophils (% and absolute count) 
 
Hemoglobin 
 
Eosinophils (% and absolute count) 
 
Red blood cell count 
 
Lymphocytes (% and absolute count) 
Platelets 
 
Monocytes (% and absolute count) 
 
Platelet count 
 
Neutrophils (% and absolute count) 
 
 
White blood cell count 
8.3.7.3. 
Urine Drug Screen 
The urine drug screen includes tests for amphetamines, cocaine, tetrahydrocannabinol, 
methylenedioxymethamphetamine, and opiates. 


BARDA 
Atropine 
Protocol: BP-C-19010  Version 3.0 
 
21 November 2019 
 
34 
8.3.8. 
Pregnancy Screen 
At the Screening Visit, blood will be collected for a serum pregnancy test for female subjects of 
childbearing potential. At Visit 1 (Day 1 Predose), Visit 2 (Day 8 Predose), and Visit 3 (Day 15 
Predose), a urine dipstick pregnancy test will be performed onsite for female subjects of 
childbearing potential.   
Additionally, a urine dipstick pregnancy test will be performed at any time during study 
participation if pregnancy is suspected.   
8.3.9. 
Adverse Event Assessment 
Site staff will ask nonleading questions regarding the subject’s health status (Section 8.5.1) and 
document any new or changed AEs on the appropriate eCRF.   
8.3.10. 
Concomitant Medication Assessment 
Site staff will review concomitant medications (Section 6.2) and document any new or changed 
medications on the appropriate eCRF.  
8.4. 
Adverse and Serious Adverse Events  
8.4.1. 
Definition of Adverse Events 
8.4.1.1. 
Adverse Events 
An AE is any untoward medical occurrence associated with the use of a drug in humans, whether 
or not it is considered drug related [21 Code of Federal Regulations (CFR) 312.32(a)].  An AE 
can therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of a medicinal (investigational) 
product, whether or not related to the medicinal (investigational) product (Integrated Addendum 
to International Conference on Harmonisation [ICH] E6[R1]: Guideline for Good Clinical 
Practice [GCP] E6[R2]). 
Laboratory results and vital sign excursions of any magnitude will be defined as AEs if they are 
considered clinically significant by the investigator.   
Xerostomia will not be considered an AE for this protocol.  
Suspected adverse reaction (SAR) means any AE for which there is a reasonable possibility that 
the drug caused the AE. For the purposes of safety reporting, “reasonable possibility” means 
there is evidence to suggest a causal relationship between the drug and the AE. An SAR implies 
a lesser degree of certainty about causality than adverse reaction, which means any AE caused by 
a drug [21 CFR 312.32(a)]. 
An AE or SAR is considered “unexpected” if it is not listed in the package inserts for the study 
drugs or is not listed at the specificity or severity that has been observed. 
8.4.1.2. 
Serious Adverse Events 
An AE or SAR is considered serious if, in the view of either the investigator or BARDA, it 
results in any of the following outcomes [21 CFR 312.32(a)]:  


BARDA 
Atropine 
Protocol: BP-C-19010  Version 3.0 
 
21 November 2019 
 
35 
• Death 
• Life-threatening AE that, in the view of the investigator or BARDA, places the 
subject at immediate risk of death. This does not, however, include an event that 
might have caused death had it occurred in a more severe form. 
• Requires inpatient hospitalization or prolongs existing hospitalization. Planned 
hospitalizations will not be reported as serious adverse events (SAEs) unless 
categorized as medically important. Emergency room visits and observational 
admissions of under 24 hours, in themselves, do not qualify as SAEs. 
• Results in persistent or significant disability/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 a serious adverse drug experience, when based on 
appropriate medical judgment, they may jeopardize the subject or the subject may 
require medical or surgical intervention to prevent one of the outcomes listed in this 
definition. 
8.5. 
Collection, Recording, and Grading Severity of Adverse Events  
8.5.1. 
Collection of Adverse Events 
Adverse events of any type described above may be discovered through a variety of methods: 
• Observing the subject 
• Questioning the subject with standard nonleading questions to elicit any medically related 
changes in their well-being (e.g., Have you been hospitalized, had any medical problems, 
used any new medications, or changed or stopped any medications [both prescription and 
OTC]?) 
• Receiving an unsolicited complaint from the subject 
• An abnormal value or result from a clinical (e.g., vital signs) or laboratory evaluation  
8.5.2. 
Recording of Adverse Events 
Throughout the study, the investigator will record AEs on the appropriate eCRF. For the 
purposes of this study, any detrimental change in the subject’s condition after signing informed 
consent and up to completion of the follow-up period after the last administration of study drug 
Follow-up (Day 21) will be considered an AE and must be recorded on the eCRF. Treatment-
emergent AEs are defined as AEs occurring after the subject receives at least one dose of 
atropine. AEs will be followed per the below criteria: 
• AEs judged related to study drug will be followed to resolution (with or without 
sequelae) or until considered stable by the investigator (in consultation with the Rho 
medical monitor in situations of uncertainty). 


BARDA 
Atropine 
Protocol: BP-C-19010  Version 3.0 
 
21 November 2019 
 
36 
• AEs judged unrelated to study drug will be followed to resolution (with or without 
sequelae) or, if not resolving, until considered stable by the investigator (in consultation 
with the Rho medical monitor in situations of uncertainty), or until the end of the 
subject’s study participation, whichever comes first. 
8.5.3. 
Grading Severity of Adverse Events 
The severity of AEs and SAEs will be graded using CTCAE version 5.0.   
It is important to distinguish between serious and severe AEs. Severity is a measure of intensity, 
whereas seriousness is defined by the criteria in Section 8.4.1.2. 
8.6. 
Relationship and Attribution to Study Drug 
An investigator’s causality assessment is the determination of whether a reasonable possibility 
exists that study drug caused or contributed to an AE, and must be provided for all treatment-
emergent AEs (serious and non-serious). The investigator will assess the causality/relationship 
between the study drug and the AE and record that assessment in the appropriate eCRF.    
BARDA’s determination of attribution will be used for reporting to the appropriate health and 
regulatory authorities.   
The relation and attribution of an AE to study treatment will be determined using the descriptors 
and definitions provided in Table 4. 
Table 4: 
Attribution of Adverse Events 
Unrelated Categories 
Not Related 
The AE is clearly not related to study drug. 
Unlikely Related 
The AE is unlikely related to study drug. 
Related Categories 
Possibly Related 
The AE has a reasonable possibility to be related to study drug; evidence exists to 
suggest a causal relationship. 
Probably Related 
The AE is likely related to study drug. 
Related 
The AE is clearly related to study drug. 
AE = adverse event 
8.7. 
Reporting Safety Events to IRB 
The investigator shall report adverse events, including SAEs, in a timely fashion to the IRB in 
accordance with applicable regulations and guidelines.  
8.8. 
Reporting of Serious Adverse Events 
The following process for reporting an SAE ensures compliance with ICH guidelines. 
Investigators and other study center staff must inform Rho pharmacovigilance personnel of any 
SAE that occurs (whether or not attributable to the study drug) in the study within 24 hours of 
when he or she becomes aware of the SAE. It is the investigator’s responsibility to ensure that 
SAE reporting procedures are followed appropriately. In addition, the investigator must ensure 


BARDA 
Atropine 
Protocol: BP-C-19010  Version 3.0 
 
21 November 2019 
 
37 
that these events are entered on the SAE eCRF via Rave EDC or via paper form, if Rave EDC is 
unavailable or if reported after database lock. The form will be entered into Rave EDC or faxed 
to the Rho pharmacovigilance personnel within 24 hours. The investigator is responsible for 
informing the IRB of the SAE as per local requirements. Upon notification of any SAE, Rho will 
inform BARDA within 1 business day. 
The following variables will be recorded for each AE: verbatim/AE description, time and date 
for AE start and stop, maximum intensity, seriousness, causality rating, whether the AE caused 
the subject to discontinue, and the outcome. 
Serious Adverse Event Reporting Contact Information: 
Rho, Inc. Safety Group Email: rho_productsafety@rhoworld.com  
Serious Adverse Event Help Line: 1-888-746-7231 
Serious Adverse Event Fax Line: 1-888-746-3293 
Follow-up information on SAEs must also be reported by the investigator by the same process, 
and within the same time frames. If a non-serious AE becomes serious, this and other relevant 
follow-up information must also be provided to Rho within 24 hours as described above. SAEs 
will be followed until resolution or until they become stable in the opinion of the investigator.  
8.9. 
Pregnancy Reporting 
This study includes pregnancy as safety data. Although pregnancy is not an SAE, information 
about any pregnancy in a female study subject will be reported promptly to Rho as an SAE for 
tracking purposes (Section 8.8). 
Study treatment will be discontinued for the pregnant subject. The investigator shall counsel the 
pregnant subject and discuss the risks of continuing with the pregnancy and the possible effects 
on the fetus. Monitoring of the pregnant subject shall continue until the conclusion of the 
pregnancy.  
The pregnancy will be documented on the appropriate eCRF when identified and at its 
conclusion.   
Should pregnancy result in a congenital abnormality, birth defect, miscarriage, or medically 
indicated abortion, an SAE must be submitted to Rho using the SAE reporting procedures 
described in Section 8.8. 
8.10. 
Reporting Other Safety Information 
Investigators will promptly notify Rho, BARDA, and the IRB when an unanticipated problem 
involving risks to subjects or others is identified, which is not otherwise reportable as an AE. 


BARDA 
Atropine 
Protocol: BP-C-19010  Version 3.0 
 
21 November 2019 
 
38 
9. 
STATISTICS 
9.1. 
Endpoints 
9.1.1. 
Primary Endpoints 
The relative bioavailability of atropine administered sublingually versus intravenously as 
measured by the following key PK parameters: 
• Area under the analyte concentration versus time curve to infinity (AUC∞) 
• Area under the analyte concentration versus time curve to time of last quantifiable 
data point (AUCt) 
• Maximum measured plasma concentration (Cmax) 
• Time to Cmax (tmax) 
• Apparent terminal elimination half-life (t½) 
• Apparent total body clearance after extravascular administration (CL/F) 
• Apparent total volume of distribution after extravascular administration (Vd/F) 
9.1.2. 
Secondary Endpoints 
• All treatment-emergent AEs and SAEs occurring during study participation 
• Xerostomia assessment (Appendix 3), completed during screening and each day of 
dosing starting at predose, and every 10 minutes postdose up to 1 hour postdose 
9.1.3. 
Measures to Minimize Bias 
Permuted block randomization will be performed centrally by designated Rho staff and will 
balance enrollment between treatment dosing sequence (see Section 7.7.1 for more details).   
9.1.4. 
Analysis Plan 
Statistical analyses will be performed using SAS® software Version 9.3 or later. Phoenix 
WinNonLin Version 6.4 software will be used to generate PK estimates. 
Due to the descriptive nature of the primary objective, inferential analyses are not planned. 
Descriptive statistics (such as mean, standard errors, medians, quartiles, and ranges for 
continuous data, and percentages for categorical data) will be used to summarize subject 
characteristics and safety. These summaries will be presented overall and separately for each 
study dosage received.   
Details of the statistical analyses, methods, and data conventions will be described in the 
Statistical Analysis Plan (SAP). 


BARDA 
Atropine 
Protocol: BP-C-19010  Version 3.0 
 
21 November 2019 
 
39 
9.1.4.1. 
Analysis Populations 
9.1.4.1.1. Safety Population 
The safety population will include all subjects who are randomized and receive at least 1 study 
drug dose. Each subject’s data will be analyzed according to the corresponding study dosage 
received at that time or randomized dosing sequence, as appropriate. The safety population will 
be used for all safety analyses, including xerostomia analyses. 
9.1.4.1.2. PK Analysis Population 
The PK analysis population will include all subjects who are randomized, receive at least 1 study 
drug dose, and have PK samples collected for that period. Each subject’s data will be analyzed 
according to the corresponding study dosage received for the applicable period. The PK analysis 
population will be used for all descriptive PK analyses. Subjects in the PK analysis population 
will be considered evaluable for comparison between study dosages if they receive at least two 
study drug doses and have evaluable time-concentration profiles for the 2 applicable periods. 
9.1.4.1.3. Per Protocol Population 
The per protocol population will include all subjects who are randomized, receive all 3 study 
drug doses according to the randomized dosing sequence, and have PK samples collected for all 
3 periods. In addition, subjects with major protocol deviations may be excluded if it is 
determined that the deviations affect the integrity of PK data. Each subject’s data will be 
analyzed according to the corresponding study dosage received at that time. Primary and 
secondary analysis plans will be repeated in the per protocol population if it differs from the PK 
analysis population.  
9.1.4.2. 
Primary Analyses 
Pharmacokinetic parameters (e.g., Cmax, AUCt, AUC∞, tmax and t½) will be estimated for each 
subject and study dosage using the noncompartmental method, and will be summarized by study 
dosage using descriptive statistics. CL/F and Vd/F will be estimated and summarized similarly 
for both sublingual doses only. Each parameter will be compared between study dosages by 
analysis of variance (ANOVA), including terms for dosing sequence, dose, and period as fixed 
effects, and subject nested within sequence as a random effect in the model. Ratios of least-
squares means of key plasma PK parameters and associated 90% confidence intervals (CIs) will 
be presented for the following comparisons of interest: 
• Low Dose sublingual vs. IV 
• High Dose sublingual vs IV 
• Low Dose sublingual vs High Dose sublingual 
Additional information on statistical methods will be described in the SAP for the study. 
9.1.4.3. 
Secondary Analyses 
The frequency of AEs and SAEs will be summarized by system organ class and preferred term. 
The risk of each event will be described using event rates and corresponding 95% CIs. 


BARDA 
Atropine 
Protocol: BP-C-19010  Version 3.0 
 
21 November 2019 
 
40 
Xerostomia scores will be analyzed descriptively for each of the 3 questions on the xerostomia 
assessment at each timepoint, including mean, median, standard error, and range.  
9.1.4.4. 
Interim Analysis 
No interim analysis is planned for this study. 
9.1.4.5. 
Final Analysis 
A clinical study report will be written to include all PK, safety, and tolerability data throughout 
the study. For the final analysis, the study database will be monitored, cleaned, and locked per 
the Data Management Plan (DMP). Further details will be specified in the SAP. 
9.1.4.6. 
Exploratory Analyses 
Exploratory analyses will be defined in the SAP, if applicable. 
9.2. 
Sample Size Considerations 
The target sample size for this study is 15 subjects, allowing for a 20% dropout rate that would 
result in approximately 12 evaluable subjects (approximately 4 per dosing sequence) within the 
per protocol population. This study is descriptive in nature. 
9.3. 
Statistical Considerations 
9.3.1. 
Covariates 
Due to the small sample size and cross-over design of this study, analyses adjusted for additional 
covariates beyond those specified for the primary analysis are not planned. 
9.3.2. 
Subgroup Analyses 
All exploratory analyses, including any subgroups that require additional consideration, will be 
discussed in the SAP, if necessary. 
9.3.3. 
Missing Data 
Standard procedures will be used to ensure that the data are as complete and accurate as possible. 
Due to the exploratory nature of this study, all descriptive summaries will be based upon all 
available data, and no imputation will be done.   
9.4. 
Procedure for Documenting Deviations from the Planned Analyses 
The principal features of the design of this study and of the plan for statistical analysis of the data 
are outlined in this protocol. Additional details will be included in the SAP before initiating 
analyses. Any changes to that plan will be documented in the final clinical study report and will 
be approved by BARDA before implementing the changed analysis. 


BARDA 
Atropine 
Protocol: BP-C-19010  Version 3.0 
 
21 November 2019 
 
41 
10. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
10.1. 
Inspection of Records 
BARDA, Rho, and the IRB will be allowed to conduct site visits to the clinical facility for the 
purpose of monitoring, inspecting, or auditing any aspect of the study.   
The investigator agrees to allow BARDA, Rho, and the IRB to inspect the clinical facility, 
including the study drug storage area, and all documentation relating to the study, including but 
not limited to all source documents, eCRFs, IRB submissions and approvals, study drug 
accountability logs, study drug temperature monitoring logs, regulatory documents, and 
correspondence. 
10.2. 
Institutional Review Board  
A copy of the protocol, informed consent form (ICF), any other subject-facing documents, and 
any proposed advertising/recruitment materials will be submitted to the IRB for written approval. 
Initial IRB approval and all materials approved by the IRB for this study, including the ICF and 
recruitment materials, must be maintained by the investigator and made available for inspection. 


BARDA 
Atropine 
Protocol: BP-C-19010  Version 3.0 
 
21 November 2019 
 
42 
11. 
QUALITY CONTROL AND QUALITY ASSURANCE 
Quality assurance (QA) includes all the planned and systematic actions that are established to 
ensure that the clinical study is performed and the data are generated, documented (recorded), 
and reported according to ICH GCP and local/regional regulatory standards. 
A QA representative from Rho, who is independent of and separated from routine monitoring, 
may periodically arrange inspections/audits of the clinical study by reviewing the data obtained 
and procedural aspects. BARDA quality representatives may attend the audit with Rho QA. 
These inspections may include on-site inspections/audits and source data checks. Direct access to 
source documents is required for the purpose of these periodic inspections/audits.  
11.1. 
Data Quality Assurance 
Before enrolling any subjects in this study, BARDA personnel and the investigator will review 
the protocol, study drug package inserts, the eCRFs and instructions for their completion, the 
procedure for obtaining informed consent, and the procedure for reporting AEs and SAEs.   
As part of the responsibilities assumed by participating in the study, the investigator agrees to 
maintain adequate source documents for the subjects treated as part of the research under this 
protocol. In addition, the investigator agrees to provide access to those records to BARDA’s 
study monitor and auditor. Study monitors will verify information in the eCRFs against the 
source documents.  
Data collected at the study site will be entered accurately and contemporaneously by study staff 
into Medidata RAVE, a 21CFR11-compliant, internet-based, remote data entry system, which is 
backed up nightly with backup tapes saved in a secure, off-site location. Data will be provided 
using the subject’s unique identification number, not name or initials; Rho and BARDA will not 
collect personally identifying information such as the subject’s name or social security number. 
Subjects will provide demographic information such as race, ethnicity, and birth date. All 
elements of data entry (e.g., time, date, verbatim text, and the person performing the data entry) 
will be recorded within the RAVE system’s audit trail to allow all data changes in the database to 
be monitored and maintained in accordance with federal regulations. Data collected by the 
laboratories will be transferred electronically directly from the laboratory to Rho using standard 
secure data transfer procedures. The analysis datasets will incorporate data from both sources. 
Data collected by Rho will be held in the strictest confidence, and are protected from access that 
could reveal personally identifying information about any subject in the study. 
Clinical data management and data cleaning procedures (i.e., resolving errors and inconsistencies 
in the data) will be performed in accordance with applicable Rho and/or BARDA standards and 
validation plans to ensure the integrity of the data. Adverse events (including SAEs), medical 
history conditions, and concomitant medication terms will be coded using MedDRA and the 
World Health Organization Drug Dictionary, respectively.  
The study database will be monitored and cleaned on an ongoing basis per the DMP. For the 
final analysis, the study database will be monitored, cleaned, and locked per the DMP.   
After the end of study database lock, the study site will receive an electronic copy of all of their 
site-specific eCRF data as entered into Medidata RAVE for the study, including full discrepancy 


BARDA 
Atropine 
Protocol: BP-C-19010  Version 3.0 
 
21 November 2019 
 
43 
and audit history. Additionally, all study data (STDM and ADaM) will be sent to BARDA 
electronically for storage. Rho will maintain a duplicate copy for its records.   
11.2. 
Study Monitoring 
According to ICH GCP guidelines, the sponsor of the study is responsible for ensuring the proper 
conduct of the study with regard to protocol adherence and validity of data recorded on the 
eCRFs. This study will be monitored to ensure the maintenance of complete, accurate, legible, 
well-organized, and easily retrievable data. In addition, the study monitor will explain and 
interpret for the investigator all regulations applicable to the clinical evaluation of the study drug 
as documented in ICH guidelines. 
It is the study monitor’s responsibility to inspect the eCRFs and source documentation directly 
throughout the study to protect the rights of the subjects; to verify adherence to the protocol; to 
verify completeness, accuracy, and consistency of the data; to perform study drug accountability; 
and to confirm adherence of study conduct to any local regulations. Details will be outlined in 
the Clinical Site Monitoring Plan. 
11.3. 
Protocol Deviations 
11.3.1. 
Protocol Deviation Definition 
A protocol deviation is any noncompliance with the IRB-approved study protocol, ICH GCP 
guidelines, protocol-specific operational documents, or applicable regulatory requirements. 
Protocol deviations will be captured during the study. BARDA will determine how the 
deviations will impact the study analysis populations. Prospective permission to deviate from 
protocol requirements (i.e., “study waivers”) will not be granted for this study. 
11.3.2. 
Reporting and Managing Deviations 
The investigator has the responsibility to identify, document, and report deviations. Protocol 
deviations may also be identified during site monitoring visits or during other forms of study 
conduct review. All deviations, regardless of the cause, must be documented on the appropriate 
eCRF, which will document at a minimum the date the deviation occurred, the date it was 
identified, a description of the deviation, and documentation of a corrective/preventative action. 
In addition, the investigator will report noncompliance to the IRB, as applicable. 
Rho and/or BARDA may request discussion with the site investigator to determine the effect of 
any protocol deviation on a study subject and his/her further study participation, the effect of the 
deviation on the overall study, and corrective actions.   


BARDA 
Atropine 
Protocol: BP-C-19010  Version 3.0 
 
21 November 2019 
 
44 
12. 
ETHICS 
12.1. 
Ethics Review 
Before study initiation, the protocol, the informed consent documents, any other subject-facing 
documents, and any proposed advertising/recruitment materials will be reviewed and approved 
by the IRB. Prior to study initiation, the site will procure the BARDA-approved study drug from 
their drug depot. The site will be activated when all approvals are in place and study drug has 
been received. Any amendments to those documents will be submitted to the IRB (following 
approval by BARDA) and must be approved by the IRB before they are implemented at the site. 
Protocol documents must be re-approved by the IRB annually. Only institutions holding a 
current US Federal Wide Assurance issued by the Office for Human Research Protections at 
HHS may participate in the study. 
The investigator will promptly report all unanticipated problems involving risks to subjects to the 
IRB, as applicable. The investigator will not make any changes to the research conduct without 
BARDA and IRB approval, except where necessary to eliminate apparent immediate hazards to 
the subjects.   
The investigator will provide progress reports to the IRB as required by the IRB. The 
investigator will provide a final report to the IRB after completion of participation in the study. 
12.2. 
Ethical Conduct of the Study 
The investigator will conduct the study in accordance with this protocol, the Declaration of 
Helsinki, current ICH GCP guidelines, and 21 CFR Part 50 (Protection of Human Subjects) and 
Part 56 (IRBs).   
12.3. 
Written Informed Consent 
The IRB’s informed consent document template will be used to write the site-specific consent 
document prior to IRB approval. The investigator is responsible for ensuring that the subject 
fully understands the nature and purpose of the study during the informed consent process. 
Information will be given in both oral and written form. No subject should be obligated to 
participate in the study. The information must make clear that refusal to participate in the study 
or withdrawal from the study at any stage is without any prejudice to the subject’s subsequent 
care. Subjects must be allowed sufficient time to inquire about the details of the study and to 
decide whether they wish to participate. Written informed consent will be obtained before the 
subject undergoes any study procedures. 
The subject must be made aware of and give consent to direct access to his/her source medical 
records by study monitors, auditors, and the IRB. The subject will be informed that such access 
will not violate subject confidentiality or any applicable regulations. The subject will also be 
informed that he/she is authorizing such access by signing the ICF.   
The investigator will retain the original signed informed consent, and each subject will be given 
a signed copy to keep for his/her records.   
 


BARDA 
Atropine 
Protocol: BP-C-19010  Version 3.0 
 
21 November 2019 
 
45 
13. 
DATA HANDLING AND RECORDKEEPING 
13.1. 
Confidentiality 
Each subject will be assigned a unique identification number and these numbers, rather than 
names, will be used to collect, store, and report subject information. All biological samples will 
be labeled with a unique identification number rather than names. Site staff will not transmit 
documents containing personal health identifiers to BARDA or its representatives. Data reported 
in medical journals or scientific meetings will be presented in aggregate for subjects as a whole. 
No individual subject will be identified in any way.  
13.2. 
Retention of Records 
The investigator will retain all documentation relating to the study (including but not limited to 
ICFs, source documentation, study drug records, eCRFs, and essential documents) for a period of 
at least 2 years after completion of the study.   
If this requirement differs from any local regulations, the local regulations will take precedence 
unless the local retention policy is less than 2 years.   
At study closure, the investigator must inform BARDA, or designee, of the long-term storage 
location of the study’s records. Following study closure, the investigator must inform BARDA if 
that location changes (e.g., the investigator leaves the institution where the study was 
conducted).   
No study records will be destroyed without prior authorization from BARDA.  
 


BARDA 
Atropine 
Protocol: BP-C-19010  Version 3.0 
 
21 November 2019 
 
46 
14. 
PUBLICATION POLICY 
BARDA will be responsible for publication activities and will work with the investigators to 
define the manuscript/presentation development process, the number and order of authors, the 
publication/scientific meeting to which it will be submitted, and other related issues. BARDA 
has final approval authority over all such issues. 
Data are the property of BARDA and cannot be published without prior authorization from 
BARDA, but data and publication thereof will not be unduly withheld. 
The Assistant Secretary for Preparedness and Response (ASPR) Public Access Plan9 and the 
National Institutes of Health Public Access Policy10 will apply to this study. The ASPR-funded 
investigators will be required to submit an electronic version of final, peer-reviewed manuscripts 
resulting from this study to the National Library of Medicine’s PubMed Central upon acceptance 
for publication, to be made publicly available no later than 12 months after the official date of 
publication.   


BARDA 
Atropine 
Protocol: BP-C-19010  Version 3.0 
 
21 November 2019 
 
47 
15. 
REFERENCES 
 
1. Calvano CJ, Enzenauer RW, Eisnor DL, Mazzoli RA. Atropine Eye Drops: A Proposed 
Field Expedient Substitute in the Absence of Atropine Autoinjectors. Journal of special 
operations medicine. 2017;17(3):81-3. 
2. Schwartz MD, Sutter ME, Eisnor D, Kirk MA. Contingency medical countermeasures for 
mass nerve-agent exposure: use of pharmaceutical alternatives to community stockpiled 
antidotes. Disaster medicine and public health preparedness. 2019 Jun;13(3):605-12. 
3. Norderyd J, Graf J, Marcusson A, Nilsson K, Sjöstrand E, Steinwall G, Ärleskog E, 
Bågesund M. Sublingual administration of atropine eyedrops in children with excessive 
drooling–a pilot study. International journal of paediatric dentistry. 2017 Jan;27(1):22-9. 
4. De Simone GG, Eisenchlas JH, Junin M, Pereyra F, Brizuela R. Atropine drops for 
drooling: a randomized controlled trial. Palliative medicine. 2006 Oct;20(7):665-71. 
5. Dias BLS, Fernandes AR, Maia HS Filho. Treatment of drooling with sublingual atropine 
sulfate in children and adolescents with cerebral palsy. Arquivos de neuro-psiquiatria. 
2017 May;75(5):282-7. 
6. Matos Santana TE, Capurso NA, Ranganathan M, Yoon G. Sublingual atropine in the 
treatment of clozapine-induced sialorrhea. Schizophrenia research. 2017 Apr;182:144-5. 
7. Rajpal S, Ali R, Bhatnagar A, Bhandari SK, Mittal G. Clinical and bioavailability studies 
of sublingually administered atropine sulfate. The American journal of emergency 
medicine. 2010 Feb 1;28(2):143-50. 
8. National Institutes of Health, National Cancer Institute. Common Terminology Criteria 
for Adverse Events (CTCAE) Version 5.0. 2017 Nov 27. Available from: 
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_50 
9. Office of the Assistant Secretary for Preparedness and Response [Internet]. Public Access 
to Federally Funded Research: Publications and Data. [cited 2017 May 30]. Available 
from: https://www.phe.gov/Preparedness/planning/science/Documents/AccessPlan.pdf 
10. National Institutes of Health [Internet]. Public Access Policy. [updated 2014 Mar 18; 
cited 2017 May 30]. Available from: https://publicaccess.nih.gov/ 
11. Pai S, Ghezzi EM, Ship JA. Development of a Visual Analogue Scale questionnaire for 
subjective assessment of salivary gland dysfunction. Oral surgery, oral medicine, oral 
pathology, and oral radiology. 2001 Mar;91(3):311-6.    
 
 


BARDA 
 
 
 
 
 
 
 
 
 
 
Atropine 
Protocol: BP-C-19010  Version 3.0 
 
 
 
 
  
 
 
 
 
21 November 2019 
 
 
48 
APPENDIX 1. PUBLICATION REVIEW OF SUBLINGUAL ADMINISTRATION OF ATROPINE 
Citation 
Age of 
Population 
Population 
type 
Study Design 
Primary 
Objective 
Atropine 
Formulation 
Atropine 
Dose 
Regimen 
(mg) 
Duration of 
Atropine 
Rx. 
Total 
N 
Atropine 
Exposed 
N 
Major Safety 
Findings 
Antonello C, 
Tessier P. (1999).  
“Clozapine and 
sialorrhea: a new 
intervention for 
this bothersome 
and potentially 
dangerous side 
effect.” J 
Psychiatry 
Neurosci. May;24 
(3):250. 
Adults 
Chronic 
schizophrenia 
Case reports 
Treat 
clozapine-
induced 
Hypersaliva-
tion 
1% 
ophthalmic 
solution 
0.5 mg 
once daily 
Not reported 
3 
3 
“None of the 
patients reported 
any side 
effects.” 
Chaptini, L. A., et 
al. (2008). 
"Sublingual 
hyoscyamine spray 
as premedication 
for colonoscopy: a 
randomized 
double-blinded 
placebo-controlled 
trial." Am J Surg 
196(1): 51-55. 
Adults 
Elective 
colonoscopy 
Randomized 
double-blind, 
placebo 
controlled 
Effect on 
colonoscopy 
quality and 
comfort 
Hyoscyamine 
spray 
0.25 mg 
Single dose 
100 
50 
"No significant 
difference in 
occurrence of 
side effects 
between the 
2 groups." 
Vital signs 
comparable 
before, during 
and after 
procedure 
between the 
2 groups. 


BARDA 
 
 
 
 
 
 
 
 
 
 
Atropine 
Protocol: BP-C-19010  Version 3.0 
 
 
 
 
  
 
 
 
 
21 November 2019 
 
 
49 
Citation 
Age of 
Population 
Population 
type 
Study Design 
Primary 
Objective 
Atropine 
Formulation 
Atropine 
Dose 
Regimen 
(mg) 
Duration of 
Atropine 
Rx. 
Total 
N 
Atropine 
Exposed 
N 
Major Safety 
Findings 
Comley C, Galletly 
C, Ash D. (2000). 
“Use of atropine 
eye drops for 
clozapine induced 
hypersalivation.” 
Aust N Z J Psych. 
Dec;34(6):1033-4. 
44 years 
Chronic 
schizophrenia 
and associated 
depression 
Case report 
Treat 
clozapine-
induced 
Hypersaliva-
tion 
1% 
ophthalmic 
solution 
0.5 – 
1.0mg 
once daily 
Not reported 
1 
1 
“There have 
been no adverse 
effects from this 
treatment.” 
De Simone, G. G., 
et al. (2006). 
"Atropine drops for 
drooling: a 
randomized 
controlled trial." 
Palliat Med 20(7): 
665-671. 
Adults 
Esophageal and 
gastric cancer 
and drooling 
Double-blind, 
cross-over, 
randomized, 
placebo 
controlled 
Effectiveness 
for drooling 
0.5% 
ophthalmic 
solution 
0.5mg q6h 
48 hours 
22 
21 
No severe 
toxicity - no 
blurred vision, 
palpitations, 
heartburn, 
hesitancy, 
urinary 
retention. 
One patient 
discontinued for 
cognitive 
impairment 
thought due to 
severe chest 
infection. 
Dias, B. L. Set al. 
(2017). Treatment 
of drooling with 
sublingual atropine 
sulfate in children 
and adolescents 
with cerebral palsy. 
Arq 
Neuropsiquiatr, 
75(5), 282-287. 
2 – 17 
years 
Cerebral palsy, 
drooling 
Open-label, 
non-
controlled 
Effectiveness 
for drooling 
0.5% 
ophthalmic 
solution 
0.125mg 
thrice 
daily for 
weight 
10-19 kg; 
0.5mg 
thrice 
daily for 
weight 
>= 20 kg 
30 days 
33 
25 
Side effects in 
4/33 (12%): 
fever, flush, 
irritability, 
angioedema 


BARDA 
 
 
 
 
 
 
 
 
 
 
Atropine 
Protocol: BP-C-19010  Version 3.0 
 
 
 
 
  
 
 
 
 
21 November 2019 
 
 
50 
Citation 
Age of 
Population 
Population 
type 
Study Design 
Primary 
Objective 
Atropine 
Formulation 
Atropine 
Dose 
Regimen 
(mg) 
Duration of 
Atropine 
Rx. 
Total 
N 
Atropine 
Exposed 
N 
Major Safety 
Findings 
Dumot, J. A., et al. 
(1998). Sublingual 
hyoscyamine for 
patient comfort 
during screening 
sigmoidoscopy: a 
randomized, 
double-blind, 
placebo-controlled 
clinical trial. 
Gastrointest 
Endosc, 48(3), 
283-286. 
25 – 83 
years 
Patients 
undergoing 
screening 
sigmoidoscopy 
Double-blind, 
placebo 
controlled 
Efficacy for 
comfort during 
screening 
sigmoidoscopy 
Hyoscyamine 
0.125 mg 
tablets 
0.5 mg 
(2 tablets 
10 min 
prior to 
sigmoidos
copy) 
1 day 
150 
75 
No treatment 
related adverse 
effects reported 
Ghobrial, P. M., et 
al. (2014). Cine 
MR enterography 
grading of small 
bowel peristalsis: 
evaluation of the 
antiperistaltic 
effectiveness of 
sublingual 
hyoscyamine 
sulfate. Acad 
Radiol, 21(1), 86-
91. 
Not 
Described 
Patients 
undergoing 
magnetic 
resonance 
enterography 
(MRE) 
Open-label, 
non-
controlled 
Effect on 
peristalsis 
Hyoscyamine 
0.125 mg 
tablets 
0.5mg 1 
hour 
before 
MRE 
Single dose 
92  
92 
Safety was not 
discussed 


BARDA 
 
 
 
 
 
 
 
 
 
 
Atropine 
Protocol: BP-C-19010  Version 3.0 
 
 
 
 
  
 
 
 
 
21 November 2019 
 
 
51 
Citation 
Age of 
Population 
Population 
type 
Study Design 
Primary 
Objective 
Atropine 
Formulation 
Atropine 
Dose 
Regimen 
(mg) 
Duration of 
Atropine 
Rx. 
Total 
N 
Atropine 
Exposed 
N 
Major Safety 
Findings 
Hyson, H. C., et al. 
(2002). "Sublingual 
atropine for 
sialorrhea 
secondary to 
parkinsonism: a 
pilot study." Mov 
Disord 17(6): 
1318-1320. 
62-82 years 
Parkinson's 
disease/ 
Parkinsonism 
and drooling 
Open-label, 
non-
controlled 
Effectiveness 
for drooling 
1% 
ophthalmic 
solution 
0.5 mg 
twice 
daily 
1 week 
7 
7 
No complaints 
of worsening 
constipation, 
blurred vision, 
dizziness, 
confusion;  
Jones, J. B., & 
Dula, D. J. (1998). 
The efficacy of 
sublingual 
hyoscyamine 
sulfate and 
intravenous 
ketorolac 
tromethamine in 
the relief of 
ureteral colic. Am J 
Emerg Med, 16(6), 
557-559. 
18 years or 
older 
Ureteral colic 
due to calculi 
Randomized 
open-label, 
two-arm 
study 
Effect on 
ureteral colic 
Hyoscyamine 
sulfate  
0.125 mg  
Single dose 
49 
24 
Safety was not 
discussed 


BARDA 
 
 
 
 
 
 
 
 
 
 
Atropine 
Protocol: BP-C-19010  Version 3.0 
 
 
 
 
  
 
 
 
 
21 November 2019 
 
 
52 
Citation 
Age of 
Population 
Population 
type 
Study Design 
Primary 
Objective 
Atropine 
Formulation 
Atropine 
Dose 
Regimen 
(mg) 
Duration of 
Atropine 
Rx. 
Total 
N 
Atropine 
Exposed 
N 
Major Safety 
Findings 
Jones, J., et al. 
(2001). Sublingual 
hyoscyamine 
sulfate in 
combination with 
ketorolac 
tromethamine for 
ureteral colic: a 
randomized, 
double-blind, 
controlled trial. 
Ann Emerg Med, 
37(2), 141-146. 
18 years or 
older (44 
years 
mean) 
Ureteral colic 
Double-blind, 
two-arm 
study 
Effect on 
ureteral colic 
Hyoscyamine 
sulfate  
0.125 mg  
Single dose 
43 
23 
Safety was not 
discussed 
Lynch, C. R., et al. 
(2007). "Sublingual 
L-hyoscyamine for 
duodenal 
antimotility during 
ERCP: a 
prospective 
randomized 
double-blinded 
study." Gastrointest 
Endosc 66(4): 748-
752. 
Adults 
Patients 
undergoing 
ERCP 
Randomized 
double-blind, 
placebo 
controlled 
Effect on 
glucagon 
needed during 
ERCP 
Hyoscyamine 
0.5 mg 
Single dose 
200 
101 
No significant 
difference 
between the two 
groups in 
incidence of 
adverse drug 
effects including 
nausea, 
vomiting, and 
xerostomia at 2 
and 24 hours, 
tachycardia, 
hypotension, 
hypoxemia. 


BARDA 
 
 
 
 
 
 
 
 
 
 
Atropine 
Protocol: BP-C-19010  Version 3.0 
 
 
 
 
  
 
 
 
 
21 November 2019 
 
 
53 
Citation 
Age of 
Population 
Population 
type 
Study Design 
Primary 
Objective 
Atropine 
Formulation 
Atropine 
Dose 
Regimen 
(mg) 
Duration of 
Atropine 
Rx. 
Total 
N 
Atropine 
Exposed 
N 
Major Safety 
Findings 
Matos Santana, T. 
E., et al. (2017). 
"Sublingual 
atropine in the 
treatment of 
clozapine-induced 
sialorrhea." 
Schizophr Res 182: 
144-145. 
Adults 
Schizophrenia 
or 
schizoaffective 
disorder 
Case reports 
Effectiveness 
for clozapine-
induced 
sialorrhea 
1% 
ophthalmic 
solution 
0.5-1 mg 
once to 
twice 
daily 
> 1 week 
3 
3 
"None of the 
patients reported 
any systemic 
side effects" 
Mustafa, F. A., et 
al. (2013). 
"Sublingual 
atropine for the 
treatment of severe 
and hyoscine-
resistant clozapine-
induced 
sialorrhea." Afr J 
Psychiatry 
(Johannesbg) 
16(4): 242. 
46 years 
Adult with 
schizophrenia 
Case report 
Effectiveness 
for clozapine-
induced 
sialorrhea 
1% 
ophthalmic 
solution 
0.5 mg up 
to three 
times 
daily 
7 days 
1 
1 
Safety was not 
discussed 
Norderyd, J., et al. 
(2017). "Sublingual 
administration of 
atropine eyedrops 
in children with 
excessive drooling 
- a pilot study." Int 
J Paediatr Dent 
27(1): 22-29. 
5 - 18 years 
Non-medically 
induced 
drooling 
associated with 
disability (CP, 
ASD, Down 
syndrome, etc.) 
Open label, 
non-
controlled 
Effectiveness 
for drooling 
1% 
ophthalmic 
solution 
0.5 mg 
once to 
twice 
daily 
8 weeks 
26 
19 
Miction 
problems (3), 
obstipation (3), 
changed 
behavior (3) 


BARDA 
 
 
 
 
 
 
 
 
 
 
Atropine 
Protocol: BP-C-19010  Version 3.0 
 
 
 
 
  
 
 
 
 
21 November 2019 
 
 
54 
Citation 
Age of 
Population 
Population 
type 
Study Design 
Primary 
Objective 
Atropine 
Formulation 
Atropine 
Dose 
Regimen 
(mg) 
Duration of 
Atropine 
Rx. 
Total 
N 
Atropine 
Exposed 
N 
Major Safety 
Findings 
Protus, B. M., et al. 
(2012). Evaluation 
of atropine 1% 
ophthalmic 
solution 
administered 
sublingually for the 
management of 
terminal respiratory 
secretions. Am J 
Hosp Palliat Care, 
30(4), 388-392. 
42 - 94 
years 
Adults, hospice 
terminal care 
Retrospective 
chart review 
Effect on 
respiratory 
secretions 
1% 
ophthalmic 
solution 
0.5mg 
every 
2 hours 
until 
effect 
Varied by 
patient; 
range 1 hour 
to 6 days 
22 
22 
No adverse 
effects reported  
Rapoport, A, 
(2010). 
“Sublingual 
Atropine Drops for 
the Treatment of 
Pediatric 
Sialorrhea.”, J. of 
Pain and Symptom 
Management 40(5): 
783-788. 
14 years 
Metachromatic 
leukodystrophy 
(MLD) and 
excessive 
drooling 
Case report 
Effect on 
sialorrhea 
0.5% 
ophthalmic 
solution 
0.25 mg 
up to three 
times 
daily 
2 weeks 
1 
1 
Tongue 
fasciculation and 
dystonia 
developed after 
2 weeks, 
determined to be 
due to 
metoclopramide. 
Sublingual 
atropine 
restarted without 
recurrence. No 
facial flushing, 
change in 
behavior, or 
tachycardia. 


BARDA 
 
 
 
 
 
 
 
 
 
 
Atropine 
Protocol: BP-C-19010  Version 3.0 
 
 
 
 
  
 
 
 
 
21 November 2019 
 
 
55 
Citation 
Age of 
Population 
Population 
type 
Study Design 
Primary 
Objective 
Atropine 
Formulation 
Atropine 
Dose 
Regimen 
(mg) 
Duration of 
Atropine 
Rx. 
Total 
N 
Atropine 
Exposed 
N 
Major Safety 
Findings 
Rothrock, S.G, et 
al. (1993) 
Successful 
Resuscitation From 
Cardiac Arrest 
Using Sublingual 
Injection for 
Medication 
Delivery. Ann 
Emerg Med. 
22(4):751-3. 
7 months 
Infant with 
cardio-
pulmonary 
arrest 
Case report 
Effect in 
cardiac arrest 
Not stated 
0.15 mg 
(estimated 
0.02 
mg/kg) 
Single dose 
1 
1 
Safety was not 
discussed 
Sharma, A., et al. 
(2004). Intraoral 
application of 
atropine sulfate 
ophthalmic 
solution for 
clozapine-induced 
sialorrhea. Ann 
Pharmacother, 
38(9), 1538. 
55 years 
Patient taking 
clozapine 
Case report 
Effectiveness 
for clozapine-
induced 
sialorrhea 
1% 
ophthalmic 
solution 
1.0 mg 
twice 
daily 
2 weeks 
1 
1 
Clinician 
reported no 
adverse effects 
ASD = autism spectrum disorder; CP = cerebral palsy; ERCP = endoscopic retrograde cholangiopancreatography; Rx = treatment 
 
 


BARDA 
 
 
 
 
 
 
 
 
 
 
Atropine 
Protocol: BP-C-19010  Version 3.0 
 
 
 
 
  
 
 
 
 
21 November 2019 
 
 
56 
APPENDIX 2. SCHEDULE OF EVENTS 
Study Visit 
Screening 
Visit 1a  
Visit 2a  
Visit 3a  
Telephone  
Follow-up  
 
ETb 
UV 
Study Day 
Day -14 
to -1 
Day 1 Predose 
Day 1 
Dosing 
Day 8 (±1 Day) 
Predose 
Day 8 
(±1 Day) 
Dosing 
Day 15 (±1 Day) 
Predose  
Day 15 
(±1 Day) 
Dosing 
Day 21  
-1 Day/ +7 
Days 
N/A 
N/A 
Visit window based 
on actual dosing 
day 
N/A 
N/A 
N/A 
Visit 1 + 7  
±1 Day 
Visit 1 + 7 
±1 Day 
Visit 2 + 7 
±1 Day 
Visit 2 +7 
±1 Day 
Visit 3 + 6  
-1 Day/ +7 
Days 
NA 
N/A 
Procedures 
Informed consent  
X 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
Physical exam 
Xc 
Xc 
 
Xc 
 
Xc 
 
 
Xc 
Xc 
Medical history 
X 
Xd 
 
Xd 
 
Xd 
 
 
Xd 
Xd 
Tobacco/Vaping 
Questionnaire   
X 
X 
 
X 
 
X 
 
 
X 
X 
Height, weight, BMI 
X 
Xe 
 
Xe 
 
Xe 
 
 
Xe 
Xe 
Vital signs 
X 
Xf 
Xf 
Xf 
Xf 
Xf 
Xf 
 
Xf 
Xf 
12-lead ECG 
X 
 
Xg 
 
Xg 
 
Xg 
 
Xg  
Xg 
Clinical laboratories 
- CBC and chemistry 
X 
 
 
 
 
 
 
 
Xh 
Xh  
HIV antibody, 
HBsAg, anti-HCV  
X 
 
 
 
 
 
 
 
 
 
TSH 
X 
 
 
 
 
 
 
 
 
 
Serum pregnancy 
testi 
X 
 
 
 
 
 
 
 
 
 
Urine pregnancy 
testj 
 
X 
 
X 
 
X 
 
 
 
 
Urine drug screenk 
X 
 
 
 
 
 
 
 
 
 


BARDA 
 
 
 
 
 
 
 
 
 
 
Atropine 
Protocol: BP-C-19010  Version 3.0 
 
 
 
 
  
 
 
 
 
21 November 2019 
 
 
57 
Study Visit 
Screening 
Visit 1a  
Visit 2a  
Visit 3a  
Telephone  
Follow-up  
 
ETb 
UV 
Study Day 
Day -14 
to -1 
Day 1 Predose 
Day 1 
Dosing 
Day 8 (±1 Day) 
Predose 
Day 8 
(±1 Day) 
Dosing 
Day 15 (±1 Day) 
Predose  
Day 15 
(±1 Day) 
Dosing 
Day 21  
-1 Day/ +7 
Days 
N/A 
N/A 
Visit window based 
on actual dosing 
day 
N/A 
N/A 
N/A 
Visit 1 + 7  
±1 Day 
Visit 1 + 7 
±1 Day 
Visit 2 + 7 
±1 Day 
Visit 2 +7 
±1 Day 
Visit 3 + 6  
-1 Day/ +7 
Days 
NA 
N/A 
CRU admission 
 
X 
 
X 
 
X 
 
 
 
 
Study drug 
administration 
 
 
X 
 
X 
 
X 
 
 
 
PK blood collectionl 
 
 
X 
 
X 
 
X 
 
 
 
Xerostomia 
assessment 
X 
X 
Xm 
X 
Xm 
X 
Xm 
 
 
 
AEs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant 
medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Discharge from 
CRU 
 
 
X 
 
X 
 
X 
 
 
 
AE = adverse event; BMI = body mass index; CBC = complete blood count; CRU = contract research unit; ECG = electrocardiogram; ET = early termination; HBsAg = hepatitis 
B surface antigen; HCV = hepatitis C virus; HIV = human immunodeficiency virus; IV = intravenous; N/A = not applicable; PK = pharmacokinetic; TSH = thyroid-stimulating 
hormone; UV = unscheduled visit 
a Washouts will be conducted between visits. Washouts will be approximately 6 (±1) days; AEs and concomitant medications will be recorded for all 3 washout periods. 
b The ET Visit may be conducted in clinic or by phone as determined by the investigator.  
c All subjects undergo a full physical examination at screening. At subsequent visits, including Visit 1 (Day 1 Predose), Visit 2 (Day 8 Predose), Visit 3 (Day 15 Predose), ET and 
UV visits, the investigator may perform symptom-based physical examinations at their discretion. 
d Medical history updates will be collected at Visit 1 (Day 1 Predose), Visit 2 (Day 8 Predose), Visit 3 (Day 15 Predose), UV, and ET Visits.  
e Weight only will be measured at Visit 1 (Day 1 Predose), Visit 2 (Day 8 Predose), Visit 3 (Day 15 Predose). Weight may also be measured at UV or ET Visits per the 
investigator’s discretion.  
f Vital signs (heart rate, blood pressure, temperature, and respiratory rate) will be obtained prior to each dose of study drug administration. Postdose automated blood pressure and 
heart rate measurements will be recorded on the opposite arm from blood collection every 10 minutes for the first hour, every 20 minutes for the second hour, and every 30 
minutes for the third and fourth hours and thereafter as deemed clinically necessary by the investigator until the end of each visit.  Vital signs may also be performed at UV or ET 
Visits per the investigator’s discretion. 


BARDA 
 
 
 
 
 
 
 
 
 
 
Atropine 
Protocol: BP-C-19010  Version 3.0 
 
 
 
 
  
 
 
 
 
21 November 2019 
 
 
58 
g For the IV dose only, an ECG will be performed within 5 minutes after atropine has been administered; the ECG may be repeated as needed at the investigator’s discretion. ECGs 
may also be performed at UV or ET Visits per the investigator’s discretion.  
h CBC (red blood cell, total and differential white blood cell, hemoglobin, hematocrit, and platelet count) and serum chemistry (creatinine, blood urea nitrogen, aspartate 
aminotransferase, alanine aminotransferase, alkaline phosphatase, total bilirubin, direct bilirubin, total carbon dioxide, glucose, sodium, potassium, and chloride) will be obtained 
at Screening. Additional laboratory studies may also be performed at UV or ET Visits per the investigator’s discretion. 
i A serum pregnancy test will be conducted for all women of childbearing potential at Screening.  
j A urine dipstick pregnancy test will be conducted for all women of childbearing potential at Visit 1 (Day 1 Predose), Visit 2 (Day 8 Predose), and Visit 3 (Day 15 Predose). A 
urine dipstick pregnancy test will also be performed at any time during study participation if pregnancy is suspected. Results from all tests must be negative in order to proceed 
with dosing. 
k Urine drug screen includes tests for amphetamines, cocaine, tetrahydrocannabinol, methylenedioxymethamphetamine, and opiates. 
l Blood samples taken at time 0 (predose) and postdose at 2, 4, 6, 10, 15, 20, 30, 45, and 60 minutes and 2, 4, 6, and 8 hours. 
m Subjects will be asked to rate xerostomia postdose every 10 minutes until one hour has passed, or the subject scores a 10 on one or more of the xerostomia questions, or reports 
intolerable xerostomia, whichever occurs first.


BARDA 
Atropine 
Protocol: BP-C-19010  Version 3.0 
 
21 November 2019 
 
 
59 
 
APPENDIX 3. XEROSTOMIA ASSESSMENT 
Subjective self-reporting of degree of xerostomia in patients without salivary gland dysfunction 
has been successfully demonstrated in an antimuscarinic-induced (glycopyrrolate) xerostomia 
model.11 Select questions were adapted from this study and are noted below. Please note these 
questions are not validated in their current form but are included to assess anticholinergic effects 
in trial subjects. 
The following questions will be used in the assessment of xerostomia: 
1) On a scale of 0-10, with 0 being not difficult at all and 10 being very difficult, rate the 
difficulty you are currently having swallowing due to your mouth dryness. 
2) On a scale of 0-10, with 0 being not dry at all and 10 being very dry, how would you 
currently rate the dryness of your lips? 
3) On a scale of 0-10, with 0 being not dry at all and 10 being very dry, how would you 
currently rate the dryness of your tongue?  
The subject will be asked these questions before dosing and then every 10 minutes after dosing 
for 1 hour or until one of the following conditions are met: (1) The subject scores a 10 on one or 
more of the questions or, (2) the subject expresses (either verbally or nonverbally) that he/she 
cannot tolerate the oral dryness any further.   
When either of these conditions are met, the assessment will be terminated, and the subject will 
be provided water ad libitum. The time when the assessment is terminated will define when a 
subject experienced their maximum xerostomia.   

ICF_001.pdf: 
 
THIS IS AN IMPORTANT DOCUMENT - KEEP FOR FUTURE REFERENCE 
VERSION CONTROL 
jnb/11-11-19 lng/12-19-19 
APPROVED BY 
INTEGREVIEW IRB 
DECEMBER 19, 2019 
INFORMED CONSENT DOCUMENT 
AGREEMENT TO BE IN A RESEARCH STUDY 
 
NAME OF SPONSOR: 
Biomedical Advanced Research and Development 
Authority (BARDA) 
PROTOCOL NUMBER AND TITLE 
OF STUDY: 
BP-C-19010; “A Randomized, Three-Sequence, Three- 
Period Crossover Study to Assess the Bioavailability and 
Pharmacokinetics of a Single Dose of Atropine 
Administered Sublingually in Healthy Adult Volunteers” 
 
NAME OF PERSON IN CHARGE 
OF THE RESEARCH STUDY 
(INVESTIGATOR/STUDY DOCTOR): 
Melanie Fein, MD 
 
TELEPHONE NUMBER(S), DAYTIME: 
336-841-0700 
24 HOURS: 
336-862-0634 
 
KEY INFORMATION 
 
You may be eligible to take part in a research study. This form gives you important information about the 
study. It describes the purpose of the study, and the risks and possible benefits of participating in the 
study. Please take time to review this information carefully. After you have finished, you should talk to 
the study doctors and nurses about the study and ask them any questions you have. You may also wish to 
talk to others (for example, your friends, family, or other doctors) about your participation in this study. If 
you decide to take part in the study, you will be asked to sign this form. Before you sign this form, be sure 
you understand what the study is about, including the risks and possible benefits to you. Your 
participation in this study is voluntary – you can choose whether to participate or not. 
 
This research study is a pharmacokinetics or PK study. This means that what is being studied is how your 
body processes, and eliminates the study drug. This study is comparing the pharmacokinetics (PK) of 2 
different forms of atropine sulfate; atropine sulfate eye drops, delivered under the tongue, and atropine 
sulfate injection form, delivered in a needle in your vein (intravenously or IV). The goal of this study is to 
find out if the body processes the atropine sulfate eye drops under the tongue like it does the atropine 
given through an IV. There is no direct benefit to you from your participation in the study. Information 
learned from the study may help other people in the future. 
 
If you choose to participate in this study, you will have 4 study visits and one telephone call over a period 
of about 35 days. Study visit procedures will occur in a single day, and the study visits will last about 8 
hours for each visit. A screening visit will determine if you are eligible to participate in the study. If you 
pass the screening visit you will be asked to return for Visit 1 within the next two weeks. Everyone who 
participates in this study will receive 2 different dosages of atropine sulfate under the tongue and one 
dosage of atropine sulfate by vein over the course of the study. The order in which the three different 
dosages are given will be randomly assigned (like a flip of a coin) during Visit 1. During the study visits, 
a variety of procedures will be performed including physical exams, blood draws, and drug tests. You will 
be asked to complete two questionnaires, and information about your medical and substance use history 
will be collected. 


Protocol number BP-C-19010 
Informed Consent 
Melanie Fein, MD 
Page 2 of 17 
APPROVED BY 
INTEGREVIEW IRB 
DECEMBER 19, 2019 
 
 
THIS IS AN IMPORTANT DOCUMENT - KEEP FOR FUTURE REFERENCE 
VERSION CONTROL 
jnb/11-11-19 lng/12-19-19 
 
After Visit 1, you will be released from the clinic and will return to the clinic in about 6 days for Visit 2. 
The time between clinic visits is called a washout period. This time is necessary to allow your body to 
remove all traces of atropine from the previous dose. Visit 2 will be similar to Visit 1, and Visit 3 will be 
similar to Visit 1. The difference between the visits will be the amount of atropine you are given and how 
it will be given to you (under your tongue, or through an IV). You will have one follow-up phone call 
about 6 days after Visit 3 where you will be asked about any new symptoms and medications. 
 
Atropine sulfate and the study procedures have risks and side effects that you should be aware of. The 
main risks you should be aware of are: a fast heart rate, temporary blurry vision, dry mouth and a 
temporary feeling of warmth. A complete list of known risks is listed later in this informed consent form. 
If you choose to participate in this study and are eligible, you will be expected to attend all study visits 
and follow instructions for all study procedures. 
 
INTRODUCTION 
 
You are deciding if you would like to volunteer for a medical research study. You must read and sign this 
form before you agree to take part in this study. This form will give you more information about this study. 
Please ask as many questions as you need to before you decide if you want to be in the study. Do not sign 
this form if you have any questions that have not been answered. 
The investigator is being paid by the sponsor, Biomedical Advanced Research and Development 
Authority (BARDA), to conduct this research study. BARDA is part of the U.S. government Department 
of Health and Human Services. 
 
You must be honest with the study doctor and study about your health history or you may harm yourself by 
participating in this study. It is extremely important to your health and safety to tell the truth about your 
medical history and any and all medications that you are currently taking or have taken within the time 
required for the study. For your continued safety, if you develop any new conditions or start any new 
medications during the study, you should inform the study doctor right away. A list of people who will have 
access to this information is listed in the Confidentiality section below. 
PURPOSE OF THE STUDY 
 
This study drug (atropine sulfate eye drops) is an approved, marketed drug for the use of dilating the 
pupils in the eyes to allow for eye examinations. Atropine sulfate is also an approved, marketed drug in  
an injectable form for the treatment of poisoning by mushrooms and is also used for treatment of nerve 
gas poisoning. This research study is not intended to treat any condition. This research study is a 
pharmacokinetics or PK study. This means that what is being studied is how your body absorbs, 
processes, and eliminates the study drug. This study is comparing the pharmacokinetics (PK) of 2 
different forms of atropine sulfate; atropine sulfate eye drops, delivered under the tongue, and atropine 
sulfate injection form, delivered with an IV. The goal of this study is to find out if the body processes the 
atropine sulfate eye drops under the tongue like it does the atropine given through an IV. There is no 
direct benefit to you from your participation in the study. Information learned from the study may help 
other people in the future. 
In this document, you may see the terms “medication” and “treatment”; 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 drugs and parts of the study where you will receive the study 
drug. 


Protocol number BP-C-19010 
Informed Consent 
Melanie Fein, MD 
Page 3 of 17 
APPROVED BY 
INTEGREVIEW IRB 
DECEMBER 19, 2019 
 
 
THIS IS AN IMPORTANT DOCUMENT - KEEP FOR FUTURE REFERENCE 
VERSION CONTROL 
jnb/11-11-19 lng/12-19-19 
 
If you qualify for the study, you will receive two doses (0.5 mg and 1.0 mg) of atropine sulfate 
sublingually (delivered under the tongue). You will also receive an injected dose (1.0 mg) of atropine 
sulfate. The order of the drug you receive will be assigned by chance, like the flip of a coin. 
Administration of the drug is described below: 
 
• 
A small amount of atropine sulfate (low dose; 0.5 mg) will be dropped under your tongue on one 
visit; 
• 
A slightly larger amount of atropine sulfate (high dose; 1.0 mg) will be dropped under your tongue on 
another visit; 
• 
A small amount of atropine sulfate (1.0 mg) will be injected into a vein in your arm on another visit. 
 
HOW LONG THE STUDY WILL LAST AND HOW MANY PEOPLE WILL BE IN THE STUDY 
 
The study will last about 35 days and will require 4 one day visits to the clinic. About 15 healthy men and 
women, ages 18 through 55, are expected to be in this study. 
TO BE IN THIS STUDY 
 
You cannot be in this study if you are in another research study or if you have been in any other research 
study in the last 30 days. You cannot be in this study if you are taking any controlled substances (illegal 
and/or prescription). A urine test will be performed to check for the use of these drugs. 
 
Subject Responsibilities: 
 
Meals and snacks will be served at scheduled times during your stay in the study clinic. You can eat only 
the food and drink provided to you. You can eat only at the times food is provided. Some of the 
requirements and restrictions for this study are listed below. 
You must agree to follow all the study restrictions and research center rules and regulations. These will  
be reviewed with you by the study staff. You will be given the rules and regulations to read and sign 
during the Screening Visit and provided with a copy of the rules. You will be required to wear an ID  
band for the duration of the in-patient portions of the study, as well as one during any outpatient visits 
(Screening and Unscheduled Visits). Failure to follow the study restrictions, rules and regulations may 
result in your compensation being reduced or your participation in the study coming to an end, which will 
require you to leave the study site. 
 
You can be tested for illicit drug or alcohol use at any time during the study at the discretion of the 
investigator. If you are discharged from the study because you have a positive drug or alcohol screen 
result, or refusal to give a specimen or providing urine samples that do not meet temperature 
requirements, you will not be compensated for any of your participation in the study. 
 
While participating in this research study, you will need to: 
• 
Be willing and able to follow the study directions and procedures 
• 
Tell the study staff about any side effects or problems 
• 
Ask questions as you think of them 
• 
Tell the investigator or the study staff if you change your mind about staying in the study. 


Protocol number BP-C-19010 
Informed Consent 
Melanie Fein, MD 
Page 4 of 17 
APPROVED BY 
INTEGREVIEW IRB 
DECEMBER 19, 2019 
 
 
THIS IS AN IMPORTANT DOCUMENT - KEEP FOR FUTURE REFERENCE 
VERSION CONTROL 
jnb/11-11-19 lng/12-19-19 
 
WHAT WILL HAPPEN DURING THE STUDY? 
Screening: 
 
Before the study starts, you will be asked to sign this consent form, give your health history, and tell  
study staff if you take any over-the-counter or prescription medicines, vitamins, minerals or herbal 
products. You will also be asked if you currently or have ever used tobacco or vaping products and if you 
do use them, how often and how much. An assessment of adverse events (AEs) also called side effects 
will also be done. 
The investigator will do some tests to find out if you can be in the study. These tests include: 
• 
Physical exam including height and weight 
• 
Vital signs (blood pressure, temperature, heart and breathing rates) 
• 
Blood collection for HIV and hepatitis B and C, laboratory tests, and pregnancy test for female 
subjects 
• 
Electrocardiogram (ECG; used to assess heart rhythm): To perform the ECG, you will have stickers 
placed on select locations on your chest, arms and legs. The machine connects to these stickers and 
records the activity of your heart. If there is hair where the stickers need to be placed, small areas  
may need to be shaved. After the ECG is complete, these stickers will be removed. 
• 
Dry mouth questionnaire 
• 
Vaping and tobacco use questionnaire 
The investigator will conduct safety assessments, that may include breath alcohol testing, to decide if you 
qualify to participate in the study. The investigator may determine that you are not suitable for the study 
based on protocol requirements or other concerns. If you qualify to take part in this study and go on to 
participate and receive the study drug, then the following will happen: 
Visit 1: 
After completing the screening visit, you will be asked to return to the research site some time from the 
next day to about two weeks later. 
You will be assigned by chance to determine the order in which you will receive each of the 3 different 
doses of atropine at your 3 visits to the site. The order of getting the drug will be defined and is shown in 
the overall study design figure (Figure 1) below. You have an equal chance of being assigned to any of 
the 3 dosing sequences. This is an open-label study. This means that you, the Investigator, study staff, and 
the Sponsor will know the study drugs and the doses that you are given. 


Protocol number BP-C-19010 
Informed Consent 
Melanie Fein, MD 
Page 5 of 17 
APPROVED BY 
INTEGREVIEW IRB 
DECEMBER 19, 2019 
 
 
THIS IS AN IMPORTANT DOCUMENT - KEEP FOR FUTURE REFERENCE 
VERSION CONTROL 
jnb/11-11-19 lng/12-19-19 
 
Figure 1: 
Overall Study Design 
 
There are also periods between the treatments that are called washout. The washout is designed to allow 
your body to remove all of the drug before getting the next dose. The washout periods are about 6 days 
long. 
 
When you return to the clinic (Visit 1), the study drug will be administered to you and you will stay for 
about 8 hours after completion of dosing. During this visit, the following procedures will occur in this 
order: 
 
Visit 1: Prior to study drug administration 
 
The following will be obtained prior to each dose: 
 
• 
Medical history 
• 
Whether you have taken any prescription or over-the-counter medicines, vitamins, or herbal 
preparations. 
• 
If you currently use tobacco or vaping products, the last time you used them. 
• 
Weight 
• 
Vital signs 
• 
Blood collection for PK assessment, before receiving atropine 
• 
Urine collection to test for pregnancy, if female 
• 
Assessment of side effects (AEs) and medications 
• 
Dry mouth questionnaire 
• 
Vaping and tobacco use questionnaire 
 
In addition, the investigator will conduct safety assessments that may include breath alcohol testing, to 
decide if you should receive each dose. 
 
Study drug administration 
 
You will not be allowed food or drink 1 hour prior to receiving the atropine dose. After 1 hour, you will 
receive either the low dose or high dose atropine sulfate under your tongue or the atropine in an IV. The 


Protocol number BP-C-19010 
Informed Consent 
Melanie Fein, MD 
Page 6 of 17 
APPROVED BY 
INTEGREVIEW IRB 
DECEMBER 19, 2019 
 
 
THIS IS AN IMPORTANT DOCUMENT - KEEP FOR FUTURE REFERENCE 
VERSION CONTROL 
jnb/11-11-19 lng/12-19-19 
 
order of the atropine doses will be based on your assigned dosing sequence. The low and high dose 
atropine sulfate will be placed under your tongue and you will be asked to try and not swallow for 30 
seconds. After 30 seconds, you can swallow as normal. The atropine injection will be performed via an  
IV in a vein in your arm. 
 
After study drug administration 
 
The following information will be collected and procedures performed: 
• 
Blood pressure and heart rate every 10 minutes for the first hour, every 20 minutes at the second hour, 
and every 30 minutes for the next 2 hours. 
• 
Blood collection for PK assessments at 2, 4, 6, 10, 15, 20, 30, 45, and 60 minutes, and 2, 4, 6, and 8 
hours post-dose from a catheter in your arm; if for some reason the catheter cannot be used, blood 
sample(s) may be drawn by needle stick 
• 
Dry mouth questionnaire every 10 minutes for one hour 
• 
Assessment of sides effects (AEs) and medications 
• 
Electrocardiogram within 5 minutes, if your dose was the IV dose of atropine. The electrocardiogram 
may be repeated if the investigator believes it is necessary. 
 
The dry mouth questionnaire will be done by asking you to rate from 1-10 (10 being most dry) the 
dryness of your mouth, lip and tongue. 
 
You will not be allowed to drink water for 1 hour after dosing. After 1 hour, you will be allowed to drink 
as much water as you want. Also, based on the dry mouth questionnaire, you may receive water earlier 
than one hour if certain conditions are met. You will be discharged from the clinic after you have finished 
all the study assessments. 
 
Visits 2 and 3: 
 
After Visit 1, you will return to the clinic in about 6 days for Visit 2. This is called a washout period and 
is necessary to allow your body to remove all traces of atropine. Visit 2 will be similar to Visit 1 with 
respect to dosing and procedures. 
 
After Visit 2, you will return to the clinic in about 6 days for Visit 3. Visit 3 will be similar to Visit 2 with 
respect to dosing and procedures. 
 
Blood Samples: 
 
Blood samples for screening will be taken from your left or right arm using a needle and a collection vial. 
The total amount of blood dawn at screening will be about 4 teaspoons (20 mL). 
 
Two teaspoons (10 mL) of blood will be collected each time a PK sample is taken at Visits 1, 2 and 3. 
The blood will be taken from a flexible tube called a catheter in your left or right arm. If the catheter 
cannot be used, blood may be drawn by needle stick. You cannot choose how the blood is taken. There 
will be 14 blood draws in a single dosing visit for the PK samples. The total amount of blood drawn for 
PK samples over the study will be about 2 cups (440 mL). For comparison, the standard blood donation  
is about 2 cups (480 mL). Because a catheter is being used to collect the PK blood samples, a small 
amount of blood will be drawn and discarded to clear the line before each PK blood draw. The amount 
drawn to be discarded is approximately 84 mL (about 1/3 cup). 


Protocol number BP-C-19010 
Informed Consent 
Melanie Fein, MD 
Page 7 of 17 
APPROVED BY 
INTEGREVIEW IRB 
DECEMBER 19, 2019 
 
 
THIS IS AN IMPORTANT DOCUMENT - KEEP FOR FUTURE REFERENCE 
VERSION CONTROL 
jnb/11-11-19 lng/12-19-19 
 
Telephone follow up: 
 
After Visit 3, you will be released from the clinic and about 6 days later will have a follow-up telephone 
call from the clinic. During this call you will be asked if there were any changes to your general health, 
and if you have taken any over-the-counter or prescription medicines, vitamins, minerals or herbal 
products. An assessment of side effects (AEs) will be collected. 
 
HIV AND HEPATITIS TESTING 
 
As required by the study, you must have your blood tested for the hepatitis viruses and for HIV. HIV is 
the virus that causes AIDS. If you have a positive HIV or hepatitis test you cannot be in the study. 
 
If the HIV test is positive, a follow-up test will be done. If the follow-up test is also positive, you will be 
told in private and you will also be told about counseling. 
 
In the interest of public and participant safety, if we cannot reach you by phone to provide you with the 
HIV, Hepatitis B and/or Hepatitis C results, or you do not respond to the return receipt letter; we will mail 
positive results to your address of record via certified mail. 
 
It may take weeks or months after being infected with HIV for the test to be positive. The HIV test is not 
always right. 
 
Positive test results are required to be reported to the State Department of Health. If you have any 
questions about what information is required to be reported please ask the investigator or study staff. 
 
Although this testing is supposed to be private, this cannot be guaranteed. For example, it is possible for  
a court of law to get health or study records without your permission. 
 
POSSIBLE SIDE EFFECTS AND RISKS 
 
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. 
 
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. 
 
Below is a list of the most common side effects of atropine sulfate ophthalmic solution, USP 1%, when 
administered as eye drops: 
 
• 
Sensitivity to light 
• 
Blurred vision 
• 
Eye pain/stinging 
• 
Reduced tears 
• 
Dry skin, mouth and throat 
• 
Increased blood pressure 
• 
Increased heart rate 
• 
Restlessness 
• 
Irritability 


Protocol number BP-C-19010 
Informed Consent 
Melanie Fein, MD 
Page 8 of 17 
APPROVED BY 
INTEGREVIEW IRB 
DECEMBER 19, 2019 
 
 
THIS IS AN IMPORTANT DOCUMENT - KEEP FOR FUTURE REFERENCE 
VERSION CONTROL 
jnb/11-11-19 lng/12-19-19 
 
• 
Confusion 
• 
Flushed skin 
• 
Allergic reactions 
 
In published medical articles, atropine sulfate ophthalmic solution has been given safely to over 400 
people under the tongue. The most common side effect has been dry mouth. 
 
Below is a list of the most common side effects of atropine sulfate injection solution, USP 1%: 
 
• 
Increased heart rate (with recurrent use) 
• 
Increased blood pressure 
• 
Dry skin, mouth and throat 
• 
Blurred vision 
• 
Increased eye pressure 
• 
Intestinal problems like constipation and in rare cases a blockage 
• 
Trouble urinating 
• 
Thickening of mucus 
• 
Flushed skin 
• 
Trouble with producing sweat 
 
These effects are generally short-lived and go away within hours. You will be monitored closely after you 
have received atropine at each visit 
 
Administration of the study drug, like any medication, may cause an allergic reaction. Symptoms of any 
allergic reaction can include a rash, hives, itching, and/or difficulty breathing, closing of the throat, and 
swelling of the lips, tongue, or face. It may rarely cause death. You will be monitored carefully after 
administration of the study drug for signs of an allergic reaction. There are trained medical staff and 
emergency equipment and medicines available at the study site to treat you in the event of an allergic 
reaction. If you experience any of the above symptoms or any other significant symptoms, dial 9-1-1 and 
seek medical attention immediately, and notify the study staff listed on the first page of this consent 
document. 
Subjects who develop any visible skin reaction may have the area photographed to document the extent of 
the reaction. These photographs will only be labeled with your subject ID number and will not contain 
any personal information. 
 
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. 
 
ADDITIONAL RISKS OR DISCOMFORTS 
 
Blood collection: 
 
There are side effects of having blood drawn during the screening visit and for PK samples. 


Protocol number BP-C-19010 
Informed Consent 
Melanie Fein, MD 
Page 9 of 17 
APPROVED BY 
INTEGREVIEW IRB 
DECEMBER 19, 2019 
 
 
THIS IS AN IMPORTANT DOCUMENT - KEEP FOR FUTURE REFERENCE 
VERSION CONTROL 
jnb/11-11-19 lng/12-19-19 
 
There may be side effects of having blood drawn such as: 
 
• 
Fainting 
• 
Redness 
• 
Pain 
• 
Bruising 
• 
Bleeding 
• 
Infection 
• 
Nerve damage 
• 
Blood clots, which may cause inflammation, swelling and pain 
If you feel faint, tell the study staff right away. 
Electrocardiogram (ECG): 
 
The ECG test is a recording of the electrical activity of your heart. The sticky pads used may be cold 
when applied and sometimes cause some discomfort such as redness or itching. If the hair under the 
patches needs to be shaved, irritation from shaving could occur. Sometimes hair is almost removed when 
the sticky pads are removed. All efforts will be made to avoid this. 
Risks of Intravenous (IV) Injection: 
 
• 
Infection 
• 
Pain 
• 
Redness 
• 
Bruising 
• 
Irritation from the fluids or medication being given 
• 
Local swelling 
• 
Accidental injecting into a muscle 
• 
Fainting 
 
BIRTH CONTROL, DANGERS OF PREGNANCY AND BREASTFEEDING 
 
If you are a female, you must not get pregnant while in this study. The only certain way to not get 
pregnant is to not have sex. If you are a female of childbearing potential (able to become pregnant) and 
choose to have sex with a male partner, you must have used one of the following methods of birth control 
for at least 2 months prior to the Screening visit and agree to continue using an acceptable form for the 
duration of the study (through Telephone Follow-up {Day 21}). 
 
Adequate contraception is defined as a contraceptive method with a failure rate of less than 1% per year 
when used consistently and correctly and when applicable, in accordance with the product label and 
includes: 
 
• 
Oral contraceptives 
• 
Injectable progestogen 
• 
Implants of etenogestrel or levonorgestrel 
• 
Estrogenic vaginal ring 
• 
Percutaneous contraceptive patches 


Protocol number BP-C-19010 
Informed Consent 
Melanie Fein, MD 
Page 10 of 17 
APPROVED BY 
INTEGREVIEW IRB 
DECEMBER 19, 2019 
 
 
THIS IS AN IMPORTANT DOCUMENT - KEEP FOR FUTURE REFERENCE 
VERSION CONTROL 
jnb/11-11-19 lng/12-19-19 
 
• 
Intrauterine device (IUD) or intrauterine system 
• 
Male partner sterilization at least 6 months prior to the female subject’s screening visit 
 
A female of childbearing potential is defined as post onset menarche and premenopausal female capable 
of becoming pregnant. This does not include females who meet any of the following conditions: 
menopausal (no menstrual period) > 2 years, tubal ligation (tubes tied) > 1 year, bilateral salpingo- 
oophorectomy (removal of both ovaries and fallopian tubes), or hysterectomy (removal of the uterus). 
 
Even if you use birth control during the study, there is a chance you (if you are female) could become 
pregnant. If you or your partner are pregnant or become pregnant during the study, the study drug may 
involve unforeseeable risks to the unborn baby. A pregnancy test is not always right, especially in the 
early stages of pregnancy. 
 
You cannot be in the study if you are breastfeeding. It is not known whether the study drug can be given 
to breast fed babies. Therefore, if you are breastfeeding a child you cannot participate in the study. 
 
POSSIBLE BENEFITS OF THE STUDY 
 
You will get no medical benefit from this study, other than the possible benefit of free medical tests. 
Information learned from the study may help other people in the future. 
 
ALTERNATIVES TO PARTICIPATING IN THE STUDY 
 
Since this study is for research only, the only other choice would be not to be in the study. 
 
CONFIDENTIALITY 
 
Your records of being in this study will be kept private except when ordered by law. The following 
people will have access to your study records: 
 
• 
The investigator 
• 
BARDA, High Point Clinical Trials Center, and Rho, Inc.; including monitors and auditors 
• 
The United States Food and Drug Administration (FDA) 
• 
Other state or federal regulatory agencies 
• 
IntegReview IRB 
 
Your information or bio-specimens will not be used or distributed for future research studies even if 
identifiers are removed. 
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by U.S. 
Law. This Web site will not include information that can identify you. At most, the Web site will include 
a summary of the results. You can search this Web site at any time. 
 
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. 


Protocol number BP-C-19010 
Informed Consent 
Melanie Fein, MD 
Page 11 of 17 
APPROVED BY 
INTEGREVIEW IRB 
DECEMBER 19, 2019 
 
 
IN CASE OF STUDY RELATED INJURY 
 
If you become ill or are injured while you are in the study, seek medical attention right away, and notify 
the study staff listed on the first page of this consent document. You should inform the healthcare 
professional treating you that you are participating in this study. 
The study doctor may ask you to stay longer at your current visit, have additional testing or return to the 
clinic for an additional visit. If you tell the study staff that you think you have been injured, the study  
staff may ask you to visit the office or refer you to other medical providers for medical care, even after 
you have completed your regular study visits. 
If you are injured as a result of taking the study drug(s) or from procedures done for the purpose of this 
study, the sponsor will pay for those medical expenses necessary to treat your injury that are not covered 
by your medical insurance or any other third-party coverage. You will not lose any of your legal rights or 
release the sponsor, the Investigator, the study staff, or study site from liability for mistakes by signing 
this consent document. 
To pay medical expenses, the sponsor will need to know some information about you like your name, 
date of birth, and Medicare Beneficiary Identifier (MBI). This is because the sponsor has to check to see 
whether you receive Medicare and, if you do, report the payment it makes to Medicare. 
LEGAL RIGHTS 
You will not lose any of your legal rights by signing this consent form. 
CONTACT INFORMATION 
If you have questions, concerns, or complaints about this study or to report a study related injury, contact: 
Melanie Fein, MD 
(336) 841-0700 
(336) 862-0634 (24-hour phone) 
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 and then notify the study 
staff listed on the first page of this consent document. 
If you do not want to talk to the investigator or study staff, if you have concerns or complaints about the 
research, or to ask questions about your rights as a study subject you may contact IntegReview. 
IntegReview is a group of people that has reviewed this research study. The main goal of this review is to 
protect the rights and well-being of the human subjects participating in research studies. IntegReview’s 
policy indicates that all concerns/complaints are to be submitted in writing for review at a convened IRB 
meeting to: 
 
Mailing Address: 
OR 
Email Address: 
Chairperson 
IntegReview IRB 
3815 S. Capital of Texas Highway 
Suite 320 
Austin, Texas 78704 
integreview@integreview.com 
 
THIS IS AN IMPORTANT DOCUMENT - KEEP FOR FUTURE REFERENCE 
VERSION CONTROL 
jnb/11-11-19 lng/12-19-19 


Protocol number BP-C-19010 
Informed Consent 
Melanie Fein, MD 
Page 12 of 17 
APPROVED BY 
INTEGREVIEW IRB 
DECEMBER 19, 2019 
 
 
THIS IS AN IMPORTANT DOCUMENT - KEEP FOR FUTURE REFERENCE 
VERSION CONTROL 
jnb/11-11-19 lng/12-19-19 
 
If you are unable to provide your concerns/complaints in writing or if this is an emergency situation 
regarding subject safety, contact our office 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. 
 
PAYMENT FOR BEING IN THE STUDY 
 
You may receive up to $1,350.00 for being in the study. You will be paid per completed visit as follows: 
 
Visit 
Compensation (amount) 
Screening 
$0 – You will NOT be compensated for this visit 
Visit 1 
$375.00 
Visit 2 
$375.00 
Visit 3 
$375.00 
Follow-up Telephone Call 
$225.00 
 
Total compensation for study completion will be up to $1,350.00 for completion of all study visits and the 
Follow-up Telephone Call. If it is determined by your study doctor that you should stop the study early,  
or you choose to withdraw from the research study, study payment will be prorated based on the study 
visits you complete as detailed in the table above; this means you will only be paid for the study days you 
participate in. If you check-into the facility for Visit 1, 2 or 3 and are discharged from the study prior to 
that day’s dosing, therefore not completing that day’s activities, you will receive $125.00 compensation 
for that day’s visit within seven (7) days of the visit. 
 
The amount provided for each visit is intended to provide you with compensation for travel and the cost 
of inconvenience for participating in this clinical study. Please ensure you bring enough funds with you 
for transport home from all visits. You will receive your compensation within seven (7) days of study 
completion. 
 
If it is necessary for High Point Clinical Trials Center to obtain medications; study supplies that you were 
supposed to provide; clothing; toiletries; or transportation outside of what is described in this consent, you 
will be responsible for these costs. If you are unable to pay the fees upfront, High Point Clinical Trials 
Center will pay for these expenses and may deduct the cost from your stipend check. High Point Clinical 
Trials Center is not liable for your safety during travel to and from our site. 
 
If it is necessary for you to return to the research unit for additional safety follow up visits, you will be 
compensated for travel expenses at $100.00 for each completed visit. For more information, please talk to 
your study doctor. 
 
No deductions will be withheld from your compensation check for tax purposes; you are responsible for 
reporting any payment on your state and federal tax returns; being in this study does not make you an 


Protocol number BP-C-19010 
Informed Consent 
Melanie Fein, MD 
Page 13 of 17 
APPROVED BY 
INTEGREVIEW IRB 
DECEMBER 19, 2019 
 
 
THIS IS AN IMPORTANT DOCUMENT - KEEP FOR FUTURE REFERENCE 
VERSION CONTROL 
jnb/11-11-19 lng/12-19-19 
 
employee of the sponsor or the study site; at the end of each year, the study site will notify the IRS of all 
stipends you have received throughout the year. 
 
VOLUNTEERING TO BE IN THE STUDY 
 
It is your choice if you want to be in the study. No one can force you to be in the study. You may not 
want to be in this study or you may leave the study at any time without penalty or loss of benefits to 
which you are otherwise entitled. 
 
The investigator, the sponsor, IntegReview, or the FDA 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 
• 
If you become pregnant 
• 
At the request of the sponsor 
• 
At the request of the IRB 
 
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 early, an Early Termination (ET) visit 
assessments will be performed, when possible. The ET visit may be conducted in clinic or by phone as 
determined by the investigator. If the investigator determines this ET visit should be conducted in the 
clinic, the investigator may want to perform a physical exam, including vital signs, an ECG or perform a 
blood draw to conduct laboratory tests, at their discretion. 
 
NEW FINDINGS 
 
If there is new information or any significant new findings that could relate to your willingness to 
continue participation, we will tell you. You can then decide if you still want to be in the study. 


Protocol number BP-C-19010 
Informed Consent 
Melanie Fein, MD 
Page 14 of 17 
APPROVED BY 
INTEGREVIEW IRB 
DECEMBER 19, 2019 
 
 
THIS IS AN IMPORTANT DOCUMENT - KEEP FOR FUTURE REFERENCE 
VERSION CONTROL 
jnb/11-11-19 lng/12-19-19 
 
AGREEMENT TO BE IN THE STUDY 
 
If you do not feel that you will be able to comply with any of the restrictions or procedures, please discuss 
with the study staff prior to signing and dating this consent form. 
 
This consent form contains important information to help you decide if you want to be in the study. If you 
have any questions that are not answered in this consent form, ask one of the study staff. 
 
Please answer YES or NO to the following questions: 
 
A. Is this document in a language you understand? 
 Yes 
 No 
 
B. Do you understand the information in this consent form? 
 Yes 
 No 
 
C. Have you been given enough time to ask questions and talk about the study? 
 Yes 
 No 
 
D. Have all your questions been answered to your satisfaction? 
 Yes 
 No 
 
E. Do you think you received enough information about the study? 
 Yes 
 No 
 
F. Do you volunteer to be in this study of your own free will and without being pressured by the study 
doctor or study staff? 
 Yes 
 No 
 
G. Do you know that you can leave the study at any time without giving a reason and without affecting 
your health care? 
 Yes 
 No 
 
H. Do you know that your health records from this study may be reviewed by the sponsor company and 
by government authorities? 
 Yes 
 No 
 
I. Do you know that you cannot be in another study while you are in this study? 
 Yes 
 No 
 
J. You are aware that the study drug is for investigational purposes only and only for your use, and you 
are not allowed to share it with any other person. 
 Yes 
 No 
 
K. You are aware that HPCTC is a research facility and not a treating facility and therefore you should 
continue to obtain your routine medical care with the provider of your choice. You are also aware 
that HPCTC will refer you to outside medical care if treatment is needed as a result of the study drug 
or study procedures. 
 Yes 
 No 


Protocol number BP-C-19010 
Informed Consent 
Melanie Fein, MD 
Page 15 of 17 
APPROVED BY 
INTEGREVIEW IRB 
DECEMBER 19, 2019 
 
 
THIS IS AN IMPORTANT DOCUMENT - KEEP FOR FUTURE REFERENCE 
VERSION CONTROL 
jnb/11-11-19 lng/12-19-19 
 
IF YOU ANSWERED “NO” TO ANY OF THE ABOVE QUESTIONS, 
OR YOU ARE UNABLE TO ANSWER ANY OF THE ABOVE QUESTIONS, 
YOU SHOULD NOT SIGN AND DATE THIS CONSENT FORM. 
 
 
 
Printed Name of Adult Subject 
Time 
 
 
Signature of Adult Subject 
Date 
 
 
Printed Name of Person Explaining Consent 
Time 
 
 
Signature of Person Explaining Consent 
Date 
 
You will be given a signed and dated copy of this consent form to keep. 


Protocol number BP-C-19010 
Informed Consent 
Melanie Fein, MD 
Page 16 of 17 
APPROVED BY 
INTEGREVIEW IRB 
DECEMBER 19, 2019 
 
 
THIS IS AN IMPORTANT DOCUMENT - KEEP FOR FUTURE REFERENCE 
VERSION CONTROL 
jnb/11-11-19 lng/12-19-19 
 
AUTHORIZATION TO USE AND DISCLOSE 
PROTECTED HEALTH INFORMATION 
 
If you decide to be in this study, the study doctor and research team will use and share health data about 
you to conduct the study. Health data may include: 
 
• 
Your name. 
• 
Address. 
• 
Phone number. 
• 
Date of birth. 
• 
Medical history. 
• 
Information from your study visits, including all test results. 
 
Health data may come from your study records or from existing records kept by your doctor or other 
health care workers. 
 
For this study, the research team may share health data about you with authorized users. Authorized users 
may include: 
 
• 
Representatives of BARDA, the sponsor 
• 
Representatives of High Point Clinical Trials Center, the research center 
• 
Representatives of Rho, Inc, a Contract Research Organization that is coordinating and monitoring 
the study. 
• 
Representatives of IntegReview IRB (an Institutional Review Board that reviews this study). 
• 
The Food and Drug Administration (FDA) and other US federal and state agencies. 
• 
Government agencies to whom certain diseases (like HIV, hepatitis, and STDs) must be reported. 
• 
Governmental agencies of other countries. 
• 
Outside individuals and companies, such as laboratories and data storage companies, that work with 
the researchers and sponsor and need to access your information to conduct this study. 
• 
Other research doctors and medical centers participating in this research, if applicable. 
• 
A data safety monitoring board which oversees this research, if applicable. 
 
Your health data will be used to conduct and oversee the research, including for instance: 
 
• 
Other research activities related to the study drug. 
 
Once your health data has been shared with authorized users, it may no longer be protected by federal 
privacy law and could possibly be used or disclosed in ways other than those listed here. 
 
Your permission to use and share health data about you will end in 50 years unless you revoke it (take it 
back) sooner. 
 
You may revoke (take back) your permission to use and share health data about you at any time by 
writing to the study doctor. If you do this, you will not be able to stay in this study. No new health data 
that identifies you will be gathered after your written request is received. However, health data about you 
that has already been gathered may still be used and given to others as described in this form. 


Protocol number BP-C-19010 
Informed Consent 
Melanie Fein, MD 
Page 17 of 17 
APPROVED BY 
INTEGREVIEW IRB 
DECEMBER 19, 2019 
 
 
THIS IS AN IMPORTANT DOCUMENT - KEEP FOR FUTURE REFERENCE 
VERSION CONTROL 
jnb/11-11-19 lng/12-19-19 
 
Your right to access your health data in the study records will be suspended during the study to keep from 
changing the study results. When the study is over, you can access your study health data. 
 
If you decide not to sign and date this form, you will not be able to take part in the study. 
 
STATEMENT OF AUTHORIZATION 
 
I have read this form and its contents were explained. My questions have been answered. I voluntarily 
agree to allow study staff to collect, use and share my health data as specified in this form. I will receive a 
signed and dated copy of this form for my records. I am not giving up any of my legal rights by signing 
and dating this form. 
 
 I Voluntarily Agree to allow study staff to collect, use and share my health data as specified in this 
form. 
 
 I DO NOT Agree to allow study staff to collect, use and share my health data as specified in this form. 
 
 
Printed Name of Subject 
 
 
Signature of Subject 
Date 
 
 
Printed Name of the Person Obtaining the Authorization 
 
 
Signature of the Person Obtaining the Authorization 
Date