A Two-Period, Two-Sequence, Two-Treatment, Single-Dose Crossover Study of Atropine Sulfate Ophthalmic Solution (1%) Administered Sublingually vs Atropine Sulfate Administered Intramuscularly for Bioequivalence Determination
Phase: PHASE1
Conditions: Atropine Bioequivalence
Sponsor: Biomedical Advanced Research and Development Authority

HHS/ASPR/BARDA 
 
SABER 
Protocol BP-C-24-0001 Version 1.0 
 
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BP-C-24-0001 
 
A TWO-PERIOD, TWO-SEQUENCE, TWO-
TREATMENT, SINGLE-DOSE CROSSOVER STUDY OF 
ATROPINE SULFATE OPHTHALMIC SOLUTION (1%) 
ADMINISTERED SUBLINGUALLY VERSUS ATROPINE 
SULFATE ADMINISTERED INTRAMUSCULARLY FOR 
BIOEQUIVALENCE DETERMINATION 
Sublingual Atropine Bioequivalence by Route of Administration 
(SABER) 
Sponsor: 
 
Biomedical Advanced Research and Development Authority  
(BARDA) 
200 Independence Ave. 
Washington, DC 20201 
ATTN: ASPR/BARDA 
 
Version of Protocol:  
1.0 
Date of Protocol:  
 
13 February 2024 
 
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. 
 
 
 

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STATEMENT OF COMPLIANCE 
Each institution engaged in this research will hold a current Federalwide Assurance (FWA) 
issued by the Office of Human Research Protection (OHRP) for federally funded research. The 
Institutional Review Board (IRB)/ Independent Ethics Committee (IEC) must be registered with 
OHRP as applicable to the research.   
The study will be carried out in accordance with the following as applicable: 
• United States Code of Federal Regulations (CFR) 45 CFR Part 46: Protection of 
Human Subjects 
• Food and Drug Administration (FDA) Regulations: 21 CFR Part 50 (Protection of 
Human Subjects), 21 CFR Part 54 (Financial Disclosure by Clinical Investigators), 21 
CFR Part 56 (Institutional Review Boards), 21 CFR Part 11 (Electronic Records; 
Electronic Signatures), and 21 CFR Part 312 (Investigational New Drug Application), 
and/or 21 CFR 812 (Investigational Device Exemptions) 
• The International Council for Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use (ICH) E6(R2) Good Clinical 
Practice, and the Belmont Report: Ethical Principles and Guidelines for the Protection 
of Human Subjects of Research, Report of the National Commission for the 
Protection of Human Subjects of Biomedical and Behavioral Research 
• Any additional Federal, State, and Local Regulations and Guidance 
The signature below provides the necessary assurance that this study will be conducted 
according to all stipulations of the protocol including statements regarding confidentiality, and 
according to local legal and regulatory requirements, US federal regulations, and ICH E6(R2) 
Good Clinical Practice (GCP) guidelines. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Printed Name of Investigator 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Investigator 
 
 
 
 
 
 
 
 
 
Date 
 

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2. 
SYNOPSIS 
Name of Sponsor/Company: Biomedical Advanced Research and Development Authority 
(BARDA) 
Name of Study Drug:  
Test Drug: Atropine Sulfate Ophthalmic Solution, USP 1% (NDC 82260-0001-01) 
Reference Drug: Atropine Sulfate Injection, USP 8 mg/20 mL (0.4 mg/mL) in a multidose vial 
presentation (NDC 63323–580-20)  
Name of Active Ingredient: Atropine sulfate 
Title of Study: A Two-period, Two-sequence, Two-treatment, Single-dose Crossover Study of 
Atropine Sulfate Ophthalmic Solution (1%) Administered Sublingually vs Atropine Sulfate 
Administered Intramuscularly for Bioequivalence Determination 
Short Title: Sublingual Atropine Bioequivalence by Route of Administration (SABER) 
Protocol Number: BP-C-24-0001 
Version Number: 1.0 
Study center(s): 1 (one) 
Study period (years): 0.5 
Estimated date first participant enrolled: April 2024 
Estimated date last participant completed: August 2024 
Phase of development: Phase 1 
 
Study Objectives: 
Primary Objective: 
• 
To establish bioequivalence of Atropine Sulfate Ophthalmic Solution, USP 1% given 
sublingually (SL) vs intramuscular (IM) 8 mg/20 mL (0.4 mg/mL) atropine sulfate injection. 
Secondary Objective: 
• To compare the bioavailability of Atropine Sulfate Ophthalmic Solution, USP 1% given SL 
vs IM 8 mg/20 mL (0.4 mg/mL) atropine sulfate injection. 
Methodology: This is a randomized, two-period, two-sequence, crossover study to assess the 
bioequivalence, bioavailability, and pharmacokinetics (PK) of a single dose of atropine administered 
SL or IM in healthy adult volunteers. Approximately 46 healthy male and non-pregnant female 
volunteers will be enrolled to obtain approximately 36 evaluable participants in the per protocol 
population. Additional participants may be randomized if participants are withdrawn prior to 
receiving one or both doses of study drug. Eligible participants will be randomized at a 1:1 ratio to 
receive one of two treatment dosing sequences (A or B) as depicted in the table below: 
Study Design Scheme by Dosing Sequence 
Dosing Sequence 
Targeted Number of 
Randomized 
Participants (N) 
Targeted Number 
of Evaluable 
Participants (N) 
 
Period 1 (Visit 1; 
Day 1) 
Period 2 (Visit 2; 
Day 8) 
A 
23 
18 
SL 
IM 
B 
23 
18 
IM 
SL 

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Volunteers will be screened for study participation from Days -14 to -3. After Screening on Day 1, 
eligible participants will be enrolled and will be randomized to receive one of two dosing sequences 
as presented in the table above. Once randomized, each participant will receive 2 doses of atropine 
separated by a wash out period of 6 ±1 days. During Visit 1 (Day 1) and Visit 2 (Day 8), participants 
will be administered SL or IM atropine, according to their randomly assigned dosing sequence. At 
each dosing visit, blood samples for PK will be collected at time 0 (pre-dose) and at 13 time points 
post-dose at 5, 10, 15, 20, 30, 45, 60, and 90 minutes and 2, 2.5, 4, 6, and 8 hours after dosing. 
Participants will be discharged from the clinic after the 8-hour blood sample collection. Participants 
will be followed for approximately 6 days after their last dose.  
Number of participants (planned): Approximately 46 enrolled for 36 evaluable 
Diagnosis and main criteria for inclusion: Healthy male and non-pregnant female participants aged 
18 through 65 years, inclusive.  
Eligibility criteria will be assessed at Screening and must be reviewed just prior to each dose of 
atropine. Criteria specified as only being evaluated at Screening or at Pre-dose Visits will be assessed 
only at those visits. If the participant no longer meets applicable eligibility criteria, the investigator, in 
consultation with the medical monitor in cases of uncertainty, must determine whether the participant 
should receive the atropine dose or be terminated early from study drug. 
Participant Inclusion Criteria 
1. Healthy male and non-pregnant female volunteers between the ages of 18 and 65 years, 
inclusive, at time of consent. 
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 adequate method of birth control for at least 2 months prior to Screening and 
must agree to continue using an adequate method of birth control from Screening through 
Follow-up (Day 15). 
a. A female of childbearing potential is defined as a post onset of 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 participant’s Screening Visit. 
4. In the judgment of the investigator, the participant 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 Screening laboratory assessments, 
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 
Assessments. 
Participant Exclusion Criteria 
1. Females who have a positive pregnancy test or who are breastfeeding.  
2. Participants 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 
Screening test will not be repeated prior to subsequent dosing).  

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3. Participants with aspartate aminotransferase (AST), alanine aminotransferase (ALT), or 
serum creatinine >1.5 × ULN at Screening. (These Screening 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. 
Participants who have been effectively treated for hepatitis C, as evidenced by a negative 
hepatitis C RNA confirmation test and who no longer require antiviral therapy, are eligible 
for participation. (These Screening tests will not be repeated prior to subsequent dosing.)  
5. Participants 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 participant 
should be terminated from further dosing.  
6. Participants 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 participant should be terminated from further 
dosing.  
7. Participants who are current smokers or are currently using any oral nicotine/oral tobacco 
product (e.g. snuff, chew, lozenges, nicotine gum, pouches) or electronic cigarette or vaping 
device (e.g., e-cigarette, mod, vape pen, JUUL, e-cigar, e-hookah, e-pipe, vape pods) or have 
used any of these products within 6 months prior to Screening. 
8. Participants with glaucoma and/or history of ocular surgery (including LasikTM), ocular 
trauma, or congenital ocular disorder. 
9. Participants with any history of heart disease, including but not limited to hypertension, 
coronary artery disease, arrhythmia (treated or untreated), congestive heart failure, 
pacemaker, history of vasovagal syncope, any supraventricular tachycardia, peripheral 
vascular disease, or claudication. 
10. Participants 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. 
11. Participants with a history of partial organic pyloric stenosis, chronic constipation, 
gastroparesis, or other gastrointestinal motility issues.  
12. Participants with a history of xerostomia due to an underlying disease or previous radiation 
therapy to the head and neck. 
13. Males with history of symptomatic prostatic hypertrophy; males or females with a history of 
urinary hesitancy or retention. 
14. Participants with a blood pressure >140/90 mm Hg taken after the participant has been seated 
and resting for at least five minutes. 
15. Participants with a history or current diagnosis of myasthenia gravis.  
16. Participants who have donated blood within 8 weeks of Screening or intend to donate blood 
during the study period.  
17. Participants 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.) 
18. Participants with a known sensitivity or prior adverse reaction to atropine. 
19. Participants who have consumed alcohol within 24 hours prior to each Pre-dose Visit. (This 
will be assessed only at Visit 1 [Pre-dose] and Visit 2 [Pre-dose].) 

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20. Participants with any other condition that, in the opinion of the investigator, would pose a 
health risk to the participant if enrolled, would interfere with SL or IM administration of 
study drug, or would otherwise interfere with interpretation of study results. 
Participants cannot be rescreened for exclusionary laboratory test results. Potentially exclusionary 
vital sign results may be repeated once. If a participant’s repeat vitals remain exclusionary or the 
investigator determines that the repeat vital signs could pose a risk to participating in the study, then 
the participant will be excluded. 
Test drug, dosage, and mode of administration: Atropine Sulfate Ophthalmic Solution USP, 1% 
(NDC 82260-0001-01), 1 mg (100 µL of a 1% w/v solution), administered SL by pipette with at least 
a 30 second dwell time without swallowing 
Duration of treatment: Participants will receive two doses of atropine sulfate separated by 
approximately 7 days  
Reference drug, dosage, and mode of administration: Atropine Sulfate Injection, USP 8 mg/20 mL 
(0.4 mg/mL) in a multidose vial presentation (NDC 63323–580-20), 1 mg (2.5 ml) administered by 
IM injection into the mid-anterolateral thigh 
Criteria for evaluation: Pharmacokinetic parameters only (bioequivalence/bioavailability) 
Study Endpoints 
Primary Endpoints 
The bioequivalence of atropine sulfate administered SL versus administered IM as measured by the 
following 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) 
Secondary Endpoints 
The relative bioavailability of atropine sulfate administered SL versus IM as measured by the 
following PK parameters: 
• 
Area under the analyte concentration versus time curve to time 45, 60, 90, 120, 150, and 
240 minutes (AUC45, AUC60, AUC90, AUC120, AUC150, and AUC240, respectively) 
• 
Maximum measured plasma concentration (Cmax) 
• 
Time to Cmax (tmax)  
• 
Apparent terminal elimination half-life (t1/2)  
• 
Terminal elimination rate constant (λz) 
• 
Volume of distribution (Vd/F)  
• 
Total body clearance (CL/F) 
• 
Absorption rate constant (Ka) 

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Statistical methods: 
Analysis Plan 
Statistical analyses will be performed using SAS® software Version 9.4 or later. Phoenix WinNonLin 
software Version 8.3 or later will be used to generate PK parameter estimates. 
Descriptive statistics will be used to summarize participant characteristics and safety. These 
summaries will be presented overall and separately for each route of administration.   
Pharmacokinetic parameter estimates will be summarized using descriptive statistics. Bioavailability 
of SL administration of atropine sulfate relative to that of IM atropine sulfate will be assessed based 
on ratios of least-square means and their associated 90% confidence intervals (CIs) generated from 
linear mixed models including terms for dosing sequence, route, and period as fixed effects, and 
subject nested within dosing sequence as a random effect. Bioequivalence will be considered met if 
the 90% CI of the ratio for AUC∞ and AUCt lie within 80.00 to 125.00%.     
Additional details of the statistical analyses, methods, and data conventions will be described in the 
Statistical Analysis Plan (SAP). 
Final Analyses  
A clinical study report will be written to include all PK and safety data collected throughout the study. 
For the final analysis, the study database will be monitored, cleaned, and locked per associated study 
plans. Further details will be specified in the SAP. 
Analysis Populations 
PK Analysis Population 
The PK analysis population will include all participants who are randomized, receive at least 1 study 
drug dose, and have PK samples collected for that period. Each participant’s data will be analyzed 
according to the corresponding route of administration for the applicable period. The PK analysis 
population will be used for all PK analyses.  
Per Protocol Population 
The per protocol population will include all participants who are randomized, receive atropine via 
both routes of administration according to their randomized dosing sequence, and have PK samples 
collected for both periods. In addition, participants with major protocol deviations may be excluded if 
it is determined that the deviations affect the integrity of PK data. Each participant’s data will be 
analyzed according to the corresponding route of administration for the applicable period. Primary 
and secondary analyses will be repeated in the per protocol population if it differs from the PK 
analysis population. 
Safety Population 
The safety population will include all participants who are randomized and receive at least 1 study 
drug dose. Each participant’s data will be analyzed according to the corresponding route of 
administration for the applicable period. The safety population will be used for all safety displays. 
 
 

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3. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF 
FIGURES  
TABLE OF CONTENTS 
1. 
TITLE PAGE ................................................................................................................1 
2. 
SYNOPSIS ...................................................................................................................4 
3. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES .................9 
Table of Contents .............................................................................................................................9 
List of Tables .................................................................................................................................13 
List of Figures ................................................................................................................................14 
4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS .............................15 
5. 
INTRODUCTION ......................................................................................................17 
5.1. 
Background .................................................................................................................17 
5.2. 
Study Rationale ...........................................................................................................17 
5.3. 
Previous Clinical Studies ............................................................................................18 
6. 
STUDY OBJECTIVES ..............................................................................................20 
7. 
INVESTIGATIONAL PLAN .....................................................................................21 
7.1. 
Overall Study Design ..................................................................................................21 
7.2. 
Number of Participants ...............................................................................................22 
7.3. 
Treatment Assignment ................................................................................................22 
7.4. 
Individual Participant Dosing and Study Stopping Rules ..........................................22 
7.4.1. 
Early Termination of Dosing for an Individual Participant ........................................22 
7.4.2. 
Study Pausing Rules ...................................................................................................23 
7.5. 
Criteria for Study Suspension or Termination ............................................................23 
8. 
SELECTION AND WITHDRAWAL OF PARTICIPANTS .....................................25 
8.1. 
Selection of Study Population ....................................................................................25 
8.1.1. 
Participant Inclusion Criteria ......................................................................................25 
8.1.2. 
Participant Exclusion Criteria .....................................................................................25 
8.2. 
Participant Withdrawal ...............................................................................................27 
8.2.1. 
Participant Withdrawal Criteria ..................................................................................27 
8.2.2. 
Randomization of Additional Study Participants .......................................................28 
9. 
TREATMENT OF PARTICIPANTS .........................................................................29 
9.1. 
Description of Study Drug ..........................................................................................29 

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9.1.1. 
Atropine Sulfate Ophthalmic Solution, USP 1% ........................................................29 
9.1.2. 
Atropine Sulfate Injection, USP .................................................................................29 
9.2. 
Concomitant Medications ...........................................................................................30 
9.2.1. 
Prohibited and Permitted Concomitant Medications ..................................................30 
9.3. 
Treatment Compliance ................................................................................................31 
10. 
STUDY DRUG MATERIALS AND MANAGEMENT ...........................................32 
10.1. 
Study Drug ..................................................................................................................32 
10.2. 
Study Drug Packaging and Labeling ..........................................................................32 
10.3. 
Study Drug Storage .....................................................................................................32 
10.4. 
Study Drug Preparation and Administration ..............................................................32 
10.5. 
Study Drug Accountability .........................................................................................33 
10.6. 
Study Drug Handling and Disposal ............................................................................33 
10.7. 
Randomization and Blinding ......................................................................................33 
10.7.1. 
Randomization ............................................................................................................33 
10.7.2. 
Blinding ......................................................................................................................33 
11. 
ASSESSMENT OF PHARMACOKINETICS ...........................................................34 
12. 
ASSESSMENT OF SAFETY .....................................................................................35 
12.1. 
Safety Parameters .......................................................................................................35 
12.1.1. 
Demographic/Medical History ...................................................................................35 
12.1.2. 
Vital Signs ..................................................................................................................35 
12.1.3. 
Weight and Height ......................................................................................................35 
12.1.4. 
Physical Examination .................................................................................................35 
12.1.5. 
Electrocardiogram (ECG) ...........................................................................................36 
12.1.6. 
Clinical Laboratory Assessments ...............................................................................36 
12.1.6.1. 
Complete blood count with differential ......................................................................36 
12.1.6.2. 
Serum Chemistry, Liver Function, and Thyroid-stimulating Hormone 
Assessments ................................................................................................................36 
12.1.6.3. 
Virus Serology ............................................................................................................37 
12.1.6.4. 
Urine Drug Screen ......................................................................................................37 
12.1.6.5. 
Pregnancy Screen ........................................................................................................37 
12.1.7. 
Adverse Event Assessment .........................................................................................37 
12.1.8. 
Concomitant Medication Assessment .........................................................................37 
12.2. 
Adverse and Serious Adverse Events .........................................................................38 

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12.2.1. 
Definition of Adverse Events .....................................................................................38 
12.2.1.1. 
Adverse Event (AE) ....................................................................................................38 
12.2.1.2. 
Serious Adverse Event (SAE) ....................................................................................38 
12.3. 
Collection, Recording, and Grading Severity of Adverse Events ..............................39 
12.3.1. 
Collection of Adverse Events .....................................................................................39 
12.3.2. 
Recording Adverse Events .........................................................................................39 
12.3.3. 
Grading Severity of Adverse Events ..........................................................................39 
12.4. 
Relationship and Attribution to Study Drug ...............................................................40 
12.5. 
Reporting Safety Events to IRB .................................................................................40 
12.6. 
Pregnancy Reporting ..................................................................................................40 
12.7. 
Reporting Other Safety Information ...........................................................................41 
13. 
STATISTICS ..............................................................................................................42 
13.1. 
Endpoints ....................................................................................................................42 
13.1.1. 
Measures to Minimize Bias ........................................................................................42 
13.1.2. 
Analysis Plan ..............................................................................................................42 
13.1.2.1. 
Analysis Populations ..................................................................................................42 
13.1.2.2. 
Primary Analysis ........................................................................................................43 
13.1.2.3. 
Secondary Analyses ....................................................................................................43 
13.1.2.4. 
Safety Reviews ...........................................................................................................44 
13.1.2.5. 
Final Analysis .............................................................................................................44 
13.1.2.6. 
Exploratory Analyses ..................................................................................................44 
13.2. 
Sample Size Considerations .......................................................................................44 
13.3. 
Statistical Considerations ............................................................................................44 
13.3.1. 
Covariates ...................................................................................................................44 
13.3.2. 
Multicenter Studies .....................................................................................................44 
13.3.3. 
Multiple Comparisons and Multiplicity ......................................................................44 
13.3.4. 
Subgroup Analyses .....................................................................................................45 
13.3.5. 
Missing Data ...............................................................................................................45 
13.4. 
Procedures for Documenting Deviations from Planned Analyses .............................45 
14. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS .........................................46 
14.1. 
Inspection of Records .................................................................................................46 
14.2. 
Institutional Review Board .........................................................................................46 
15. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................47 

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15.1. 
Data Quality Assurance ..............................................................................................47 
15.2. 
Study Monitoring ........................................................................................................48 
15.3. 
Protocol Deviations ....................................................................................................48 
15.3.1. 
Protocol Deviation Definition .....................................................................................48 
15.3.2. 
Reporting and Managing Deviations ..........................................................................48 
16. 
REGULATORY AND ETHICAL CONSIDERATIONS ..........................................49 
16.1. 
Ethics Review .............................................................................................................49 
16.2. 
Ethical Conduct of the Study ......................................................................................49 
16.3. 
Written Informed Consent ..........................................................................................49 
17. 
DATA HANDLING AND RECORD KEEPING ......................................................51 
17.1. 
Confidentiality ............................................................................................................51 
17.2. 
Retention of Records ..................................................................................................51 
18. 
PUBLICATION POLICY ..........................................................................................52 
19. 
RESEARCH-RELATED INJURIES ..........................................................................53 
20. 
PROTOCOL AMENDMENT HISTORY ..................................................................54 
21. 
LIST OF REFERENCES ............................................................................................55 
22. 
APPENDICES ............................................................................................................56 
APPENDIX 1. PUBLICATION REVIEW OF SUBLINGUAL ADMINISTRATION 
OF ATROPINE ..........................................................................................................57 
APPENDIX 2. SCHEDULE OF ASSESSMENTS .......................................................................65 
APPENDIX 3. PREP ACT ............................................................................................................67 
 
 
 

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LIST OF TABLES 
Table 1:  
Abbreviations and Specialist Terms ...........................................................................15 
Table 2:  
Study Objectives and Endpoints .................................................................................20 
Table 3: 
Study Design Scheme by Dosing Sequence ...............................................................21 
Table 4: 
Summary of Study Drugs ...........................................................................................30 
Table 5: 
Complete Blood Count with Differential ...................................................................36 
Table 6: 
Serum Chemistry, Liver Function, and TSH Assessments .........................................37 
Table 7: 
Attribution of Adverse Events ....................................................................................40 
Table 8: 
Protocol Amendment History .....................................................................................54 
 
 
 

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LIST OF FIGURES 
Figure 1:   Overall Study Design .................................................................................................22 
 
  

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4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
The following abbreviations and specialist terms are used in this study protocol. 
Table 1:  
Abbreviations and Specialist Terms 
Abbreviation or Specialist Term 
Explanation 
AE 
Adverse event 
anti-HCV 
Hepatitis C antibody 
ASPR 
Administration for Strategic Preparedness and Response 
ALT 
Alanine transaminase 
AST 
Aspartate aminotransferase 
BARDA 
Biomedical Advanced Research and Development 
Authority  
BMI 
Body mass index 
CAPA 
Corrective and Preventative Action  
CFR 
Code of Federal Regulations 
CI 
Confidence interval 
CICP 
Countermeasures Injury Compensation Program 
CRU 
Clinical research unit 
CSN 
Clinical Studies Network 
CTCAE 
Common Terminology Criteria for Adverse Events 
DSMP 
Data safety monitoring plan 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EDTA 
Ethylenediaminetetraacetic acid 
ET 
Early termination 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HBsAg 
Hepatitis B surface antigen 
HCG 
Human chorionic gonadotropin 
HHS 
Health and Human Services 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
IM 
Intramuscular(ly) 

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Abbreviation or Specialist Term 
Explanation 
IRB 
Institutional Review Board 
IV 
Intravenous 
LFT 
Liver function test 
LLN 
Lower limit of normal 
MCM 
Medical countermeasures 
MedDRA 
Medical Dictionary for Regulatory Activities 
MOP 
Manual of Procedures 
NA 
Nerve agent 
NCI 
National Cancer Institute 
OTC 
Over the counter 
PK 
Pharmacokinetic 
POC 
Point-of-care 
PREP 
Public Readiness and Emergency Preparedness 
QA 
Quality assurance 
QC 
Quality control 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SAR 
Suspected Adverse Reaction 
SL 
Sublingual(ly) 
SME 
Subject Matter Expert 
TSH 
Thyroid-stimulating hormone 
ULN 
Upper limit of normal 
US 
United States 
USP 
United States Pharmacopoeia 

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5. 
INTRODUCTION 
5.1. 
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 Food and Drug Administration (FDA) approval and inclusion into the 
Strategic National Stockpile. However, in the event of widespread nerve agent (NA) poisoning, 
pre-deployed MCMs are likely to be inadequate due to limited availability of community caches 
(Chempack), logistical challenges in bringing the resources 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 pharmacokinetics (PK) of an alternative (sublingual [SL]) 
route of administration of atropine sulfate ophthalmic solution (1%) compared with the 
reference, atropine sulfate injected intramuscularly (IM).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 is 
available in multiple dosing forms and is commonly administered by IM injection, intravenous 
(IV) injection, and as ocular drops. The ocular drop formulation is also given off-label SL 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 children.3-6 
This randomized, open-label, two-period, two-sequence, phase 1 study is designed to assess the 
bioequivalence, bioavailability, and PK of SL administered Atropine Sulfate Ophthalmic 
Solution, United States Pharmacopeia (USP) 1% (1 mg; test) compared to Atropine Sulfate 
Injection, USP administered IM (1 mg; reference) in healthy adult volunteers. 
5.2. 
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 effects may take a few minutes to achieve maximum 
effect. In contrast, the IM 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. 

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Administration of atropine sulfate ophthalmic solution via the SL route may be an alternative 
means of delivering a rapid therapeutic dose of atropine to individuals exposed to NA while 
overcoming the stockpile supply deficits identified above.  
The purpose of the current study is to assess the bioequivalence, bioavailability, and PK of SL 
administered Atropine Sulfate Ophthalmic Solution, USP 1% compared to Atropine Sulfate 
Injection, USP administered IM in healthy adult volunteers. 
5.3. 
Previous Clinical Studies 
Prior to conducting study BP-C-19010 (ClinicalTrials.gov Identifier: NCT04290039)8, BARDA 
conducted an extensive literature review and identified 110 published English language articles 
involving the administration of atropine by SL, 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 participants were exposed to varying doses and 
regimens of SL atropine, including the ophthalmic formulation, or hyoscyamine in these reports. 
In several reports, atropine was administered SL 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 SL 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 SL 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. evaluated 9 healthy male volunteers (mean age 20.8 ± 4.7 years, mean weight 
59.67 ± 4.76 kg) administered a single SL injection of 2 mg atropine sulfate (in 0.1 mL).7 Three 
of the participants had 99mTc-labeled diethylene triamine pentaacetic acid added to their 
injection to monitor the release rate of atropine sulfate. Within 10 minutes, 85% of the injected 
dose was released from the SL site of injection. This compared to only 24% released at 10 
minutes from one participant who received IM atropine. The remaining six participants 
underwent blood sampling for PK and clinical monitoring for signs of atropinization (heart rate, 
pupil diameter, and mouth dryness). The peak serum concentration of SL atropine was 20 ng/mL 
at 15 minutes compared to peak serum concentrations of 6 to 8 ng/mL at 30 minutes following 
IM administration. All volunteers who received atropine by SL 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 SL injection achieves 
clinically important serum levels more rapidly than by IM administration. Adverse events were 
not reported in this trial. 
BARDA conducted, BP-C-19010, a randomized, 3-sequence, 3-period phase I crossover study to 
assess the bioavailability and PK of a single dose (0.5 mg and 1.0 mg) of 1% ophthalmic 

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atropine sulfate solution administered SL to 15 healthy adult volunteers.8,9 The primary endpoint 
was evaluation of the bioavailability of each of the two SL doses against a 1.0 mg reference IV 
atropine dose. Secondary endpoints included the safety and tolerability (xerostomia scale) of 
atropine sulfate administered SL. Sublingual atropine was safe (no severe AEs or serious adverse 
events [SAEs] were reported with either dose) and well tolerated, with a single participant 
reaching maximum xerostomia on a single dosing day. The geometric mean AUC∞ was 286.40, 
493.81, and 816.47 min×ng/mL for the 0.5 mg and 1.0 mg SL doses and the 1.0 mg IV dose, 
respectively. Compared to IV administration, the 1.0 mg SL dose produced 0.60 (90% CI: 0.55-
0.66) of the overall concentration of atropine over time (AUC∞). 
Based on the reported experience to date, the administration of atropine via the SL 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. 
 

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6. 
STUDY OBJECTIVES 
Table 2:  
Study Objectives and Endpoints 
Objectives  
Endpoints 
Primary 
 
To establish bioequivalence of Atropine Sulfate Ophthalmic 
Solution, USP 1% given sublingually vs intramuscular 8 mg/20 
mL (0.4 mg/mL) atropine sulfate injection. 
• AUC∞ 
• AUCt  
 
Secondary 
 
To compare the bioavailability of Atropine Sulfate Ophthalmic 
Solution, USP 1% given sublingually vs intramuscular 8 mg/20 
mL (0.4 mg/mL) atropine sulfate injection. 
• AUC45, AUC60, AUC90, 
AUC120, AUC150, 
AUC240 
• Cmax 
• tmax 
• t1/2 
• λz 
• Vd/F 
• CL/F 
• Ka  
 

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7. 
INVESTIGATIONAL PLAN 
7.1. 
Overall Study Design 
This is a randomized, open-label, two-period, two-sequence, crossover study to assess the 
bioequivalence, bioavailability, and PK of a single dose of atropine administered SL or IM in 
healthy adult volunteers. Approximately 46 healthy male and non-pregnant female volunteers 
will be enrolled to obtain approximately 36 evaluable participants in the per protocol population. 
Additional participants may be randomized if participants are withdrawn prior to receiving one 
or both doses of study drug. Eligible participants will be randomized at a 1:1 ratio to receive one 
of two treatment dosing sequences (A or B) as depicted in Table 3.  
Table 3: 
Study Design Scheme by Dosing Sequence 
Dosing 
Sequence 
Targeted Number of 
Randomized 
Participants (N) 
Targeted Number of 
Evaluable 
Participants (N) 
Period 1  
(Visit 1; Day 1) 
Period 2  
(Visit 2; Day 8) 
A 
23 
18 
SL 
IM 
B 
23 
18 
IM 
SL 
Figure 1 presents a diagram of the overall study design. Volunteers will be screened for study 
participation from Days -14 to -3. After Screening on Day 1, eligible participants will be enrolled 
and will be randomized to one of two treatment dosing sequences as presented in Table 3. Once 
randomized, each participant will receive 2 doses of atropine separated by a wash out period of 6 
±1 days. During Visit 1 (Day 1) and Visit 2 (Day 8), participants will be administered SL or IM 
atropine, according to their randomly assigned dosing sequence. At each dosing visit, blood 
samples for PK will be collected at time 0 (pre-dose) and at 13 time points post-dose at 5, 10, 15, 
20, 30, 45, 60, and 90 minutes and 2, 2.5, 4, 6, and 8 hours after dosing. Participants will be 
discharged from the clinic after the 8-hour blood sample collection. Participants will be followed 
for approximately 6 days after their last dose.  
At the Screening Visit, participants will receive instructions regarding preparation for dosing 
visits, and information about conduct during dosing visits. On the day of atropine administration, 
site staff will review eligibility criteria with each participant (except for those criteria specified 
as only being applicable at Screening; see Section 8.1). In addition to meeting eligibility criteria, 
participants will not be dosed with study drug until they meet the following pre-dose 
requirements:  
1. Have fasted from food and drink for 2 hours prior to drug administration. 
2. Have abstained from any other oral product that has the potential to interfere with SL 
atropine absorption (e.g., candy, chewing gum, mints, etc.) for 2 hours prior to study drug 
administration. 
Following administration of study drug, participants:  
1. Will abstain from food and drink through 2 hours after drug administration or until the 
participant expresses their xerostomia is intolerable, whichever occurs first. After 2 

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• Participant 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.  
• Participant no longer meets eligibility criteria in such a way that, in the judgment of 
the investigator, the safety of the participant may be compromised by continued 
participation or interpretation of the participant’s subsequent study data are likely to 
be significantly compromised. 
Once a participant has been reviewed by the medical monitor and the BARDA 
Pharmacovigilance SME and/or BARDA Medical Officer, they will recommend to either (1) 
continue dosing per the protocol or (2) discontinue further dosing of the participant.   
Participants who do not complete both study drug doses for any reason will continue to be 
followed for safety for at least six days following the last dose. If a participant reports an AE 
judged at least possibly related to study drug, the event will be followed to resolution (with or 
without sequelae) or until considered stable by the investigator (in consultation with the medical 
monitor in situations of uncertainty).  
The reason for early discontinuation of dosing will be captured in the electronic case report form 
(eCRF).   
7.4.2. 
Study Pausing Rules 
If the following criterion is met, further dosing of all participants will be paused.  
• Two or more participants experience a grade 3 or higher AE in the same Medical 
Dictionary for Regulatory Activities (MedDRA) system organ class deemed at least 
possibly related to the study drug by the site investigator in consultation with the medical 
monitor. 
• One grade 5 AE (death) deemed at least possibly related to the study drug by the site 
investigator in consultation with the medical monitor. 
At that time, the medical monitor, and the BARDA Pharmacovigilance SME and/or BARDA 
Medical Officer will convene to discuss and review these cases. The site investigator may be 
present at these meetings to provide additional information. 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. As the trial sponsor, BARDA will make 
the final decision.  
7.5. 
Criteria for Study Suspension or Termination 
BARDA retains the right to suspend, modify, or terminate the study at any time. In case of 
premature termination or suspension and safety review of the study, Allucent 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). 
This study may be prematurely terminated if there is sufficient reasonable cause, including but 
not limited to: 
1. Determination of unexpected, significant, or unacceptable risk to participants 

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2. Insufficient compliance to protocol requirements 
3. If required by regulatory authority(ies) 
Study participants will be contacted, as applicable, and be informed of changes to their study 
visit schedule. The site investigator will assure appropriate follow-up for the participants, as 
necessary. 
  
 
 
 

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8. 
SELECTION AND WITHDRAWAL OF PARTICIPANTS 
8.1. 
Selection of Study Population 
This study will include all healthy adult male and non-pregnant female participants, between the 
ages of 18 and 65 years, inclusive, who meet all of the inclusion and none of the exclusion 
criteria. Eligibility criteria will be assessed at Screening and must be reviewed just prior to each 
dose of atropine. Criteria specified as only being evaluated at Screening or at Pre-dose Visits will 
be assessed only at those visits. If the participant no longer meets applicable eligibility criteria, 
the investigator, in consultation with the medical monitor in cases of uncertainty, must determine 
whether the participant 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 participant safety. Therefore, adherence to the 
criteria specified in the protocol is essential. 
8.1.1. 
Participant Inclusion Criteria 
1. Healthy male and nonpregnant female volunteers between the ages of 18 and 65 years, 
inclusive, at time of consent. 
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 adequate method of birth control for at least 2 months prior to 
Screening, and must agree to continue using an adequate method of birth control from 
Screening through Follow-up (Day 15) 
a. A female of childbearing potential is defined as a post onset of 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 
participant’s Screening Visit. 
4. In the judgment of the investigator, the participant 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 Screening laboratory assessments, 
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 Assessments (Appendix 2). 
8.1.2. 
Participant Exclusion Criteria 
1. Females who have a positive pregnancy test or who are breastfeeding. 

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2. Participants 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 Screening test will not be repeated prior to subsequent dosing.)  
3. Participants with aspartate aminotransferase (AST), alanine aminotransferase (ALT), or 
serum creatinine > 1.5 × ULN at Screening. (These Screening 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. Participants who have been effectively treated for hepatitis C, as evidenced by 
a negative hepatitis C RNA confirmation test and who no longer require antiviral therapy, 
are eligible for participation. (These Screening tests will not be repeated prior to 
subsequent dosing.) 
5. Participants 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 participant should be terminated from further dosing. 
6. Participants 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 participant should be terminated 
from further dosing.  
7. Participants who are current smokers or are currently using any oral nicotine/oral tobacco 
product (e.g. snuff, chew, lozenges, nicotine gum, pouches) or electronic cigarette or 
vaping device (e.g., e-cigarette, mod, vape pen, JUUL, e-cigar, e-hookah, e-pipe, vape 
pods) or have used any of these products within 6 months prior to Screening. 
8. Participants with glaucoma and/or history of ocular surgery (including LasikTM), ocular 
trauma, or congenital ocular disorder.  
9. Participants with any history of heart disease, including but not limited to hypertension, 
coronary artery disease, arrhythmia (treated or untreated), congestive heart failure, 
pacemaker, history of vasovagal syncope, any supraventricular tachycardia, peripheral 
vascular disease, or claudication. 
10. Participants 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.  
11. Participants with a history of partial organic pyloric stenosis, chronic constipation, 
gastroparesis, or other gastrointestinal motility issues. 
12. Participants with a history of xerostomia due to an underlying disease or previous 
radiation therapy to the head and neck.  
13. Males with history of symptomatic prostatic hypertrophy; males or females with a history 
of urinary hesitancy or retention.  
14. Participants with a blood pressure > 140/90 mm Hg taken after the participant has been 
seated and resting for at least five minutes.  

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15. Participants with a history or current diagnosis of myasthenia gravis.  
16. Participants who have donated blood within 8 weeks of Screening or intend to donate 
blood during the study period.  
17. Participants 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.)  
18. Participants with a known sensitivity or prior adverse reaction to atropine. 
19. Participants who have consumed alcohol within 24 hours prior to each Pre-dose Visit. 
(This will be assessed only at Visit 1 [Pre-dose] and Visit 2 [Pre-dose].) 
20. Participants with any other condition that, in the opinion of the investigator, would pose a 
health risk to the participant if enrolled, would interfere with SL or IM administration of 
study drug, or would otherwise interfere with interpretation of study results. 
Participants cannot be rescreened for exclusionary laboratory test results. Potentially 
exclusionary vital sign results may be repeated once. If a participant’s repeat vitals remain 
exclusionary or the investigator determines that the repeat vital signs could pose a risk to 
participating in the study, then the participant will be excluded. 
8.2. 
Participant Withdrawal  
8.2.1. 
Participant Withdrawal Criteria 
Every participant has the right to refuse participation in the study (i.e., withdraw consent) at any 
time without providing any justification for withdrawal. A participant’s participation must be 
terminated immediately upon his/her request, and the reason(s) for discontinuation documented 
accordingly in the corresponding eCRF.  
Any participant who meets one or more of the following criteria will be removed from the study 
without prejudice: 
• Participant request. 
• Participant noncompliance, defined as refusal or inability to adhere to the study 
protocol or any other instances determined by the site investigator or BARDA. 
• Participant lost to follow-up. 
• Site investigator no longer believes participation is in the best interest of the 
participant. 
• At request of BARDA or the IRB 
For any participant who is withdrawn prior to completion of the Follow-up (Day 15) Visit, the 
Early Termination (ET) Visit assessments will be performed as outlined in the Schedule of 
Assessments (Appendix 2), when possible. The ET Visit may be conducted in clinic or by phone, 
as determined by the investigator. 

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8.2.2. 
Randomization of Additional Study Participants 
In order to achieve the target number of evaluable participants within the per protocol analysis 
population, additional participants will be randomized to account for any participants who are 
randomized but do not receive the first dose of study drug. 
If a participant is withdrawn from the clinical study after receipt of the first dose of study drug at 
Visit 1 and prior to completing the second dose of study drug at Visit 2, the participant will be 
removed from the per protocol population. Additional participants may be randomized to achieve 
the target number of evaluable participants within the per protocol analysis population. 
 

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9. 
TREATMENT OF PARTICIPANTS 
9.1. 
Description of Study Drug 
9.1.1. 
Atropine Sulfate Ophthalmic Solution, USP 1% 
Atropine Sulfate Ophthalmic Solution, USP 1% manufactured by Bausch & Lomb Americas 
Inc., is a sterile topical anti-muscarinic indicated for mydriasis, cycloplegia, and penalization of 
the healthy eye in the treatment of amblyopia.11 Each mL of Atropine Sulfate Ophthalmic 
Solution USP, 1% contains the active ingredient atropine sulfate 10 mg, equivalent to 8.3 mg of 
atropine. Inactive ingredients include boric acid, hydroxypropyl methylcellulose, and water for 
injection, USP; hydrochloric acid and/or sodium hydroxide may be added to adjust pH (3.5 to 
6.0). 
Atropine Sulfate Ophthalmic Solution, USP 1% will be supplied in 0.4 mL single-dose vials. 
Each vial will only be used to administer a single dose to a single participant.   
9.1.2. 
Atropine Sulfate Injection, USP 
Atropine sulfate injection, USP is a muscarinic antagonist indicated for temporary blockade of 
severe or life-threatening muscarinic effects, e.g., as an antisialagogue, as an antivagal agent, as 
an antidote for organophosphorus, carbamate, or muscarinic mushroom poisoning, and to treat 
symptomatic bradycardia.12  
Atropine Sulfate Injection, USP, 8 mg/20 mL (0.4 mg/mL) manufactured by Fresenius Kabi 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; and sodium chloride 9 mg; it may also contain sulfuric acid for pH 
adjustment, pH 3.5 (3.0 to 3.8). 
Atropine Sulfate Injection, USP will be supplied in 8 mg/20 mL multidose vials (0.4 mg/mL). 
Each vial will be used to administer multiple doses to multiple participants.  
A summary of study drugs to be evaluated in this study is presented in Table 4.  

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Table 4: 
Summary of Study Drugs 
 
Study Drug 
Drug Name: 
Atropine Sulfate Ophthalmic 
Solution, USP, 1% 
Atropine Sulfate Injection  
Route of Administration 
SL  
IM 
Dosage Form: 
1% USP solution  
8 mg/20 mL (0.4 mg/mL) 
USP injectable solution 
 
Unit Dose 
100 μL 
(1.0 mg atropine sulfate) 
2.5 mL  
(1.0 mg atropine sulfate)  
Physical Description 
Clear solution 
Clear solution 
Manufacturer 
Bausch & Lomb Americas 
Inc. 
Fresenius Kabi  
9.2. 
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. Concomitant therapies will also be recorded on 
the applicable eCRF. Any changes, additions, and/or deletions in concomitant medications or 
therapies will be recorded in the participant’s eCRF throughout the course of the participant’s 
participation in the study.  
If it is discovered that a participant is using a prohibited concomitant medication after he or she 
is enrolled in the study, the site investigator, in consultation with the medical monitor in cases of 
uncertainty, should determine the impact on the participant’s participation. All instances of use 
of prohibited concomitant medications or therapies must be documented. 
9.2.1. 
Prohibited and Permitted Concomitant Medications  
The following concomitant medications are allowed during study participation:  
• Contraceptive medications and estrogen or estrogen/progesterone hormone 
replacement therapy are permitted for female participants.  
• Nonsteroidal anti-inflammatory drugs and acetaminophen are permitted for all 
participants. 
Except for the permitted medications listed above, all other concomitant medications are 
prohibited from Screening until the end of study participation (i.e., after the Telephone Follow-

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up Visit). In addition, all prescription medications are exclusionary if taken within 30 days prior 
to Screening, and prohibited until the end of study participation. All over-the-counter 
medications, vitamins, and herbal supplements are exclusionary if taken within 72 hours prior to 
Screening, and prohibited until the end of study participation. 
9.3. 
Treatment Compliance 
The study drug will be administered by an unblinded study staff member and thus is an observed 
compliance. Participant compliance will be determined by the number and percentage of 
participants who receive study drug at Visits 1 and 2 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. 

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10. 
STUDY DRUG MATERIALS AND MANAGEMENT 
10.1. 
Study Drug 
Refer to Section 9.1 for detailed information regarding Atropine Sulfate Ophthalmic Solution, 
USP 1% and Atropine Sulfate Injection, USP. 
10.2. 
Study Drug Packaging and Labeling 
Study drug will be packaged and labeled according to applicable local and regulatory 
requirements.  
10.3. 
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 Solution, USP 1% and Atropine Sulfate 
Injection, USP should be kept at controlled room temperature between 20° and 25°C (68° to 
77°F), inclusive. Atropine Sulfate Ophthalmic Solution, USP 1% is provided as 5 single-dose 
vials in foil pouches; vials should be stored as packaged until use. The temperature of the storage 
unit must be monitored, and documentation of proper storage must be maintained.   
10.4. 
Study Drug Preparation and Administration 
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 
taking the initial dose from each vial.  
For SL administration, 100 μL of Atropine Sulfate Ophthalmic Solution, USP 1% will be 
administered SL by pipette to deliver 1.0 mg of atropine sulfate. Before administration of SL 
atropine, participants will be asked to swallow. Following administration, participants will be 
instructed to attempt not to swallow for 30 seconds and thereafter swallow as they normally 
would. Atropine Sulfate Ophthalmic Solution, USP 1% for SL administration will be provided in 
0.4 mL single-dose vials, and each vial of atropine will only be used to administer a single dose.  
For IM administration, 2.5 mL of Atropine Sulfate Injection, USP (8 mg/20 mL; 0.4 mg/mL) 
will be injected into the mid-anterolateral thigh to deliver 1.0 mg of atropine sulfate. Appropriate 
needle length for IM administration depends on age and body mass of the participant. The needle 
length should be sufficient to reach the muscle mass and prevent the atropine dose from seeping 
into subcutaneous tissue, but not so long as to involve underlying nerves, blood vessels, or bone. 
For most adults receiving an intramuscular administration in the anterolateral thigh, a 1-1.5" 
needle inserted at a 90-degree angle to the skin should be utilized to ensure the IM dose is 
administered appropriately. Atropine Sulfate Injection, USP will be supplied in multi-dose vials. 
Multi-dose vials for IM administration will be dated and timed in the appropriate label areas 
upon initial puncture to indicate the first time of entry into the vial. No dose shall be 
administered from the opened vial after 24 hours of first entry (i.e., the beyond use date/time). 
After initial use of single-dose vials for SL administration, or after the beyond use date/time of 
multi-dose vials for IM administration, the used vials should be maintained in a separate location 
from the unused vials until drug accountability has been reconciled. 

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10.5. 
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 (participant-
by-participant accounting), and a detailed accounting of any drug accidentally or deliberately 
destroyed. 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 
participant and the date and quantity of study drug dispensed. All records regarding the 
disposition of the study drug will be available for inspection by the study monitor and BARDA. 
10.6. 
Study Drug Handling and Disposal 
After dosing has been completed for all participants, 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. 
10.7. 
Randomization and Blinding 
10.7.1. 
Randomization 
Participants 18 through 65 years of age, inclusive, will be randomized 1:1 to one of two 
treatment dosing sequences (A or B) as specified in Table 3. The randomization schedule will be 
generated by the statistical team at Rho using a web-based randomization system.  
10.7.2. 
Blinding 
This study is not blinded. 

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11. 
ASSESSMENT OF PHARMACOKINETICS 
Blood samples will be collected from each participant for PK assessments by a designated, 
qualified individual from the study research team. At Visit 1 (Day 1) and Visit 2 (Day 8), an 
indwelling venous catheter will be placed before dose administration for blood sample collection 
for serial determinations at the following times: 0 (pre-dose) and at 13 time points post-dose at 5, 
10, 15, 20, 30, 45, 60, and 90 minutes, and 2, 2.5, 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 until analysis.  
Pharmacokinetic samples will be analyzed by a bioanalytical facility approved by BARDA.   
 

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12. 
ASSESSMENT OF SAFETY 
12.1. 
Safety Parameters 
Safety will be evaluated utilizing the assessments defined in this section. If deemed clinically 
necessary, additional safety assessments not currently specified in the protocol may be 
performed at the discretion of the site investigator in consultation with the medical monitor and 
BARDA. 
12.1.1. 
Demographic/Medical History 
In order to define a baseline for potential AEs, the demographics and medical history of each 
participant will be collected at the Screening Visit.  
12.1.2. 
Vital Signs 
Vital sign measurements, including oral temperature, heart rate, respiratory rate, and diastolic 
and systolic blood pressure (after the participant is seated for at least 5 minutes), will be 
collected at Screening, Visit 1 (Day 1 Pre-dose), and Visit 2 (Day 8 Pre-dose) prior to any blood 
draws. Post-dose automated blood pressure and heart rate measurements will be recorded on the 
opposite arm from blood collection every 15 ± 5 minutes for the first hour, every 20 ± 5 minutes 
for the second hour, and every 30 ± 5 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 an Unscheduled or Early Termination (ET) Visit per the investigator’s discretion.  
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. 
12.1.3. 
Weight and Height 
Participant’s height and weight will be measured at the Screening Visit. Body mass index (BMI) 
will be derived automatically from height and weight measurements in the electronic data 
capture system. Participant’s weight will be assessed again at Visit 1 (Day 1 Pre-dose) and Visit 
2 (Day 8 Pre-dose). Weight may be measured at an Unscheduled or ET Visit per the 
investigator’s discretion.  
12.1.4. 
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, oral cavity, 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. A symptom-based physical examination 
may be performed at dosing visits, or at an Unscheduled or ET Visit per the investigator’s 
discretion. In general, clinically significant abnormal findings are expected to be associated with 
an item recorded in the participant’s medical history (when detected at Screening) or as an AE 
(when detected after Screening).    

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12.1.5. 
Electrocardiogram (ECG) 
A standard 12-lead ECG will be recorded and assessed at the Screening Visit, Visit 1 (Day 1 Pre-
dose), and Visit 2 (Day 2 Pre-dose). Additionally, an ECG may be performed for any complaints 
of chest discomfort, lightheadedness, and/or palpitations per the investigator’s discretion and 
repeated as needed during Visit 1 (Day 1 Post-dose) and Visit 2 (Day 2 Post-dose). ECGs may 
also be performed at an Unscheduled or ET Visit 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 participant’s medical history (when detected at Screening) or as an AE 
(when detected after Screening).    
12.1.6. 
Clinical Laboratory Assessments 
At the Screening Visit, venous blood and urine will be collected for all participants for Screening 
laboratory assessments. All clinical laboratory assessments provided in this section will be 
performed at Screening. 
Clinical laboratory assessments may be repeated at an Unscheduled or ET Visit as clinically 
indicated per the investigator’s discretion.  
Samples will be analyzed by the local lab. 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 data to assess 
eligibility and identify and document AEs as applicable. 
The clinical laboratory assessments planned for this study are as follows:  
12.1.6.1. Complete blood count with differential 
Table 5 lists the parameters of the complete blood count with differential.  
Table 5: 
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 
12.1.6.2. Serum Chemistry, Liver Function, and Thyroid-stimulating Hormone 
Assessments 
The clinical chemistry, liver function, and TSH assessments planned for this study are provided 
in Table 6: 

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Table 6: 
Serum Chemistry, Liver Function, and TSH Assessments 
• Chem 7 panel 
− Blood urea nitrogen (BUN) 
− Carbon dioxide 
− Creatinine 
− Glucose 
− Serum chloride 
− Serum potassium 
− Serum sodium 
• Liver function tests (LFTs);  
− Aspartate aminotransferase (AST) 
− Alanine transaminase (ALT) 
− Alkaline phosphatase (ALP) 
− Direct bilirubin 
− Total bilirubin (fractionated for 
values for total bilirubin > ULN) 
• Thyroid-stimulating hormone (TSH) 
with reflex to T4 
12.1.6.3. Virus Serology 
At the Screening Visit, participant medical history will be reviewed for known human 
immunodeficiency virus (HIV) infection, and acute or chronic hepatitis B or hepatitis C 
infection. In addition, blood samples will be collected at the Screening Visit for HIV, hepatitis B 
surface antigen (HBsAg), and hepatitis C antibody (anti-HCV) tests.  
12.1.6.4. Urine Drug Screen 
A urine drug screen will be performed at the Screening Visit and will include tests for 
amphetamines, cocaine, tetrahydrocannabinol, methylenedioxymethamphetamine, and opiates. 
12.1.6.5. Pregnancy Screen 
At the Screening Visit, blood will be collected for a serum quantitative beta-human chorionic 
gonadotropin (beta-HCG) assay for female participants of childbearing potential. At Visit 1 (Day 
1 Pre-dose) and Visit 2 (Day 8 Pre-dose), a urine point-of-care (POC) pregnancy test will be 
performed onsite for female participants of childbearing potential.   
Additionally, a urine POC pregnancy test will be performed at any time during study 
participation if pregnancy is suspected.   
12.1.7. 
Adverse Event Assessment 
At all visits and phone contacts, including an ET or Unscheduled Visit, site staff will ask 
nonleading questions regarding the participant’s health status (Section 12.3.1) and document any 
new or changed AEs. Adverse events occurring during washout periods (i.e., between Visit 1 and 
Visit 2, and between Visit 2 and the Telephone Follow-up Visit) should be collected at the next 
participant contact.  
12.1.8. 
Concomitant Medication Assessment 
Site staff will review concomitant medications (Section 9.2) at Screening, as well as Visit 1 (Day 
1 Pre-dose) and Visit 2 (Day 8 Pre-dose) prior to administration of study drug. On Visit 1 (Day 1 
Post-dose) and Visit 2 (Day 8 Post-dose), any medications or treatments administered to the 

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participant during attendance at the Clinical Research Unit (CRU) will also be recorded. 
Concomitant medications will also be reviewed during the Follow-Up telephone contact and at 
an Unscheduled or ET Visit.  
12.2. 
Adverse and Serious Adverse Events 
12.2.1. 
Definition of Adverse Events 
12.2.1.1. Adverse Event (AE) 
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 Council for 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 site investigator. A lab or vital sign result should 
generally be considered clinically significant and an AE if, regardless of degree out of range, it 
has a reasonable probability of reflecting or contributing to a disturbance of homeostasis or 
pathological process or outcome.  
Suspected adverse reaction (SAR) means any AE for which there is a reasonable possibility that 
the drug caused the event. For the purposes of safety reporting, “reasonable possibility” means 
there is evidence to suggest a causal relationship between the drug and the AE. A 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. 
12.2.1.2. Serious Adverse Event (SAE) 
An AE or SAR is considered “serious” if, in the view of either the site investigator or BARDA, it 
results in any of the following outcomes [21 CFR 312.32(a)]: 
• Death 
• Life-threatening adverse event that in the view of the site investigator or BARDA, places 
the participant at immediate risk of death. This does not, however, include an event that, 
had it occurred in a more severe form, might have caused death. 
• Requires inpatient hospitalization or prolongs existing hospitalization. Planned 
hospitalizations will not be reported as 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 
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• 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 participant, or the participant may 
require medical or surgical intervention to prevent one of the outcomes listed in this 
definition. 
12.3. 
Collection, Recording, and Grading Severity of Adverse Events 
12.3.1. 
Collection of Adverse Events 
Adverse events of any type described above may be discovered through a variety of methods: 
• Observing the participant 
• Questioning the participant with standard nonleading questions to elicit any medically 
related changes in their well-being (e.g., Have you been hospitalized, had any 
accidents, used any new medications, or changed any medications [both prescription 
and OTC]?) 
• Receiving an unsolicited complaint from the participant 
• An abnormal value or result from a clinical (e.g., vital signs) or laboratory evaluation 
12.3.2. 
Recording Adverse Events 
Throughout the study, the investigator will record AEs on the eCRF. SAEs must be reported to 
Rho pharmacovigilance personnel within 1 business day of the site’s awareness of the event. For 
the purposes of this study, any detrimental change in the participant’s condition after signing 
informed consent and up to completion of the follow-up period after the last administration of 
study drug (i.e., through Follow-up [Day 15]) will be considered an AE and must be recorded. 
Treatment-emergent AEs are defined as AEs occurring after the participant receives at least one 
dose of atropine. AEs will be followed per the below criteria: 
• AEs judged at least possibly related to study drug will be followed to resolution (with or 
without sequelae) or until considered stable by the investigator (in consultation with the 
medical monitor in situations of uncertainty).  
• 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 medical monitor in situations of uncertainty), or until the end of the participant’s 
study participation, whichever comes first. 
12.3.3. 
Grading Severity of Adverse Events 
The severity of AEs and SAEs will be graded as defined by criteria set forth in the NCI-CTCAE 
Manual Version 5.0. AEs will be graded on a scale from 1 to 5 according to the following 
standards in the NCI-CTCAE manual: 
Grade 1 = mild AE 
Grade 2 = moderate AE 

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the possible effects on the fetus. Monitoring of the pregnant participant shall continue until the 
conclusion of the pregnancy.  
The pregnancy will be documented 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 12.3.2.  
12.7. 
Reporting Other Safety Information 
Site investigators should promptly notify Rho, Allucent, BARDA, and the IRB when an 
unanticipated problem involving risks to participants or others, which is not otherwise reportable 
as an AE, is identified. 

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13. 
STATISTICS 
13.1. 
Endpoints 
Endpoints are summarized in Table 2 under Section 6. 
The bioequivalence of atropine sulfate administered SL versus administered IM as measured by 
the following PK parameters using noncompartmental analysis (NCA) methods: 
• 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) 
The relative bioavailability of atropine sulfate administered SL versus IM as measured by the 
following PK parameters using NCA methods: 
• Area under the analyte concentration versus time curve to 45, 60, 90, 120, 150, and 240 
minutes (AUC45, AUC60, AUC90, AUC120, AUC150, and AUC240, respectively) 
• Maximum measured plasma concentration (Cmax) 
• Time to Cmax (tmax) 
• Apparent terminal elimination half-life (t½) 
• 
Terminal elimination rate constant (λz) 
• Volume of distribution (Vd/F)  
• Total body clearance (CL/F) 
• Absorption rate constant (Ka)  
13.1.1. 
Measures to Minimize Bias 
Permuted block randomization will be performed centrally by designated Rho staff and will 
balance enrollment between treatment dosing sequences (see Section 10.7 for more details). 
13.1.2. 
Analysis Plan 
Statistical analyses will be performed using SAS® software Version 9.4 or later. Phoenix 
WinNonLin Version 8.3 software will be used to generate PK parameter estimates. 
Descriptive statistics will be used to summarize participant characteristics and safety. These 
summaries will be presented overall and separately for each route of administration.   
Details of the statistical analyses, methods, and data conventions will be described in the 
Statistical Analysis Plan (SAP). 
13.1.2.1. Analysis Populations 
13.1.2.1.1. PK Analysis Population 
The PK analysis population will include all participants who are randomized, receive at least 1 
study drug dose, and have PK samples collected for that period. Each participant’s data will be 

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analyzed according to the corresponding route of administration for the applicable period. The 
PK analysis population will be used for all PK analyses.  
13.1.2.1.2. Per Protocol Population 
The per protocol population will include all participants who are randomized, receive atropine 
via both routes of administration according to their randomized dosing sequence, and have PK 
samples collected for both periods. In addition, participants with major protocol deviations may 
be excluded if it is determined that the deviations affect the integrity of PK data. Each 
participant’s data will be analyzed according to the corresponding route of administration for the 
applicable period. Primary and secondary analyses will be repeated in the per protocol 
population if it differs from the PK analysis population. 
13.1.2.1.3. Safety Population 
The safety population will include all participants who are randomized and receive at least 1 
study drug dose. Each participant’s data will be analyzed according to the corresponding route of 
administration for the applicable period. The safety population will be used for all safety 
displays. 
13.1.2.2. Primary Analysis 
Pharmacokinetic parameters AUC∞ and AUCt will be estimated for each participant and route 
using the noncompartmental method and will be summarized by route of administration using 
descriptive statistics. 
Relative bioavailability of SL administration of atropine sulfate compared to that of IM atropine 
sulfate will be assessed based on ratios of least-square means and their associated 90% 
confidence intervals (CIs) generated from linear mixed models including terms for dosing 
sequence, route, and period as fixed effects, and subject nested within dosing sequence as a 
random effect. Bioequivalence will be considered met if the 90% CI of the ratio for AUC∞ and 
AUCt lie within 80.00 and 125.00%. 
Additional details of the statistical analyses, methods, and data conventions will be described in 
the Statistical Analysis Plan (SAP). 
13.1.2.3. Secondary Analyses 
The AUC45, AUC60, AUC90, AUC120, AUC150, and AUC240, Cmax, tmax, t1/2, λz, Vd/F, CL/F, and Ka 
will also be estimated for each participant and route of administration using the 
noncompartmental method and will be summarized by route using descriptive statistics. Each 
parameter will be compared between routes, where applicable, using linear mixed models, 
including terms for dosing sequence, route, and period as fixed effects, and subject nested within 
sequence as a random effect in the model. Ratios of least-squares means and associated 90% CIs 
will be presented. 
13.1.1.4. Interim Analysis  
No interim analysis is planned for this study. 

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13.1.2.4. Safety Reviews 
In the event a study pausing rule is met, the medical monitor and the BARDA 
Pharmacovigilance SME and/or BARDA Medical Officer will convene to discuss and review 
relevant cases. No pre-planned interim safety reviews will be conducted for this study.   
13.1.2.5. Final Analysis 
A clinical study report will be written to include all PK and safety data collected throughout the 
study. For the final analysis, the study database will be monitored, cleaned, and locked per 
associated study plans. Further details will be specified in the SAP. 
13.1.2.6. Exploratory Analyses  
No exploratory analyses are planned. 
13.2. 
Sample Size Considerations 
The target sample size for randomization for this study is approximately 46 participants, 
allowing for a 20% dropout rate that would result in approximately 36 evaluable participants 
(approximately 18 per dosing sequence) within the per protocol population. Additional 
participants may be randomized if participants are withdrawn prior to receiving one or both 
doses of study drug (Section 8.2.2).   
The sample size was determined for an equivalence test of the ratio of means using two one-
sided tests on data from a two-period cross-over design. In the previous PK study of SL 
administration of atropine (BP-C-19010),8 the standard deviation for the dose-adjusted log10 
difference in high (1.0 mg) versus low (0.5 mg) SL dosing for AUC∞ and Cmax were 0.102 and 
0.146, respectively. Since the intra-participant variability in PK parameters between SL and IM 
administration is unknown, the standard deviations were conservatively multiplied by a factor of 
1.25 to determine power and sample size for this study. Corresponding coefficients of variance 
were estimated as 0.212 and 0.304 for AUC∞ and Cmax, respectively. A sample size of 36 
achieves greater than 99% power to test bioequivalence for AUC∞ and 86% power for Cmax at the 
0.05 significance level when the true ratio of means is 1.0 and the equivalence limits are 0.80 and 
1.25. Even if the true ratio of means are within ±5% of 1.0, the study still maintains 96% and 
77% power for AUC∞ and Cmax, respectively. 
13.3. 
Statistical Considerations 
13.3.1. 
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. 
13.3.2. 
Multicenter Studies 
This is a single center study thus study data will be analyzed as a whole. 
13.3.3. 
Multiple Comparisons and Multiplicity 
No adjustments will be made for multiple comparisons. 

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13.3.4. 
Subgroup Analyses 
Any subgroups requiring more consideration will be discussed in the SAP as needed. 
13.3.5. 
Missing Data 
Standard procedures will be used to ensure that the data are as complete and accurate as possible. 
All descriptive summaries will be based upon all available data, and no imputation will be done. 
13.4. 
Procedures for Documenting Deviations from 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 being initiated. 

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14. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
14.1. 
Inspection of Records 
BARDA, its designees, other authorized representatives of BARDA, Rho or its designees, 
Allucent or its designees, representatives of the IRB, and/or regulatory agencies may inspect all 
source documents and records required to be maintained by the site investigator, including but 
not limited to, medical (office, clinic, or hospital) and pharmacy records for the participants in 
this study; eCRFs, IRB submissions and approvals, study drug accountability logs, study drug 
temperature monitoring logs, regulatory documents, correspondence, and all other essential 
documents. The clinical study site will permit site visits and access to (and when required by 
applicable law to copy) such records. 
The site investigator also agrees to promptly notify BARDA and other authorized representatives 
of the sponsor of any inspections scheduled by any regulatory authority, or audits by other 
parties and promptly forward copies of any reports received to BARDA. 
14.2. 
Institutional Review Board 
A copy of the protocol, informed consent forms (ICFs), any other participant 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 
participant consent form and recruitment materials, must be maintained by the site investigator 
and made available for inspection. 
 

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15. 
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 International Council for Harmonisation (ICH) Good Clinical Practice 
(GCP) and local/regional regulatory standards. 
To ensure the reliability of study data, the participating site(s) will have a plan in place to 
describe:  
• routine internal quality control (QC) and QA activities for the purposes of measuring, 
documenting and reporting study conduct, protocol adherence, human subjects’ 
protections, and reliability of the protocol-driven data collected;  
• a process for addressing in a timely manner any data quality issues (i.e., collecting, 
recording and reporting data), systemic issues (i.e., protocol conduct, non-
compliance, human subject protections), and implementation of corrective and 
preventative action (CAPA) procedures. 
A quality assurance representative from BARDA (or designee), who is independent of and 
separated from routine monitoring, may periodically arrange audits of the clinical study by 
reviewing the data obtained and procedural aspects. These audits may include on site or remote 
audits and source data checks. Direct access to source documents is required for the purpose of 
these periodic audits. 
15.1. 
Data Quality Assurance  
Data collected at the study site will be entered accurately and contemporaneously by study staff 
into a 21 CFR 11-compliant, internet-based, remote data entry system, which is backed up 
nightly. Data will be provided using the participant’s unique identification number, not name or 
initials; Rho will not collect personally identifying information such as the participant’s name or 
social security number. Participants will provide demographic information such as biological sex 
at birth, race, ethnicity, and age. All elements of data entry (e.g., time, date, verbatim text, and 
the person performing the data entry) will be recorded within the remote data entry 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 personal information about 
any participant in the study. 
Clinical data management and data cleaning procedures (e.g., 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) and concomitant medication terms will be coded using the MedDRA and the World 
Health Organization Drug dictionaries, respectively. 
After study monitors verify the data and prior to the final study analysis, the investigator must 
sign each eCRF at the participant level to confirm the integrity of the data recorded. 

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After database lock, the study site will receive an electronic copy of all of their site-specific 
eCRF data as entered into the remote data entry system for the study, including full discrepancy 
and audit history. Additionally, all of the study’s analysis datasets will be sent to BARDA 
electronically for storage. Rho will maintain a duplicate copy for its records and will upload a 
copy to the BARDA Clinical Studies Network (CSN) archive. 
15.2. 
Study Monitoring  
Site monitoring is conducted to ensure that the rights and well-being of trial participants are 
protected, that the reported trial data are accurate, complete, and verifiable, and that the conduct 
of the trial is in compliance with the currently IRB/IEC approved protocol/amendment(s), ICH 
GCP, and applicable regulatory requirement(s). Clinical monitoring also verifies any critical 
study procedures are completed following specific instructions in ancillary documents referenced 
in the protocol. 
Monitoring for this study will be performed by BARDA’s authorized representatives at Allucent. 
Details of clinical site monitoring are documented in a monitoring plan. The monitoring plan 
describes in detail who will conduct the monitoring, at what frequency monitoring will be done, 
at what level of detail monitoring will be performed, and the distribution of monitoring reports. 
Monitoring visits will include, but are not limited to, review of regulatory files, accountability 
records, eCRFs, ICFs, medical and laboratory reports, site study drug storage records, training 
records, and protocol and GCP compliance. Site monitors will have access to the participating 
site facilities, study personnel, and all study documentation according to the monitoring plan. 
Study monitors will meet with site investigators to discuss any problems and outstanding issues, 
and will document site visit findings and discussions. 
15.3. 
Protocol Deviations 
15.3.1. 
Protocol Deviation Definition 
A protocol deviation is any noncompliance with the IRB-approved study protocol, ICH GCP 
guidelines, or protocol-specific Manual(s) of Procedures (MOPs). Any deviation that affects the 
rights or safety of the participant or the integrity of the data will be considered a major protocol 
deviation. Prospective permission to deviate from protocol requirements, also known as protocol 
waivers or exemptions, will not be granted for this study. 
15.3.2. 
Reporting and Managing Deviations 
The site 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 in accordance with 
GCP. Documentation at a minimum, will include the date the deviation occurred, the date it was 
identified, a description of the deviation, whether the deviation resulted in an AE or SAE, and 
documentation of a corrective action plan. In addition, the site investigator will report 
noncompliance to the IRB/IEC, as applicable. 
Rho, Allucent, and/or BARDA may request discussion with the site investigator to determine the 
effect of any major protocol deviation on a study participant and his/her further study 
participation, the effect of the deviation on the overall study, and corrective actions. 

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16. 
REGULATORY AND ETHICAL CONSIDERATIONS 
16.1. 
Ethics Review 
Before study initiation, the site will obtain IRB approval for this protocol; ICF(s); participant 
recruitment procedures; written information to be provided to participants; information about 
payments and compensation available to participants; and any other documents that the IRB may 
require to fulfill its responsibilities. Any amendments to the protocol will require IRB approval 
before implementation except for changes necessary to eliminate an immediate hazard to a 
participant. 
IRB review and approval of protocol documents will occur at least annually throughout the 
enrollment and follow-up of participants, as per applicable regulations and the IRB.   
The site investigator will promptly report all unanticipated problems involving risks to 
participants to the IRB. 
The site investigator will notify the IRB of events such as deviations, SAEs, etc. as applicable to 
the IRB policy. 
Participants may be compensated for their participation in this study. Compensation will be in 
accordance with the IRB’s policies and procedures, and subject to IRB approval. 
16.2. 
Ethical Conduct of the Study 
The site investigator should conduct the study in accordance with this protocol, the Declaration 
of Helsinki, current ICH GCP guidelines, US 21 CFR Part 50 (Protection of Human Subjects), 
and Part 56 (Institutional Review Boards).  
16.3. 
Written Informed Consent 
Informed consent is a process that is initiated prior to an individual agreeing to participate in a 
trial and continuing throughout the individual’s trial participation. Before any study procedures 
are performed, informed consent will be obtained and documented. Potential participants will 
receive a concise and focused presentation of key information about the study, verbally and with 
a written consent form. The key information about the purpose of the study, the procedures and 
experimental aspects of the study, study interventions, study drugs, probability for random 
assignment to dosing schedules, risks and discomforts, the expected duration of the participant’s 
participation in the trial, any expected benefits to the participant, and alternative treatments and 
procedures that may be available to the participant. The explanation will be organized and 
presented in lay terminology and language that facilitates understanding why one might or might 
not want to participate. 
Participants will receive an explanation as to whether any compensation and any medical 
treatments are available if injury occurs, and, if so, what they consist of, or where further 
information may be obtained. Participants will be informed of the anticipated financial expenses, 
if any, to the participant for participating in the study, as well as any anticipated prorated 
payments, if any, to the participant for participating in the study. They will be informed of whom 
to contact (e.g., the site investigator) for answers to any questions relating to the research project. 
Information will also include the foreseeable circumstances and/or reasons under which the 

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participant’s participation in the study may be terminated. The participants will be informed that 
participation is voluntary and that they are free to withdraw from the study for any reason at any 
time without penalty or loss of benefits to which the participant is otherwise entitled.   
Participants will be informed that records identifying the participant will be kept confidential, 
and, to the extent permitted by the applicable laws and/or regulations, will not be made publicly 
available and, if the results of the trial are published, the participant’s identity will remain 
confidential. Participants will be informed whether private information collected from this 
research and/or specimens will be used for additional research, even if identifiers are removed.  
Participants will be informed that the monitor(s), auditor(s), IRB, BARDA, and regulatory 
authority(ies) will be granted direct access to the participant’s original medical records for 
verification of study procedures and/or data without violating the confidentiality of the 
participant, to the extent permitted by the applicable laws and regulations, and that, by signing a 
written ICF, the participant is authorizing such access.  
Participants will be allowed sufficient time to consider participation in this research study and 
have the opportunity to discuss this study with their family, friends or legally authorized 
representative, or think about it prior to agreeing to participate. 
Participants will be informed of the Public Readiness and Emergency Preparedness Act (PREP 
Act) and the Countermeasures Injury Compensation Program (CICP) (Appendix 3).   
Informed consent forms will be IRB-approved and participants will be asked to read and review 
the consent form. Participants must sign the ICF prior to starting any study procedures being 
done specifically for this study. Once signed, a copy of the ICF will be given to the participant(s) 
for their records. 
New information will be communicated by the site investigator to participants who consent to 
participate in this study in accordance with IRB requirements. The informed consent document 
will be updated, and participants will be re-consented per IRB requirements, if necessary.   
Using the ICF, participants who consent to participate in this study will be asked to consent to 
permission to be contacted with a request to participate in future clinical studies related to 
atropine administration. 
 

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17. 
DATA HANDLING AND RECORD KEEPING 
17.1. 
Confidentiality 
Participant confidentiality is strictly held in trust by the participating site investigators, their 
staff, and the sponsor(s) and their designees. This confidentiality is extended to cover clinical 
information relating to participants, test results of biological samples, and all other information 
generated during participation in the study. No identifiable information concerning participants 
in the study will be released to any unauthorized third party. Participant confidentiality will be 
maintained when study results are published or discussed in conferences.   
The study monitor, other authorized representatives of the sponsor, representatives of the IRB, 
and/or regulatory agencies may inspect all documents and records required to be maintained by 
the site investigator, including but not limited to, medical (office, clinic, or hospital) and 
pharmacy records for the participants in this study. The clinical study site will permit access to 
such records. 
All source records including electronic data will be stored in secured systems in accordance with 
institutional policies and federal regulations.   
All study data and research specimens that leave the site (including any electronic transmission 
of data) will be identified only by a coded number that cannot be linked to a participant. 
17.2. 
Retention of Records 
The site investigator should 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 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 site investigator must inform BARDA, or designee, of the long-term 
storage location of the study’s records. Following study closure, the site investigator must inform 
BARDA if that location changes (e.g., the site investigator leaves the institution where the study 
was conducted).  
No study records will be destroyed without prior authorization from BARDA.  

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18. 
PUBLICATION POLICY 
BARDA will be responsible for publication activities and for defining 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 National Institutes of Health Public Access Policy will apply to this study.13 ASPR-funded 
site 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. 
All applicable clinical trials supported by BARDA must be registered on ClinicalTrials.gov, no 
later than 21 days after the enrollment of the first participant. This will include a description of 
the clinical trial as required by US Law. This web site will not include information that can 
identify participants. Results information from those trials must be submitted no later than one 
year after the trial's primary completion date. 
As required, the following will be posted on ClinicalTrials.gov: Protocol, ICF (that has been 
used to enroll participants), and SAP. 
 

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19. 
RESEARCH-RELATED INJURIES 
For any potential research related injury, the site investigator or designee will assess the 
participant. The site investigator should then determine if an injury occurred as a direct result of 
the tests or treatments that are done for this study. As needed, referrals to appropriate health care 
facilities will be provided to the participant. 

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20. 
PROTOCOL AMENDMENT HISTORY 
The table below is intended to capture changes of IRB-approved versions of the protocol, 
including a description of the change and rationale. 
 
Table 8: 
Protocol Amendment History 
Version 
Date 
Description of Change  
Brief Rationale 
 1.0 
13 February 2024 
N/A 
 Initial version 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
 

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21. 
LIST OF 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. ClinicalTrials.gov [Internet]. NCT04290039: Sublingual vs IV Atropine Bioavailability 
Study. [updated 2023 June 22; cited 2024 Jan 23]. Available from: 
https://clinicaltrials.gov/study/NCT04290039 
9. Schwartz MD, Raulli R, Laney JW, Coley W, Walker R, O’Rourke AW, Raine K, 
Horwith G, Gao Y, Eisnor DL, Lu D et al. Systemic Bioavailability of Sublingual 
Atropine Ophthalmic Solution: a Phase I Study in Healthy Volunteers with Implications 
for Use as a Contingency Medical Countermeasure. Journal of Medical Toxicology. 2022 
Jul;18(3):187-97. 
10. 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/docs/ctcae_v5_quic
k_reference_5x7.pdf 
11. Atropine Sulfate (Atropine Sulfate Solution); Atropine Sulfate Ophthalmic Solution, USP 
1% [package insert]. Bridgewater, NJ: Bausch & Lomb Americas Inc. 
12. Atropine Sulfate Injection, USP; [package insert]. Lake Zurich, IL. Fresenius Kabi. 
13. National Institutes of Health [Internet]. Public Access Policy. [updated 2022 Aug 29; 
cited 2024 Jan 23]. Available from: https://publicaccess.nih.gov. 

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22. 
APPENDICES 
APPENDIX 1. PUBLICATION REVIEW OF SUBLINGUAL ADMINISTRATION OF 
ATROPINE 
APPENDIX 2. SCHEDULE OF ASSESSMENTS  
APPENDIX 3. PREP ACT 

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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 
schizophreni
a 
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 
Randomize
d 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. 

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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 
schizophreni
a 
and 
associated 
depression 
Case report 
Treat 
clozapine-
induced 
Hypersaliva-
tion 
1% 
ophthalmic 
solution 
0.5 – 1.0 mg 
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 
0.5 mg q6h 
48 hours 
22 
21 
No severe 
toxicity - 
no blurred 
vision, 
palpitations
, heartburn, 
hesitancy, 
urinary 
retention. 
One patient 
discontinue
d for 
cognitive 
impairment 
thought due 
to severe 
chest 
infection. 

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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 
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 
0.125 mg thrice 
daily for weight 
10-19 kg; 0.5 
mg thrice daily 
for weight 
>= 20 kg 
30 days 
33 
25 
Side effects 
in 4/33 
(12%): 
fever, 
flush, 
irritability, 
angioedem
a 
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 
sigmoidosco
py 
Double-
blind, 
placebo 
controlled 
Efficacy for 
comfort 
during 
screening 
sigmoidoscop
y 
Hyoscyamine 
0.125 mg 
tablets 
0.5 mg 
(2 tablets 10 
min prior to 
sigmoidoscopy) 
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 
MRE 
Open-label, 
non-
controlled 
Effect on 
peristalsis 
Hyoscyamine 
0.125 mg 
tablets 
0.5 mg 1 hour 
before MRE 
Single dose 
92  
92 
Safety was 
not 
discussed 

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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/ 
Parkinsonis
m 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 
constipatio
n, 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 
Randomize
d open-
label, two-
arm study 
Effect on 
ureteral colic 
Hyoscyamine 
sulfate  
0.125 mg  
Single dose 
49 
24 
Safety was 
not 
discussed 
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 

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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 
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 
Randomize
d 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
, 
hypotensio
n, 
hypoxemia. 
Matos Santana, T. 
E., et al. (2017). 
"Sublingual atropine 
in the treatment of 
clozapine-induced 
sialorrhea." 
Schizophr Res 182: 
144-145. 
Adults 
Schizophren
ia or 
schizoaffecti
ve disorder 
Case 
reports 
Effectiveness 
for clozapine-
induced 
sialorrhea 
1% 
ophthalmic 
solution 
0.5-1.0 mg once 
to twice daily 
> 1 week 
3 
3 
"None of 
the patients 
reported 
any 
systemic 
side 
effects" 

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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 
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 
schizophreni
a 
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) 
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 
Retrospecti
ve chart 
review 
Effect on 
respiratory 
secretions 
1% 
ophthalmic 
solution 
0.5 mg every 
2 hours until 
effect 
Varied by 
patient; 
range 
1 hour to 
6 days 
22 
22 
No adverse 
effects 
reported  

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CONFIDENTIAL AND PROPRIETARY 
63 
 
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 
Rapoport, A, (2010). 
“Sublingual 
Atropine Drops for 
the Treatment of 
Pediatric 
Sialorrhea.”, J. of 
Pain and Symptom 
Management 40(5): 
783-788. 
14 years 
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 
fasciculatio
n and 
dystonia 
developed 
after 2 
weeks, 
determined 
to be due to 
metoclopra
mide. 
Sublingual 
atropine 
restarted 
without 
recurrence. 
No facial 
flushing, 
change in 
behavior, 
or 
tachycardia
. 
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 

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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 
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; min = minute; MLD = metachromatic 
leukodystrophy; MRE = magnetic resonance enterography; q6h = every 6 hours; Rx = treatment 
 
 

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APPENDIX 2. SCHEDULE OF ASSESSMENTS  
Study Visit 
Screening 
Visit 1 a 
 
Visit 2 a  
Telephone 
Follow-up 
ET b 
Unscheduled 
Study Day 
Day -14 to -3 
Day 1 Pre-dose 
(Baseline) 
Day 1 Dosing 
Day 8 Pre-dose 
(Baseline) 
Day 8 Dosing 
Day 15,-1/+7d 
N/A 
N/A 
Visit window based on actual 
dosing day 
N/A 
N/A 
V1+7d,±1 
V2+7d,-1/+7 
N/A 
N/A 
Informed Consent 
X 
 
 
 
 
 
 
 
Inclusion/Exclusion 
X 
X c 
 
X c 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
Demographic/Medical History  
X 
 
 
 
 
 
 
 
Height, weight, BMI 
X 
X d 
 
X d 
 
 
X d 
X d 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
X 
Physical Exam 
X e 
X f 
 
X f 
 
 
X f 
X f 
Vital Signs g 
X 
X 
X 
X 
X 
 
X 
X 
12-lead ECG 
X 
X 
X h 
X 
X h 
 
X i 
X i 
Urine drug screen j 
X 
 
 
 
 
 
  
 
Serum quantitative beta-HCG 
assay 
X 
 
 
 
 
 
 
 
HIV antibody, HBsAg, anti-HCV 
X 
 
 
 
 
 
 
 
Laboratory Assessments k 
X 
 
 
 
 
 
X l 
X l 
Urine POC pregnancy test m 
 
X 
 
X 
 
 
X n 
X n 
CRU admission 
 
X 
 
X 
 
 
 
 
Other pre-dose eligibility o 
 
X 
 
X 
 
 
 
 
Study drug administration 
 
 
X 
 
X 
 
 
 
Plasma PK p 
 
X 
X 
X 
X 
 
 
 
AEs 
X 
X 
X 
X 
X 
X 
X 
X 
Discharge from CRU 
 
 
X 
 
X 
 
 
 
AE = adverse event; BMI = body mass index; CBC = complete blood count; CRU = clinical research unit; d = day; ECG = electrocardiogram; ET = early 
termination; HBsAg = hepatitis B surface antigen; HCG = human chorionic gonadotropin; HCV = hepatitis C virus; HIV = human immunodeficiency virus; 
N/A = not applicable; LFT=liver function test; PK = pharmacokinetic; POC = point-of-care; SL = sublingual; TSH = thyroid-stimulating hormone. 

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a Washouts of 6 ± 1 days will occur between visits. Adverse events and concomitant medications will be recorded for both washout periods. 
b The ET Visit may be conducted in clinic or by phone as determined by the investigator.  
c Eligibility criteria must be reviewed just prior to each dose of atropine, unless the criterion is specified as only being evaluated at Screening. 
d Weight only will be measured at Visit 1 (Day 1 Pre-dose) and Visit 2 (Day 8 Pre-dose). Weight may also be measured at an ET or Unscheduled Visit per the 
investigator’s discretion. 
e All participants will undergo a physical examination at Screening. The examination will include a general assessment of the skin, head, ears, eyes, nose, throat, 
neck, oral cavity, 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. 
f At Visit 1 (Day 1 Pre-dose), Visit 2 (Day 8 Pre-dose), ET, and Unscheduled visits, the investigator may perform symptom-based physical examinations at their 
discretion. 
g Vital signs (heart rate, blood pressure, temperature, and respiratory rate) will be obtained prior to each dose of study drug. Post-dose automated blood pressure 
and heart rate measurements will be recorded on the opposite arm from blood collection every 15 ± 5 minutes for the first hour, every 20 ± 5 minutes for the 
second hour, and every 30 ± 5 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 an Unscheduled or ET Visit per the investigator’s discretion. 
h At Visit 1 (Post-dose) and Visit 2 (Post-dose), an ECG may be performed for any complaints of chest discomfort, lightheadedness, and/or palpitations per the 
investigator’s discretion and repeated as needed. 
i An ECG will be performed at an ET or Unscheduled Visit if deemed necessary by the investigator. 
j Urine drug screen will include tests for amphetamines, cocaine, tetrahydrocannabinol, methylenedioxymethamphetamine, and opiates. 
k Clinical laboratory assessments performed at the Screening Visit will include CBC with differential (red blood cell, total and differential white blood cell, 
hemoglobin, hematocrit, and platelet count), Chem 7 panel (blood urea nitrogen, total carbon dioxide, creatinine, glucose, chloride, potassium, sodium), liver 
function tests (aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, total bilirubin, direct bilirubin), and TSH with reflex to T4.  
l Clinical laboratory assessments may be performed at an ET or Unscheduled Visit per the investigator’s discretion.  
m A urine POC pregnancy test will be conducted for all women of childbearing potential at Visit 1 (Day 1 Pre-dose) and Visit 2 (Day 8 Pre-dose). Results from 
all tests must be negative to proceed with dosing. 
n A urine POC pregnancy test may be performed on females of childbearing potential at an ET or Unscheduled Visit if pregnancy is suspected.  
o Participants must have fasted from food and drink for 2 hours prior to study drug administration, and must have abstained from any other oral product that has 
the potential to interfere with SL atropine absorption (e.g., candy, chewing gum, mints, etc.) for 2 hours prior to study drug administration.  
p Blood samples for PK analysis will be taken at time 0 (pre-dose) and at 13 time points post-dose at 5, 10, 15, 20, 30, 45, 60, and 90 minutes and 2, 2.5, 4, 6, and 
8 hours. 
 
 

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APPENDIX 3. PREP ACT  
The following language applies only to Clinical Research Sites located in the United States. 
Public Readiness and Emergency Preparedness Act 
The drug atropine and the efforts for this clinical trial are covered under the Public Readiness 
and Emergency Preparedness Act (PREP Act) and the Declaration issued by the Secretary of the 
U.S. Department of Health and Human Services under that Act. Under the PREP Act and the 
Declaration, covered persons (such as manufacturers, distributers, program planners, and other 
qualified persons who prescribe, administer or dispense study drug) are immune from liability 
from the administration, or use of a covered countermeasure, such as atropine. The PREP Act 
provides immunity for covered persons from liability, unless the injury was caused by willful 
misconduct.  
The PREP Act also established the Countermeasures Injury Compensation Program (CICP) to 
provide compensation for serious injuries or death that occur as the direct result of the 
administration or use of certain countermeasures. Any requests for compensation must be filed 
within one year of the administration or use of the covered countermeasure. Requests for 
Benefits must be made to the Health Resources and Services Administration’s Countermeasures 
Injury Compensation Program (http://www.hrsa.gov/cicp/) by filing a Request for Benefits Form 
and all required medical records and supporting documentation. Additional information on filing 
a Request for Benefits is available on the CICP’s website at http://www.hrsa.gov/cicp/. 
Compensation may then be available for reasonable and necessary medical benefits, lost wages 
and/or death benefits to eligible individuals for certain injuries in accordance with regulations 
published by the Secretary of HHS (found at 42 CFR part 110). 
If an individual suffers a serious physical injury or death from the administration or use of a 
covered countermeasure in this study, the individual, the individual’s legal or personal 
representative, the administrator/executor of a deceased individual’s estate, or certain survivors 
may request benefits from the CICP. A serious physical injury means an injury that warranted 
hospitalization (whether or not the person was actually hospitalized) or that led to a significant 
loss of function or disability. The CICP is the payer of last resort. This means that it only covers 
expenses or provides benefits that other third-party payers (such as health insurance, the 
Department of Veterans Affairs, or Workers’ Compensation programs) do not have an obligation 
to pay. 
If the Secretary of HHS does not make a final determination on the individual’s request within 
240 days, or if the individual decides not to accept the compensation, the injured individual or 
his representative may pursue a tort claim in the US District Court for the District of Columbia, 
but only if the claim involves willful misconduct and meets the other requirements for suit under 
the PREP Act. Any award is reduced by any public or private insurance or worker’s 
compensation available to the injured individual. Awards for non-economic damages, such as 
pain, suffering, physical impairment, mental anguish, and loss of consortium are also limited. If 
the individual accepts compensation, or if there is no willful misconduct, then the individual does 
not have a tort claim that can be filed in a US Federal or a State court.