Clinical trial NCT03518125
Conditions: Anthrax
Keywords: Anthrax Bacillaceae Infections Gram-Positive Bacterial Infections Bacterial Infections Anthrax Vaccine Adsorbed BioThrax AV7909 CPG 7909 Adjuvant Vaccines Post-exposure Prophylaxis
Sponsor: Biomedical Advanced Research and Development Authority
Start date: 2018-05-09; Completion date: 2019-12-09
Enrollment: 305 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study is designed to assess the safety and ability of BioThrax and AV7909 anthrax vaccines to generate an immune response in adults ≥ 66 years of age in stable health in comparison to adults 18-50 years of age in stable health.

Detailed description:
This is a phase 2, randomized, active-controlled, double-blinded, multi-site study to assess the safety and immunogenicity of BioThrax (Anthrax Vaccine Adsorbed) and AV7909 (Anthrax Vaccine Adsorbed plus CPG 7909 adjuvant) using a post-exposure prophylaxis dosing regimen in adults ≥ 66 years of age in stable health. The safety and immunogenicity profile of BioThrax and AV7909 in adults ≥ 66 years of age will also be compared to the safety and immunogenicity profile of subjects 18-50 years of age in stable health. The main study goal is to determine optimal dosing for AV7909 in the elderly population. Subjects will receive either 3 doses of BioThrax, 3 doses of AV7909, or 2 doses of AV7909 and 1 dose of placebo. Doses will be administered approximately 14 days apart. Subjects will be followed for safety assessment for 12 months following the last dose. The expected study duration is approximately 14 months per subject.

Arms: arm 1: Subjects dosed on Days 1, 15, and 29 with 0.5 mL BioThrax. arm 2: Subjects dosed on Days 1, 15, and 29 with 0.5 mL AV7909. arm 3: Subjects dosed on Days 1 and 15 with 0.5 mL AV7909 and on Day 29 with 0.5 mL placebo. arm 4: Subjects dosed on Days 1 and 29 with 0.5 mL AV7909 and on Day 15 with 0.5 mL placebo. arm 5: Subjects dosed on Days 1, 15, and 29 with 0.5 mL BioThrax. arm 6: Subjects dosed on Days 1 and 15 with 0.5 mL AV7909 and on Day 29 with 0.5 mL placebo.
Interventions: intervention 1: BioThrax intervention 2: AV7909 intervention 3: Sodium chloride injection USP, 0.9% (placebo)
Intervention descriptions: intervention 1: Other Names:

Anthrax Vaccine Adsorbed (AVA) intervention 2: Anthrax Vaccine Absorbed plus CPG 7909 Adjuvant intervention 3: Other Names:

Saline Solution

Protocol documents:
Prot_002.pdf: 
BARDA 
BioThrax and AV7909 
Protocol: BP-C-17001 Version 2.0 
16 April 2018 
1 
CLINICAL STUDY PROTOCOL  
Randomized, Active-Comparison, Double-Blind, Phase 2 Study to Assess the Safety and 
Immunogenicity of Anthrax Vaccine Adsorbed (BioThrax®) without and with CPG 7909 
Adjuvant (AV7909 Anthrax Vaccine), Using a Post-Exposure Prophylaxis Dosing Regimen 
in Adults 66 Years of Age or Older in Stable Health in Comparison to Adults 18-50 Years 
of Age in Stable Health   
BARDA Securing Anthrax Immunity For the Elderly (B-SAFE) 
BP-C-17001 
Sponsor: 
Biomedical Advanced Research and Development Authority 
(BARDA) 
 
 
Sponsor Contact: 
  
 
 
 
 
 
Medical Monitor: 
  
 
 
 
 
Version of Protocol:  
 
2.0 
Date of Protocol:  
 
 
16 April 2018 
Previous Date and Version: 20 February 2018; Version 1.0 
CONFIDENTIAL 
All financial and nonfinancial support for this study will be provided by BARDA.  The concepts 
and information contained in this document or generated during the study are considered 
proprietary and may not be disclosed in whole or in part without the expressed, written consent 
of BARDA.  The study will be conducted according to the Integrated Addendum to International 
Conference on Harmonisation (ICH) E6 (R1): Guideline for Good Clinical Practice (GCP)  E6 
(R2). 
 




BARDA 
BioThrax and AV7909 
Protocol: BP-C-17001 Version 2.0 
16 April 2018 
3 
Investigator’s Agreement 
 
Study Title 
Randomized, Active-Comparison, Double-Blind, Phase 2 Study to 
Assess the Safety and Immunogenicity of Anthrax Vaccine Adsorbed 
(BioThrax®) without and with CPG 7909 Adjuvant (AV7909 Anthrax 
Vaccine), Using a Post-Exposure Prophylaxis Dosing Regimen in Adults 
66 Years of Age or Older in Stable Health in Comparison to Adults 
18-50 Years of Age in Stable Health 
Short Title  
BARDA Securing Anthrax Immunity For the Elderly (B-SAFE) 
Protocol Number 
BP-C-17001 
Protocol Version 
Version 2.0 
Protocol Date 
16 April 2018 
 
I have read and understood all sections of the above referenced protocol, the current package 
insert for BioThrax, and the investigator’s brochure for AV7909 Anthrax Vaccine. 
I agree to supervise all aspects of the protocol at my clinical research site and to conduct the 
clinical investigation in accordance with the protocol and the International Conference on 
Harmonisation (ICH) regulations and US IND regulations in 21 CFR 312.  I will not make 
changes to the protocol before consulting with BARDA or implement protocol changes without 
institutional review board approval except to eliminate an immediate risk to subjects.  I agree to 
administer study treatment only to subjects under my personal supervision or the supervision of a 
subinvestigator. 
I will not supply the investigational product to any person not authorized to receive it.  
Confidentiality will be protected.  Subject identity will not be disclosed to third parties or appear 
in any study reports or publications. 
I will not disclose information regarding this clinical investigation or publish results of the 
investigation without authorization from BARDA. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Printed Name of Investigator 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Investigator  
 
 
 
 
 
 
 
 
 
 
 
 
Date 
 
 
 


BARDA 
BioThrax and AV7909 
Protocol: BP-C-17001 Version 2.0 
16 April 2018 
4 
Emergency Contact Information 
 
Table 1: 
Emergency Contact Information 
Role in Study 
Name 
Address and Telephone Number 
Sponsor Contact 
 
 
  
 
 
 
 
Medical Monitor 
 
 
 
 
 
 
 
 


BARDA 
BioThrax and AV7909 
Protocol: BP-C-17001 Version 2.0 
16 April 2018 
5 
1. 
SYNOPSIS 
Name of Sponsor/Company:  Biomedical Advanced Research and Development Authority (BARDA) 
Name of Investigational Product:  BioThrax and AV7909 Anthrax Vaccine (AV7909) 
Name of Active Ingredients:  
Antigen: Anthrax Vaccine Adsorbed (AVA)  
Adjuvant: cytosine-guanine dinucleotide (CPG) 7909 
Title of Study:  Randomized, Active-Comparison, Double-Blind, Phase 2 Study to Assess the Safety 
and Immunogenicity of Anthrax Vaccine Adsorbed (BioThrax®) without and with CPG 7909 Adjuvant 
(AV7909 Anthrax Vaccine), Using a Post-Exposure Prophylaxis Dosing Regimen in Adults 66 Years of 
Age or Older in Stable Health in Comparison to Adults 18-50 Years of Age in Stable Health 
Short Title: BARDA Securing Anthrax Immunity For the Elderly (B-SAFE) 
Protocol Number: BP-C-17001 
Version Number: 2.0 
Study center(s): Approximately 4 clinical sites in the United States (US) 
Study period (years):  
Estimated date first subject enrolled: Quarter (Q)2 2018 
Estimated date last subject completed: Q4 2019 
Phase of development:  2 
 
Study Objectives:  
Primary Objectives 
Safety 
 
To evaluate safety and reactogenicity, as determined by solicited local and systemic 
reactogenicity symptoms (within 8 days after each vaccination, inclusive of the vaccination 
day, excluding reactogenicity on the contralateral arm), of BioThrax or AV7909 
administered to adults ≥66 years of age.  
Immunogenicity 
 
To evaluate the seroprotection, defined as toxin neutralization antibody (TNA) 50% 
neutralization factor (NF50) ≥0.56, rate at Day 64 for BioThrax or AV7909 administered to 
adults ≥66 years of age. 
Secondary Objectives 
Safety  
 
To evaluate the occurrence of treatment-emergent unsolicited adverse events (AEs) (defined 
as all AEs other than solicited local and systemic reactogenicity symptoms), serious adverse 
events (SAEs), and medically attended adverse events (MAAEs), including potentially 
immune-mediated medical conditions (PIMMCs) from the time of the first dose of study 
investigational product (IP) through 12 months following the last dose of study IP. 
 
To evaluate the occurrence of solicited local reactogenicity symptoms on the contralateral 
arm (within 8 days after each vaccination, inclusive of the vaccination day). 


BARDA 
BioThrax and AV7909 
Protocol: BP-C-17001 Version 2.0 
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Immunogenicity 
 
To assess the TNA NF50 antibody levels, seroprotection rates, and seroconversion (defined 
as a ≥4-fold increase over baseline levels, or a ≥4-fold increase over the lower limit of 
quantification [LLOQ] if the baseline value is < LLOQ) rates for each study group at each 
applicable timepoint through Day 394.  
 
To assess the TNA effective dilution resulting in 50% neutralization (ED50) antibody levels 
and seroconversion rates for each study group at each applicable timepoint through 
Day 394. 
 
To assess the enzyme-linked immunosorbent assay (ELISA) anti-protective antigen (PA) 
immunoglobulin G (IgG) antibody levels and seroconversion rates for each study group at 
each applicable timepoint through Day 394. 
 
To compare the TNA NF50 antibody levels, seroprotection rates, and seroconversion rates 
through Day 394 between younger adults (18 through 50 years) and older adults (≥66 years 
of age) within the following groups at each applicable timepoint: 
1. BioThrax given at Days 1, 15, and 29  
2. AV7909 given at Days 1 and 15 and placebo given at Day 29  
 
To compare the TNA ED50 antibody levels and seroconversion rates through Day 394 
between younger adults (18 through 50 years) and older adults (≥66 years of age) within the 
following groups at each applicable timepoint: 
1. BioThrax given at Days 1, 15, and 29  
2. AV7909 given at Days 1 and 15 and placebo given at Day 29  
 
To compare the ELISA anti-PA IgG antibody levels and seroconversion rates through 
Day 394 between younger adults (18 through 50 years) and older adults (≥66 years of age) 
within the following groups at each applicable timepoint: 
1. BioThrax given at Days 1, 15, and 29  
2. AV7909 given at Days 1 and 15 and placebo given at Day 29  
Methodology:  
After screening, subjects meeting all of the inclusion criteria and none of the exclusion criteria will be 
randomized to receive either BioThrax or AV7909.  Randomization will be stratified by sex and age 
(18-50, 66-74, and ≥75 years).  Subjects ≥66 years of age will be randomized 1:1:1:1 within stratum 
across 4 treatment arms (approximately 50 subjects per group), and subjects 18 through 50 years of age 
will be randomized 1:1 within stratum across 2 treatment arms (approximately 50 subjects per group).  
Once randomized, subjects will receive 3 vaccinations, each separated by approximately 14 days, on 
Day 1, Day 15, and Day 29, based on their assigned treatment arm.   
Immunogenicity assessments will include TNA NF50, TNA ED50, and ELISA anti-PA IgG antibody 
levels.   
Safety assessments will be based on solicited AEs (local and systemic reactogenicity symptoms) 
occurring within 8 days of each vaccination, treatment-emergent unsolicited AEs (all occurring through 
Day 50 and only those defined as SAEs, MAAEs, and PIMMCs following Day 50), and treatment-
emergent SAEs, MAAEs, and PIMMCs throughout the study.  Safety assessments will also include 
physical examination, vital signs, standard 12-lead electrocardiogram (ECG), high-sensitivity C-reactive 
protein (hs-CRP) assay, autoantibody assays (if needed), and clinical laboratory tests (chemistry, 
hematology, and urinalysis).  Safety for each subject will be assessed from the time of the first dose of 
IP through 12 months following the last dose of IP.  


BARDA 
BioThrax and AV7909 
Protocol: BP-C-17001 Version 2.0 
16 April 2018 
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Number of subjects (planned):  
The proposed enrollment for this study is approximately 300 subjects in stable health (200 subjects aged 
≥66 years and 100 subjects aged 18 through 50 years, inclusive).  Although not required, ideally ≥1/3 of 
the elderly subjects enrolled would be in the ≥75 years of age stratum.   
There will be 6 study groups (approximately 50 subjects per group). 
Study 
Group 
Age Group 
Arm 
Investigational 
Product 
Dose 1 
Day 1  
Dose 2 
Day 15  
Dose 3 
Day 29  
Group 1 
Age ≥66 
1 
BioThrax 
BioThrax 
BioThrax 
BioThrax 
Group 2 
Age ≥66 
2 
AV7909 
AV7909 
AV7909 
AV7909 
Group 3 
Age ≥66 
3 
AV7909 
AV7909 
AV7909 
Placebo 
Group 4 
Age ≥66 
4 
AV7909 
AV7909 
Placebo 
AV7909 
Group 5 
Age 18-50 
1 
BioThrax 
BioThrax 
BioThrax 
BioThrax 
Group 6 
Age 18-50 
3 
AV7909 
AV7909 
AV7909 
Placebo 
Diagnosis and main criteria for inclusion:  
Subjects will be randomized to study treatment only if they meet all of the applicable inclusion criteria 
and none of the exclusion criteria.  In addition, applicable eligibility criteria must be reviewed just prior 
to each vaccination; if the subject no longer meets applicable eligibility criteria, the investigator, in 
consultation with the medical monitor in cases of uncertainty, must determine whether the subject 
should receive the IP dose or be terminated early from study IP.  
Deviations from the inclusion and exclusion criteria are not allowed because they can potentially 
jeopardize the scientific integrity of the study, regulatory acceptability, or subject safety.  Therefore, 
adherence to the criteria specified in the protocol is essential.   
Subject Inclusion Criteria 
1. Male or nonpregnant females, 66 years of age or older at the time of randomization for the 
elderly population, or 18 through 50 years of age at the time of randomization for the younger 
population. 
2. Females who are of childbearing potential and are sexually active with a male partner must 
agree to use an acceptable method of birth control from Screening to Day 64 and must have used 
a reliable birth control method for at least 2 months prior to Screening. 
a. A female of childbearing potential is defined as post onset menarche and pre-
menopausal 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, either 
combined or progestogen alone; injectable progestogen; implants of etenogestrel or 
levonorgestrel; estrogenic vaginal ring; percutaneous contraceptive patches; intrauterine 
device or intrauterine system; male partner sterilization at least 6 months prior to the 
female subject’s Screening Visit, and this male is the sole partner for that subject (the 
information on the male partner’s sterility can come from the site personnel’s review of 
the subject’s medical records or interview with the subject on her medical history); male 


BARDA 
BioThrax and AV7909 
Protocol: BP-C-17001 Version 2.0 
16 April 2018 
8 
condom combined with a vaginal spermicide (foam, gel, film, cream, or suppository); 
male condom combined with a female diaphragm, either with or without a vaginal 
spermicide (foam, gel, film, cream, or suppository). 
3. Able to provide written informed consent prior to initiation of any study procedures.  As part of 
the consent process, subjects must be able to demonstrate understanding by passing the 
“Assessment of Understanding Questionnaire” within 2 attempts.  Passing is defined as being 
able to answer all questions correctly.   
4. In relatively stable health based on site investigator’s judgment, as determined by medical 
history, physical examination, and the following criteria:  
a. Stable health for age (defined as no new conditions per medical history, new 
medications in a different therapeutic class, or change in daily dose of existing 
prescription medications within the 45 days preceding Screening).  Effective treatment 
(to resolution) of an acute infection (e.g., urinary tract infection, cellulitis, otitis, or 
bronchitis) with an antibiotic within 45 days preceding Screening will not be considered 
a deviation from this inclusion criterion as long as the antibiotic therapy was completed 
at least one week prior to Screening and no signs or symptoms of the infection have 
been present since the completion of treatment.  Any prescription change that is due to 
change of health care provider or insurance company, or that is made for reasons that do 
not reflect a change in disease status (e.g., financial considerations), as long as within 
the same general class of medication, will not be considered a deviation from this 
inclusion criterion.  Any change in prescription medication due to improvement of a 
disease outcome, as determined by the site investigator, will not be considered a 
deviation from this inclusion criterion. 
b. Subjects may be on chronic or as needed medications if, in the opinion of the site 
investigator, these pose no additional risk to subject safety or assessment of 
reactogenicity and immunogenicity and their use is not for management of a worsening 
of medical diagnosis or condition.  Note: Topical, nasal, and inhaled medications (with 
the exception of steroids, as outlined in the subject exclusion criteria) and vitamins are 
permitted.  
5. Have a body mass index (BMI) less than 35.0 kg/m2 at Screening.  (BMI will not be reassessed 
prior to subsequent vaccinations.)  
6. Have access to a consistent and reliable means of telephone contact, which may be home, 
workplace, or by personal mobile electronic device.  
7. Are available and can comply with all study visits. 
Subject Exclusion Criteria 
1. Females who have a positive urine pregnancy test at Screening or within 24 hours prior to each 
study vaccination or women who are breastfeeding. 
2. Have a requirement for skilled nursing care. 
3. Have a history of severe reactions to components of AVA or CPG 7909, e.g. formaldehyde, 
benzethonium chloride (phemerol), or aluminum. 
4. Have a history of latex sensitivity.  
5. Have a history of ever receiving a vaccine for anthrax prior to Screening, or had an anthrax 
infection. 
6. Have any medical, psychiatric, or social condition that, in the opinion of the site investigator, 
unfavorably alters the risk-benefit of subject participation, or is likely to interfere with study 
compliance or assessments, or is likely to confound interpretation of safety or immunogenicity 
data.   


BARDA 
BioThrax and AV7909 
Protocol: BP-C-17001 Version 2.0 
16 April 2018 
9 
7. Have any diagnosis, current or past, of a potentially immune-mediated medical condition, such 
as Guillain-Barré syndrome, narcolepsy, or an autoimmune or chronic inflammatory disease.  
8. Have any diagnosis, current or past, of schizophrenia or bipolar disorder. 
9. Have been hospitalized for psychiatric illness, have a history of suicide attempt, or confinement 
for danger to self or others within the preceding 10 years prior to Screening and each study 
vaccination. 
10. Have a history of alcohol or drug abuse (per investigator’s judgment) within 5 years prior to 
Screening and each study vaccination, or test positive for drugs of abuse at Screening (including 
for cannabis, even where legal).  Benzodiazepines for anxiety disorders and stimulants for 
attention deficit hyperactivity disorder are not exclusionary if the subject has been on a stable 
dose for more than 3 months prior to Screening and each study vaccination and if the subject can 
produce a valid, current prescription for the medication.  Propoxyphene, opioids, or 
combinations containing these medications (including as used for opioid addiction) are not 
permitted regardless of prescription status. Note: A positive Screening urine drug screen may 
not be repeated.  (Drug screen will not be repeated prior to subsequent vaccinations.)  
11. Have known human immunodeficiency virus (HIV), or acute or chronic hepatitis B or hepatitis 
C infection based on medical history; or test positive for any of these at Screening.  Subjects 
who have been effectively treated for hepatitis C, as evidenced by a negative hepatitis C 
ribonucleic acid (RNA) confirmation test and who no longer require antiviral therapy, are 
eligible for participation. (Screening tests will not be repeated prior to subsequent vaccinations.)  
12. Have known active neoplastic disease or a history of any hematologic malignancy.  However, 
subjects with superficial skin cancer who do not require intervention other than local excision 
are not excluded.  
13. Have immunosuppression as a result of an underlying illness or treatment, or use of anticancer 
chemotherapy (cytotoxic) or radiation therapy within 3 years prior to Screening and each study 
vaccination. 
14. Have taken any systemic immunosuppressive agents, including immunomodulators, 6 months 
prior to Screening and each study vaccination. Allergen immunotherapy (desensitization) is not 
exclusionary. Allergen immunotherapy (desensitization) does not include systemic antibodies 
such as benralizumab, mepolizumab, or omalizumab; these are exclusionary. 
15. Are suffering from or have a history of neuralgia, paresthesia, or neuritis within 90 days prior to 
Screening and each study vaccination; or have any history of stroke. 
16. Have had convulsions or encephalomyelitis within three years prior to Screening and each study 
vaccination. 
17. Have received immunoglobulin or other blood products (with the exception of Rho[D] immune 
globulin) within 90 days prior to Screening and each study vaccination. 
18. Have received an experimental agent within 180 days prior to the first study vaccination, or 
expects to participate in another clinical trial with an interventional agent during the study 
period.  This includes licensed or unlicensed vaccines, drugs, biologics, devices, blood products, 
or medications. Participation in an observational study is not exclusionary as long as it doesn’t 
interfere with study visits or procedures (e.g., blood collection volume restrictions). 
19. Have taken oral or parenteral corticosteroids of any dose within 30 days prior to each study 
vaccination. 
20. Have taken high-dose inhaled corticosteroids within 30 days prior to each study vaccination.  
High-dose is defined as >800 mcg/day of beclomethasone dipropionate or equivalent.  Lower 
doses of inhaled corticosteroids are not exclusionary.  
21. Have received any licensed live vaccine within 30 days prior to the first study vaccination or 


BARDA 
BioThrax and AV7909 
Protocol: BP-C-17001 Version 2.0 
16 April 2018 
10 
planned receipt from the first study vaccination through Visit 10 (Day 64).   
22. Have received any licensed inactivated vaccine within 14 days prior to the first study 
vaccination or planned receipt from the first study vaccination through Visit 10 (Day 64).  
23. Have an acute illness, as determined by the site investigator, within 72 hours prior to each study 
vaccination.   
a. If subject’s oral temperature is above 100.0°F (37.8°C), the subject may be re-assessed 
for eligibility within the visit window (+3 Days). 
b. An acute illness that is nearly resolved, with only minor residual symptoms remaining, 
is allowable if, in the opinion of the site investigator, the residual symptoms will not 
interfere with the ability of study staff to assess safety parameters as required by the 
protocol. 
c. For bacterial infections that have been successfully treated with antibiotics, inclusion 
criterion 4a applies. 
24. Have a history of myocardial infarction or ischemia, or have ECG findings of myocardial 
infarction, ischemia, strain, complete bundle branch block, or ventricular arrhythmias (other 
than unifocal premature ventricular contractions ≤2/minute).  Additionally, other cardiac history 
or ECG findings, which in the opinion of the investigator represent a potentially unstable or 
unacceptably high risk of an adverse cardiac outcome, are exclusionary.  (ECG will not be 
repeated prior to subsequent vaccinations.) 
25. Have any laboratory test result or clinical findings (including vital signs) that singly or in 
combination are, in the investigator’s opinion, likely to unfavorably alter the risk-benefit of 
subject participation or to confound study safety or immunogenicity results.  Additionally, the 
following are exclusionary:  
a. Any clinically significant Grade 3 laboratory or vital sign result, or any Grade 4 
laboratory or vital sign result (regardless of assessed significance) at Screening.  For 
subsequent vaccinations, abnormal laboratory results and vital sign results post-
vaccination will be assessed against the rules for early termination of dosing.    
b. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >2 times the 
upper limit of normal (ULN), or bilirubin >1.5 times the ULN unless isolated Gilbert’s 
syndrome.  
c. Creatinine >1.5 times ULN for age and sex. 
d. White blood cell count <3,000/µL or >12,500/µL; absolute neutrophil count <1200/µL; 
absolute lymphocyte count <750/µL; hemoglobin <10 g/dL females, or <11.5 g/dL 
males; platelet count <75,000/µL.  
e. Hemoglobin A1C  (HbA1C) >7.0% at Screening. (HbA1C will not be repeated prior to 
subsequent vaccinations.) 
Subjects cannot be rescreened for exclusionary laboratory test results.  Potentially exclusionary vital sign 
results may be repeated, but unless they have resolved to a Grade 3 designation or less and are not 
considered clinically significant, the subject should be excluded.  The most recent laboratory and vital 
sign results will be used when determining eligibility for subsequent vaccinations. 
Investigational product, dosage and mode of administration: Subjects will receive either 3 doses of 
active IP (BioThrax or AV7909) or 2 doses of active IP (AV7909) and 1 dose of placebo IP.  BioThrax 
(0.5 mL) should be administered by subcutaneous (SC) injection over the deltoid muscle.  AV7909 
(0.5 mL) should be administered by intramuscular (IM) injection in the deltoid muscle.  Placebo IP 
(0.5 mL) will be administered IM in the deltoid muscle.   
Duration of treatment: Subjects will receive 3 study vaccinations, separated by approximately 14 days, 


BARDA 
BioThrax and AV7909 
Protocol: BP-C-17001 Version 2.0 
16 April 2018 
11 
and will be followed for 12 months after their last IP dose.  The expected study duration is 
approximately 14 months per subject.  
Reference therapy, dosage and mode of administration: Not applicable 
Criteria for evaluation: 
Primary Endpoints 
There are 2 primary endpoints for this study. 
 
All solicited local and systemic reactogenicity symptoms occurring within 8 days after each 
vaccination, inclusive of the vaccination day, excluding reactogenicity symptoms on the 
contralateral arm. 
 
Seroprotection at Day 64, defined as a TNA NF50 antibody level ≥0.56.  
Secondary Endpoints 
Secondary Safety Endpoints 
 
All treatment-emergent unsolicited AEs. 
 
All treatment-emergent SAEs occurring during study participation. 
 
All treatment-emergent MAAEs occurring during study participation. 
 
All treatment-emergent PIMMCs occurring during study participation. 
 
All solicited local reactogenicity symptoms on the contralateral arm occurring within 8 days 
after each vaccination, inclusive of the vaccination day. 
Secondary Immunogenicity Endpoints 
 
TNA NF50 antibody levels at Days 1, 8, 22, 29, 36, 43, 50, 64, 85, 181, and 394. 
 
TNA ED50 antibody levels at Days 1, 8, 22, 29, 36, 43, 50, 64, 85, 181, and 394. 
 
ELISA anti-PA IgG antibody levels at Days 1, 8, 22, 29, 36, 43, 50, 64, 85, 181, and 394. 
 
Seroprotection based on TNA NF50 at Days 1, 8, 22, 29, 36, 43, 50, 85, 181, and 394. 
 
Seroconversion based on TNA NF50 at Days 8, 22, 29, 36, 43, 50, 64, 85, 181, and 394, 
defined as a ≥4-fold increase over baseline levels, or a ≥4-fold increase over the lower limit 
of quantification (LLOQ) if the baseline value is below the LLOQ. 
 
Seroconversion based on TNA effective dilution resulting in 50% neutralization (ED50) at 
Days 8, 22, 29, 36, 43, 50, 64, 85, 181, and 394. 
 
Seroconversion based on ELISA anti-PA IgG at Days 8, 22, 29, 36, 43, 50, 64, 85, 181, and 
394. 
Statistical methods: 
Analysis Plan 
Due to the exploratory nature of the primary objectives, inferential analyses are planned only as part of 


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BioThrax and AV7909 
Protocol: BP-C-17001 Version 2.0 
16 April 2018 
12 
the secondary analyses.  Descriptive statistics (such as medians, quartiles, and ranges for continuous 
data, and percentages for categorical data) will be used to summarize subject characteristics, safety, and 
immunogenicity parameters.  These summaries will be presented overall and separately for the subjects 
in the different study groups, as well as for pooled groups by treatment arm (regardless of age group) 
and by age group (regardless of treatment arm).  Details of the statistical analyses, methods, and data 
conventions will be described in the Statistical Analysis Plan (SAP).  
Interim Analysis 
An interim analysis will be performed based on cumulative immunogenicity and safety data through 
Day 64 for all subjects.  Data for the interim analysis will be presented solely at the group level, thus, the 
blinding at the subject level will be maintained for those outside of the unblinded team until database 
lock of all data through Day 394 for the clinical study report.  All primary and secondary endpoint 
analyses up through Day 64 will be performed for the interim analysis.  
Safety Monitoring Committee Reviews 
The Safety Monitoring Committee (SMC) will perform a planned review of interim safety data after 
40 subjects ≥66 years of age have completed Visit 7 (Day 36).  Enrollment and dosing will continue 
during this planned SMC review.  In addition, ad hoc reviews will occur in the event that 
pausing/stopping rules are met or a review is deemed necessary by the SMC chair.  
The final SMC safety displays will be provided to the SMC members when the last study subject 
completes Visit 10 (Day 64). 
Data displays for each SMC review will be generated by an unblinded statistician.  Safety analyses for 
this study will be descriptive rather than inferential.  Detailed listings and summary tabulations will be 
generated as specified in the SMC charter.  The safety analyses will be completed using the safety 
population. 
Final Analyses 
A clinical study report will be written to include all safety and immunogenicity data through Day 394.  
Study data will be unblinded to prepare the study report.  Further details will be specified in the SAP. 
Analysis Populations 
Safety Population 
The safety population will include all subjects who are randomized and receive at least 1 IP dose.  Each 
subject will be analyzed as part of the study group corresponding to the actual treatment received for the 
applicable dose for individual dose summaries.  For all other analyses by study group, each subject will 
be analyzed corresponding to the actual treatment received for the first dose.  The safety population will 
be used for all safety analyses. 
Immunogenicity Full Analysis Population 
The immunogenicity full analysis population (IFAP) will include all subjects who are randomized, 
receive at least 1 IP dose, and have at least one determinate assay result at any post-vaccination visit.  
Each subject will be analyzed based on the treatment and dosing schedule actually received, regardless 
of the treatment arm assignment.  The IFAP will be used only for analysis of seroprotection based on 
TNA NF50 antibody levels at Day 64 as a secondary analysis.  Any additional immunogenicity analyses 
on the IFAP will be defined in the SAP. 


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Immunogenicity Per Protocol Population 
The immunogenicity per protocol population (IPPP) will include all subjects in the IFAP who meet the 
following criteria: 
 
Receive a full dose of IP at Day 1, Day 15, and Day 29 within protocol specified visit 
windows (- 1 Day, +3 Days). 
 
Receive the correct treatment as assigned by randomization at Day 1, Day 15, and Day 29. 
 
Have no other major protocol deviations that may have an impact on immunogenicity 
assessments. 
 
Have determinate assay results at the Day 64 visit. 
The IPPP will be used for all primary and secondary immunogenicity endpoint assessments.  
 


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2. 
TABLE OF CONTENTS  
CLINICAL STUDY PROTOCOL ..................................................................................................1 
Protocol Approval - Sponsor Signatory ...........................................................................................2 
Investigator’s Agreement .................................................................................................................3 
Emergency Contact Information ......................................................................................................4 
1. 
SYNOPSIS ...................................................................................................................5 
2. 
TABLE OF CONTENTS ...........................................................................................14 
LIST OF TABLES .........................................................................................................................19 
LIST OF FIGURES .......................................................................................................................19 
3. 
LIST OF ABBREVIATIONS.....................................................................................20 
4. 
INTRODUCTION ......................................................................................................22 
4.1. 
Background .................................................................................................................22 
4.2. 
Study Rationale ...........................................................................................................23 
4.3. 
Previous Clinical Studies ............................................................................................23 
4.3.1. 
BioThrax Post-Exposure Prophylaxis.........................................................................23 
4.3.2. 
AV7909 .......................................................................................................................24 
5. 
STUDY OBJECTIVES ..............................................................................................25 
5.1. 
Primary Objectives .....................................................................................................25 
5.1.1. 
Safety ..........................................................................................................................25 
5.1.2. 
Immunogenicity ..........................................................................................................25 
5.2. 
Secondary Objectives .................................................................................................25 
5.2.1. 
Safety ..........................................................................................................................25 
5.2.2. 
Immunogenicity ..........................................................................................................25 
6. 
INVESTIGATIONAL PLAN .....................................................................................27 
6.1. 
Overall Study Design ..................................................................................................27 
6.2. 
Number of Subjects ....................................................................................................28 
6.3. 
Treatment Assignment ................................................................................................28 
6.4. 
Individual Subject Dosing and Study Stopping Rules ................................................29 
6.4.1. 
Early Termination of Dosing for an Individual Subject .............................................29 
6.4.2. 
Safety Monitoring Committee ....................................................................................30 
6.4.2.1. 
Safety Monitoring Committee Reviews .....................................................................30 
6.4.2.2. 
Study Pausing/Stopping Rules ....................................................................................30 


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7. 
SELECTION AND WITHDRAWAL OF SUBJECTS ..............................................32 
7.1. 
Selection of Study Population ....................................................................................32 
7.1.1. 
Subject Inclusion Criteria ...........................................................................................32 
7.1.2. 
Subject Exclusion Criteria ..........................................................................................33 
7.2. 
Subject Withdrawal Criteria .......................................................................................36 
7.2.1. 
Replacements ..............................................................................................................36 
8. 
TREATMENT OF SUBJECTS ..................................................................................37 
8.1. 
Description of Study Investigational Products ...........................................................37 
8.1.1. 
BioThrax .....................................................................................................................37 
8.1.2. 
AV7909 Anthrax Vaccine ..........................................................................................37 
8.1.3. 
Placebo ........................................................................................................................38 
8.2. 
Concomitant Medications ...........................................................................................38 
8.2.1. 
Prohibited Concomitant Medications and Therapies ..................................................38 
8.2.2. 
Permitted Concomitant Medications ..........................................................................39 
8.3. 
Treatment Compliance ................................................................................................39 
9. 
STUDY INVESTIGATIONAL PRODUCT MATERIALS AND 
MANAGEMENT .......................................................................................................40 
9.1. 
Study Investigational Product .....................................................................................40 
9.2. 
Study Investigational Product Packaging and Labeling .............................................40 
9.3. 
Study Investigational Product Storage........................................................................40 
9.4. 
Study Investigational Product Preparation and Administration .................................40 
9.5. 
Study Investigational Product Accountability ............................................................41 
9.6. 
Study Investigational Product Handling and Disposal ...............................................41 
9.7. 
Randomization and Blinding ......................................................................................41 
9.7.1. 
Randomization ............................................................................................................41 
9.7.2. 
Blinding ......................................................................................................................41 
9.7.3. 
Breaking the Blind ......................................................................................................42 
10. 
ASSESSMENT OF IMMUNOGENICITY ................................................................43 
11. 
ASSESSMENT OF SAFETY .....................................................................................44 
11.1. 
Safety Parameters .......................................................................................................44 
11.1.1. 
Demographic/Medical History ...................................................................................44 
11.1.2. 
Vital Signs ..................................................................................................................44 
11.1.3. 
Height and Weight ......................................................................................................44 


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11.1.4. 
Physical Examination .................................................................................................44 
11.1.5. 
Electrocardiogram .......................................................................................................45 
11.1.6. 
High-sensitivity C-Reactive Protein ...........................................................................45 
11.1.7. 
Autoantibody Sample Collection ................................................................................45 
11.1.8. 
Clinical Laboratory Assessments ...............................................................................45 
11.1.8.1. 
Chemistry ....................................................................................................................46 
11.1.8.2. 
Hematology .................................................................................................................46 
11.1.8.3. 
Urine Drug Screen and Urinalysis ..............................................................................46 
11.1.9. 
Pregnancy Screen ........................................................................................................46 
11.1.10. 
Diary Cards .................................................................................................................46 
11.1.11. 
Post-vaccination Evaluation .......................................................................................47 
11.1.12. 
Injection Site Evaluation .............................................................................................48 
11.1.13. 
Adverse Event Assessment .........................................................................................48 
11.1.14. 
Concomitant Medication Assessment .........................................................................48 
11.2. 
Adverse and Serious Adverse Events .........................................................................48 
11.2.1. 
Definition of Adverse Events .....................................................................................48 
11.2.1.1. 
Adverse Events ...........................................................................................................48 
11.2.1.2. 
Solicited and Unsolicited Adverse Events ..................................................................49 
11.2.1.3. 
Serious Adverse Events ..............................................................................................49 
11.2.1.4. 
Medically Attended Adverse Events ..........................................................................50 
11.2.1.5. 
Potentially Immune-Mediated Medical Conditions ....................................................50 
11.3. 
Collection, Recording, and Grading Severity of Adverse Events ..............................50 
11.3.1. 
Collection of Adverse Events .....................................................................................50 
11.3.2. 
Recording of Adverse Events .....................................................................................50 
11.3.3. 
Grading Severity of Adverse Events ..........................................................................52 
11.4. 
Relationship and Attribution to Study Investigational Product ..................................52 
11.5. 
Reporting Safety Events to Regulatory Authorities ...................................................53 
11.6. 
Pregnancy Reporting ..................................................................................................54 
11.7. 
Reporting Other Safety Information ...........................................................................54 
12. 
STATISTICS ..............................................................................................................55 
12.1. 
Endpoints ....................................................................................................................55 
12.1.1. 
Primary Endpoints ......................................................................................................55 
12.1.2. 
Secondary Endpoints ..................................................................................................55 


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12.1.2.1. 
Secondary Safety Endpoints .......................................................................................55 
12.1.2.2. 
Secondary Immunogenicity Endpoints .......................................................................55 
12.1.3. 
Measures to Minimize Bias ........................................................................................55 
12.1.4. 
Analysis Plan ..............................................................................................................56 
12.1.4.1. 
Analysis Populations ..................................................................................................56 
12.1.4.2. 
Primary Analyses ........................................................................................................57 
12.1.4.3. 
Secondary Analyses ....................................................................................................57 
12.1.4.4. 
Interim Analysis ..........................................................................................................57 
12.1.4.5. 
SMC Reviews .............................................................................................................58 
12.1.4.6. 
Final Analyses ............................................................................................................58 
12.1.4.7. 
Exploratory Analyses ..................................................................................................58 
12.2. 
Sample Size Considerations .......................................................................................58 
12.3. 
Statistical Considerations ............................................................................................59 
12.3.1. 
Covariates ...................................................................................................................59 
12.3.2. 
Multi-center Studies ....................................................................................................59 
12.3.3. 
Multiple Comparisons and Multiplicity......................................................................60 
12.3.4. 
Subgroup Analyses .....................................................................................................60 
12.3.5. 
Missing Data ...............................................................................................................60 
12.4. 
Procedure for Documenting Deviations from the Planned Analyses .........................60 
13. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS.........................................61 
13.1. 
Inspection of Records .................................................................................................61 
13.2. 
Institutional Review Board .........................................................................................61 
14. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................62 
14.1. 
Data Quality Assurance ..............................................................................................62 
14.2. 
Study Monitoring ........................................................................................................63 
14.3. 
Protocol Deviations ....................................................................................................63 
14.3.1. 
Protocol Deviation Definition .....................................................................................63 
14.3.2. 
Reporting and Managing Deviations ..........................................................................63 
15. 
ETHICS ......................................................................................................................64 
15.1. 
Ethics Review .............................................................................................................64 
15.2. 
Ethical Conduct of the Study ......................................................................................64 
15.3. 
Written Informed Consent ..........................................................................................64 
16. 
DATA HANDLING AND RECORDKEEPING .......................................................66 


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16.1. 
Confidentiality ............................................................................................................66 
16.2. 
Retention of Records ..................................................................................................66 
17. 
PUBLICATION POLICY ..........................................................................................67 
18. 
REFERENCES ...........................................................................................................68 
APPENDIX 1. SCHEDULE OF ASSESSMENTS ....................................................................70 
APPENDIX 2. TABLES FOR CLINICAL AND LABORATORY ABNORMALITIES .........73 
APPENDIX 3. LIST OF POTENTIALLY IMMUNE-MEDIATED MEDICAL 
CONDITIONS ............................................................................................................77 


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LIST OF TABLES 
Table 1: 
Emergency Contact Information ...................................................................................4 
Table 2: 
Study Groups ..............................................................................................................29 
Table 3: 
Complete Blood Count with Differential ...................................................................46 
Table 4: 
Schedule of Diary Cards .............................................................................................47 
Table 5: 
Attribution of Adverse Events ....................................................................................53 
Table 6: 
Probability of Observing at Least 1 Safety Event of Interest under Different 
True Event Rates .........................................................................................................59 
Table 7: 
Power for Detecting a Lower 95% Confidence Limit of ≥40% about an 
Observed Seroprotection Rate ....................................................................................59 
Table 8: 
Tables for Clinical Abnormalities ..............................................................................73 
Table 9: 
Tables for Laboratory Abnormalities .........................................................................74 
 
LIST OF FIGURES 
Figure 1: 
Overall Study Design ..................................................................................................28 
Figure 2: 
Safety Data Reporting Periods ....................................................................................52 
 
  


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3. 
LIST OF ABBREVIATIONS 
Abbreviation or Specialist Term 
Explanation 
AE 
adverse event 
ALT 
alanine aminotransferase 
ASPR 
Assistant Secretary for Preparedness and Response 
AST 
aspartate aminotransferase 
AVA 
Anthrax Vaccine Adsorbed 
AV7909 
AV7909 Anthrax Vaccine  
B. anthracis 
Bacillus anthracis 
BARDA 
Biomedical Advanced Research and Development 
Authority 
BMI 
body mass index 
B-SAFE 
BARDA Securing Anthrax Immunity For the Elderly 
CFC 
chlorofluorocarbon  
CFR 
Code of Federal Regulations 
CI 
confidence interval 
CPG 
cytosine-guanine dinucleotide 
DMP 
Data Management Plan 
eCRF 
electronic case report form 
ED50 
effective dilution resulting in 50% neutralization 
ECG 
Electrocardiogram 
ELISA 
enzyme-linked immunosorbent assay 
Emergent 
Emergent BioSolutions 
ET 
early termination 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HbA1C 
hemoglobin A1C 
HHS 
Department of Health and Human Services 
hs-CRP 
high-sensitivity C-reactive protein 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 


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Abbreviation or Specialist Term 
Explanation 
IFAP 
immunogenicity full analysis population 
IgG 
immunoglobulin G 
IM 
Intramuscular 
IP 
investigational product 
IPPP 
immunogenicity per protocol population 
IRB 
institutional review board 
IWRS 
interactive web response system 
kit ID 
unique kit number  
LLOQ 
lower limit of quantification 
MAAE 
medically attended adverse event 
NF50 
50% neutralization factor 
OTC 
over-the-counter 
PA 
protective antigen 
PEP 
post-exposure prophylaxis  
PIMMC 
potentially immune-mediated medical condition 
Q 
quarter 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SAR 
suspected adverse reaction 
SC 
Subcutaneous 
SIP 
Strategy and Implementation Plan 
SMC 
Safety Monitoring Committee 
SUSAR 
serious and unexpected suspected adverse reaction 
TEAE 
Treatment-emergent adverse event 
TNA 
toxin neutralization antibody 
ULN 
upper limit of normal 
US 
United States 


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4. 
INTRODUCTION 
4.1. 
Background 
Anthrax is a zoonotic, acute infectious disease caused by the Gram-positive, spore-forming 
bacterium Bacillus anthracis (B. anthracis), which can cause human disease via gastrointestinal, 
cutaneous, inhalational (pulmonary), or injection routes.  Although clinical manifestations of the 
disease differ by route, inhalation anthrax is the most lethal.  Inhalation anthrax infection usually 
develops within a week after exposure, but it can take up to 2 months.  Without treatment, only 
about 10 to 15% of patients with inhalation anthrax survive; with aggressive treatment, however, 
about 55% of patients survive.  Although anthrax is rare in the United States (US), people who 
handle animal products and members of the US military are at greater risk of exposure.  In 
addition, B. anthracis is one of the most likely agents to be used in a bioterrorist attack.  In 2001, 
anthrax spores were put in letters mailed through the US postal system resulting in 22 people 
infected, from which 5 died. 1   
The mission of the Biomedical Advanced Research and Development Authority (BARDA) 
within the Department of Health and Human Services (HHS) is to develop and procure medical 
countermeasures that address the public health and medical consequences of chemical, 
biological, radiological, and nuclear accidents, incidents, and attacks; pandemic influenza; and 
emerging infectious diseases.  The HHS’ involvement in the development and acquisition of 
anthrax antitoxins and vaccines is coincident with the signing of the Project BioShield Act of 
2004.2  Several medical interventions contribute to mitigating the high morbidity and mortality 
from inhalation anthrax, including vaccines, antibiotics, and antitoxins, all part of the HHS 
anthrax medical countermeasures strategy.  Since the majority of individuals are not vaccinated 
against anthrax, strategies to implement post-exposure prophylaxis (PEP) in case of a bioterrorist 
attack are needed. 
The only Food and Drug Administration (FDA)-approved vaccine for anthrax (Anthrax Vaccine 
Adsorbed [AVA], BioThrax®) is licensed in the US for adults 18 through 65 years of age.  
BioThrax is made from cell-free filtrates of microaerophilic cultures of an avirulent, 
nonencapsulated strain of B. anthracis, and induces antibodies against protective antigen (PA) 
that may contribute to protection by neutralizing the activities of the lethal toxin and edema toxin 
of B. anthracis.3  B. anthracis proteins other than PA may be present in BioThrax, but their 
contribution to protection has not been determined.  BioThrax is approved in the US for general 
use pre-exposure prophylaxis in individuals who are at high risk of infection (e.g. military and 
lab workers); the current regimen calls for a three-dose priming series (0, 1, and 6 months) with 
boosters at 12 and 18 months (via the intramuscular [IM] route) after the initial priming series, 
and annual boosters thereafter.  BioThrax is also approved for PEP, which calls for a  series of 
3 immunizations at 0, 2, and 4 weeks when administered in conjunction with recommended 
antibacterial drugs.4  For the PEP indication, BioThrax is administered by the subcutaneous (SC) 
route.  


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4.2. 
Study Rationale 
In 2016, the Public Health Emergency Medical Countermeasures Enterprise published its revised 
Strategy and Implementation Plan (SIP).  Of the objectives outlined within the SIP, one primary 
goal is to address medical countermeasure gaps for all sectors of the US civilian population.  
Two primary population gaps, pediatric and geriatric, exist for FDA approved/licensed medical 
countermeasures, including anthrax.  In an effort to address these medical countermeasures gaps, 
BARDA is working to generate data to help inform policy makers on the appropriate use of 
medical countermeasures in these “at-risk” populations.   
Antibody responses to vaccination with BioThrax diminish in progressively older age cohorts up 
to 65 years of age when compared to younger adults.5  It is anticipated that further reductions in 
antibody response to BioThrax will occur in individuals 66 years of age and older and the 
inclusion of an adjuvant will improve immunogenicity without major increases in acute post-
vaccination adverse event rates.   
AV7909 Anthrax Vaccine (henceforth AV7909), a combination product containing BioThrax 
and the adjuvant cytosine-guanine dinucleotide (CPG) 7909, is under development as a potential 
next generation anthrax vaccine.  CPG 7909 is a synthetic immunostimulatory 
oligodeoxynucleotide that has been shown to be a potent vaccine adjuvant.  CPG 7909 is a 
Toll-like receptor 9 agonist designed to induce both an enhanced antigen-specific antibody 
response and a natural killer  T-cell immune response when used in combination with 
prophylactic (preventative) or therapeutic vaccines.6,7,8,9  Earlier studies have suggested that 
AV7909 vaccine has achieved, compared with BioThrax vaccine, higher serum toxin 
neutralization antibody (TNA) levels, an accelerated immune response, and fewer injections to 
confer protection in subjects 18 through 50 years old.10,11,12 While BioThrax is administered by 
the subcutaneous route for its PEP indication, AV7909 is being developed for intramuscular 
administration. 
This randomized, phase 2, active-controlled, double-blinded, multi-site study is designed to 
assess the safety and immunogenicity of BioThrax and AV7909 using a PEP dosing regimen in 
adults ≥66 years of age in stable health compared to subjects 18 through 50 years of age in stable 
health.  Three different PEP dosing regimens for AV7909 will be explored to determine optimal 
dosing (Table 2). 
4.3. 
Previous Clinical Studies 
4.3.1. 
BioThrax Post-Exposure Prophylaxis  
In 2015, FDA approved BioThrax for PEP in adults 18 through 65 years of age when 
administered in conjunction with recommended antibacterial drugs.4  BioThrax became the first 
vaccine to receive licensure for a new indication based on FDA’s Animal Rule.13  The PEP 
regimen was approved based on adequate and well-controlled animal studies in rabbits and 
nonhuman primates demonstrating that serum TNA and anti-PA immunoglobulin G (IgG) titers 
were reliable predictors of survival following lethal B. anthracis challenge.  A 70% probability 
of survival was associated with a TNA 50% neutralization factor (NF50) level of 0.56 in rabbits 
and 0.29 in nonhuman primates. 


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Based on the rabbit model-derived TNA threshold, a pivotal clinical study was conducted to 
evaluate the immunogenicity and safety of a PEP SC administration schedule of BioThrax in 
healthy adults following 3 doses at 0, 2, and 4 weeks.  Two hundred subjects were enrolled and 
followed for 128 days.  The primary objective was to assess immunogenicity using TNA 
following the completion of 3 SC doses of BioThrax.  The primary immunogenicity endpoint 
was the proportion of subjects achieving a threshold TNA NF50 value ≥0.56 at Day 63, 5 weeks 
after the third vaccination.  Success was concluded if the lower bound of the 2-sided 95% 
confidence interval (CI) of the proportion of human subjects achieving the TNA NF50 threshold 
was ≥40%.  Overall, 71.2% of subjects achieved a TNA NF50 value ≥0.56 on Day 63 in the 
pivotal study.  The lower bound of the 95% CI was 64.1%. 
No studies in subjects ≥66 years old have been performed with BioThrax.  
4.3.2. 
AV7909  
Emergent sponsored three clinical studies in healthy subjects 18 through 50 years of age as part 
of the AV7909 development program including a phase 1, a phase 1/2, and a phase 2 trial.10,11,12  
A total of 241 subjects have been exposed to a combination of AVA and CPG 7909.  In the 
initial trial, a formulation with AVA + 1.0 mg CPG 7909 was tested and was well tolerated with 
a trend toward increased frequency and severity of local and systemic reactions in the AV7909 
formulation compared to BioThrax.12  The second trial identified a formulation of AV7909 with 
a lower CPG 7909 concentration (0.25 mg CPG 7909) for further clinical development that 
produced an enhanced immune response without increased reactogenicity.11  This formulation 
was evaluated in the phase 2 trial described below and is the formulation to be tested in the 
current study. 
In 2014, a phase 2, randomized, double-blinded, BioThrax-controlled study was conducted to 
evaluate the safety and immunogenicity of 3 IM vaccination schedules and 2 dose levels of 
AV7909 in 168 healthy adults.10  The results of this study found that AV7909 was well tolerated 
(>90 subjects with adverse events [AEs] of Grade 1 or 2 [based on a modified version of the 
Guidance for Industry “Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers 
Enrolled in Preventive Vaccine Clinical Trials” (September 2007),14 henceforth referred to as 
FDA’s standard toxicity grading scales]; 4.2% of subjects discontinued vaccination due to AEs; 
no serious adverse events (SAEs) were reported that were potentially vaccine related; no 
reported AEs of potential autoimmune etiology) and produced a more rapid immune response 
compared to BioThrax with protective titers of TNA NF50 values (TNA ≥0.56) obtained through 
Day 63. 
No studies in subjects ≥66 years old have been performed with AV7909.  
 


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5. 
STUDY OBJECTIVES  
5.1. 
Primary Objectives 
5.1.1. 
Safety 
 To evaluate safety and reactogenicity, as determined by solicited local and systemic 
reactogenicity symptoms (within 8 days after each vaccination, inclusive of the 
vaccination day, excluding reactogenicity on the contralateral arm), of BioThrax or 
AV7909 administered to adults ≥66 years of age.  
5.1.2. 
Immunogenicity 
 To evaluate the seroprotection, defined as TNA NF50 ≥0.56, rate at Day 64 for 
BioThrax or AV7909 administered to adults ≥66 years of age. 
5.2. 
Secondary Objectives 
5.2.1. 
Safety 
 To evaluate the occurrence of treatment-emergent unsolicited AEs (defined as all AEs 
other than solicited local and systemic reactogenicity symptoms), SAEs, and 
medically attended adverse events (MAAEs), including potentially immune-mediated 
medical conditions (PIMMCs) from the time of the first dose of study investigational 
product (IP) through 12 months following the last dose of study IP. 
 To evaluate the occurrence of solicited local reactogenicity symptoms on the 
contralateral arm (within 8 days after each vaccination, inclusive of the vaccination 
day) 
5.2.2. 
Immunogenicity 
 To assess the TNA NF50 antibody levels, seroprotection rates, and seroconversion 
(defined as a ≥4-fold increase over baseline levels, or a ≥4-fold increase over the 
lower limit of quantification [LLOQ] if the baseline value is < LLOQ) rates for each 
study group at each applicable timepoint through Day 394.  
 To assess the TNA effective dilution resulting in 50% neutralization (ED50) antibody 
levels and seroconversion rates for each study group at each applicable timepoint 
through Day 394. 
 To assess the enzyme-linked immunosorbent assay (ELISA) anti-PA IgG antibody 
levels and seroconversion rates for each study group at each applicable timepoint 
through Day 394. 
 To compare the TNA NF50 antibody levels, seroprotection rates, and seroconversion 
rates through Day 394 between younger adults (18 through 50 years) and older adults 
(≥66 years of age) within the following groups at each applicable timepoint: 
1. BioThrax given at Days 1, 15, and 29  


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2. AV7909 given at Days 1 and 15 and placebo given at Day 29  
 To compare the TNA ED50 antibody levels and seroconversion rates through Day 394 
between younger adults (18 through 50 years) and older adults (≥66 years of age) 
within the following groups at each applicable timepoint: 
1. BioThrax given at Days 1, 15, and 29  
2. AV7909 given at Days 1 and 15 and placebo given at Day 29  
 To compare the ELISA anti-PA IgG antibody levels and seroconversion rates through 
Day 394 between younger adults (18 through 50 years) and older adults (≥66 years of 
age) within the following groups at each applicable timepoint: 
1. BioThrax given at Days 1, 15, and 29  
2. AV7909 given at Days 1 and 15 and placebo given at Day 29  
 


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6. 
INVESTIGATIONAL PLAN 
6.1. 
Overall Study Design 
This is a phase 2, randomized, active-controlled, double-blinded, multi-site study to assess the 
safety and immunogenicity of BioThrax and AV7909 using a PEP dosing regimen in adults 
≥66 years of age in stable health.  The safety and immunogenicity profile of BioThrax and 
AV7909 in adults ≥66 years of age will also be compared to the safety and immunogenicity 
profile of subjects 18 through 50 years of age in stable health.  The main study goal is to 
determine optimal dosing for AV7909.   
Approximately 300 male and nonpregnant female adults (200 aged ≥66 years and 100 aged 
18 through 50 years, inclusive) will be enrolled in the study (Section 7.1). 
Figure 1 presents a diagram of the overall study design.  After screening, subjects meeting all of 
the inclusion criteria and none of the exclusion criteria will be randomized to receive either 
BioThrax or AV7909.  Randomization will be stratified by sex and age (18-50, 66-74, and 
≥75 years).  Subjects ≥66 years of age will be randomized 1:1:1:1 within stratum across 
4 treatment arms (approximately 50 subjects per group), and subjects 18 through 50 years of age 
will be randomized 1:1 within stratum across 2 treatment arms (approximately 50 subjects per 
group) as specified in Table 2.  Once randomized, subjects will receive 3 vaccinations, each 
separated by approximately 14 days, on Day 1, Day 15, and Day 29, based on their assigned 
treatment arm.   
Immunogenicity assessments will include TNA NF50, TNA ED50, and ELISA anti-PA IgG 
antibody levels.  Additional details regarding the immunogenicity assessments are presented in 
Section 10.  
Safety assessments will be based on solicited AEs (local and systemic reactogenicity symptoms) 
occurring within 8 days of each vaccination, treatment-emergent unsolicited AEs (all occurring 
through Day 50 and only those defined as SAEs, MAAEs, and PIMMCs following Day 50), and 
treatment-emergent SAEs, MAAEs, and PIMMCs throughout the study (Figure 1).  Safety for 
each subject will be assessed from the time of the first dose of IP through 12 months following 
the last dose of IP.  Section 11 provides a detailed description of the safety parameters to be 
assessed during this study.  
The expected study duration is approximately 14 months per subject.  
The Schedule of Assessments can be found in Appendix 1.  
 


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Figure 1: 
Overall Study Design 
 
AE = adverse event; ED50 = effective dilution resulting in 50% neutralization of anthrax lethal toxin; ELISA = 
enzyme-linked immunosorbent assay; IgG = immunoglobulin G; MAAEs = medically attended adverse events; 
NF50 = 50% neutralization factor; PA = protective antigen; PIMMCs = potentially immune-mediated medical 
conditions; SAEs = serious adverse events; TNA = toxin neutralization antibody 
6.2. 
Number of Subjects 
The proposed enrollment for this study is approximately 300 subjects in stable health 
(200 subjects aged ≥66 years and 100 subjects aged 18 through 50 years, inclusive).  Although 
not required, ideally ≥1/3 of the elderly subjects enrolled would be in the ≥75 years of age 
stratum.   
6.3. 
Treatment Assignment 
Subjects will receive either 3 doses of active IP (BioThrax or AV7909) or 2 doses of active IP 
(AV7909) and 1 dose of placebo IP, separated by approximately 14 days, based on their assigned 
treatment arm.  There will be 6 study groups (approximately 50 subjects per group) as presented 
in Table 2.  Randomization will be stratified by sex and age group (18-50, 66-74, and ≥75 years).  
Subjects ≥66 years of age will be randomized in a 1:1:1:1 ratio within stratum across 4 treatment 
arms and will compose Groups 1 through 4.  Adults aged 18 through 50 years will be 
randomized in a 1:1 ratio within stratum across 2 treatment arms and will compose 
Groups 5 and 6.   


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Table 2: 
Study Groups 
Study 
Group 
Number 
of 
Subjects 
Age 
Group 
Arm 
Investigational 
Product 
Route 
Dose 1 
Day 1  
Dose 2 
Day 15  
Dose 3 
Day 29  
Group 1 
50 
Age ≥66 
Arm 1 
BioThrax 
SC 
BioThrax 
BioThrax 
BioThrax 
Group 2 
50 
Age ≥66 
Arm 2 
AV7909 
IM 
AV7909 
AV7909 
AV7909 
Group 3 
50 
Age ≥66 
Arm 3 
AV7909 
IM 
AV7909 
AV7909 
Placebo 
Group 4 
50 
Age ≥66 
Arm 4 
AV7909 
IM 
AV7909 
Placebo 
AV7909 
Group 5 
50 
Age 18-50 
Arm 1 
BioThrax 
SC 
BioThrax 
BioThrax 
BioThrax 
Group 6 
50 
Age 18-50 
Arm 3 
AV7909 
IM 
AV7909 
AV7909 
Placebo 
IM = intramuscular; SC = subcutaneous 
6.4. 
Individual Subject Dosing and Study Stopping Rules 
6.4.1. 
Early Termination of Dosing for an Individual Subject  
Vaccinations in a subject are to be stopped if the subject experiences any of the following and 
will preclude further administration of study vaccine until the specific AE can be evaluated and 
is shown to resolve completely.  In situations of ambiguity or uncertainty, the investigator is 
encouraged to discuss the situation and any questions with the medical monitor before making a 
decision on subject disposition. 
1. Any Grade 4 AE that is assessed as other than unrelated to the receipt of the IP (Refer to 
Section 11.4, Table 5, and Appendix 2). 
2. Two or more Grade 3 AEs that are assessed as other than unrelated to the receipt of the 
IP. 
3. A clinically significant Grade 3 laboratory value assessed as other than unrelated to IP 
that remains clinically significant and at Grade 3 or higher upon repeat testing (Refer to 
Section 11.1.8). 
4. Any SAE assessed as other than unrelated to the receipt of the IP. 
5. Any PIMMC irrespective of relatedness to IP. 
6. Anaphylaxis within 4 hours of vaccination or that is assessed as other than unrelated to 
IP.  
7. Intolerable AE. 
8. Pregnancy.  
9. Subject no longer meets eligibility criteria in such a way that, in the judgment of the 
investigator, the safety of the subject may be compromised by continued participation or 
interpretation of the subject’s subsequent study data are likely to be significantly 
compromised. 
10. Any other condition that, in the judgment of the investigator or Safety Monitoring 
Committee (SMC), would make further vaccination unsafe or render the subject unable to 
comply with protocol-mandated safety follow-up. 


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The reason for early termination of dosing will be captured in the electronic case report form 
(eCRF).   
Subjects who do not receive a full vaccination series for any reason will continue to be followed 
for immunogenicity and safety through Visit 13 (Day 394).  Subjects who become pregnant 
during the study will only be followed for safety and will not provide blood for the 
immunogenicity assays.  
6.4.2. 
Safety Monitoring Committee 
6.4.2.1. 
Safety Monitoring Committee Reviews 
There will be 1 planned SMC review of interim safety data after the first 40 subjects ≥66 years 
have completed Visit 7 (Day 36).  Enrollment and dosing will continue during this planned SMC 
review.   
The SMC chair will receive and evaluate reports of all SAEs and Grade 3 and higher AEs, 
irrespective of relatedness to IP, on an ongoing basis.  Upon review of these reports, the SMC 
chair will determine whether an ad hoc review by the entire SMC is necessary.  Ad hoc reviews 
will also occur in the event that study pausing/stopping rules are met (Section 6.4.2.2).   
In order to preserve the blinded nature of IP assignments during the open session meetings, 
safety data will be presented overall and not by group assignment. Fully unblinded safety data 
will be provided by the unblinded statistical team for closed SMC sessions.  
Following each review, the SMC will advise the sponsor on their recommendation regarding 
individual subject disposition or study disposition per guidelines in the SMC Charter. The SMC 
may recommend continuation of the study with no modifications, continuation of the study with 
modification, discontinuation of specific study groups, or study termination. 
The final SMC safety displays will be provided to the SMC members when the last study subject 
completes Visit 10 (Day 64). 
6.4.2.2. 
Study Pausing/Stopping Rules 
The blinded medical monitor will assess cumulative safety information for this study per the 
Medical Monitoring Plan and advise BARDA should she/he become aware of any of the safety 
findings listed below.  Occurrence of 1 or more of the following will result in immediate 
suspension of further IP administration (as applicable per the study timeline) at all study sites 
and review of the safety data by the SMC. 
1. One or more subjects experience an SAE assessed as other than unrelated to IP by the 
investigator, sponsor, or SMC chair. 
2. One or more subjects have an anaphylactic reaction within 4 hours of vaccination or that 
is assessed as other than unrelated to IP. 
3. Three or more subjects have a Grade 3 AE (excluding local reactogenicity that decreases 
to below Grade 3 within 1 day, vital signs, and laboratory values) assessed as other than 
unrelated to IP.  


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4. Three or more subjects have clinically significant Grade 3 vital sign(s) assessed as other 
than unrelated that remain clinically significant and at Grade 3 or higher upon repeat 
testing (Refer to Section 11.1.2).  
5. Three or more subjects have clinically significant Grade 3 laboratory value(s) assessed as 
other than unrelated that remain clinically significant and at Grade 3 or higher upon 
repeat testing (Refer to Section 11.1.8).  
6. One or more subjects have a Grade 4 AE assessed as other than unrelated to IP.  
7. A pattern of clinically significant symptoms, physical findings, AEs, or clinically 
significant laboratory abnormalities that in the opinion of the sponsor, medical monitor, 
or SMC chair, collectively represent a potential safety concern.  
BARDA retains the right to suspend or end the study or to discontinue specific study groups at 
any time.  In case of premature termination or suspension and safety review of the study, 
BARDA will inform regulatory authorities, and Rho will promptly inform the investigators of 
the termination or suspension of the study and the reason for termination or suspension.  
 
 


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7. 
SELECTION AND WITHDRAWAL OF SUBJECTS 
7.1. 
Selection of Study Population 
Subjects will be randomized to study treatment only if they meet all of the applicable inclusion 
criteria and none of the exclusion criteria.  In addition, applicable eligibility criteria must be 
reviewed just prior to each vaccination; if the subject no longer meets applicable eligibility 
criteria, the investigator, in consultation with the medical monitor in cases of uncertainty, must 
determine whether the subject should receive the IP dose or be terminated early from study IP.  
Deviations from the inclusion and exclusion criteria are not allowed because they can potentially 
jeopardize the scientific integrity of the study, regulatory acceptability, or subject safety.  
Therefore, adherence to the criteria specified in the protocol is essential.   
7.1.1. 
Subject Inclusion Criteria 
1. Male or nonpregnant females, 66 years of age or older at the time of randomization for 
the elderly population, or 18 through 50 years of age at the time of randomization for the 
younger population. 
2. Females who are of childbearing potential and are sexually active with a male partner 
must agree to use an acceptable method of birth control from Screening to Day 64 and 
must have used a reliable birth control method for at least 2 months prior to Screening. 
a. A female of childbearing potential is defined as post onset menarche and 
pre-menopausal 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, either 
combined or progestogen alone; injectable progestogen; implants of etenogestrel or 
levonorgestrel; estrogenic vaginal ring; percutaneous contraceptive patches; 
intrauterine device or intrauterine system; male partner sterilization at least 6 months 
prior to the female subject’s Screening Visit, and this male is the sole partner for that 
subject (the information on the male partner’s sterility can come from the site 
personnel’s review of the subject’s medical records or interview with the subject on 
her medical history); male condom combined with a vaginal spermicide (foam, gel, 
film, cream, or suppository); male condom combined with a female diaphragm, either 
with or without a vaginal spermicide (foam, gel, film, cream, or suppository). 
3. Able to provide written informed consent prior to initiation of any study procedures.  As 
part of the consent process, subjects must be able to demonstrate understanding  by 
passing the “Assessment of Understanding Questionnaire” within 2 attempts.  Passing is 
defined as being able to answer all questions correctly. 
4. In relatively stable health based on site investigator’s judgment, as determined by 
medical history, physical examination, and the following criteria:  


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a. Stable health for age (defined as no new conditions per medical history, new 
medications in a different therapeutic class, or change in daily dose of existing 
prescription medications within the 45 days preceding Screening).  Effective 
treatment (to resolution) of an acute infection (e.g., urinary tract infection, cellulitis, 
otitis, or bronchitis) with an antibiotic within 45 days preceding Screening will not be 
considered a deviation from this inclusion criterion as long as the antibiotic therapy 
was completed at least one week prior to Screening and no signs or symptoms of the 
infection have been present since the completion of treatment. Any prescription 
change that is due to change of health care provider or insurance company, or that is 
made for reasons that do not reflect a change in disease status (e.g., financial 
considerations), as long as within the same general class of medication, will not be 
considered a deviation from this inclusion criterion.  Any change in prescription 
medication due to improvement of a disease outcome, as determined by the site 
investigator, will not be considered a deviation from this inclusion criterion. 
b. Subjects may be on chronic or as needed (prn) medications if, in the opinion of the 
site investigator, these pose no additional risk to subject safety or assessment of 
reactogenicity and immunogenicity and their use is not for management of a 
worsening of medical diagnosis or condition.  Note: Topical, nasal, and inhaled 
medications (with the exception of steroids, as outlined in the subject exclusion 
criteria) and vitamins are permitted.  
5. Have a body mass index (BMI) less than 35.0 kg/m2 at Screening.  (BMI will not be 
reassessed prior to subsequent vaccinations.)  
6. Have access to a consistent and reliable means of telephone contact, which may be home, 
workplace, or by personal mobile electronic device.  
7. Are available and can comply with all study visits. 
7.1.2. 
Subject Exclusion Criteria 
1. Females who have a positive urine pregnancy test at Screening or within 24 hours prior to 
each study vaccination or women who are breastfeeding. 
2. Have a requirement for skilled nursing care. 
3. Have a history of severe reactions to components of AVA or CPG 7909, e.g., 
formaldehyde, benzethonium chloride (phemerol), or aluminum. 
4. Have a history of latex sensitivity.  
5. Have a history of ever receiving a vaccine for anthrax prior to Screening, or had an 
anthrax infection. 
6. Have any medical, psychiatric, or social condition that, in the opinion of the site 
investigator, unfavorably alters the risk-benefit of subject participation, or is likely to 
interfere with study compliance or assessments, or is likely to confound interpretation of 
safety or immunogenicity data.   
7. Have any diagnosis, current or past, of a potentially immune-mediated medical condition, 
such as Guillain-Barré syndrome, narcolepsy, or an autoimmune or chronic inflammatory 
disease (Appendix 3).  


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8. Have any diagnosis, current or past, of schizophrenia or bipolar disorder. 
9. Have been hospitalized for psychiatric illness, have a history of suicide attempt, or 
confinement for danger to self or others within the preceding 10 years prior to Screening 
and each study vaccination. 
10. Have a history of alcohol or drug abuse (per investigator’s judgment) within 5 years prior 
to Screening and each study vaccination, or test positive for drugs of abuse at Screening 
(including for cannabis, even where legal).  Benzodiazepines for anxiety disorders and 
stimulants for attention deficit hyperactivity disorder are not exclusionary if the subject 
has been on a stable dose for more than 3 months prior to Screening and each study 
vaccination and if the subject can produce a valid, current prescription for the medication.  
Propoxyphene, opioids, or combinations containing these medications (including as used 
for opioid addiction) are not permitted regardless of prescription status. Note: A positive 
Screening urine drug screen may not be repeated.  (Drug screen will not be repeated prior 
to subsequent vaccinations.) 
11. Have known human immunodeficiency virus (HIV), or acute or chronic hepatitis B or 
hepatitis C infection based on medical history; or test positive for any of these at 
Screening.  Subjects who have been effectively treated for hepatitis C, as evidenced by a 
negative hepatitis C ribonucleic acid (RNA) confirmation test and who no longer require 
antiviral therapy, are eligible for participation. (Screening tests will not be repeated prior 
to subsequent vaccinations.)  
12. Have known active neoplastic disease or a history of any hematologic malignancy.  
However, subjects with superficial skin cancer who do not require intervention other than 
local excision are not excluded.  
13. Have immunosuppression as a result of an underlying illness or treatment, or use of 
anticancer chemotherapy (cytotoxic) or radiation therapy within 3 years prior to 
Screening and each study vaccination. 
14. Have taken any systemic immunosuppressive agents, including immunomodulators, 
6 months prior to Screening and each study vaccination. Allergen immunotherapy 
(desensitization) is not exclusionary. Allergen immunotherapy (desensitization) does not 
include systemic antibodies such as benralizumab, mepolizumab, or omalizumab; these 
are exclusionary. 
15. Are suffering from or have a history of neuralgia, paresthesia, or neuritis within 90 days 
prior to Screening and each study vaccination; or have any history of stroke.  
16. Have had convulsions or encephalomyelitis within three years prior to Screening and 
each study vaccination. 
17. Have received immunoglobulin or other blood products (with the exception of Rho[D] 
immune globulin) within 90 days prior to Screening and each study vaccination. 
18. Have received an experimental agent within 180 days prior to the first study vaccination, 
or expects to participate in another clinical trial with an interventional agent during the 
study period.  This includes licensed or unlicensed vaccines, drugs, biologics, devices, 
blood products, or medications. Participation in an observational study is not 


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exclusionary as long as it doesn’t interfere with study visits or procedures (e.g., blood 
collection volume restrictions). 
19. Have taken oral or parenteral corticosteroids of any dose within 30 days prior to each 
study vaccination. 
20. Have taken high-dose inhaled corticosteroids within 30 days prior to each study 
vaccination.  High-dose is defined as >800 mcg/day of beclomethasone dipropionate or 
equivalent.  Lower doses of inhaled corticosteroids are not exclusionary.  
21. Have received any licensed live vaccine within 30 days prior to the first study vaccination 
or planned receipt from the first study vaccination through Visit 10 (Day 64).   
22. Have received any licensed inactivated vaccine within 14 days prior to the first study 
vaccination or planned receipt from the first study vaccination through Visit 10 (Day 64).  
23. Have an acute illness, as determined by the site investigator, within 72 hours prior to each 
study vaccination.   
a. If subject’s oral temperature is above 100.0°F (37.8°C), the subject may be 
re-assessed for eligibility within the visit window (+3 Days). 
b. An acute illness that is nearly resolved, with only minor residual symptoms 
remaining, is allowable if, in the opinion of the site investigator, the residual 
symptoms will not interfere with the ability of study staff to assess safety parameters 
as required by the protocol. 
b. For bacterial infections that have been successfully treated with antibiotics, inclusion 
criterion 4a applies. 
24. Have a history of myocardial infarction or ischemia, or have electrocardiogram (ECG) 
findings of myocardial infarction, ischemia, strain, complete bundle branch block, or 
ventricular arrhythmias (other than unifocal premature ventricular contractions 
≤2/minute).  Additionally, other cardiac history or ECG findings, which in the opinion of 
the investigator represent a potentially unstable or unacceptably high risk of an adverse 
cardiac outcome, are exclusionary.  (ECG will not be repeated prior to subsequent 
vaccinations.) 
25. Have any laboratory test result or clinical findings (including vital signs) that singly or in 
combination are, in the investigator’s opinion, likely to unfavorably alter the risk-benefit 
of subject participation or to confound study safety or immunogenicity results.  
Additionally, the following are exclusionary:  
a. Any clinically significant Grade 3 laboratory or vital sign result, or any Grade 4 
laboratory or vital sign result (regardless of assessed significance) at Screening.  For 
subsequent vaccinations, abnormal laboratory results and vital sign results post-
vaccination will be assessed against the rules for early termination of dosing 
(Section 6.4.1).    
b. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >2 times the 
upper limit of normal (ULN), or bilirubin >1.5 times the ULN unless isolated 
Gilbert’s syndrome.  
c. Creatinine >1.5 times ULN for age and sex. 


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d. White blood cell  count <3,000/µL or >12,500/µL; absolute neutrophil count 
<1200/µL; absolute lymphocyte count <750/µL; hemoglobin <10 g/dL females, or 
<11.5 g/dL males; platelet count <75,000/µL.  
e. Hemoglobin A1C (HbA1C) >7.0% at Screening. (HbA1C will not be repeated prior 
to subsequent vaccinations.) 
Subjects cannot be rescreened for exclusionary laboratory test results.  Potentially exclusionary 
vital sign results may be repeated, but unless they have resolved to a Grade 3 designation or less 
and are not considered clinically significant, the subject should be excluded.  The most recent 
laboratory and vital sign results will be used when determining eligibility for subsequent 
vaccinations. 
7.2. 
Subject Withdrawal Criteria 
Every subject has the right to refuse participation in the study (i.e., withdraw consent) at any 
time without providing any reason for withdrawal.  A subject’s participation must be terminated 
immediately upon his/her request, and the reason(s) for discontinuation documented accordingly 
in the corresponding eCRF.  
Any subject who meets 1 or more of the following criteria will be removed from the study 
without prejudice: 
 Subject request.  
 Subject noncompliance, defined as refusal or inability to adhere to the study protocol 
or any other instances determined by the investigator or BARDA. 
 Subject lost to follow-up. 
 Investigator no longer believes participation is in the best interest of the subject. 
 At request of BARDA, regulatory agencies, or the institutional review board (IRB). 
For any subject who meets the above criteria prior to completion of Visit 10 (Day 64), the early 
termination (ET) visit assessments should be performed as outlined in Appendix 1, when 
possible.  If not possible to conduct a visit, site staff should make every effort to obtain updated 
safety information (AE assessment including pregnancy information) by phone.  
7.2.1. 
Replacements 
If a subject is withdrawn from the clinical study after receipt of the first dose of IP, the subject 
will not be replaced. 
If a subject is randomized but does not receive the first dose of IP, the subject will be withdrawn 
and will not be counted toward the total enrollment goal.  Additional subjects will be randomized 
to achieve enrollment goals.  


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8. 
TREATMENT OF SUBJECTS 
8.1. 
Description of Study Investigational Products 
8.1.1. 
BioThrax 
BioThrax, manufactured by Emergent BioSolutions (Emergent) in the US, is a vaccine indicated 
for active immunization for the prevention of disease caused by B. anthracis in persons 18 to 
65 years of age, inclusive.  BioThrax is approved by the FDA for the following indications: 
1. Pre-exposure prophylaxis of disease in persons at high risk of exposure to B. anthracis. 
2. Post-exposure prophylaxis of disease following suspected or confirmed B. anthracis 
exposure, when administered in conjunction with recommended antibacterial drugs. 
BioThrax is a sterile, milky-white suspension for IM or SC injection made from cell-free filtrates 
of microaerophilic cultures of an avirulent, non-encapsulated strain of B. anthracis.  The 
production cultures are grown in a chemically defined protein-free medium consisting of a 
mixture of amino acids, vitamins, inorganic salts, and sugars.  The final product, prepared from 
the sterile filtrate culture fluid contains proteins, including the 83kDa PA protein, released during 
the growth period and contains no dead or live bacteria.  The final product is formulated to 
contain 1.2 mg/mL aluminum, added as aluminum hydroxide in 0.85% sodium chloride.  The 
final product is formulated to contain 25 mcg/mL benzethonium chloride and 100 mcg/mL 
formaldehyde, added as preservatives. 
BioThrax will be supplied in 5.0 mL multidose vials containing ten 0.5 mL doses.  Each vial will 
only be used to administer a single dose. 
8.1.2. 
AV7909 Anthrax Vaccine 
AV7909 is being developed by Emergent as a next-generation anthrax vaccine indicated for PEP 
to reduce the risk of anthrax after exposure to B. anthracis.  
AV7909 is a pre-formulated combination product containing AVA and CPG 7909 for IM 
injection.  The AV7909 drug product is a sterile, milky-white suspension made from cell-free 
filtrates of microaerophilic cultures of an avirulent, non-encapsulated strain of B. anthracis that 
has been adsorbed to aluminum hydroxide + CPG 7909 adjuvant.  The drug product is 
formulated to contain 1.2 mg/mL aluminum, added as aluminum hydroxide (Alhydrogel).  It also 
contains 0.85% sodium chloride and, as preservatives, 25 mcg/mL benzethonium chloride and 
100 mcg/mL formaldehyde.   
The formulation contains 0.5 mL of AVA and 0.25 mg of CPG 7909 per dose.  The amount of 
free (unbound) CPG 7909 per dose is expected to be ≤ 0.045 mg. 
AV7909 is supplied in 6 mL (nominal fill volume) clear borosilicate glass multi-dose vials 
(approximately 6.1 mL/vial) with a rubber stopper and flip-top aluminum seal.  Each vial will 
only be used to administer a single dose. 


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8.1.3. 
Placebo 
Commercially available sterile, preservative-free sodium chloride for injection (Sodium Chloride 
Injection, USP 0.9%) will be used as placebo in the study.  Each mL contains sodium chloride 
9 mg and water for injection q.s.  It contains no bacteriostat, antimicrobial agent, or added buffer.  
The solution may contain hydrochloric acid and/or sodium hydroxide for pH adjustment 
(pH 4.5-7.0).   
Each 10.0 mL vial of sodium chloride will only be used to administer a single 0.5 mL dose.  
Additional information is provided in the Sodium Chloride Injection, USP package insert. 
8.2. 
Concomitant Medications 
Any treatment including all prescription drugs, herbal products, vitamins, minerals, and over-the-
counter (OTC) medications or therapies administered from the time of consent through the end 
of study participation is considered a concomitant medication.  Concomitant medication use will 
be recorded in the eCRF and will include the medication name, dose, frequency, route of 
administration, and the dates of administration.  All concomitant medications used by the subject 
from the time of consent until Visit 9 (Day 50) will be recorded in the subject’s eCRF.  
Following Visit 9 (Day 50), concomitant medications will only be recorded if they are used for 
the treatment of a MAAE, SAE, or PIMMC.  Any changes, additions, and/or deletions in 
concomitant medications throughout the course of the subject’s participation in the study will be 
recorded in the subject’s eCRF.  
If a subject is discovered to be using a prohibited concomitant medication after he or she is 
enrolled in the study, the investigator, in consultation with the medical monitor in cases of 
uncertainty, should determine the impact on the subject’s participation.  All instances of use of 
prohibited concomitant medications must be documented on the appropriate eCRFs. 
In addition, any nonstudy vaccines received 30 days prior to the Screening Visit and nonstudy 
vaccines received through Visit 10 (Day 64) will be recorded in the subject’s eCRF.  Prior 
medications used within 30 days of the Screening Visit will also be recorded in the subject’s 
eCRF. 
8.2.1. 
Prohibited Concomitant Medications and Therapies 
The following concomitant medications and therapies are prohibited for the duration of the study 
unless otherwise specified. 
 Anticancer chemotherapy (cytotoxic) or radiation therapy.   
 Systemic immunosuppressive agents, including immunomodulators. Allergen 
immunotherapy (desensitization) is not prohibited. Allergen immunotherapy 
(desensitization) does not include systemic antibodies such as benralizumab, 
mepolizumab, or omalizumab; these are prohibited. 
 Oral or parenteral corticosteroids. 
 High-dose inhaled corticosteroids (>800 mcg/day of beclomethasone di-iso-propionate 
CFC or equivalent).  


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 Treatment with immunoglobulin or other blood products (with the exception of Rho[D] 
immune globulin).  
 Vaccines (including seasonal influenza vaccines) from screening through 35 days 
following the third dose of the study vaccine (Screening Visit through Visit 10 [Day 64]). 
 Experimental agents (vaccine, drug, biologic, device, blood product, or medication). 
8.2.2. 
Permitted Concomitant Medications 
Other than the prohibited medications and therapies listed in Section 8.2.1, treatment with 
concomitant medications and therapies is permitted during the study.  Concomitant medication 
deemed necessary for the welfare of the subject during the study may be given at the discretion 
of the investigator.  However, it is the responsibility of the investigator to ensure that details 
regarding the medication will be recorded in full in the eCRF. 
8.3. 
Treatment Compliance 
The study IP will be administered by an unblinded study staff member and thus is an observed 
compliance.  Subject compliance will be determined by the number and percentage of subjects 
who receive study IP on Day 1, Day 15, and Day 29 by study group.  Any deviations from the 
dosing schedule outside the defined visit windows (Appendix 1) must be approved by the 
BARDA Medical Officer and will be recorded on the appropriate eCRF.  


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9. 
STUDY INVESTIGATIONAL PRODUCT MATERIALS AND 
MANAGEMENT 
9.1. 
Study Investigational Product 
Refer to Section 8.1 for detailed information regarding the BioThrax, AV7909, and placebo 
study IP. 
9.2. 
Study Investigational Product Packaging and Labeling 
Study IP will be packaged and labeled according to applicable local and regulatory requirements.  
Study IP will be provided in single-dose kits containing 1 vial of BioThrax, AV7909, or placebo.  
BioThrax, AV7909, and placebo will be provided in multi-dose vials; however, each vial will 
only be used to administer a single dose.  Vials will be labeled with a single-panel, unblinded 
label.  Each kit carton will be labeled with an unblinded label with a unique kit number (kit ID) 
and will contain 2 additional labels: 1 to be affixed to the site’s study IP accountability 
documentation, and 1 to be affixed to the syringe used for IP administration.   
The vials and kits will be labeled in English.  The BioThrax and AV7909 vial labels and kit 
labels will include a note that specifies the following “Caution: New Drug Limited by Federal 
(or United States) Law to Investigational Use,” as well as storage specifications.  The placebo kit 
labels will include the Caution statement and storage specifications.  In addition, the vial labels 
will contain the lot number.   
9.3. 
Study Investigational Product Storage 
Study IP must be stored in a secure area (e.g., a locked room or locked refrigerator), and 
protected from light and moisture.  BioThrax and AV7909 should be kept at a controlled 
standard refrigeration temperature between 2° to 8°C (36° to 46°F), inclusive.  Placebo should be 
kept between 20° to 25°C (68° to 77°F), inclusive.  The temperature of the storage unit must be 
monitored and documentation of proper storage must be maintained.  Investigational product 
should be removed from the storage unit and allowed to sit at room temperature for 
approximately 15 minutes before administration.   
9.4. 
Study Investigational Product Preparation and Administration 
Because BioThrax, AV7909, and placebo are distinguishable visually and by route of 
administration, unblinded study staff will be responsible for preparing and administering study 
IP.  Subjects will be asked to look away while the vaccine is being administered.  
Study IP should be visually inspected for particulate matter and discoloration during IP 
preparation and prior to administration; it should not be administered if either condition exists.  
Study IP vials should be shaken thoroughly to ensure that the suspension is homogeneous during 
withdrawal.  BioThrax and AV7909 should have a milky-white appearance.  Placebo should be 
clear.  The treatment syringe barrel should be covered with the subject-specific label to obscure 
the contents. 


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BioThrax (0.5 mL) should be administered by SC injection over the deltoid muscle.  AV7909 
(0.5 mL) should be administered IM in the deltoid muscle.  Placebo IP (0.5 mL) will be 
administered IM in the deltoid muscle.  The 3 IP doses for a given subject should be 
administered in alternating arms.  Investigational product doses can be administered in the same 
arm if a skin condition prevents administration in one of the arms (e.g., scar tissue, skin rash, 
etc.).  The unblinded study staff will record which arm received each dose of IP.    
9.5. 
Study Investigational Product Accountability 
The investigator is required to maintain adequate records of the disposition of the study IP, 
including the date and quantity of IP received, to whom the IP was dispensed (subject-by-subject 
accounting), and a detailed accounting of any IP accidentally or deliberately destroyed.  Records 
for receipt, storage, use, and disposition will be maintained by the study site.  An IP dispensing 
log will be kept current and will include kit ID, identification of each subject, and the date and 
quantity of IP dispensed.  All records regarding the disposition of the study product will be 
available for inspection by the unblinded study monitor. 
9.6. 
Study Investigational Product Handling and Disposal 
After dosing has been completed, to satisfy regulatory requirements regarding accountability, all 
study IP will be reconciled and returned to the study IP distributor according to applicable 
regulations.  Study IP should not be destroyed until authorized in writing by BARDA. 
9.7. 
Randomization and Blinding 
9.7.1. 
Randomization 
Subjects ≥66 years of age will be randomized 1:1:1:1 across 4 treatment arms, and subjects 
18 through 50 years of age will be randomized 1:1 across 2 study arms as specified in Table 2.  
An interactive web response system (IWRS) will be used to centrally administer the 
randomization schedule.  The randomization schedule will be generated using SAS software 
Version 9.3 or later (SAS Institute Inc., Cary, North Carolina).  Randomization will take place 
according to a fixed schedule using a permuted block design stratified by sex and age group 
(18-50, 66-74, and ≥75 years).  The IWRS will assign subjects to treatment arms based on the 
predefined randomization list.  A kit ID corresponding to the assigned treatment will be assigned 
by the IWRS at randomization and at the Day 15 and Day 29 Visits from the inventory available 
at the site.  The randomization schedule will be generated by the unblinded randomization team 
and will be kept strictly confidential, accessible only to authorized unblinded persons 
(Section 9.7.2). 
9.7.2. 
Blinding 
This is a double-blinded study.  The study staff members who will prepare and/or administer the 
study IP will be unblinded to IP assignment.  The unblinded study staff will not be involved with 
safety evaluations, nor will they perform subsequent assessments or engage in other study 
activities that could reveal the blind.  Investigators, all investigational site staff (except those 
responsible for preparing/administering the IP), and all subjects participating in this study will be 


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blinded to IP assignment.  Laboratory staff performing the safety laboratory assessments and 
immunogenicity assays will be blinded to study group. 
To preserve the study blind, a minimum number of Rho and BARDA personnel will have access 
to treatment randomization information at the individual subject level.  The unblinded Rho study 
team will include a statistician, statistical programmer, project manager or clinical team lead, 
study monitors, and the Client Support Services and IWRS teams.  During monitoring visits, the 
unblinded study monitor(s) will perform study IP accountability and will check that the blind has 
been maintained.  Blinded study monitor(s) will continuously assess the progress of the study but 
will not have access to the unblinded study records.  A BARDA representative may be unblinded 
to assist with oversight of study IP management.  In addition, as needed to meet regulatory 
reporting requirements, designated Rho and BARDA pharmacovigilance and/or regulatory 
personnel may be unblinded to the treatment status of individual subjects.  In this circumstance, 
and if there are no other concerns, neither the BARDA project coordination team nor the study 
staff will be further unblinded to treatment status. 
If an SMC meeting is needed (Section 6.4.2), the members of the SMC will review safety data 
fully unblinded at the study group and subject level during the closed session meeting.  The 
BARDA and Rho blinded teams will review unblinded data at the study group level for the 
interim analysis (Section 12.1.4.4).  
9.7.3. 
Breaking the Blind 
Unblinding of individual subjects should occur only when knowledge of the treatment 
assignment will have a direct bearing on the medical treatment or evaluation of a subject.  
Whenever possible, the need to unblind should be discussed with BARDA and the medical 
monitor prior to unblinding.  In the event of an emergency, the investigator or designated 
qualified individual may obtain the subject’s blinded treatment via IWRS.  If an individual 
designated to perform emergency unblinding does not have access to the IWRS, Rho Client 
Support Services may be contacted and can perform the unblinding for that individual.  Upon 
performance of a blind break within the IWRS, the system will send out a blinded notification to 
alert Rho and BARDA staff of the event.  
A full account of the unblinding event will be recorded in the subject’s source document and 
eCRF, including the date and time of the unblinding, the reason for the decision to unblind, the 
extent of unblinding, and the name and signature of the individual who made the decision to 
unblind.  The treatment assignment should not be included in either the source document or the 
eCRF. 
Data for the interim analysis will be presented at the group level; thus, the blinding at the subject 
level will be maintained to those outside the unblinded team until database lock of all data 
through Visit 13 (Day 394) for the clinical study report.  The blinded site and laboratory staff 
will be kept blinded at the subject level through the end of study.  


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10. 
ASSESSMENT OF IMMUNOGENICITY 
Venous blood samples will be collected for immunogenicity assays at Visit 1 (Day 1) prior to 
vaccination, Visit 3 (Day 8), Visit 5 (Day 22), Visit 6 (Day 29) prior to vaccination, Visit 7 
(Day 36), Visit 8 (Day 43), Visit 9 (Day 50), Visit 10 (Day 64), Visit 11 (Day 85), Visit 12 
(Day 181), and Visit 13 (Day 394).  Serum for immunogenicity assays will be collected at an ET 
or Unscheduled Visit only if within window for the next expected study visit at which serum is 
to be collected.  Serum will be shipped to the central laboratory for storage and subsequently 
shipped to the immunogenicity laboratory for analysis.  Good Laboratory Practice-compliant 
TNA and ELISA assays will be conducted to determine TNA and anti-PA IgG antibody titers, 
respectively. 
The details for sample handling, processing, and shipping will be provided in the Laboratory 
Manual.  


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11. 
ASSESSMENT OF SAFETY 
11.1. 
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 investigator in consultation with the medical monitor and 
BARDA.   
11.1.1. 
Demographic/Medical History 
In order to define a baseline for potential AEs, the demographics and medical history of each 
subject will be collected at the Screening Visit and recorded on the appropriate eCRFs. 
11.1.2. 
Vital Signs 
Vital sign measurements, including oral temperature, heart rate, respiratory rate, pulse oximeter 
reading and diastolic and systolic blood pressure (after the subject is seated for at least 5 
minutes), will be collected at the Screening Visit, Visit 1 (Day 1) pre-vaccination and post-
vaccination, Visit 2 (Day 3), Visit 3 (Day 8), Visit 4 (Day 15) pre-vaccination and post-
vaccination, Visit 5 (Day 22), Visit 6 (Day 29) pre-vaccination and post-vaccination, Visit 7 
(Day 36), Visit 9 (Day 50), Visit 10 (Day 64), ET Visit, and Unscheduled Visit and will be 
recorded on the appropriate eCRF.  Vital signs should be taken prior to any blood draws.  Post-
vaccination vital signs will be taken 30 minutes (±5 minutes) and 1 hour (±5 minutes) post-
vaccination prior to discharge.  Respiratory rate, if regular, may be assessed over 30 seconds and 
doubled, but in no case should it be assessed over a period of less than 30 seconds.  Heart rate, if 
performed manually, must be assessed over at least 15 seconds.   
Post-vaccination clinically significant Grade 3 and Grade 4 abnormal vitals should be reassessed 
prior to subsequent vaccinations, including the subject attending an unscheduled visit as needed.  
As the subject will self-assess oral temperature between clinic visits when solicited AEs are 
being collected (within 8 days after each vaccination, inclusive of the vaccination day) (see 
Section 11.2.1.2), sites will train each subject at Visit 1 (subjects will take their own temperature 
in front of site staff to confirm correct measurement before leaving the clinic).  Diary cards 
(Section 11.1.10) will include instructions, and sites will reinforce proper assessment at each 
applicable visit to continually assess subject competency.  
11.1.3. 
Height and Weight 
Subject’s height and weight will be taken and BMI calculated at the Screening Visit and 
recorded on the appropriate eCRF. 
11.1.4. 
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, thyroid, lungs, heart, abdomen, lymph nodes, and musculoskeletal 


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system/extremities, and a neurological examination; the results will be recorded on the 
appropriate eCRF. 
A symptom-directed physical examination will be performed at Visit 1 (Day 1), Visit 2 (Day 3), 
Visit 3 (Day 8), Visit 4 (Day 15), Visit 5 (Day 22), Visit 6 (Day 29), Visit 7 (Day 36), Visit 9 
(Day 50), Visit 10 (Day 64), ET Visit, and Unscheduled Visit.  Results will be recorded on the 
appropriate eCRF. 
11.1.5. 
Electrocardiogram  
A standard 12-lead ECG will be recorded and assessed at the Screening Visit, Visit 7 (Day 36), 
and Visit 13 (Day 394).  The ECG will be reviewed by a medically qualified individual to 
confirm review of the ECG and verify whether any abnormalities are clinically significant.  In 
general, abnormal, clinically significant ECGs are expected to be associated with an item 
recorded in the subject’s medical history or with an AE.    
11.1.6. 
High-sensitivity C-Reactive Protein  
Serum samples will be collected for high-sensitivity C-reactive protein (hs-CRP) assay only in 
subjects ≥66 years of age at Visit 1 (Day 1) prior to vaccination and at Visit 2 (Day 3).  The 
samples will be shipped to the central laboratory for analysis.  The details for sample handling, 
processing, and shipping will be provided in the Laboratory Manual.   
11.1.7. 
Autoantibody Sample Collection 
Serum samples will be collected at Visit 1 (Day 1) prior to vaccination, and at Visit 10 (Day 64) 
or at an ET Visit prior to Day 64.  The samples will be shipped to the central laboratory and will 
be frozen for potential testing of antinuclear antibodies, anti-double-stranded deoxyribonucleic 
acid (anti-dsDNA), and rheumatoid factor titers if needed.  The details for sample handling, 
processing, and shipping will be provided in the Laboratory Manual.   
11.1.8. 
Clinical Laboratory Assessments 
Venous blood and urine samples will be collected for routine clinical laboratory safety 
evaluations at the Screening Visit, Visit 3 (Day 8), Visit 5 (Day 22), Visit 7 (Day 36), and at ET 
and Unscheduled Visits (if deemed clinically indicated by the investigator), and will be shipped 
to the central laboratory for analysis.  Post-vaccination Grade 3 and Grade 4 abnormal laboratory 
results will be evaluated with an unscheduled repeat test.  Repeat tests should be scheduled to 
ensure test results can be assessed in time to avoid an impact on the protocol-defined window for 
administration of Dose 2 or Dose 3.  The details for sample handling, processing, and shipping 
will be provided in the Laboratory Manual. 
Individual results will be sent to the applicable site, and the investigator will perform a clinical 
assessment of all laboratory safety data to assess eligibility and identify and document AEs as 
applicable.  All results will be transferred electronically directly from the central laboratory to 
Rho using standard secure data transfer procedures. 
The clinical laboratory assessments planned for this study include chemistry, hematology, and 
urinalysis assessments as follows. 


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11.1.8.1. 
Chemistry 
 ALT 
 Creatinine 
 AST 
 Glucose, random, serum 
 Blood urea nitrogen 
 Total bilirubin (fractionated for values for total 
bilirubin > ULN) 
11.1.8.2. Hematology  
Table 3 lists the parameters of the complete blood count with differential. 
Table 3: 
Complete Blood Count with Differential 
Red blood cells 
White blood cells 
 
Hematocrit 
 
Basophils (% and absolute count) 
 
Hemoglobin 
 
Eosinophils (% and absolute count) 
 
Red blood cell count 
 
Lymphocytes (% and absolute count) 
Platelets 
 
Monocytes (% and absolute count) 
 
Platelet count 
 
Neutrophils (% and absolute count) 
 
 
White blood cell count 
11.1.8.3. Urine Drug Screen and Urinalysis 
Urine will be collected for a drug screen at the Screening Visit.  The urine drug screen includes 
tests for amphetamines, barbiturates, benzodiazepines, cocaine, tetrahydrocannabinol, 
methylenedioxymeth-amphetamine, opiates, oxycodone, phencyclidine, and propoxyphene. 
Urine will be collected at the Screening Visit, Visit 3 (Day 8), Visit 5 (Day 22), Visit 7 (Day 36), 
and at ET and Unscheduled Visits (if deemed clinically indicated by the investigator) for 
urinalysis.  Urinalysis parameters include appearance, color, pH, specific gravity, ketones, 
protein, glucose, bilirubin, nitrite, urobilinogen, and occult blood.   
11.1.9. 
Pregnancy Screen 
At the Screening Visit, Visit 1 (Day 1), Visit 4 (Day 15), and Visit 6 (Day 29), a urine dipstick 
pregnancy test will be performed onsite for female subjects of childbearing potential.  For 
Visits 1, 4, and 6, the test must be performed within 24 hours prior to vaccination, and results 
must be final and negative prior to vaccination.  
Additionally, a urine dipstick pregnancy test should be performed at any time during study 
participation if pregnancy is suspected.   
11.1.10. 
Diary Cards  
All subjects will be provided with diary cards (see Table 4 and Figure 2) to aid in their recording 
of solicited local and systemic symptoms to the study IP and other unsolicited symptoms, 
including start and stop dates (see Section 11.1.12 and Section 11.2.1.2).  In addition, the diary 


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cards will include training information on temperature measurements (Section 11.1.2) and 
injection site reaction assessment.  
The investigator or his/her designee will review the information from the diary card or from 
memory with the subject at each applicable visit and assess whether any AE criteria are met 
based on FDA’s standard toxicity grading scales (Section 11.3.3 and Appendix 2).  Once 
confirmed to be an AE, the investigator or designee will enter the information into the 
appropriate eCRF.  In addition, any changes in concomitant medications will be documented on 
the appropriate eCRF. 
The diary cards will be collected from the subjects and stored as source documents. 
Table 4: 
Schedule of Diary Cards 
Diary Card 
Type of Event Vaccination 
Collection Period:  
Days After Dosing 
Collection 
Period: Study 
Days 
Diary Card 1A 
Solicited and 
Unsolicited 
Dose 1 
Days 1-8 Post-vaccination, 
inclusive of vaccination day 
Days 1-8 
Diary Card 1B 
Unsolicited 
Dose 1 
Days 8-15 Post-vaccination 
Days 8-15 
Diary Card 2A 
Solicited and 
Unsolicited 
Dose 2 
Days 1-8 Post-vaccination, 
inclusive of vaccination day 
Days 15-22 
Diary Card 2B 
Unsolicited 
Dose 2 
Days 8-15 Post-vaccination 
Days 22-29 
Diary Card 3A 
Solicited and 
Unsolicited 
Dose 3 
Days 1-8 Post-vaccination, 
inclusive of vaccination day 
Days 29-36 
Diary Card 3B 
Unsolicited 
Dose 3 
Days 8-21 Post-vaccination 
Days 36-50 
11.1.11. 
Post-vaccination Evaluation 
At Visit 1 (Day 1), Visit 4 (Day 15), and Visit 6 (Day 29), subjects will be monitored for at least 
1 hour after vaccination; any safety events and concomitant medications will be recorded on the 
appropriate eCRFs. Details regarding collection and reporting of solicited local and systemic 
reactogenicity symptoms are presented in Section 11.1.10, Section 11.1.12 and Section 11.2.1.2. 
The following evaluations will be performed: 
1. Vital sign measurements will be obtained at 30 minutes (±5 minutes) and 1 hour 
(±5 minutes) post-vaccination as described in Section 11.1.2. 
2. Injection site evaluation will be completed at 1 hour (±5 minutes) post-vaccination 
(Section 11.1.12).   


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11.1.12. 
Injection Site Evaluation 
Injection site evaluations will be performed to assess injection site warmth, tenderness, itching, 
pain, restriction of range of arm motion, erythema/redness, palpable or observable lump, 
induration/swelling, and bruising. The Dose 1 injection site will be examined at Visit 1 (Day 1) 
at 1 hour (±5 minutes) post-vaccination, Visit 2 (Day 3), Visit 3 (Day 8), and at Visit 4 (Day 15 
prior to Dose 2 vaccination). The Dose 2 injection site and the Dose 1 injection site (contralateral 
arm, if applicable) will be examined at Visit 4 (Day 15) at 1 hour (±5 minutes) post-vaccination, 
Visit 5 (Day 22), and Visit 6 (Day 29 prior to Dose 3 vaccination). The Dose 3 injection site and 
the Dose 2 injection site (contralateral arm, if applicable) will be examined at Visit 6 (Day 29) at 
1 hour (±5 minutes) post-vaccination, Visit 7 (Day 36), and Visit 8 (Day 43). Results will be 
recorded on the appropriate eCRF. 
If a visible injection site abnormality is observed,  
1. The abnormality will be documented with a photograph if the subject consented.   
2. The area (largest diameter) of erythema/redness and/or induration/swelling will be 
measured and documented. 
Photographs will be taken by study staff only in the event of abnormal findings for accurate 
description and evaluation of the findings and safety reviews, and will be retained with subject 
source documents.  There are no digital format requirements; the photographs will not be stored 
in the study database and will not be used as part of the safety analysis.  They may, however, be 
shared with the medical monitor, BARDA, and the SMC in a secure and blinded manner without 
exposing personally identifiable information.   
11.1.13. 
Adverse Event Assessment 
Site staff will ask nonleading questions regarding the subject’s health status (Section 11.3.1) and 
document any new or changed AEs on the appropriate eCRF.  Due to the known increased risk 
of the elderly population to cardiac and neurovascular events, the need for special attention to 
these AEs in this population will be stressed at investigator meetings and site trainings.  
11.1.14. 
Concomitant Medication Assessment 
Site staff will review concomitant medications (Section 8.2) and document any new or changed 
medications on the appropriate eCRF.  
11.2. 
Adverse and Serious Adverse Events  
11.2.1. 
Definition of Adverse Events 
11.2.1.1. Adverse Events 
An AE is any untoward medical occurrence associated with the use of a drug in humans, whether 
or not it is considered drug related [21 Code of Federal Regulations [CFR] 312.32(a)].  An AE 
can therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of a medicinal (investigational) 
product, whether or not related to the medicinal (investigational) product (Integrated Addendum 


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to International Conference on Harmonisation (ICH) E6[R1]: Guideline for Good Clinical 
Practice (GCP) E6[R2]). 
Laboratory results and vital sign excursions of any magnitude will be defined as AEs if they are 
considered clinically significant by the investigator.  Any Grade 4 laboratory value should be 
considered an AE. 
Suspected adverse reaction (SAR) means any AE for which there is a reasonable possibility that 
the drug caused the AE.  For the purposes of safety reporting, “reasonable possibility” means 
there is evidence to suggest a causal relationship between the drug and the adverse event.  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 BioThrax package insert or 
AV7909 investigator brochure or is not listed at the specificity or severity that has been 
observed. 
11.2.1.2. Solicited and Unsolicited Adverse Events 
For the purposes of this study, local reactions and specific systemic AEs will be solicited from 
the subject for 8 days post-vaccination, inclusive of the vaccination day (Section 11.1.10).   
 Solicited local injection site and prior injection site reactions are defined in 
Section 11.1.12.  
 Solicited systemic reactions will include fatigue, myalgia/muscle ache, headache, and 
fever. 
All other AEs reported by the subject will be defined as unsolicited AEs. All unsolicited AEs 
during the early part of the study (through Day 50, Section 11.1.10) will be recorded. Following 
Day 50, unsolicited AEs will only be recorded if they are defined as SAEs, MAAEs, or 
PIMMCs. 
11.2.1.3. Serious Adverse Events 
An AE or SAR is considered serious if, in the view of either the investigator or BARDA, it 
results in any of the following outcomes [21 CFR 312.32(a)]:  
 Death. 
 Life-threatening AE that, in the view of the investigator or BARDA, places the 
subject at immediate risk of death.  This does not, however, include an event that 
might have caused death had it occurred in a more severe form. 
 Requires inpatient hospitalization or prolongs existing hospitalization.  Planned 
hospitalizations will not be reported as SAEs unless categorized as medically 
important.  Emergency room visits and observational admissions of under 24 hours, 
in themselves, do not qualify as SAEs. 
 Results in persistent or significant disability/incapacity or substantial disruption of the 
ability to conduct normal life functions. 
 Congenital anomaly/birth defect. 


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 Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse drug experience, when based on 
appropriate medical judgment, they may jeopardize the subject or the subject may 
require medical or surgical intervention to prevent one of the outcomes listed in this 
definition. 
11.2.1.4. Medically Attended Adverse Events 
The FDA requires that clinical trials of preventive vaccines with CPG 7909 adjuvant implement 
collection and analysis of data relating to MAAEs among subjects in all study groups from the 
time of the first dose of study IP through 12 months following the last dose of study IP, due to 
the theoretical potential for induction of autoimmune or autoinflammatory diseases.   
MAAEs are defined as AEs with medically attended visits including hospital, emergency room, 
urgent care clinic, or other visits to or from medical personnel for any reason. Adverse events 
(e.g., abnormal vitals) identified at a routine study visit will not be considered MAAEs.  
11.2.1.5. Potentially Immune-Mediated Medical Conditions 
The FDA requires that clinical trials of preventive vaccines with CPG 7909 adjuvant implement 
collection and analysis of data relating to PIMMCs among subjects in all study groups from the 
time of the first dose of study IP through 12 months following the last dose of study IP, due to 
the theoretical potential for induction of autoimmune or autoinflammatory diseases.   
For this study, the occurrence of a PIMMC is considered to be unexpected and will be reported 
as a serious and unexpected suspected adverse reaction (SUSAR) per 21 CFR 312.32.  
A list of PIMMCs defined for this study is presented in Appendix 3.  
11.3. 
Collection, Recording, and Grading Severity of Adverse Events  
11.3.1. 
Collection of Adverse Events 
AEs of any type described above may be discovered through a variety of methods: 
 Observing the subject 
 Reviewing and discussing the diary cards with the subject (Section 11.1.10) 
 Questioning the subject with standard nonleading questions to elicit any medically related 
changes in their well-being (e.g., Have you been hospitalized, had any medical problems, 
used any new medications, or changed or stopped any medications [both prescription and 
OTC]?) 
 Receiving an unsolicited complaint from the subject 
 An abnormal value or result from a clinical (e.g., vital signs) or laboratory evaluation  
11.3.2. 
Recording of Adverse Events 
Throughout the study, the investigator will record AEs on the appropriate eCRF.  Any clinically 
significant safety assessments that are associated with an underlying disease present at screening, 
unless judged by the investigator to be more severe than expected for the subject’s condition, are 


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not to be reported as AEs or SAEs.  Due to expectedness of mild fever, and mild redness and 
swelling at the injection site, any symptoms of redness, swelling and fever that do not meet the 
Grade 1 lower thresholds in Table 8 are not to be reported as AEs.  
Treatment-emergent AEs (TEAEs) will be recorded during the periods defined below. 
 Solicited AEs:  
o Those occurring within 8 days after each vaccination, inclusive of the vaccination 
day (Day 1 through Day 8, Day 15 through Day 22, and Day 29 through Day 36). 
o Those judged related to study IP 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).  
o Those judged unrelated to study IP 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 subject’s study participation, whichever comes first. 
 Treatment-Emergent Unsolicited AEs: 
o All AEs other than solicited local and systemic reactogenicity symptoms  
occurring from the time the subject receives the first vaccination until Visit 9 
(Day 50).  Following Day 50, unsolicited AEs will only be recorded if they are 
defined as SAEs, MAAEs, or PIMMCs. 
o Those judged related to study IP 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). 
o Those judged unrelated to study IP 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 subject’s study participation, whichever comes first. 
  Treatment-Emergent SAEs, MAAEs, and PIMMCs: 
o Those occurring from the time the subject receives the first vaccination until exit 
from the study. 
o SAEs and PIMMCs will be reported to Rho pharmacovigilance personnel within 
1 business day of the site’s awareness of the event.  Only MAAEs meeting SAE 
criteria must be reported within 1 business day.  
o Those judged related to study IP 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). 
o Those judged unrelated to study IP 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 subject’s study participation, whichever comes first. 


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Figure 2 provides the safety data reporting periods used in this study. 
Figure 2: Safety Data Reporting Periods 
 
AE= adverse event; MAAE = medically attended adverse event; PIMMC = potentially immune-mediated medical 
condition; SAE = serious adverse event 
Note:  All unsolicited AEs will be collected through the end of the Visit 9 study visit window (i.e., Day 50, 21 days 
after the third vaccination). Following Day 50, unsolicited AEs will only be recorded if they are defined as SAEs, 
MAAEs, or PIMMCs. 
Note:  The entire study period is from Day 1 from the time a subject receives the first study vaccination through 
Visit 13 (Day 394).   
Note:  Pregnancies that occur during a subject’s participation in the study will be followed until conclusion even if 
the pregnancy ends after Visit 13 (Day 394). 
11.3.3. 
Grading Severity of Adverse Events 
The severity of AEs and SAEs will be graded as defined by the FDA’s standard toxicity grading 
scales14 (Appendix 2).  For the local and systemic solicited AEs that are not included in 
Appendix 2 (i.e., injection site warmth, restriction of range of arm motion, palpable or 
observable lump, and bruising), the severity grading will be based upon the subject’s individual 
assessment of the extent to which the AE interfered with his/her regular daily activities as 
follows: Grade 0 (Absent)= symptom not present; Grade 1 (Mild) = symptom present but does 
not interfere with activities of daily living; Grade 2 (Moderate) = symptom causes some 
interference with activities of daily living: Grade 3 (Severe) = symptom prevents activities of 
daily living or requires treatment. 
It is important to distinguish between serious and severe AEs.  Severity is a measure of intensity, 
whereas seriousness is defined by the criteria in Section 11.2.1.3. 
11.4. 
Relationship and Attribution to Study Investigational Product 
An investigator’s causality assessment is the determination of whether a reasonable possibility 
exists that study IP caused or contributed to an AE, and must be provided for all AEs (serious 


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and non-serious).  The investigator will assess the causality/relationship between the study IP 
and the AE and record that assessment in the appropriate eCRF.    
BARDA’s determination of attribution will be used for reporting to the appropriate health and 
regulatory authorities.   
The relation and attribution of an AE to study treatment will be determined using the descriptors 
and definitions provided in Table 5. 
Table 5: 
Attribution of Adverse Events 
Unrelated Categories 
Not Related 
The AE is clearly not related to study IP. 
Unlikely Related 
The AE is unlikely related to study IP. 
Related Categories 
Possibly Related 
The AE has a reasonable possibility to be related to study IP; evidence exists to 
suggest a causal relationship. 
Probably Related 
The AE is likely related to study IP. 
Related 
The AE is clearly related to study IP. 
AE = adverse event; IP = Investigational Product 
11.5. 
Reporting Safety Events to Regulatory Authorities 
Once AEs, SAEs, and PIMMCs are recorded into the appropriate eCRF, Rho pharmacovigilance 
personnel will collaborate with BARDA and appropriate personnel to process and report events 
to the appropriate regulatory authorities within applicable regulatory timeframes.  Procedures for 
AE processing and reporting are detailed in the Data Safety Monitoring Plan. 
The sponsor will report to the FDA any suspected adverse reaction that is both serious and 
unexpected (SUSAR).  The sponsor will report an AE as a SAR only if evidence exists to 
suggest a causal relationship between the study IP and the AE, such as: 
a) A single occurrence of an event that is uncommon and known to be strongly associated 
with IP exposure (e.g., angioedema, Stevens-Johnson syndrome, Guillain-Barré 
syndrome). 
b) One or more occurrences of an event that is not commonly associated with IP exposure, 
but is otherwise uncommon in the population exposed to the IP (e.g., narcolepsy). 
c) An aggregate analysis of specific events observed in a clinical trial (such as known 
consequences of the underlying disease or condition under investigation or other events 
that commonly occur in the study population independent of treatment) that indicates 
those events occur more frequently in the study group than in a concurrent or historical 
control group [21CFR 312.32(a)]. 
d) PIMMCs (Section 11.2.1.5) will be submitted as SUSARs. 


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11.6. 
Pregnancy Reporting 
This study includes pregnancy as safety data.  Although pregnancy is not an SAE, information 
about any pregnancy in a female study subject should be reported promptly to Rho on the same 
timeline as an SAE for tracking purposes (Section 11.3.2). 
Study vaccination will be discontinued for the pregnant subject.  The investigator shall counsel 
the pregnant subject and discuss the risks of continuing with the pregnancy and the possible 
effects on the fetus.  Monitoring of the pregnant subject shall continue until the conclusion of the 
pregnancy.  
The pregnancy will be documented on the appropriate eCRF when identified and at its 
conclusion.   
Should pregnancy result in a congenital abnormality, birth defect, miscarriage, or medically 
indicated abortion, an SAE must be submitted to Rho using the SAE reporting procedures 
described in Section 11.3.2. 
11.7. 
Reporting Other Safety Information 
Investigators should promptly notify Rho, BARDA, and the IRB when an unanticipated problem 
involving risks to subjects or others is identified, which is not otherwise reportable as an AE. 


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12. 
STATISTICS 
12.1. 
Endpoints 
12.1.1. 
Primary Endpoints 
There are 2 primary endpoints for this study. 
 All solicited local and systemic reactogenicity symptoms occurring within 8 days 
after each vaccination, inclusive of the vaccination day, excluding reactogenicity 
symptoms on the contralateral arm. 
 Seroprotection at Day 64, defined as a TNA NF50 antibody level ≥0.56.  
12.1.2. 
Secondary Endpoints 
12.1.2.1. Secondary Safety Endpoints 
 All treatment-emergent unsolicited AEs. 
 All treatment-emergent SAEs occurring during study participation. 
 All treatment-emergent MAAEs occurring during study participation. 
 All treatment-emergent PIMMCs occurring during study participation. 
 All solicited local reactogenicity symptoms on the contralateral arm occurring within 
8 days after each vaccination, inclusive of the vaccination day. 
12.1.2.2. Secondary Immunogenicity Endpoints 
 TNA NF50 antibody levels at Days 1, 8, 22, 29, 36, 43, 50, 64, 85, 181, and 394. 
 TNA ED50 antibody levels at Days 1, 8, 22, 29, 36, 43, 50, 64, 85, 181, and 394. 
 ELISA anti-PA IgG antibody levels at Days 1, 8, 22, 29, 36, 43, 50, 64, 85, 181, and 
394. 
 Seroprotection based on TNA NF50 at Days 1, 8, 22, 29, 36, 43, 50, 85, 181, and 394. 
 Seroconversion based on TNA NF50 at Days 8, 22, 29, 36, 43, 50, 64, 85, 181, and 
394, defined as a ≥4-fold increase over baseline levels, or a ≥4-fold increase over the 
LLOQ if the baseline value is below the LLOQ. 
 Seroconversion based on TNA ED50 at Days 8, 22, 29, 36, 43, 50, 64, 85, 181, and 
394. 
 Seroconversion based on ELISA anti-PA IgG at Days 8, 22, 29, 36, 43, 50, 64, 85, 
181, and 394. 
12.1.3. 
Measures to Minimize Bias 
Stratified block randomization will be performed centrally and will balance enrollment between 
treatment arms within the same age group and within each sex (see Section 9.7.1  for more 


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details).  Clinical staff observing the subject post-vaccination, laboratory personnel analyzing 
samples, and study subjects will be blinded to study group (Section 9.7.2).  Site staff will be 
trained in procedures to ensure blinding is maintained for all blinded individuals. 
An independent unblinded team (Section 9.7.2) will generate, interpret, and report each analysis 
using appropriate study groups and will not modify any programs used to perform analyses.   
12.1.4. 
Analysis Plan 
Statistical analyses will be performed using SAS® software Version 9.3 or later.  
Due to the exploratory nature of the primary objectives, inferential analyses are planned only as 
part of the secondary analyses. 
Descriptive statistics (such as medians, quartiles, and ranges for continuous data, and 
percentages for categorical data) will be used to summarize subject characteristics, safety, and 
immunogenicity parameters.  These summaries will be presented overall and separately for the 
subjects in the different study groups, as well as for pooled groups by treatment arm (regardless 
of age group) and by age group (regardless of treatment arm).   
Details of the statistical analyses, methods, and data conventions will be described in the 
Statistical Analysis Plan (SAP). 
12.1.4.1. Analysis Populations 
12.1.4.1.1. Safety Population 
The safety population will include all subjects who are randomized and receive at least 1 IP dose.  
Each subject will be analyzed as part of the study group corresponding to the actual treatment 
received for the applicable dose for individual dose summaries.  For all other analyses by study 
group, each subject will be analyzed corresponding to the actual treatment received for the first 
dose.  The safety population will be used for all safety analyses. 
12.1.4.1.2. Immunogenicity Full Analysis Population 
The immunogenicity full analysis population (IFAP) will include all subjects who are 
randomized, receive at least 1 IP dose, and have at least one determinate assay result at any post-
vaccination visit.  Each subject will be analyzed based on the treatment and dosing schedule 
actually received, regardless of the treatment arm assignment.  The IFAP will be used only for 
analysis of seroprotection based on TNA NF50 antibody levels at Day 64 as a secondary analysis.  
Any additional immunogenicity analyses on the IFAP will be defined in the SAP.  
12.1.4.1.3. Immunogenicity Per Protocol Population 
The immunogenicity per protocol population (IPPP) will include all subjects in the IFAP who 
meet the following criteria: 
 Receive a full dose of IP at Day 1, Day 15, and Day 29 within protocol specified visit 
windows (- 1 Day, +3 Days). 
 Receive the correct treatment as assigned by randomization at Day 1, Day 15, and 
Day 29. 


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 Have no major protocol deviations that may have an impact on immunogenicity 
assessments. 
 Have determinate assay results at the Day 64 visit. 
The IPPP will be used for all primary and secondary immunogenicity endpoint assessments. 
12.1.4.2. Primary Analyses 
12.1.4.2.1. Primary Safety Analyses 
The frequency of solicited local and systemic reactogenicity symptoms, as defined in Section 
11.1.12 and Section 11.2.1.2, will be summarized by system organ class and preferred term.  The 
risk of the event in each study group will be described using event rates and corresponding 95% 
CIs.  Events will be included in the primary endpoint only if they occur within 8 days of 
vaccination, inclusive of the vaccination day (i.e., Day 1 through Day 8, Day 15 through Day 22, 
and Day 29 through Day 36), excluding reactogenicity symptoms on the contralateral arm. 
12.1.4.2.2. Primary Immunogenicity Analyses 
Proportions of subjects who achieve seroprotection based on TNA NF50 antibody levels at 
Day 64 will be reported for each study group with the corresponding 95% CI for that group.   
12.1.4.3. Secondary Analyses 
The 5 secondary safety endpoints (Section 12.1.2.1) will be summarized in the same manner as 
the primary safety endpoint.  Additionally, both primary and secondary safety endpoints will be 
summarized by vaccination dose (i.e., Dose 1, 2, or 3), onset days post each vaccination, grade, 
duration, and relationship to study IP.   
Continuous TNA NF50, TNA ED50, and ELISA anti-PA IgG antibody levels will be summarized 
as geometric mean levels by study group and visit with the corresponding 95% CIs about the 
geometric mean for each group.   
Secondary immunogenicity endpoints related to seroprotection and seroconversion will be 
summarized in the same manner as the primary immunogenicity endpoint.  Definitions of 
seroprotection and seroconversion can be found in Section 12.1.1 and Section . 
Comparisons between study groups in binary outcomes will be made using either a Pearson 
chi-square test or a Fisher’s exact test, as appropriate.  Rate differences will be reported, along 
with 95% CIs and p-values.  Continuous outcome comparisons between study groups will be 
made using a t-test, and geometric mean ratios with corresponding 95% CIs and p-values will be 
reported. 
Additional information regarding exploratory analyses, listings, and tabular summaries of safety 
assessments and immunogenicity measures will be specified in the SAP. 
12.1.4.4. Interim Analysis 
An interim analysis will be performed based on cumulative immunogenicity and safety data 
through Day 64 for all subjects.  At the interim analysis, the study database (all data through 
Day 64) will be monitored and cleaned per the Data Management Plan (DMP).  Data for the 


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interim analysis will be presented solely at the group level, thus, the blinding at the subject level 
will be maintained for those outside of the unblinded team until database lock of all data through 
Day 394 for the clinical study report.  
All primary and secondary endpoint analyses up through Day 64 will be performed for the 
interim analysis as specified in Section 12.1.4.2 and Section 12.1.4.3.  Since all subjects will 
have completed Day 64 and no formal statistical comparisons are being made as part of the 
primary objectives, there will be no penalty for an early look at the data. 
Further details will be specified in the SAP. 
12.1.4.5. SMC Reviews 
The SMC will perform a planned review of interim safety data after 40 subjects ≥66 years of age 
have completed Visit 7 (Day 36).  Enrollment and dosing will continue during this planned SMC 
review.  In addition, ad hoc reviews will occur in the event that pausing/stopping rules are met or 
a review is deemed necessary by the SMC chair (Section 6.4.2).   
The final SMC safety displays will be provided to the SMC members when the last study subject 
completes Visit 10 (Day 64). 
Data displays for each SMC review will be generated by an unblinded statistician.  Safety 
analyses for this study will be descriptive rather than inferential.  Detailed listings and summary 
tabulations will be generated as specified in the SMC charter.  The safety analyses will be 
completed using the safety population. 
12.1.4.6. Final Analyses 
A clinical study report will be written to include all safety and immunogenicity data through 
Day 394.  For the final analysis, the study database will be monitored, cleaned, and locked per 
the DMP.  Study data will be unblinded to prepare the study report.  Further details will be 
specified in the SAP. 
12.1.4.7. Exploratory Analyses 
Exploratory analyses will be defined in the SAP, if applicable. 
12.2. 
Sample Size Considerations 
The sample size for this study is approximately 300 subjects:  200 subjects ≥66 years of age 
(older cohort) and 100 subjects 18 through 50 years of age (younger cohort).  Approximately 
50 subjects will be randomized into each of 6 study groups. 
The proposed sample size for this study is based on previous experience with similar BioThrax 
studies in individuals aged 18 to 65 years.  The previous studies had study arms of similar size 
that proved to be sufficient to allow the collection of meaningful data, especially with respect to 
local and systemic reactogenicity symptoms and antibody levels.  
Though no hypothesis testing will be performed as part of the primary analyses, Table 6 and 
Table 7 show the probability of observing a safety event and statistical power to detect crossing a 
threshold in seroprotection rate, respectively, under a variety of hypothetical scenarios.  Within 
each table, separate calculations are performed for each pooled group of interest.   


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Probabilities of detecting a safety event were calculated using the binomial distribution 
(Table 6).   
Table 6: 
Probability of Observing at Least 1 Safety Event of Interest under Different 
True Event Rates 
True Probability of a 
Safety Event of Interest 
Per Study 
Group (N=50) 
Pooled Study 
Groups 
(N=100) 
Pooled ≥66 
Years of Age 
Cohort (N=200) 
Overall 
(N=300) 
0.0001 
0.005 
0.010 
0.020 
0.030 
0.005 
0.222 
0.394 
0.633 
0.778 
0.01 
0.395 
0.634 
0.866 
0.951 
0.02 
0.636 
0.867 
0.982 
0.998 
0.05 
0.923 
0.994 
>0.999 
>0.999 
0.1 
0.995 
>0.999 
>0.999 
>0.999 
A lower bound of 40% is considered to be a meaningful threshold of success for the 
seroprotection rate for BioThrax.4  Assuming a one-sided alpha level of 0.025, an exact binomial 
test was used to calculate the power to detect the lower bound of an exact 95% CI about an 
observed seroprotection rate being ≥40%, using sample size and hypothetical true seroprotection 
rate scenarios shown in Table 7. 
Table 7: 
Power for Detecting a Lower 95% Confidence Limit of ≥40% about an 
Observed Seroprotection Rate 
Hypothetical 
True 
Seroprotection 
Rate (%) 
Per Study Group 
(N=50) 
Pooled Study 
Groups (N=100) 
Pooled ≥66 Years 
of Age Cohort 
(N=200) 
Overall (N=300) 
50 
0.240 
0.460 
0.782 
0.926 
60 
0.766 
0.973 
>0.999 
>0.999 
70 
0.988 
>0.999 
>0.999 
>0.999 
80 
>0.999 
>0.999 
>0.999 
>0.999 
12.3. 
Statistical Considerations 
12.3.1. 
Covariates 
Since no statistical models will be used for the primary and secondary endpoints, adjustments for 
covariates will not be necessary. 
12.3.2. 
Multi-center Studies 
By-site analyses planned for this study will be defined in the SAP. 


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12.3.3. 
Multiple Comparisons and Multiplicity 
All safety and immunogenicity comparisons of study groups are considered exploratory in 
nature.  As such, no adjustments will be required for multiple comparisons. 
12.3.4. 
Subgroup Analyses 
All exploratory analyses, including any subgroups that require additional consideration, will be 
discussed in the SAP, if necessary. 
12.3.5. 
Missing Data 
Standard procedures will be used to ensure that the data are as complete and accurate as possible.  
Due to the exploratory nature of this study, all descriptive summaries will be based upon all 
available data, and no imputation will be done.   
12.4. 
Procedure for Documenting Deviations from the Planned Analyses 
The principal features of the design of this study and of the plan for statistical analysis of the data 
are outlined in this protocol.  Additional details will be included in the SAP before initiating 
analyses.  Any changes to that plan will be documented in the final clinical study report and will 
be approved by BARDA before being initiated. 


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13. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
13.1. 
Inspection of Records 
BARDA, Rho, the IRB, and regulatory authorities will be allowed to conduct site visits to the 
investigational facilities for the purpose of monitoring, inspecting, or auditing any aspect of the 
study.   
The investigator agrees to allow BARDA, Rho, the IRB, and regulatory authorities to inspect the 
clinical facilities, including the study IP storage area, and all documentation relating to the study, 
including but not limited to all source documents, eCRFs, IRB submissions and approvals, study 
IP accountability logs, study IP temperature monitoring logs, regulatory documents, and 
correspondence. 
The investigator also agrees to promptly notify BARDA and Rho of any audits or inspections 
scheduled by any regulatory authority and promptly forward copies of any audit or inspection 
reports received.  
13.2. 
Institutional Review Board  
A copy of the protocol, informed consent forms (ICFs), subject diary, any other subject facing 
documents, and any proposed advertising/recruitment materials will be submitted to the central 
IRB for written approval.  Initial IRB approval and all materials approved by the IRB for this 
study, including the subject consent form and recruitment materials, must be maintained by the 
investigator and made available for inspection. 


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14. 
QUALITY CONTROL AND QUALITY ASSURANCE 
Quality assurance includes all the planned and systematic actions that are established to ensure 
that the clinical study is performed and the data are generated, documented (recorded), and 
reported according to ICH GCP and local/regional regulatory standards. 
A quality assurance representative from BARDA (or designee), who is independent of and 
separated from routine monitoring, may periodically arrange inspections/audits of the clinical 
study by reviewing the data obtained and procedural aspects.  These inspections may include 
on-site inspections/audits and source data checks.  Direct access to source documents is required 
for the purpose of these periodic inspections/audits.  
14.1. 
Data Quality Assurance 
Before enrolling any subjects in this study, BARDA personnel and the investigator will review 
the protocol, BioThrax package insert, AV7909 investigator’s brochure, the eCRFs and 
instructions for their completion, the procedure for obtaining informed consent, and the 
procedure for reporting AEs, SAEs, MAAEs, and PIMMCs.   
As part of the responsibilities assumed by participating in the study, the investigator agrees to 
maintain adequate source documents for the subjects treated as part of the research under this 
protocol.  In addition, the investigator agrees to provide access to those records to BARDA’s 
study monitor and auditor.  Study monitors will verify information in the eCRFs against the 
source documents.  
Data collected at the study site will be entered accurately and contemporaneously by study staff 
into Medidata RAVE, a 21CFR11-compliant, internet-based, remote data entry system, which is 
backed up nightly with backup tapes saved in a secure, off-site location.  Data will be provided 
using the subject’s unique identification number, not name or initials; Rho will not collect 
personally identifying information such as the subject’s name or social security number.  
Subjects will provide demographic information such as race, ethnicity, and birth date.  All 
elements of data entry (e.g., time, date, verbatim text, and the person performing the data entry) 
will be recorded within the RAVE system’s audit trail to allow all data changes in the database to 
be monitored and maintained in accordance with federal regulations.  Data collected by the 
laboratories will be transferred electronically directly from the laboratory to Rho using standard 
secure data transfer procedures.  The analysis datasets will incorporate data from both sources.  
Data collected by Rho will be held in the strictest confidence, and are protected from access that 
could reveal personally identifying information about any subject in the study. 
Clinical data management and data cleaning procedures (i.e., resolving errors and inconsistencies 
in the data) will be performed in accordance with applicable Rho and/or BARDA standards and 
validation plans to ensure the integrity of the data.  Adverse events (including SAEs, MAAEs, 
and PIMMCs) and concomitant medication terms will be coded using the Medical Dictionary for 
Regulatory Activities and the World Health Organization Drug dictionaries, respectively.  
At the interim analysis, the study database (all data through Day 64) will be monitored and 
cleaned per the DMP.  For the final analysis, the study database will be monitored, cleaned, and 
locked per the DMP.   


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The investigator will sign each subject’s eCRF to confirm accuracy of the data recorded for the 
Day 64 interim analysis and at the end of the study.  After the end of study database lock, each 
study site will receive an electronic copy of all of their site-specific eCRF data as entered into 
Medidata RAVE for the study, including full discrepancy 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.   
14.2. 
Study Monitoring 
According to ICH GCP guidelines, the sponsor of the study is responsible for ensuring the proper 
conduct of the study with regard to protocol adherence and validity of data recorded on the 
eCRFs.  This study will be monitored to ensure the maintenance of complete, accurate, legible, 
well-organized, and easily retrievable data.  In addition, the study monitor will explain and 
interpret for the investigator all regulations applicable to the clinical evaluation of an 
investigational product as documented in ICH guidelines. 
It is the study monitor’s responsibility to inspect the eCRFs and source documentation directly 
throughout the study to protect the rights of the subjects; to verify adherence to the protocol; to 
verify completeness, accuracy, and consistency of the data; to perform study IP accountability; 
and to confirm adherence of study conduct to any local regulations.  Details will be outlined in 
the Clinical Site Monitoring Plan. 
14.3. 
Protocol Deviations 
14.3.1. 
Protocol Deviation Definition 
A protocol deviation is any noncompliance with the IRB-approved study protocol, ICH GCP 
guidelines, protocol-specific operational documents, or applicable regulatory requirements.  Any 
deviation that affects the rights or safety of the subject or the integrity of the data will be 
considered a major protocol deviation.  Prospective permission to deviate from protocol 
requirements (i.e., “study waivers”) will not be granted for this study. 
14.3.2. 
Reporting and Managing Deviations 
The investigator has the responsibility to identify, document, and report deviations.  Protocol 
deviations may also be identified during site monitoring visits or during other forms of study 
conduct review.  All deviations, regardless of the cause, must be documented on the appropriate 
eCRF, which will document at a minimum the date the deviation occurred, the date it was 
identified, a description of the deviation, and documentation of a corrective/preventative action.  
In addition, the investigator will report noncompliance to the IRB, as applicable. 
Rho and/or BARDA may request discussion with the site investigator to determine the effect of 
any major protocol deviation on a study subject and his/her further study participation, the effect 
of the deviation on the overall study, and corrective actions.   


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15. 
ETHICS 
15.1. 
Ethics Review 
Before study initiation, the protocol, the informed consent documents, the subject diary, any 
other subject facing documents, and any proposed advertising/recruitment materials will be 
reviewed and approved by the IRB centrally; in addition, each individual site will be reviewed 
and approved by the IRB prior to the shipment of study IP to and the activation of each 
individual site.  Any amendments to those documents will be submitted to the IRB (following 
approval by BARDA) and must be approved by the IRB before they are implemented at the sites.  
Protocol documents must be re-approved by the IRB annually.  Only institutions holding a 
current US Federal Wide Assurance issued by the Office for Human Research Protections at 
HHS may participate in the study. 
The investigator will promptly report all unanticipated problems involving risks to subjects to the 
IRB, as applicable.  The investigator will not make any changes to the research conduct without 
BARDA and IRB approval, except where necessary to eliminate apparent immediate hazards to 
the subjects.   
The investigator will provide progress reports to the IRB as required by the IRB.  The 
investigator will provide a final report to the IRB after completion of participation in the study. 
15.2. 
Ethical Conduct of the Study 
The investigator should conduct the study in accordance with this protocol, the Declaration of 
Helsinki, current ICH GCP guidelines, and 21 CFR Part 50 (Protection of Human Subjects) and 
Part 56 (IRBs).   
15.3. 
Written Informed Consent 
The informed consent document template, including site-specific versions, will be approved by 
the IRB.  The investigator is responsible for ensuring that the subject fully understands the nature 
and purpose of the study during the informed consent process. Information should be given in 
both oral and written form.  Given that this study includes a vulnerable elderly population, 
subject comprehension will be assessed by administering an “Assessment of Understanding 
Questionnaire”  during the consent process.  No subject should be obliged to participate in the 
study.  The information must make clear that refusal to participate in the study or withdrawal 
from the study at any stage is without any prejudice to the subject’s subsequent care.  Subjects 
must be allowed sufficient time to inquire about the details of the study and to decide whether 
they wish to participate.  Written informed consent will be obtained before the subject undergoes 
any study procedures. 
The subject must be made aware of and give consent to direct access to his/her source medical 
records by study monitors, auditors, the IRB, and regulatory authorities.  The subject should be 
informed that such access will not violate subject confidentiality or any applicable regulations.  
The subject should also be informed that he/she is authorizing such access by signing the ICF.   


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The investigator will retain the original signed informed consent, and each subject will be given 
a signed copy to keep for his/her records.   
Using the ICF, subjects who consent to participate in this study will also be asked to consent to 
the following: 
 Permission to have a photograph of a visible injection site abnormality for the 
purpose of medical management and safety evaluations. 
 Permission to be contacted with a request to participate in future clinical studies of 
subjects who have been vaccinated against B. anthracis, such as longer interval 
prime-boost studies. 
 Permission to store any leftover serum for future investigations unrelated to this 
study.  Leftover serum will be stored indefinitely.  Subjects who provide consent may 
withdraw that consent for future investigations during their participation in the study 
by contacting the study doctor identified on the consent form.  After their 
participation in the study has ended, subjects can contact BARDA’s Chief Medical 
Officer (202-260-1200).  Leftover serum will be destroyed, but any data that have 
already been collected from analysis of leftover serum will remain a part of the 
research database. 
 


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16. 
DATA HANDLING AND RECORDKEEPING 
16.1. 
Confidentiality 
Each subject will be assigned a unique identification number and these numbers rather than 
names or other personal health information will be used to collect, store, and report subject 
information.  All biological samples will be labeled with a unique identification number rather 
than names or other personal health information.  Site staff will not transmit documents 
containing personal health identifiers to BARDA or its representatives.  Data reported in medical 
journals or scientific meetings will be presented in aggregate for subjects as a whole.  No 
individual subject will be identified in any way.  
16.2. 
Retention of Records 
The investigator should retain all documentation relating to the study (including but not limited 
to ICFs, source documentation, study IP records, eCRFs, and essential documents) for a period 
of at least 2 years after the last marketing application approval or, if not approved, 2 years 
following the discontinuance of the test article for investigation.   
If this requirement differs from any local regulations, the local regulations will take precedence 
unless the local retention policy is less than 2 years.   
At study closure, the investigator must inform BARDA, or designee, of the long-term storage 
location of the study’s records.  Following study closure, the investigator must inform BARDA if 
that location changes (e.g., the investigator leaves the institution where the study was 
conducted).   
No study records will be destroyed without prior authorization from BARDA.  
 


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17. 
PUBLICATION POLICY 
BARDA will be responsible for publication activities and will work with the investigators to 
define the manuscript/presentation development process, the number and order of authors, the 
publication/scientific meeting to which it will be submitted, and other related issues.  BARDA 
has final approval authority over all such issues. 
Data are the property of BARDA and cannot be published without prior authorization from 
BARDA, but data and publication thereof will not be unduly withheld. 
The Assistant Secretary for Preparedness and Response (ASPR) Public Access Plan15 and the 
National Institutes of Health  Public Access Policy16 will apply to this study.  The ASPR-funded 
investigators will be required to submit an electronic version of final, peer-reviewed manuscripts 
resulting from this study to the National Library of Medicine’s PubMed Central upon acceptance 
for publication, to be made publicly available no later than 12 months after the official date of 
publication.   


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18. 
REFERENCES 
1. Centers for Disease Control and Prevention [Internet]. US Department of Health & 
Human Services [updated 2017 Jan 31; cited 2017 Nov 06]. Available from: 
https://www.cdc.gov/anthrax 
2. Library of Congress [Internet].  Congress.gov [updated 2004 Jul 21; cited 2017 Nov 20]. 
Available from:  https://www.congress.gov/bill/108th-congress/senate-bill/15 
3. Brachman P, Friedlander A, Grabenstein J. 2008. Anthrax Vaccine. In: Vaccines, Fifth 
Edition, Plotkin, S.A.: Orenstein W.A. and Offit P.A. (eds.), 111-126. 
4. BioThrax® (Anthrax Vaccine Adsorbed); Suspension for Intramuscular or Subcutaneous 
Injection [package insert]. Lansing, MI: Emergent BioDefense Operations Lansing LLC, 
2015. 
5. Wright JG, Plikaytis BD, Rose CE, et al.  Effect of reduced dose schedules and 
intramuscular injection of anthrax vaccine adsorbed on immunological response and 
safety profile: A randomized trial.  Vaccine, Feb 2014; 32(8):1019-1028.  Supplemental 
material in on line version: http://dx.doi.org/10.1016/j.vaccine.2013.10.039 
6. Krieg  AM. Lymphocyte activation by CpG 7909 dinucleotide motifs in prokaryotic 
DNA. Trends Microbiol. 1996; 4:73-86. 
7. Pisetsky DS. Immune activation by bacterial DNA: a new genetic code. Immunity.1996; 
5:303-310. 
8. Kim SK, Ragupathi G, Musselli C, Choi SJ, Park YS, Livingston PO. Comparison of the 
effect of different immunological adjuvants on the antibody and T-cell response to 
immunization with MUC1-KLH and GD3-KLH conjugate cancer vaccines. Vaccine. 
1999; 18:597-603. 
9. Stewart VA, McGrath S, Krieg AM, Larson NS, Angov E, Smith CL, et al. Activation of 
innate immunity in healthy Macaca mulatta macaques by a single subcutaneous dose of 
GMP CpG 7909: safety data and interferon-inducible protein-10 kinetics for humans and 
macaques. Clin Vaccine Immunol. 2008; 15(2):221-226. 
10. Hopkins RJ, Kalsi G, Montalvo-Lugo VM, Sharma M, Wu Y, Muse DD, et al. 
Randomized, double-blind, active-controlled study evaluating the safety and 
immunogenicity of three vaccination schedules and two dose levels of AV7909 vaccine 
for anthrax post-exposure prophylaxis in healthy adults. Vaccine. 2016 Apr 19; 34(18): 
2096–105. 
11. Hopkins RJ, Daczkowski NF, Kaptur PE, Muse D, Sheldon E, LaForce C, et al. 
Randomized, double-blind, placebo-controlled, safety and immunogenicity study of 4 
formulations of Anthrax Vaccine Adsorbed plus CPG 7909 (AV7909) in healthy adult 
volunteers. Vaccine. 2013 Jun 26; 31(30): 3051-8. 
12. Rynkiewicz D, Rathkopf M, Sim I, Waytes AT, Hopkins RJ, Giri L, et al. Marked 
enhancement of the immune response to BioThrax® (Anthrax Vaccine Adsorbed) by the 
TLR9 agonist CPG 7909 in healthy volunteers. Vaccine. 2011 Aug 26; 29(37): 6313-20. 


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BioThrax and AV7909 
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13. Longstreth J, Skiadopoulos MH, Hopkins RJ. Licensure strategy for pre- and 
post-exposure prophylaxis of biothrax vaccine: the first vaccine licensed using the FDA 
animal rule. Expert Rev Vaccines. 2016 Dec; 15(12): 1467-79. 
14. FDA Guidance for Industry: Toxicity Grading Scale for Healthy Adult and Adolescent 
Volunteers Enrolled in Preventive Vaccine Clinical Trials. September 2007. 
15. Office of the Assistant Secretary for Preparedness and Response [Internet]. Public Access 
to Federally Funded Research: Publications and Data. [cited 2017 May 30]. Available 
from:  https://www.phe.gov/Preparedness/planning/science/Documents/AccessPlan.pdf 
16. National Institutes of Health [Internet].  Public Access Policy. [updated 2014 Mar 18; 
cited 2017 May 30]. Available from:  https://publicaccess.nih.gov/  


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APPENDIX 1. SCHEDULE OF ASSESSMENTS 
Study Visit 
Screen-
ing 
V1 
V2a 
V3 
V4b 
C1c,b 
V5b 
V6b 
C2c,b 
V7b 
V8 b 
V9 
V10 
V11 
V12d 
C3c 
V13 
ETd 
UV 
Study Day 
D-1 to 
D-14 
D1 
D3 
±1 D 
D8 
+2 D 
D15 
-1 to 
+3 D 
D17 
±1 D 
D22 
+2 D 
D29  
-1 to 
+3 D  
D31 
±1 D 
D36 
+2 D 
D43 
-2 to 
+1 D 
D50 
±2 D 
D64 
±3 D 
D85 
±3 D 
D181 
±14 D 
D366 
±7 D 
D394 
±14 D 
N/A 
N/A 
Visit window 
based on actual 
Vaccination Day 
N/A 
N/A 
V1+2
±1 D 
V1+7 
+2 D 
V1+14 
-1 to 
+3 D 
V4+2
±1 D 
V4+7
+2 D 
V4+14
-1 to 
+3 D 
V6+2
±1 D 
V6+7 
+2 D 
V6+14 
-2 to 
+1 D 
V1+49 
±2 D 
V1+63 
±3 D 
V1+84
±3 D 
V1+180 
±14 D 
V1+365 
±7 D 
V6+365 
±14 D 
N/A 
N/A 
Procedure 
 
 
Obtain Informed 
Consent  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclu-
sion Criteria 
Assessmente 
X 
Xf 
 
 
Xf 
 
 
Xf 
 
 
 
 
 
 
 
 
 
 
 
Urine Pregnancy 
Testg 
X 
Xf 
 
 
Xf 
 
 
Xf 
 
 
 
 
 
 
 
 
 
 
 
Physical Exam, 
Medical History, 
Height, and 
Weight 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Symptom-
Directed PE 
 
X 
X 
X 
X 
 
X 
X 
 
X 
 
X 
X 
 
 
 
 
X 
X 
Vital Signsh 
X 
Xf 
X 
X 
Xf 
 
X 
Xf 
 
X 
 
X 
X 
 
 
 
 
X 
X 
Post-vaccination 
Vital Signsi 
 
X 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
HIV/HBV/HCV, 
HbA1C, and 
urine drug screenj, 
k  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECG 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
CBC and 
Chemistryl  
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
Xm 
Xm 
hsCRPa 
 
Xf 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Autoantibodyn 
 
Xf 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
Urinalysiso  
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
Xm 
Xm 


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Study Visit 
Screen-
ing 
V1 
V2a 
V3 
V4b 
C1c,b 
V5b 
V6b 
C2c,b 
V7b 
V8 b 
V9 
V10 
V11 
V12d 
C3c 
V13 
ETd 
UV 
Study Day 
D-1 to 
D-14 
D1 
D3 
±1 D 
D8 
+2 D 
D15 
-1 to 
+3 D 
D17 
±1 D 
D22 
+2 D 
D29  
-1 to 
+3 D  
D31 
±1 D 
D36 
+2 D 
D43 
-2 to 
+1 D 
D50 
±2 D 
D64 
±3 D 
D85 
±3 D 
D181 
±14 D 
D366 
±7 D 
D394 
±14 D 
N/A 
N/A 
Visit window 
based on actual 
Vaccination Day 
N/A 
N/A 
V1+2
±1 D 
V1+7 
+2 D 
V1+14 
-1 to 
+3 D 
V4+2
±1 D 
V4+7
+2 D 
V4+14
-1 to 
+3 D 
V6+2
±1 D 
V6+7 
+2 D 
V6+14 
-2 to 
+1 D 
V1+49 
±2 D 
V1+63 
±3 D 
V1+84
±3 D 
V1+180 
±14 D 
V1+365 
±7 D 
V6+365 
±14 D 
N/A 
N/A 
Immunogenicity 
Profilep 
 
Xf 
 
X 
 
 
X 
Xf 
 
X 
X 
X 
X 
X 
X 
 
X 
Xq 
Xq 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vaccination and 
Post-vaccination 
Observation 
 
X 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Injection Site 
Evaluationr 
 
X 
X 
X 
X 
 
X 
X 
 
X 
X 
 
 
 
 
 
 
 
 
Dispense and or 
Review Diarys 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
Xt 
Xt 
AE/SAE/MAA
E/PIMMC 
assessment 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Prior and 
Concomitant 
Medicationsu 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AE = adverse event; ANA = anti-nuclear antibody; C = Contact; CBC = complete blood count; D = day; dsDNA = double-stranded deoxyribonucleic acid; eCRF = electronic case 
report form; ECG = electrocardiogram; ET = early termination; HbA1C = hemoglobinA1C;  hsCRP = high-sensitivity C-reactive protein; Ig = immunoglobulin; MAAE = 
medically attended adverse event; N/A = not applicable; PA = protective antigen; PE = physical examination; PIMMC = potentially immune-mediated medical condition; SAE = 
serious adverse event; TNA = toxin neutralization antibody; UV = unscheduled visit; V = visit 
a Only for subjects ≥66 years of age.  
b  If a subject discontinues the vaccination series only the following procedures should be completed: 1) Visit 4 and Visit 6 – Symptom-Directed PE, Vital Signs, Review Diary, 
AE/SAE/MAAE/PIMMC assessment, Concomitant Medications, and Immunogenicity Profile (Visit 6 only); 2) Contact 1 and Contact 2 – AE/SAE/MAAE/PIMMC assessment 
and Concomitant Medications; 3) Visit 5 and Visit 7, if a subject was not vaccinated at Visit 4 and/or Visit 6 – Symptom-Directed PE, Vital Signs, AE/SAE/MAAE/PIMMC 
assessment, Concomitant Medications, and Immunogenicity Profile; 4) Visits 5, 6, 7, and 8 – Injection site evaluation for the previous vaccination will be performed as 
applicable. Subjects who become pregnant during the study will only be followed for safety as presented above, and will not provide blood for the Immunogenicity Profile.  
c Telephone visit 
d Early Termination Visit procedures are to be performed for subjects who discontinue study participation prior to Day 64. If subjects are unable to return to the site for an ET 
visit, an attempt should be made to assess AE/SAE/MAAE/PIMMC and pregnancy information via telephone at a minimum. 
e If a subject has a fever at a vaccination visit, they can be re-assessed for eligibility within the visit window (+3 Days) and vaccinated for the 2nd or 3rd IP dose if eligibility criteria 
are met.  
f Prior to vaccination 


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g Only in women of childbearing potential; onsite urine pregnancy test must be performed at Screening and within 24 hours prior to each vaccination, and pregnancy test results 
must be final and negative prior to vaccination.  
h Vital signs include systolic and diastolic blood pressure (sitting for at least 5 minutes), pulse oximeter reading, heart rate, respiratory rate, and oral temperature; obtain vital signs 
before vaccination at Visits 1, 4, and 6. Obtain vital signs prior to any blood draws.  
i Vital signs will be taken 30 minutes (±5 minutes) and 1 hour (±5 minutes) post-vaccination prior to discharge. 
j Includes HIV antibody, hepatitis B surface antigen, and hepatitis C antibody.   
k Urine drug screen includes tests for amphetamines, barbiturates, benzodiazepines, cocaine, tetrahydrocannabinol, methylenedioxymeth-amphetamine, opiates, oxycodone, 
phencyclidine, and propoxyphene.  
l Complete blood count with differential and chemistry including alanine aminotransferase, aspartate aminotransferase, blood urea nitrogen, creatinine, glucose (random, serum),   
and total bilirubin.   
m  If clinically indicated in the investigator’s judgment.  
n Serum samples will be collected and frozen for potential testing of ANA, anti-dsDNA, and rheumatoid factor titers if needed. 
o Urinalysis parameters include appearance, color, pH, specific gravity, ketones, protein, glucose, bilirubin, nitrite, urobilinogen and occult blood. 
p Immunogenicity profile includes serum for TNA and anti-PA IgG determinations; obtain sample prior to each vaccination on vaccination days. 
q Only collect immune profile sample at ET Visit or UV if within the acceptable window for the next expected study visit. 
r The Dose 1 injection site will be examined at Visit 1 (Day 1) at 1 hour (±5 minutes) post-vaccination, Visit 2 (Day 3), Visit 3 (Day 8), and at Visit 4 (Day 15 prior to Dose 2 
vaccination). The Dose 2 injection site and the Dose 1 injection site (contralateral arm, if applicable) will be examined at Visit 4 (Day 15) at 1 hour (±5 minutes) post-
vaccination, Visit 5 (Day 22), and Visit 6 (Day 29 prior to Dose 3 vaccination). The Dose 3 injection site and the Dose 2 injection site (contralateral arm, if applicable) will be 
examined at Visit 6 (Day 29) at 1 hour (±5 minutes) post-vaccination, Visit 7 (Day 36), and Visit 8 (Day 43). If  a visible injection site abnormality is observed, the abnormality 
will be documented with a photograph if the subject consented.  
s Diary cards will be dispensed at Visits 1, 4, and 6. Diary cards 1A, 2A, and 3A will be used to collect solicited and unsolicited local and systemic symptoms, concomitant 
medication changes, and temperatures within 8 days after each vaccination, inclusive of the vaccination day. Diary cards 1B, 2B, and 3B will be used to collect unsolicited local 
and systemic symptoms on days 8-15 after Dose 1 and 2 and days 8-21 after Dose 3.  Study site staff will train each subject at Visit 1 to take their own temperature in front of 
site staff to confirm correct measurement before leaving the clinic and will train subjects on how to measure injection site reactions.    
t If applicable, according to the protocol period, collect and review diary card with subject.  
u Prior medications taken in the past 6 months and vaccinations within 30 days will be assessed at Screening to determine eligibility. Prior medications and vaccinations 
administered within 30 days of Screening will be recorded on the subject’s eCRF. All concomitant medications used by the subject from the time of consent until Visit 9 
(Day 50) will be recorded in the subject’s eCRF.  Following Visit 9 (Day 50), concomitant medications will only be recorded if they are used for the treatment of an MAAE, 
SAE, or PIMMC.  Nonstudy vaccines received through Visit 10 (Day 64) will also be recorded in the subject’s eCRF.  
 


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BioThrax and AV7909 
Protocol: BP-C-17001 Version 2.0 
16 April 2018 
 
73  
APPENDIX 2. TABLES FOR CLINICAL AND LABORATORY 
ABNORMALITIES 
The tables for clinical and laboratory abnormalities are presented in Table 8 and Table 9, 
respectively, according to the FDA Guidance for Industry: Toxicity Grading Scale for Healthy 
Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials 
(September 2007). 
Table 8: 
Tables for Clinical Abnormalities 
Local Reaction to 
Injectable Product 
Mild  
(Grade 1) 
Moderate  
(Grade 2) 
Severe  
(Grade 3) 
Potentially Life 
Threatening  
(Grade 4) 
Pain 
Does not interfere with 
activity 
Repeated use of 
non-narcotic pain 
reliever >24 hours or 
interferes with activity 
Any use of narcotic 
pain reliever or 
prevents daily activity 
Emergency room visit 
or hospitalization 
Tenderness 
Mild discomfort to 
touch 
Discomfort with 
movement 
Significant discomfort 
at rest 
Emergency room visit 
or hospitalization 
Erythema/rednessa 
2.5-5 cm 
5.1-10 cm 
>10 cm 
Necrosis or exfoliative 
dermatitis 
Induration/swellingb 
2.5-5 cm and does not 
interfere with activity 
5.1-10 cm or interferes 
with activity 
>10 cm or prevents 
daily activity 
Necrosis 
a In addition to grading the measured local reaction at the greatest single diameter, the measurement should be 
recorded as a continuous variable. 
b Induration/swelling should be evaluated and graded using the functional scale as well as the actual measurement. 
 
Vital Signsa 
Mild  
(Grade 1) 
Moderate  
(Grade 2) 
Severe  
(Grade 3) 
Potentially Life 
Threatening  
(Grade 4) 
Fever (°C)b 
           (°F)b 
38.0-38.4 
100.4-101.1 
38.5-38.9 
101.2-102.0 
39.0-40 
102.1-104 
>40 
>104 
Tachycardia – beats 
per minute 
101-115 
116-130 
>130 
ER visit or 
hospitalization for 
arrhythmia 
Bradycardia – beats 
per minutec 
50-54 
45-49 
<45 
ER visit or 
hospitalization for 
arrhythmia 
Hypertension (systolic) 
– mm Hg 
141-150 
151-155 
>155 
ER visit or 
hospitalization for 
malignant hypertension 
Hypertension 
(diastolic) – mm Hg 
91-95 
96-100 
>100 
ER visit or 
hospitalization for 
malignant hypertension 
Hypotension (systolic) 
– mm Hg 
85-89 
80-84 
<80 
ER visit or 
hospitalization for 
hypotensive shock 


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Vital Signsa 
Mild  
(Grade 1) 
Moderate  
(Grade 2) 
Severe  
(Grade 3) 
Potentially Life 
Threatening  
(Grade 4) 
Respiratory rate – 
breaths per minute 
17-20 
21-25 
>25 
Intubation 
ER = emergency room 
a Subject should be at rest for all vital sign measurements. 
b Oral temperature; no recent hot or cold beverages or smoking. 
c When resting heart rate is between 60 to 100 beats per minute. Use clinical judgment when characterizing 
bradycardia among some healthy subject populations, for example, conditioned athletes. 
 
Systemic (General) 
Mild  
(Grade 1) 
Moderate  
(Grade 2) 
Severe  
(Grade 3) 
Potentially Life 
Threatening  
(Grade 4) 
Nausea/vomiting 
No interference with 
activity or 1-2 
episodes/24 hours 
Some interference with 
activity or >2 
episodes/24 hours 
Prevents daily activity, 
requires outpatient IV 
hydration 
ER visit or 
hospitalization for 
hypotensive shock 
Diarrhea 
2-3 loose stools or 
<400 g/24 hours 
4-5 stools or 400-800 
g/24 hours 
6 or more watery 
stools or >800 
g/24 hours or requires 
outpatient IV hydration 
ER visit or 
hospitalization 
Headache 
No interference with 
activity 
Repeated use of 
non-narcotic pain 
reliever >24 hours or 
some interference with 
activity 
Significant; any use of 
narcotic pain reliever 
or prevents daily 
activity 
ER visit or 
hospitalization  
Fatigue 
No interference with 
activity 
Some interference with 
activity 
Significant; prevents 
daily activity 
ER visit or 
hospitalization 
Myalgia 
No interference with 
activity 
Some interference with 
activity 
Significant; prevents 
daily activity 
ER visit or 
hospitalization 
Illness or clinical 
adverse event (as 
defined according to 
applicable regulations) 
No interference with 
activity 
Some interference with 
activity not requiring 
medical intervention 
Prevents daily activity 
and requires medical 
intervention 
ER visit or 
hospitalization 
ER = emergency room; IV = intravenous 
 
Table 9: 
Tables for Laboratory Abnormalities 
Seruma 
Mild  
(Grade 1) 
Moderate  
(Grade 2) 
Severe  
(Grade 3) 
Potentially Life 
Threatening 
(Grade 4)b 
Sodium – hyponatremia 
mEq/L 
132-134 
130-131 
125-129 
<125 
Sodium – hypernatremia 
mEq/L 
144-145 
146-147 
148-150 
>150 
Potassium – hyperkalemia 
mEq/L 
5.1-5.2 
5.3-5.4 
5.5-5.6 
>5.6 
Potassium – hypokalemia 
mEq/L 
3.5-3.6 
3.3-3.4 
3.1-3.2 
<3.1 


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Seruma 
Mild  
(Grade 1) 
Moderate  
(Grade 2) 
Severe  
(Grade 3) 
Potentially Life 
Threatening 
(Grade 4)b 
Glucose – hypoglycemia 
mg/dL 
65-69 
55-64 
45-54 
<45 
Glucose – hyperglycemia 
Fasting - mg/dL 
Random - mg/dL 
 
100-110 
110-125 
 
111-125 
126-200 
 
>125 
>200 
Insulin requirements 
or hyperosmolar coma 
Blood urea nitrogen mg/dL 
23-26 
27-31 
>31 
Requires dialysis 
Creatinine mg/dL 
1.5-1.7 
1.8-2.0 
2.1-2.5 
>2.5 or requires 
dialysis 
Calcium-hypocalcemia 
mg/dL 
8.0-8.4 
7.5-7.9 
7.0-7.4 
<7.0 
Calcium-hypercalcemia 
mg/dL 
10.5-11.0 
11.1-11.5 
11.6-12.0 
>12.0 
Magnesium- 
hypomagnesemia mg/dL 
1.3-1.5 
1.1-1.2 
0.9-1.0 
<0.9 
Phosphorus – 
hypophosphatemia mg/dL 
2.3-2.5 
2.0-2.2 
1.6-1.9 
<1.6 
CPK - mg/dL 
1.25-1.5 × ULN 
1.6-3.0 × ULN 
3.1-10 × ULN 
>10 × ULN 
Albumin – 
hypoalbuminemia g/dL 
2.8-3.1 
2.5-2.7 
<2.5 
– 
Total protein – 
hypoproteinemia g/dL 
5.5-6.0 
5.0-5.4 
<5.0 
– 
Alkaline phosphate – 
increase by factor 
1.1-2.0 × ULN 
2.1-3.0 × ULN 
3.1-10 × ULN 
>10 × ULN 
Liver function tests – ALT, 
AST increase by factor 
1.1-2.5 × ULN 
2.6-5.0 × ULN 
5.1-10 × ULN 
>10 × ULN 
Bilirubin – when 
accompanied by any 
increase in liver function 
test increase by factor 
1.1-1.25 × ULN 
1.26-1.5 × ULN 
1.51-1.75 × ULN 
>1.75 × ULN 
Bilirubin – when liver 
function test is normal; 
increase by factor 
1.1-1.5 × ULN 
1.6-2.0 × ULN 
2.0-3.0 × ULN 
>3.0 × ULN 
Cholesterol mg/dL 
201-210 
211-225 
>226 
- 
Pancreatic enzymes – 
amylase, lipase 
1.1-1.5 × ULN 
1.6-2.0 × ULN 
2.1-5.0 × ULN 
>5.0 × ULN 
ALT = alanine aminotransferase; AST = aspartate aminotransferase; CPK = creatine phosphokinase; ULN = upper 
limit of normal. 
a The laboratory values provided in the tables serve as guidelines and are dependent upon institutional normal 
parameters.  Institutional normal reference ranges should be provided to demonstrate that they are appropriate. 
b The clinical signs or symptoms associated with laboratory abnormalities might result in characterization of the 
laboratory abnormalities as Potentially Life Threatening (Grade 4).  For example, a low sodium value that falls 
within a Grade 3 parameter (125-129 mE/L) should be recorded as a Grade 4 hyponatremia event if the subject had 
a new seizure associated with the low sodium value. 


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76  
Hematologya 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Potentially Life 
Threatening 
(Grade 4) 
Hemoglobin (female) – 
g/dL 
11.0-12.0 
9.5-10.9 
8.0-9.4 
<8.0 
Hemoglobin (female) 
change from baseline value 
– g/dL 
Any decrease – 1.5 
1.6-2.0 
2.1-5.0 
>5.0 
Hemoglobin (male) – g/dL 
12.5-13.5 
10.5-12.4 
8.5-10.4 
<8.5 
Hemoglobin (male) change 
from baseline value – g/dL 
Any decrease – 1.5 
1.6-2.0 
2.1-5.0 
>5.0 
WBC increase – cell/mm3 
10,800-15,000 
15,001-20,000 
20,001-25,000 
>25,000 
WBC decrease – cell/mm3 
2,500-3,500 
1,500-2,499 
1,000-1,499 
<1,000 
Lymphocytes decrease – 
cell/mm3 
750-1 000 
500-749 
250-499 
<250 
Neutrophils decrease – 
cell/mm3 
1,500-2,000 
1,000-1,499 
500-999 
<500 
Eosinophils – cell/mm3 
650-1 500 
1501-5 000 
>5 000 
Hypereosinophilic 
Platelets decrease – 
cell/mm3 
125,000-140,000 
100,000-124,000 
25,000-99,000 
<25,000 
PT – increase by factor 
1.0-1.10 × ULN 
1.11-1.20 × ULN 
1.21-1.25 × ULN 
>1.25 x ULN 
PTT – increase by factor 
1.0-1.2 × ULN 
1.21-1.4 × ULN 
1.41-1.5 × ULN 
>1.5 x ULN 
Fibrinogen increase – 
mg/dL 
400-500 
501-600 
>600 
– 
Fibrinogen decrease – 
mg/dL 
150-200 
125-149 
100-124 
<100 or associated 
with gross bleeding or 
disseminated 
intravascular 
coagulation 
PPT = partial thromboplastin time; PT = prothrombin time; ULN =  upper limit of normal; WBC = white blood cell. 
a The laboratory values provided in the tables serve as guidelines and are dependent upon institutional normal 
parameters. Institutional normal reference ranges should be provided to demonstrate that they are appropriate. 
 
Urinea 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Potentially Life 
Threatening 
(Grade 4) 
Protein 
Trace 
1+ 
2+ 
Hospitalization or 
dialysis 
Glucose 
Trace 
1+ 
2+ 
Hospitalization or 
hyperglycemia 
Blood (microscopic) – red 
blood cells per high power 
field 
1-10 
11-50 
>50 and/or gross blood 
Hospitalization or 
packed red blood cells 
transfusion 
a The laboratory values provided in the tables serve as guidelines and are dependent upon institutional normal 
parameters.  Institutional normal reference ranges should be provided to demonstrate that they are appropriate.  


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Protocol: BP-C-17001 Version 2.0 
16 April 2018 
 
77  
APPENDIX 3. LIST OF POTENTIALLY IMMUNE-MEDIATED 
MEDICAL CONDITIONS 
Gastrointestinal disorders 
 Celiac disease 
 Crohn’s disease 
 Ulcerative colitis 
 Ulcerative proctitis 
 Microscopic colitis 
 Autoimmune pancreatitis 
Hematologic disorders 
 Pernicious anemia 
 Autoimmune thrombocytopenia 
 Autoimmune hemolytic anemia 
 Autoimmune neutropenia 
 Autoimmune pancytopenia 
Liver disorders 
 Autoimmune cholangitis 
 Autoimmune hepatitis 
 Primary biliary cirrhosis 
 Primary sclerosing cholangitis 
Metabolic/Endocrine diseases 
 Addison’s disease 
 Autoimmune thyroiditis (including Hashimoto thyroiditis) 
 Diabetes mellitus type I 
 Grave's or Basedow’s disease 
 Polyglandular autoimmune syndrome 
 Autoimmune hypophysitis 
Musculoskeletal disorders 
 Antisynthetase syndrome 
 Dermatomyositis 
 Juvenile chronic arthritis (including Still’s disease) 
 Mixed connective tissue disorder 


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16 April 2018 
 
78  
 Polymyalgia rheumatic 
 Polymyositis 
 Psoriatic arthropathy 
 Relapsing polychondritis 
 Rheumatoid arthritis 
 Scleroderma, including diffuse systemic form and CREST (calcinosis, Raynaud 
phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasia) syndrome 
 Spondyloarthritis, including ankylosing spondylitis, reactive arthritis (Reiter's Syndrome) 
and undifferentiated spondyloarthritis 
 Systemic lupus erythematosus 
 Systemic sclerosis 
Neuroinflammatory disorders 
 Acute disseminated encephalomyelitis, including site-specific variants (e.g., 
non-infectious encephalitis, encephalomyelitis, myelitis, radiculomyelitis 
 Cranial nerve disorders, including paralyses/paresis (e.g., Bell’s palsy) 
 Guillain-Barré syndrome, including Miller Fisher syndrome and other variants 
 Immune-mediated peripheral neuropathies and plexopathies, including chronic 
inflammatory demyelinating polyneuropathy, multifocal motor neuropathy and 
polyneuropathies associated with monoclonal gammopathy 
 Multiple sclerosis 
 Narcolepsy 
 Optic neuritis 
 Transverse myelitis 
 Myasthenia gravis 
 Lambert-Eaton syndrome 
Skin disorders 
 Alopeci areata 
 Autoimmune bullous skin diseases, including pemphigus, pemphigoid, and dermatitis 
herpetiformis 
 Cutaneous lupus erythematosus 
 Erythema nodosum 
 Morphoea 
 Lichen planus 
 Psoriasis 
 Sweet’s syndrome 
 Vitiligo 


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BioThrax and AV7909 
Protocol: BP-C-17001 Version 2.0 
16 April 2018 
 
79  
 Stevens-Johnson syndrome 
Vasculitides 
 Large vessel vasculitis including giant cell arteritis such as Takayasu's arteritis and 
temporal arteritis 
 Medium sized and/or small vessel vasculitis including polyarteritis nodosa, Kawasaki's 
disease, microscopic polyangiitis, Wegener's granulomatosis, Churg–Strauss syndrome 
(allergic granulomatous angiitis), Buerger’s disease (thromboangiitis obliterans), 
necrotizing vasculitis and antineutrophil cytoplasmic antibody (ANCA)-positive 
vasculitis (type unspecified), Henoch-Schonlein purpura, Behcet's syndrome, 
leukocytoclastic vasculitis 
Others 
 Antiphospholipid syndrome 
 Autoimmune glomerulonephritis (including IgA nephropathy, glomerulonephritis rapidly 
progressive, membranous glomerulonephritis, membranoproliferative glomerulonephritis, 
and mesangioproliferative glomerulonephritis) 
 Autoimmune myocarditis/cardiomyopathy 
 Goodpasture syndrome 
 Idiopathic pulmonary fibrosis 
 Raynaud’s phenomenon 
 Sarcoidosis 
 Sjögren’s syndrome 
 Uveitis 
 

SAP_001.pdf: 
HHS/ASPR/BARDA 
 
BioThrax and AV7909 
SAP: BP-C-17001 Version 2.0 
 
11 April 2019 
CONFIDENTIAL AND PROPRIETARY  
1 
 
STATISTICAL ANALYSIS PLAN 
PHASE II 
 
VERSION: 2.0 
DATE OF PLAN: 
APRIL 11, 2019 
 
BASED ON: 
Protocol V2.0 
CRF V2.0 
 
STUDY DRUG: 
BioThrax® 
AV7909 
PROTOCOL NUMBER: 
BP-C-17001 
STUDY TITLE: 
Randomized, Active-Comparison, Double-Blind, Phase 2 Study to Assess the Safety and 
Immunogenicity of Anthrax Vaccine Adsorbed (BioThrax®) without and with CPG 7909 
Adjuvant (AV7909 Anthrax Vaccine), Using a Post Exposure Prophylaxis Dosing Regimen in 
Adults 66 Years of Age or Older in Stable Health in Comparison to Adults 18 50 Years of Age 
in Stable Health 
SPONSOR: 
Biomedical Advanced Research and Development Authority (BARDA) 
 
 
 
This study is being conducted in compliance with good clinical practice, including the archiving 
of essential documents. 
 


HHS/ASPR/BARDA 
 
BioThrax and AV7909 
SAP: BP-C-17001 Version 2.0 
 
11 April 2019 
CONFIDENTIAL AND PROPRIETARY 
2 
 
 
 
 
 
  
 
SIGNATURE PAGE 
This document has been reviewed and accepted by: 
 
 
 
 
 
 
 
Rho 
 
Signature 
 
Date 
 
 
 
 
 
 
 
Biomedical Advanced Research and  
Development Authority (BARDA) 
 
Signature 
 
Date 
 
Document History 
Version 
Date 
Change(s) 
Author 
1.0 
28 Jun 2018 
Initial Version 
 
2.0 
11 Apr 2019 
Added definitions for seroconversion 
using TNA ED50 and ELISA anti-PA 
IgG; replace LLOD/ULOD with 
LLOQ/ULOQ; updated IPPP 
population protocol deviation criteria; 
added modified IPPP and 
corresponding analyses; added a 
column for MIPPP visit windows; 
deleted imputation methods for 
immunogenicity data; fixed minor 
grammatical errors; added exploratory 
immunogenicity comparisons; added 
AE tables by dose; modified blinding of 
AE and other tables for interim 
analysis; added solicited systemic 
reactogenicity symptoms by 
relationship tables; updated wording of 
safety and IFAP populations to include 
incorrectly randomized subjects; 
updated list of interim analysis tables; 
added clarification of SMC interim 
report; added criteria for using low 
level term instead of preferred term for 
some events 
 


HHS/ASPR/BARDA 
 
BioThrax and AV7909 
SAP: BP-C-17001 Version 2.0 
 
11 April 2019 
CONFIDENTIAL AND PROPRIETARY 
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TABLE OF CONTENTS 
STATISTICAL ANALYSIS PLAN ................................................................................................1 
SIGNATURE PAGE .......................................................................................................................2 
LIST OF TABLES ...........................................................................................................................7 
1. 
LIST OF ABBREVIATIONS .......................................................................................8 
2. 
INTRODUCTION ......................................................................................................10 
3. 
STUDY OBJECTIVES ..............................................................................................11 
3.1. 
Primary Objectives .....................................................................................................11 
3.1.1. 
Safety ..........................................................................................................................11 
3.1.2. 
Immunogenicity ..........................................................................................................11 
3.2. 
Secondary Objective ...................................................................................................11 
3.2.1. 
Safety ..........................................................................................................................11 
3.2.2. 
Immunogenicity ..........................................................................................................11 
4. 
STUDY DESIGN .......................................................................................................13 
4.1. 
Sample Size Justification ............................................................................................14 
5. 
STUDY DURATION AND VISIT SCHEDULE ......................................................16 
6. 
CLINICAL ASSESSMENTS .....................................................................................17 
6.1. 
Screening and Baseline Assessments .........................................................................17 
6.2. 
Post-Baseline Assessments .........................................................................................17 
6.3. 
Final Evaluation or Early Termination Visit ..............................................................18 
7. 
DEFINITIONS AND CONVENTIONS ....................................................................19 
7.1. 
General Summary Table and Individual Subject Data Listing Considerations ..........19 
7.1.1. 
Imputation of Missing Data ........................................................................................20 
7.2. 
Calculations Using Dates ............................................................................................20 
7.3. 
Baseline .......................................................................................................................20 
7.3.1. 
Visit Windows Relative to the First Dose of Study Medication ................................20 
7.4. 
Analysis Populations ..................................................................................................22 
7.4.1. 
Screen Failures ............................................................................................................22 
7.4.2. 
Randomized Population ..............................................................................................22 
7.4.3. 
Safety Population ........................................................................................................22 
7.4.4. 
Immunogenicity Full Analysis Population .................................................................22 


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7.4.5. 
Immunogenicity Per Protocol Population ...................................................................23 
7.4.6. 
Modified Immunogenicity Per Protocol Population ...................................................23 
8. 
DATA PRESENTATIONS AND DATA MANAGEMENT .....................................24 
8.1. 
Data Presentations ......................................................................................................24 
8.2. 
Data Management .......................................................................................................24 
8.3. 
General Post Text Summary Table and Individual Subject Data Listing 
Format Considerations ................................................................................................24 
9. 
SUBJECT ACCOUNTING AND DEMOGRAPHIC PROFILE OF 
SCREEN FAILURES .................................................................................................25 
9.1. 
Subject Accounting by Treatment Group and Sex .....................................................25 
9.2. 
Subject Distribution by Site ........................................................................................25 
9.3. 
Screen Failures ............................................................................................................25 
10. 
SUBJECT DISPOSITION ..........................................................................................26 
11. 
BASELINE SUBJECT DATA ...................................................................................27 
11.1. 
Baseline Demographic and Physical Characteristics ..................................................27 
11.1.1. 
Listing of Subject Inclusion and Exclusion Criteria ...................................................27 
11.2. 
Medical History and Medical Conditions Present at Entry ........................................27 
11.3. 
Prior Medication History and Medications Present at Entry ......................................27 
11.4. 
Screening Laboratory Data .........................................................................................28 
12. 
IMMUNOGENICITY ................................................................................................29 
12.1. 
General Considerations ...............................................................................................29 
12.2. 
Statement of the Null and Alternate Hypotheses ........................................................29 
12.3. 
Subgroup Analyses .....................................................................................................30 
12.4. 
Multiple Comparisons and Multiplicity ......................................................................30 
12.5. 
Analysis of the Primary Immunogenicity Endpoint ...................................................30 
12.6. 
Analysis of the Secondary Immunogenicity Endpoints ..............................................30 
12.6.1. 
Presentation of the Secondary Immunogenicity Results ............................................31 
12.6.1.1. 
Antibody Levels ..........................................................................................................31 
12.6.1.2. 
Seroprotection and Seroconversion Rates ..................................................................31 
12.7. 
Analysis of the Exploratory Immunogenicity Endpoints ...........................................32 
12.7.1. 
Antibody level correlations .........................................................................................32 
12.7.2. 
Additional pairwise comparisons ...............................................................................32 
13. 
SAFETY AND TOLERABILITY ..............................................................................33 


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13.1. 
Overall Summary of Tolerability ................................................................................33 
13.2. 
Adverse Event Preferred Term and System Organ Class Summary Tables ...............33 
13.2.1. 
Summaries of Adverse Event Incidence Rates for All Subjects .................................34 
13.2.2. 
Missing and Partial AE Onset Dates ..........................................................................35 
13.2.3. 
Early Termination of Investigational Product due to Adverse Event, Subject 
Study Withdrawal due to Adverse Event, and Death .................................................36 
13.3. 
Pregnancy Monitoring and Assessment ......................................................................36 
13.4. 
Safety Endpoint Analyses ...........................................................................................36 
13.4.1. 
General Considerations ...............................................................................................36 
13.4.2. 
Statement of the Null and Alternate Hypotheses ........................................................36 
13.4.3. 
Subgroup Analyses .....................................................................................................36 
13.4.4. 
Analysis of the Primary Safety Endpoint ...................................................................36 
13.4.5. 
Analysis of the Secondary Safety Endpoints ..............................................................37 
13.4.6. 
Summary of Reasons for Safety Non-evaluability/Exclusion from Safety 
Analyses ......................................................................................................................37 
13.5. 
Investigational Product Administration Compliance ..................................................37 
13.6. 
Concomitant and Other Medications ..........................................................................37 
13.6.1. 
Missing and Partial Concomitant and Other Medication Start and Stop Dates ..........38 
13.7. 
Investigational Product Administration Site Examination .........................................38 
13.8. 
Diary Card Measurements ..........................................................................................39 
13.9. 
Clinical Laboratory Data ............................................................................................39 
13.10. 
Vital Signs ..................................................................................................................39 
13.11. 
Physical Examination .................................................................................................40 
13.12. 
Other Safety Assessments ...........................................................................................40 
13.13. 
Subject Study Withdrawal Status ...............................................................................40 
14. 
PROTOCOL DEVIATIONS ......................................................................................41 
15. 
MAINTAINING THE BLIND ...................................................................................42 
15.1. 
Immunogenicity Data .................................................................................................42 
16. 
INTERIM ANALYSES ..............................................................................................43 
17. 
SAFETY MONITORING COMMITTEE MEETINGS ............................................44 
18. 
CHANGES TO COMPLETED REPORTS ................................................................45 
19. 
REFERENCES ...........................................................................................................46 
20. 
APPENDIX .................................................................................................................47 


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20.1. 
Table of Contents for Data Display Specifications ....................................................47 


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11 April 2019 
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LIST OF TABLES 
Table 1: 
Study Groups ..............................................................................................................13 
Table 2: 
Probability of Observing at Least 1 Safety Event of Interest under Different 
True Event Rates .........................................................................................................14 
Table 3: 
Power for Detecting a Lower 95% Confidence Limit of ≥40% about an 
Observed Seroprotection Rate ....................................................................................15 
Table 4: 
Visit Schedule .............................................................................................................21 


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1. 
LIST OF ABBREVIATIONS 
Abbreviation 
Term 
ADaM 
Analysis Data Model 
AE 
adverse event 
ATC 
Anatomical Therapeutic Chemical 
AV7909 
AV7909 Anthrax Vaccine 
BARDA 
Biomedical Advanced Research and Development Authority 
BMI 
body mass index 
B-SAFE 
BARDA Securing Anthrax Immunity For the Elderly 
CI 
confidence interval 
CSR 
Clinical Study Report 
DOB 
date of birth 
DSMP 
Data Safety Monitoring Plan 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
ED50 
effective dilution resulting in 50% neutralization 
EDC 
electronic data capture 
ELISA 
enzyme-linked immunosorbent assay 
GM 
geometric mean 
H0
null hypothesis 
HA
alternative hypothesis 
HbA1C 
hemoglobin A1C 
HBV 
hepatitis B vaccine 
HCV 
hepatitis C vaccine 
HEENT 
head, eyes, ears, nose and throat 
HIV 
human immunodeficiency virus 
hs-CRP 
high-sensitivity C-reactive protein 
ID 
identification number 
IFAP 
immunogenicity full analysis population 
IgG 
immunoglobulin G 
IM 
intramuscular 
IP 
investigational product 


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IPPP 
immunogenicity per protocol population 
LLOQ 
lower limit of quantitation 
MAAE 
medically attended adverse event 
max 
maximum 
MCMC 
Markov chain Monte Carlo 
MedDRA 
Medical Dictionary for Regulatory Activities Terminology 
min 
minimum 
MIPPP 
modified immunogenicity per protocol population 
NF50 
50% neutralization factor 
OC 
observed cases 
PA 
protective antigen 
PIMMC 
potentially immune-mediated medical condition 
PT 
preferred term 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SC 
subcutaneous 
SCR 
seroconversion rate 
SD 
standard deviation 
SDTM 
Study Data Tabulation Model 
SI 
International System of Units 
SMC 
Safety Monitoring Committee 
SOC 
system organ class 
SPR 
seroprotection rate 
TNA 
toxin neutralization antibody 
ULOQ 
upper limit of quantitation 
WHO 
World Health Organization 


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2. 
INTRODUCTION 
The purpose of this statistical analysis plan (SAP) is to describe the planned analyses and data 
displays to be included in the interim analysis and Clinical Study Report (CSR) for Protocol 
BP-C-17001.  Additionally, this document provides details on study populations and on how the 
variables will be derived, how missing data will be handled as well as details on statistical 
methods to be used to analyze the safety and immunogenicity data 
All decisions regarding final analysis, as defined in this SAP document, will be made prior to 
Database Freeze (unblinding) of the study data. Further information can be found in the protocol. 
Deviations from the final approved SAP will be noted in the CSR. 
If additional analyses are required to supplement the planned analyses described in this SAP, 
they will be identified in the CSR.  Table, figure, and listing specifications are provided in 
separate documents. 


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3. 
STUDY OBJECTIVES 
3.1. 
Primary Objectives 
3.1.1. 
Safety 

To evaluate safety and reactogenicity, as determined by solicited local and systemic
reactogenicity symptoms (within 8 days after each vaccination, inclusive of the
vaccination day, excluding reactogenicity on the contralateral arm), of BioThrax or
AV7909 administered to adults ≥66 years of age.
3.1.2. 
Immunogenicity 

To evaluate the seroprotection, defined as toxin neutralization antibody (TNA) 50%
neutralization factor (NF50) ≥0.56, rate at Day 64 for BioThrax or AV7909 administered
to adults ≥66 years of age.
3.2. 
Secondary Objective 
3.2.1. 
Safety 

To evaluate the occurrence of treatment-emergent unsolicited adverse events (AEs)
(defined as all AEs other than solicited local and systemic reactogenicity symptoms),
serious adverse events (SAEs), and medically attended adverse events (MAAEs),
including potentially immune-mediated medical conditions (PIMMCs) from the time of
the first dose of study investigational product (IP) through 12 months following the last
dose of study IP.

To evaluate the occurrence of solicited local reactogenicity symptoms on the contralateral
arm (within 8 days after each vaccination, inclusive of the vaccination day).
3.2.2. 
Immunogenicity 

To assess the TNA NF50 antibody levels, seroprotection rates, and seroconversion
(defined as a ≥4-fold increase over baseline levels, or a ≥4-fold increase over the lower
limit of quantitation [LLOQ] if the baseline value is < LLOQ) rates for each study group
at each applicable timepoint through Day 394.

To assess the TNA effective dilution resulting in 50% neutralization (ED50) antibody
levels and seroconversion rates (defined as a ≥4-fold increase over baseline levels, or a
≥4-fold increase over LLOQ if the baseline value is < LLOQ) for each study group at
each applicable timepoint through Day 394.

To assess the enzyme-linked immunosorbent assay (ELISA) anti-protective antigen (PA)
immunoglobulin G (IgG) antibody levels and seroconversion (defined as a ≥4-fold
increase over baseline levels, or a ≥4-fold increase over LLOQ if the baseline value is <
LLOQ) rates for each study group at each applicable timepoint through Day 394.


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
To compare the TNA NF50 antibody levels, seroprotection rates, and seroconversion rates
through Day 394 between younger adults (18 through 50 years) and older adults
(≥66 years of age) within the following groups at each applicable timepoint:
1. BioThrax given at Days 1, 15, and 29
2. AV7909 given at Days 1 and 15 and placebo given at Day 29

To compare the TNA ED50 antibody levels and seroconversion rates through Day 394
between younger adults (18 through 50 years) and older adults (≥66 years of age) within
the following groups at each applicable timepoint:
1. BioThrax given at Days 1, 15, and 29
2. AV7909 given at Days 1 and 15 and placebo given at Day 29

To compare the ELISA anti-PA IgG antibody levels and seroconversion rates through
Day 394 between younger adults (18 through 50 years) and older adults (≥66 years of
age) within the following groups at each applicable timepoint:
1. BioThrax given at Days 1, 15, and 29
2. AV7909 given at Days 1 and 15 and placebo given at Day 29


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4. 
STUDY DESIGN 
This is a phase 2, randomized, active-controlled, double-blinded, multi-site study to assess the 
safety and immunogenicity of BioThrax and AV7909 using a PEP dosing regimen in adults 
≥66 years of age in stable health.  The safety and immunogenicity profile of BioThrax and 
AV7909 in adults ≥66 years of age will also be compared to the safety and immunogenicity 
profile of subjects 18 through 50 years of age in stable health.  The main study goal is to 
determine optimal dosing for AV7909.   
Approximately 300 male and nonpregnant female adults (200 aged ≥66 years and 100 aged 18 
through 50 years, inclusive) will be enrolled in the study.   
After screening, subjects meeting all of the inclusion criteria and none of the exclusion criteria 
will be randomized to receive either BioThrax or AV7909.  Randomization will be stratified by 
sex and age (18-50, 66-74, and ≥75 years).  Subjects ≥66 years of age will be randomized 1:1:1:1 
within stratum across 4 treatment arms (approximately 50 subjects per group), and subjects 18 
through 50 years of age will be randomized 1:1 within stratum across 2 treatment arms 
(approximately 50 subjects per group) as specified in Table 1.  Once randomized, subjects will 
receive 3 IP administrations, each separated by approximately 14 days, on Day 1, Day 15, and 
Day 29, based on their assigned treatment arm.   
Table 1: 
Study Groups 
Study 
Group 
Number of 
Subjects 
Age 
Group 
Arm 
Investigational 
Product 
Route 
Dose 1 
Day 1 
Dose 2 
Day 15 
Dose 3 
Day 29 
Group 1 
50 
Age ≥66 
1 
BioThrax 
SC 
BioThrax 
BioThrax 
BioThrax 
Group 2 
50 
Age ≥66 
2 
AV7909 
IM 
AV7909 
AV7909 
AV7909 
Group 3 
50 
Age ≥66 
3 
AV7909 
IM 
AV7909 
AV7909 
Placebo 
Group 4 
50 
Age ≥66 
4 
AV7909 
IM 
AV7909 
Placebo 
AV7909 
Group 5 
50 
Age 18-50 
1 
BioThrax 
SC 
BioThrax 
BioThrax 
BioThrax 
Group 6 
50 
Age 18-50 
3 
AV7909 
IM 
AV7909 
AV7909 
Placebo 
Note: SC = subcutaneous; IM = intramuscular 
Immunogenicity assessments will include TNA NF50, TNA ED50, and ELISA anti-PA IgG 
antibody levels. 
Safety assessments will be based on solicited AEs (local and systemic reactogenicity symptoms) 
occurring within 8 days of each IP administration, treatment-emergent unsolicited AEs occurring 
through Day 50, and treatment-emergent SAEs, MAAEs, and PIMMCs throughout the study. 
Safety for each subject will be assessed from the time of the first dose of IP through 12 months 
following the last dose of IP.   
The expected study duration is approximately 14 months per subject. 


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4.1. 
Sample Size Justification 
The sample size for this study is approximately 300 subjects: 200 subjects ≥66 years of age 
(older cohort) and 100 subjects 18 through 50 years of age (younger cohort).  Approximately 
50 subjects will be randomized into each of 6 study groups. 
The proposed sample size for this study is based on previous experience with similar BioThrax 
studies in individuals aged 18 to 65 years.  The previous studies had study arms of similar size 
that proved to be sufficient to allow the collection of meaningful data, especially with respect to 
local and systemic reactogenicity symptoms and antibody levels.  
Though no hypothesis testing will be performed as part of the primary analyses, Table 2 and 
Table 3 show the probability of observing a safety event and statistical power to detect crossing 
a threshold in seroprotection rate, respectively, under a variety of hypothetical scenarios.  Within 
each table, separate calculations are performed for each pooled group of interest.   
Probabilities of detecting a safety event were calculated using the binomial distribution 
(Table 2). 
Table 2: 
Probability of Observing at Least 1 Safety Event of Interest under Different 
True Event Rates 
True Probability of a 
Safety Event of Interest 
Per Study 
Group (N=50) 
Pooled Study 
Groups 
(N=100) 
Pooled ≥66 
Years of Age 
Cohort 
(N=200) 
Overall 
(N=300) 
0.0001 
0.005 
0.010 
0.020 
0.030 
0.005 
0.222 
0.394 
0.633 
0.778 
0.01 
0.395 
0.634 
0.866 
0.951 
0.02 
0.636 
0.867 
0.982 
0.998 
0.05 
0.923 
0.994 
>0.999 
>0.999 
0.1 
0.995 
>0.999 
>0.999 
>0.999 
A lower bound of 40% is considered to be a meaningful threshold of success for the 
seroprotection rate for BioThrax1.  Assuming a one-sided alpha level of 0.025, an exact 
binomial test was used to calculate the power to detect the lower bound of an exact 95% 
confidence interval (CI) about an observed seroprotection rate being ≥40%, using sample size 
and hypothetical true seroprotection rate scenarios shown in Table 3. 


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Table 3: 
Power for Detecting a Lower 95% Confidence Limit of ≥40% about an 
Observed Seroprotection Rate 
Hypothetical 
True 
Seroprotection 
Rate (%) 
Per Study Group 
(N=50) 
Pooled Study 
Groups (N=100) 
Pooled ≥66 Years 
of Age Cohort 
(N=200) 
Overall (N=300) 
50 
0.240 
0.460 
0.782 
0.926 
60 
0.766 
0.973 
>0.999 
>0.999 
70 
0.988 
>0.999 
>0.999 
>0.999 
80 
>0.999 
>0.999 
>0.999 
>0.999 
 


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5. 
STUDY DURATION AND VISIT SCHEDULE 
Subjects will receive 3 study IP administrations, separated by approximately 14 days, and will be 
followed for 12 months after their last IP dose.  The expected study duration is approximately 
14 months per subject. 


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6. 
CLINICAL ASSESSMENTS 
6.1. 
Screening and Baseline Assessments 
Screening and baseline assessments include: 
1. Obtain informed consent 
2. Inclusion/exclusion criteria assessment, including the following: 
 urine pregnancy test (for females) 
 urine drug screening 
 hemoglobin A1C (HbA1C) >7.0% 
 human immunodeficiency virus (HIV), hepatitis B vaccine (HBV) and hepatitis C 
vaccine (HCV) screening 
3. Physical exam, including vital signs assessment 
4. Medical history, medication use and immunization history (within 30 days of screening) 
5. Blood and urine samples for clinical laboratory assessments (hematology, chemistry and 
urinalysis) 
6. Blood samples for baseline immunogenicity assessment parameters 
7. Autoantibody assay 
8. High-sensitivity C-reactive protein (hs-CRP) assay (for subjects ≥66 years of age) 
9. Electrocardiogram (ECG) 
6.2. 
Post-Baseline Assessments 
Post-baseline assessments include (not all are performed at each visit): 
1. Inclusion/exclusion criteria assessment for subsequent IP administrations, including urine 
pregnancy test for females 
2. Symptom-directed physical exam, including vital signs assessment 
3. Changes in medication use and immunization use 
4. Blood and urine samples for clinical laboratory assessments (hematology, chemistry and 
urinalysis) 
5. Blood samples for post-baseline immunogenicity assessment parameters 
6. Autoantibody assay 
7. High-sensitivity C-reactive protein (hs-CRP) assay (for subjects ≥66 years of age) 
8. ECG 
9. AE/SAE/MAAE/PIMMC assessment 
10. Diary dispensation and collection/review for AEs/SAEs/MAAEs/PIMMCs 


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11. Post-IP administration exam for local reactogenicity symptoms and vital signs 
6.3. 
Final Evaluation or Early Termination Visit 
Final evaluation assessments at Visit 13 (Day 394) include: 
1. Changes in medication use and immunization use 
2. Blood for post-baseline immunogenicity assessment parameters 
3. ECG 
4. AE/SAE/MAAE/PIMMC assessment 
 
For subjects who discontinue study participation prior to Visit 10 (Day 64), an early termination 
visit will be performed. Assessments that are conducted at early termination visits include: 
1. Symptom-directed physical exam, including vital signs assessment 
2. Changes in medication use and immunization use 
3. Blood and urine samples for clinical laboratory assessments (hematology, chemistry and 
urinalysis) if clinically indicated 
4. Blood samples for post-baseline immunogenicity assessment parameters if within acceptable 
window for next expected study visit 
5. Autoantibody assay 
6. AE/SAE/MAAE/PIMMC assessment 
7. Diary collection/review for AEs/SAEs/MAAEs/PIMMCs 


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7. 
DEFINITIONS AND CONVENTIONS 
 
7.1. 
General Summary Table and Individual Subject Data Listing 
Considerations 
The following analyses and reporting conventions will be used: 
 Categorical variables will be summarized using counts (n) and percentages (%) and will 
be presented in the form “n (%).”  Percentages will be rounded to one decimal place.  If 
n=0, then no percent will be shown.  To ensure completeness, all summaries for 
categorical and discrete variables will include all categories, even if none of the subjects 
had a response in a particular category. 
 Numeric variables will be summarized using n, mean, standard deviation (SD), median, 
minimum (min), maximum (max).  The min/max will be reported at the same level of 
significance as original data.  The mean and median will be reported at one more 
significant digit than the precision of the data, and SD will be reported at two more 
significant digits than the precision of the data. 
 The median will be reported as the average of the two middle numbers if the dataset 
contains an even number of observations. 
 Test statistics including t, z and F test statistics will be reported to two decimal places. 
 P-values will be reported to three decimal places if greater than or equal to 0.001.  If less 
than 0.001, the value will be reported as “<0.001.” 
 All tables, listings, and figures will be presented in landscape orientation.  
 Courier New 8-point font will be used for all tables and listings. 
 Dates will be displayed as ddmmmyyyy (e.g., 24Jan2017).  
If departures from these general conventions are present in the specific evaluations section of this 
SAP, then those conventions will take precedence over these general conventions.  
Tables, listings, and figures will include all study groups. 
Study groups will be presented in unblinded reports as shown below: 
 Study Group 1: Age ≥66 Arm 1 
 Study Group 2: Age ≥66 Arm 2 
 Study Group 3: Age ≥66 Arm 3 
 Study Group 4: Age ≥66 Arm 4 
 Study Group 5: Age 18-50 Arm 1 
 Study Group 6: Age 18-50 Arm 3 
Arms 1 through 4 will be defined in the footnotes of the displays. 


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7.1.1. 
Imputation of Missing Data 
There will be no methods of imputation used for missing data for the summaries or analyses of 
the primary and secondary endpoints.  No imputation will be implemented for safety or 
immunogenicity endpoint analyses.  
7.2. 
Calculations Using Dates 
Study days for dates on or after Visit 1 (Day 1) will be calculated as:  
𝑆𝑡𝑢𝑑𝑦 𝐷𝑎𝑦= 𝐷𝑎𝑡𝑒−𝑉𝑖𝑠𝑖𝑡 1 𝐷𝑎𝑡𝑒+ 1 
For dates prior to Visit 1 (Day 1), study days will be calculated as:  
𝑆𝑡𝑢𝑑𝑦 𝐷𝑎𝑦= 𝐷𝑎𝑡𝑒−𝑉𝑖𝑠𝑖𝑡 1 𝐷𝑎𝑡𝑒 
Total duration is calculated as:  
𝐷𝑢𝑟𝑎𝑡𝑖𝑜𝑛= 𝐸𝑛𝑑 𝐷𝑎𝑡𝑒−𝑆𝑡𝑎𝑟𝑡 𝐷𝑎𝑡𝑒+ 1 
Age (years) for randomized subjects at the time of Visit 1 (Day 1) will be calculated as an integer 
according to the following formula:  
𝐴𝑔𝑒= 𝐼𝑛𝑡𝑒𝑔𝑒𝑟 𝑝𝑜𝑟𝑡𝑖𝑜𝑛 𝑜𝑓  𝑉𝑖𝑠𝑖𝑡 1 𝐷𝑎𝑡𝑒−𝐵𝑖𝑟𝑡ℎ 𝐷𝑎𝑡𝑒+ 1
365.25
 
Age for screen failures will be based on the informed consent date as opposed to Visit 1 (Day 1) 
date. 
7.3. 
Baseline 
For data collected at both Screening and Visit 1 (Day 1) pre-IP administration, the baseline data 
will be defined as the latest non-missing value collected.  Otherwise, if data are collected at only 
one of Screening or Visit 1 (Day 1), the collected value will be considered the baseline value for 
analyses. 
7.3.1. 
Visit Windows Relative to the First Dose of Study Medication 
The visit schedule and allowable visit windows are provided in Table 4.  Relative target days and 
visit windows are generally based on the timing of Visit 1 (Day 1).  Visits occurring within 
2 weeks of the 2nd or 3rd IP administration are shown with both relative target days and visit 
windows based on Visit 1 (Day 1) and relative target days and visit windows depending on the 
actual IP administration day (in parentheses).  Similarly, the Visit 13 relative target day and visit 
windows are based on both Visit 1 (Day 1) and on the actual date of the 3rd IP administration.  
For these visits, if an applicable IP administration does not occur, the relative target day and visit 
window will be based on the date of the 1st IP administration at Visit 1 (Day 1). 


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Table 4: 
Visit Schedule 
Visit 
Relative Target 
Day 
Visit Window 
Modified 
Immunogenicity Per 
Protocol Population Visit 
Window 
Screening 
Not Applicable 
-14 – -1 
-14 – -1 
Visit 1 (1st IP 
Administration) 
1 
1 
1 
Visit 2 (≥66 years of 
age only) 
3 
2 – 4 
2 – 4 
Visit 3 
8 
8 – 10 
8 – 10 
Visit 4 (2nd IP 
Administration) 
15  
14 – 18 
12 – 23 
Telephone Visit 1 
17 (Visit 4 + 2) 
16 – 18 (Visit 4 + 2 ±1) 
16 – 18 (Visit 4 + 2 ±1) 
Visit 5 
22 (Visit 4 + 7) 
22 – 24 (Visit 4 + 7 -0/+2) 
22 – 24 (Visit 4 + 7 -0/+2) 
Visit 6 (3rd IP 
Administration) 
29 (Visit 4 + 14) 
28 – 32 (Visit 4 + 14 -
1/+3) 
26 – 37 (Visit 4 + 14 -
3/+8) 
Telephone Visit 2 
31 (Visit 6 + 2) 
30 – 32 (Visit 6 + 2 ±1) 
30 – 32 (Visit 6 + 2 ±1) 
Visit 7 
36 (Visit 6 + 7) 
36 – 38 (Visit 6 + 7 -0/+2) 
36 – 38 (Visit 6 + 7 -0/+2) 
Visit 8 
43 (Visit 6 + 14) 
41 – 44 (Visit 6 + 14 -
2/+1) 
41 – 44 (Visit 6 + 14 -
2/+1) 
Visit 9 
50 
48 – 52 
48 – 52 
Visit 10 
64 
61 – 67 
61 – 72 
Visit 11 
85 
82 – 88 
82 – 88 
Visit 12 
181 
167 –195  
167 –195  
Telephone Visit 3 
366 
359 –373  
359 –373  
Visit 13 
394 (Visit 6 + 365) 
380 – 408 (Visit 6 + 365 
±14) 
380 – 408 (Visit 6 + 365 
±14) 
 
Data from out-of-window visits will not be excluded from analyses. 
Unscheduled visits may also occur throughout the study.  Data from unscheduled visits will be 
included in listings but will generally not be included in tabular or graphical summaries.  The 
one exception is if the unscheduled visit occurs during the allowable visit window of an expected 
study visit that is missed or where some or all immunogenicity data were not collected/not 
analyzable; any available immunogenicity data from the unscheduled visit will be included in the 
summary of the expected study visit. 


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Early termination visits may occur for any subject terminating the study prior to Visit 10 
(Day 64).  These visits will be summarized together in tabular summaries, and will be included 
in listings.  As with unscheduled visits, immunogenicity data from early termination visits that 
occur within the allowable visit window of an expected study visit with some or all 
immunogenicity data missing will be included in summaries of the expected study visit. 
7.4. 
Analysis Populations 
7.4.1. 
Screen Failures 
A screen failure is defined as any subject who gives written informed consent but is not 
randomized at Visit 1 (Day 1).  In addition, all subjects who are screened and found eligible but 
are not randomized will be considered screen failures.  Besides reporting the reasons for not 
meeting inclusion/exclusion criteria, screen failures will not be included in any other analyses. 
7.4.2. 
Randomized Population 
The randomized population will include all subjects who are randomized into the study, 
regardless of actually receiving an IP dose. Each subject will be analyzed as part of the study arm 
assigned/age group combination. If any subjects of age 18-50 years are randomized in error to 
either arm 2 or arm 4 (due to randomization into the stratum for age ≥66 years), those subjects 
will be included with the study group of subjects age ≥66 years that corresponds to the 
randomized arm. 
7.4.3. 
Safety Population 
The safety population will include all subjects who are randomized and receive at least 1 IP dose.  
Each subject will be analyzed as part of the study group corresponding to the actual study group 
for the applicable dose for individual dose summaries.  For all other analyses by study group, 
each subject will be analyzed corresponding to the actual study group for the first dose.  If any 
subjects of age 18-50 years are randomized in error to either arm 2 or arm 4 (due to 
randomization into the stratum for age ≥66 years), those subjects will be included with the study 
group of subjects age ≥66 years that corresponds to the randomized arm. The safety population 
will be used for all safety analyses. 
7.4.4. 
Immunogenicity Full Analysis Population 
The immunogenicity full analysis population (IFAP) will include all subjects who are 
randomized, received at least one IP dose, and have at least one determinate assay result at any 
post-vaccination visit.  Each subject will be analyzed as part of the treatment and dosing 
schedule actually received, regardless of the treatment arm assignment.  If any subjects of age 
18-50 years are randomized in error to either arm 2 or arm 4 (due to randomization into the 
stratum for age ≥66 years), those subjects will be included with the study group of subjects age 
≥66 years that corresponds to the randomized arm. The IFAP will be used only for analysis of 
seroprotection based on TNA NF50 antibody levels at Day 64 as a secondary analysis. 


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7.4.5. 
Immunogenicity Per Protocol Population 
The immunogenicity per protocol population (IPPP) will include all subjects who meet the 
following criteria: 

Randomized

Received a full dose of IP at Visit 1 (Day 1), Visit 4 (Day 15), and Visit 6 (Day 29)
within protocol specified visit windows (- 1 day, +3 days) (see Table 4).

Received the correct treatment as assigned by randomization at Day 1, Day 15 and
Day 29.

Have no major protocol deviations that may have an impact on immunogenicity
assessments.  These are identified by a review of all protocol deviations by BARDA prior
to performing formal analyses and prior to database lock.

Have Visit 10 (Day 64) visit in-window (see Table 4).

Have determinate assay results at the Day 64 visit.
The IPPP will be used for all primary and secondary immunogenicity endpoint assessments.  
7.4.6. 
Modified Immunogenicity Per Protocol Population 
The modified immunogenicity per protocol population (MIPPP) will include all subjects who 
meet the following criteria [note that the only differences between the following criteria and the 
IPPP criteria involve visit windows around vaccinations and Visit 10 (Day 64)]: 

Randomized

Received a full dose of IP at Visit 1 (Day 1), Visit 4 (Day 15), and Visit 6 (Day 29) 
within visit windows of 3 days before to 8 days after the expected visit date (see Table 4).

Received the correct treatment as assigned by randomization at Day 1, Day 15 and
Day 29.

Have no major protocol deviations that may have an impact on immunogenicity
assessments.  These are identified by a review of all protocol deviations by BARDA prior
to performing formal analyses and prior to database lock.

Have Visit 10 (Day 64) within a visit window of 3 days before to 8 days after the 
expected visit date (see Table 4).

Have determinate assay results at the Day 64 visit.
The MIPPP will be used to perform all primary and secondary immunogenicity endpoint 
assessments as secondary analyses. 


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8. 
DATA PRESENTATIONS AND DATA MANAGEMENT 
8.1. 
Data Presentations 
Tables, listings, and figures will be created to display summary and subject level data. 
The plan for tabular presentations and analysis of the data, in general, is divided into three 
categories: 
1. Baseline and demographic profile
2. Analyses of the primary, secondary and exploratory immunogenicity objectives
3. Safety and tolerability, including analyses of primary and secondary safety objectives
All datasets (Study Data Tabulation Model [SDTM] and Analysis Data Model [ADaM] 
datasets), tables, and listings will be created using SAS software version 9.3 or higher.  Figures 
will be programmed using SAS or R version 3.4.1 or higher. 
8.2. 
Data Management 
Study centers will enter study data in an electronic data capture (EDC) system.  Laboratory data 
analyzed by central laboratories (e.g., chemistry, hematology, urinalysis and immunogenicity 
assays) will be transferred to Rho and integrated into the SDTM datasets, but will not be 
included in the EDC system. 
Refer to the Data Management Plan for information concerning the EDC system. 
8.3. 
General Post Text Summary Table and Individual Subject Data 
Listing Format Considerations 
All tables and listings will be created using RhoTables™, a suite of compiled SAS macros 
created by Rho for the generation of data displays.  For more information on programming and 
validation processes, please see the Statistical Validation Plan. 
In general, each listing will be sorted by study group (sorted according to the order in Table 1), 
subject identification number (ID) and date.  For listings involving another categorical variable 
(e.g. laboratory parameter), consideration will be made to group related results within each 
listing for ease of comparing data. 
Tables will include columns for each study group (sorted according to the order in Table 1), by 
pooled age group (regardless of study group; i.e. separate summaries for 18-50 years and 
≥66 years), by pooled study groups (regardless of age group) for arms 1 and 3, and an overall 
column. 
Tables, listings, and figures will be numbered and ordered according to a decimal system 
consistent with the corresponding CSR section.  All displays will specify the applicable analysis 
population. 


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9. 
SUBJECT ACCOUNTING AND DEMOGRAPHIC PROFILE OF 
SCREEN FAILURES 
9.1. 
Subject Accounting by Treatment Group and Sex 
The age, sex and race of screen failures will be included in the listing of eligibility criteria not 
met.  Since screen failures will not be randomized, no treatment group will be reported for these 
subjects. 
9.2. 
Subject Distribution by Site 
Screen failures will not be summarized by site.  
9.3. 
Screen Failures 
Subjects who sign informed consent and are screened but found to be ineligible will be 
considered to be screen failures.  In addition, all subjects who are screened and found eligible but 
are not randomized will be considered screen failures.  The specific eligibility criteria not met 
will be listed for these subjects.  They will be excluded from other data displays. 


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10. 
SUBJECT DISPOSITION 
The study disposition of all randomized subjects will be summarized in tables and listings. 
The numbers and percentages of subjects will be presented that meet the following criteria: 
• 
Randomized 
• 
Completed study 
• 
Early termination from study 
In summary tables, percentages will be based on all subjects randomized within the specific 
study group.  Categories for early study termination reasons will be presented, and percentages 
will be based on all subjects terminating early from the study within the specific study group. 
Visit completion will be presented in a table as counts and percentages, reporting the status of 
the visit (completed or missed) and the number of subjects with visits out of window per visit.  A 
listing of subject visit completion status will be presented. 
The counts and percentages of subjects qualifying for each analysis population will be presented 
by study group.  Percentages will be based on all subjects randomized.  The primary reason for 
exclusion from the IPPP and the MIPPP will also be summarized as counts and percentages.  A 
listing of each subject and analysis population inclusion will be presented. 
 


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11. 
BASELINE SUBJECT DATA 
11.1. 
Baseline Demographic and Physical Characteristics 
Demographic and baseline physical characteristics will be listed.  Summary statistics for 
demographic and baseline physical characteristics will be reported in tables for each analysis 
population.  Summaries by site will also be reported.  Demographic characteristics will be 
summarized based on data collected from the Screening visit and include age (years), race, 
ethnicity and sex. 
Body weight (kg), height (cm) and body mass index (BMI) (kg/(m)2) will be reported from the 
Screening Visit, rounded to 1 decimal place.  If body weight is reported in pounds, the following 
formula will be used to convert to kg: 
𝐵𝑜𝑑𝑦 𝑊𝑒𝑖𝑔ℎ𝑡 (𝑘𝑔) = 𝐵𝑜𝑑𝑦 𝑊𝑒𝑖𝑔ℎ𝑡 (𝑝𝑜𝑢𝑛𝑑𝑠)
2.2
 
 
If height is reported in inches, the following formula will be used to convert to cm: 
𝐻𝑒𝑖𝑔ℎ𝑡 (𝑐𝑚) = 𝐻𝑒𝑖𝑔ℎ𝑡 (𝑖𝑛𝑐ℎ𝑒𝑠) × 2.54 
 
BMI will be calculated automatically within the EDC system using the values of height and 
weight entered by clinical site staff, based on the following formula:  
𝐵𝑀𝐼= 𝑊𝑒𝑖𝑔ℎ𝑡 (𝑘𝑔)
(𝐻𝑒𝑖𝑔ℎ𝑡 [𝑚])2 
 
11.1.1. 
Listing of Subject Inclusion and Exclusion Criteria 
For subjects screened but found to be ineligible, specific inclusion criteria not met and exclusion 
criteria met will be listed.  Additional listings that show specific inclusion criteria not met and 
exclusion criteria met upon reassessment prior to the 2nd or 3rd IP administration will also be 
produced. 
11.2. 
Medical History and Medical Conditions Present at Entry 
Medical history items will be coded according to a standardized thesaurus (Medical Dictionary 
for Regulatory Activities [MedDRA]; refer to the Data Safety Monitoring Plan (DSMP) for the 
applicable version).  Frequencies and percentages of subjects with previous or current medical 
conditions or surgeries will be summarized by body system and study group.  Data listings will 
be prepared.  Potential body systems assessed include skin, HEENT (head, eyes, ears, nose and 
throat), respiratory, cardiovascular, gastrointestinal, endocrine/metabolic, genitourinary, 
neurological, blood/lymphatic, musculoskeletal, hepatic, allergies, and psychological/psychiatric.   
11.3. 
Prior Medication History and Medications Present at Entry 
Immunization history within 30 days prior to screening will be listed for all subjects, with 
vaccination type and date of vaccination. 


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Prior medication history will be summarized with concomitant medication summaries. 
11.4. 
Screening Laboratory Data 
HIV, HBV and HCV antibody collection date and results at screening will be listed for all 
subjects. 
HbA1C results at screening will be listed for all subjects, with date and time of collection, 
reference ranges, abnormal flags and clinical significance indicators. 
Urine drug test results at screening will be listed for all subjects, with date of collection and 
results for each test. 


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12. 
IMMUNOGENICITY 
12.1. 
General Considerations 
All primary, secondary and exploratory immunogenicity analyses will be performed on the IPPP 
and MIPPP separately, and the IFAP will be used only for the primary immunogenicity endpoint 
summaries as a secondary analysis. 
Since all hypothesis tests are performed as part of the secondary analyses, all statistical 
inferences of immunogenicity endpoints are considered exploratory in nature, including 
unadjusted 95% CIs and unadjusted p-values as appropriate. 
No formal statistical analyses for the primary and secondary endpoints will be adjusted by site or 
any other covariates.  Exploratory analyses may use site as a covariate in models, in addition to 
other covariates that are deemed appropriate. 
12.2. 
Statement of the Null and Alternate Hypotheses 
There are no comparisons or hypotheses involved in the primary immunogenicity objective. 
As supportive analyses of the primary immunogenicity objective, the specified success criterion 
for TNA NF50 antibody levels is that the 95% lower bound CI about the seroprotection rate 
(SPR) is greater than 40%.  The following null hypothesis will be tested within each study group, 
combined age group, combined treatment arm, and overall: 
1. Ho: SPR based on TNA NF50 antibody levels at Day 64 is less than or equal to 40% 
Ha: SPR based on TNA NF50 antibody levels at Day 64 is greater than 40% 
For secondary objectives comparing antibody levels in a pairwise fashion between study groups, 
the following null hypotheses will be tested for each pairwise comparison at each timepoint 
where immunogenicity data are collected: 
1. Ho: SPR based on TNA NF50 antibody levels in both groups are equal  
Ha: SPR based on TNA NF50 antibody levels differ between groups 
2. Ho: seroconversion rate (SCR) based on TNA NF50 antibody levels in both groups are 
equal  
Ha: SCR based on TNA NF50 antibody levels differ between groups 
3. Ho: SCR based on TNA ED50 antibody levels in both groups are equal  
Ha: SCR based on TNA ED50 antibody levels differ between groups 
4. Ho: SCR based on ELISA anti-PA IgG antibody levels in both groups are equal  
Ha: SCR based on ELISA anti-PA IgG antibody levels differ between groups 
5. Ho: TNA NF50 antibody levels in both groups are equal  
Ha: TNA NF50 antibody levels differ between groups 
6. Ho: TNA ED50 antibody levels in both groups are equal  
Ha: TNA ED50 antibody levels differ between groups 


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7. Ho: ELISA anti-PA IgG antibody levels in both groups are equal  
Ha: ELISA anti-PA IgG antibody levels differ between groups 
12.3. 
Subgroup Analyses 
No subgroup analysis is planned. 
12.4. 
Multiple Comparisons and Multiplicity 
For all hypothesis tests, significance will be declared at the two-sided α=0.05 level.  Due to the 
exploratory nature of secondary analyses, no adjustments will be made for multiple comparisons. 
12.5. 
Analysis of the Primary Immunogenicity Endpoint 
The primary immunogenicity endpoint for this study is seroprotection at Day 64 based on TNA 
NF50 antibody levels.  Seroprotection is defined as TNA NF50 antibody ≥0.56. 
The primary analysis for this endpoint is descriptive.  The following summary statistics will be 
displayed:  
 count of subjects with non-missing data at the visit 
 count of subjects meeting criteria for seroprotection 
 proportion of subjects meeting criteria for seroprotection  
 95% exact (Clopper-Pearson) CI corresponding to the seroprotection rate 
In addition, SPRs and corresponding 95% CIs will be displayed graphically by study group on 
Day 64. 
The supportive analysis of the primary immunogenicity objective will be analyzed using a 
one-sided one-proportion z-test. 
P-values for the supportive analysis will be displayed. 
If more than 10% of subjects in the IPPP population are seroprotected at Visit 1 (Day 1) based on 
TNA NF50 antibody levels, sensitivity analyses will be performed by repeating analyses 
described in this section excluding the subjects who are seroprotected at Visit 1 (Day 1). 
12.6. 
Analysis of the Secondary Immunogenicity Endpoints 
All secondary immunogenicity endpoints are listed below and will be analyzed according to 
Section 12.6.1.1 (antibody level endpoints) or Section 12.6.1.2 (seroprotection and 
seroconversion endpoints). 
 TNA NF50 antibody levels at Days 1, 8, 22, 29, 36, 43, 50, 64, 85, 181 and 394 
 TNA ED50 antibody levels at Days 1, 8, 22, 29, 36, 43, 50, 64, 85, 181 and 394 
 ELISA anti-PA IgG antibody levels at Days 1, 8, 22, 29, 36, 43, 50, 64, 85, 181 and 394 
 Seroprotection based on TNA NF50 antibody levels at Days 1, 8, 22, 29, 36, 43, 50, 85, 
181 and 394 


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 Seroconversion based on TNA NF50 antibody levels at Days 8, 22, 29, 36, 43, 50, 64, 85, 
181 and 394, defined as a ≥4-fold increase over baseline levels, or a ≥4-fold increase over 
the LLOQ if the baseline value is below the LLOQ. 
 Seroconversion based on TNA ED50 antibody levels at Days 8, 22, 29, 36, 43, 50, 64, 85, 
181 and 394, defined as a ≥4-fold increase over baseline levels, or a ≥4-fold increase over 
the LLOQ if the baseline value is below the LLOQ. 
 Seroconversion based on ELISA anti-PA IgG antibody levels at Days 8, 22, 29, 36, 43, 
50, 64, 85, 181 and 394, defined as a ≥4-fold increase over baseline levels, or a ≥4-fold 
increase over the LLOQ if the baseline value is below the LLOQ. 
 
12.6.1. 
Presentation of the Secondary Immunogenicity Results 
12.6.1.1. Antibody Levels 
Each secondary immunogenicity endpoint measuring TNA NF50, TNA ED50 and ELISA anti-PA 
IgG antibody levels will be summarized similarly.   
Antibody levels with a value that is less than LLOQ will be imputed for antibody level analyses 
as ½ LLOQ. 
The following summary statistics will be displayed by visit as applicable:  
• 
count of subjects with non-missing data at the visit 
• 
geometric mean (GM) antibody levels and corresponding geometric standard deviation 
(SD)  
• 
back-transformed 95% CI based on the t distribution about the GM antibody level 
• 
minimum and maximum values 
• 
median, and 1st and 3rd quartile values 
Study group summaries of GM antibody levels for TNA NF50, TNA ED50 and ELISA anti-PA 
IgG antibody levels by visit will be plotted on the log10 scale with corresponding 95% CIs.  The 
reverse cumulative distributions of GM antibody levels for TNA NF50, TNA ED50 and ELISA 
anti-PA IgG antibodies at Visit 10 (Day 64) will also be plotted. 
Hypotheses concerning the immunogenicity antibody levels will be tested using pairwise t-tests 
on log10 transformed antibody levels, and p-values, geometric mean ratios, and back-transformed 
95% CIs of the difference in log10 antibody levels will be displayed. 
12.6.1.2. Seroprotection and Seroconversion Rates 
Each secondary immunogenicity endpoint involving seroprotection and seroconversion rates will 
be summarized similarly.  The following summary statistics will be displayed by visit for each 
visit as applicable:  
 count of subjects with non-missing data at the visit 
 count of subjects meeting criteria for seroprotection or seroconversion 


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 proportion of subjects meeting criteria for seroprotection or seroconversion 
 95% exact (Clopper-Pearson) CI corresponding to the seroprotection or seroconversion 
rate 
Hypotheses concerning the primary immunogenicity endpoint (seroprotection rate at day 64) will 
be tested with a one-sample binomial test.  
Hypotheses concerning the comparison of SPR and SCR between different groups will be tested 
with a Fisher’s exact test using the IPPP and MIPPP.  Risk differences of comparisons will be 
displayed with corresponding 95% exact unconditional CIs (based on the Santner and Snell 
method) and p-values (based on two-sided Fisher’s exact test). 
A data listing of antibody levels will be prepared, which will include seroprotection (for TNA 
NF50 antibody levels only) and seroconversion status (for TNA NF50, TNA ED50 and ELISA 
anti-PA IgG antibody levels separately) at each applicable visit. 
12.7. 
Analysis of the Exploratory Immunogenicity Endpoints 
12.7.1. 
Antibody level correlations 
Correlations between 1) TNA NF50 and ELISA anti-PA IgG antibody levels and 2) TNA ED50 
and ELISA anti-PA IgG antibody levels will be calculated at Visit 10 (Day 64).  Pairwise scatter 
plots on the log10 scale with regression lines will be created.  The Pearson correlation coefficient 
will be presented with corresponding p-value.  This analysis will be performed on the IPPP and 
MIPPP. 
12.7.2. 
Additional pairwise comparisons 
The following pairwise comparisons of TNA NF50 antibody levels and seroprotection rates will 
be performed at the given visit using the hypothesis testing methodology stated in Section 
12.6.1.1: 
1. Group 1 vs. combined Groups 2 and 3 at Day 29 
2. Group 1 vs. Group 3 at Day 64 
3. Group 1 vs. Group 4 at Day 64 
4. Group 5 vs. Group 6 at Day 29 
5. Group 5 vs. Group 6 at Day 64 
The hypotheses applicable to each pairwise comparison are the following: 
Ho: TNA NF50 antibody levels (or seroprotection rates) in both groups are equal  
Ha: TNA NF50 antibody levels (or seroprotection rates) differ between groups 
These analyses will be performed on the IPPP and MIPPP by the treatment actually received. 


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13. 
SAFETY AND TOLERABILITY 
13.1. 
Overall Summary of Tolerability 
Only treatment-emergent AEs, those starting or worsening in severity on or after the first IP 
administration, are collected on the eCRF.  AEs with missing start dates will be considered 
treatment-emergent. 
All safety analyses will be carried out using the safety population defined in Section 3.1 unless 
otherwise noted.  Missing safety information will not be imputed.  These analyses will not be 
stratified by site or sex.   
The following summaries of all AEs will be given for combined dose 1, dose 2 and dose 3, as 
well as individually for dose 1, dose 2 and dose 3: 
 AEs by SOC and PT 
 AEs by AE Type (Solicited or Unsolicited) and PT 
 AEs by SOC, PT and maximum severity 
 AEs by SOC, PT and relationship to IP 
 AEs by SOC, PT and earliest days of onset 
 The count of AEs and percentage of subjects experiencing AEs that fit the following 
categories: 
o AEs (overall and related to IP) 
o SAEs (overall and related to IP) 
o Severe AEs (overall and related to IP) 
o AEs leading to early termination of IP 
o AEs leading to study withdrawal 
o AEs leading to death 
o Solicited local reactogenicity symptoms (overall and severe) 
o Solicited local contralateral reactogenicity symptoms (overall and severe) 
o Solicited systemic reactogenicity symptoms (overall and severe) 
o PIMMCs (overall and severe) 
o MAAEs (overall and severe) 
o Unsolicited AEs (overall and severe) 
13.2. 
Adverse Event Preferred Term and System Organ Class Summary 
Tables 
All AEs will be classified by system organ class (SOC) and preferred term (PT), according to 
MedDRA.  For solicited reactogenicity symptoms of injection site tenderness, the low level term 
will be used instead of preferred term to distinguish these symptoms from injection site pain, as 


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they are explicitly collected in subject diaries and vaccine site examinations.  The severity and 
attribution of AEs will be classified by the investigator on the eCRF.  Each AE is entered on the 
eCRF once at the highest severity. 
13.2.1. 
Summaries of Adverse Event Incidence Rates for All Subjects 
Separate summaries of solicited local and systemic reactogenicity symptoms and unsolicited AEs 
will be prepared for the following: 
 combined dose 1, dose 2 and dose 3 (start dates occurring in the periods of Day 1 through 
8, Day 15 through Day 22, and Day 29 through 36) 
 dose 1 only (start dates occurring in the period of Day 1 through 8) 
 dose 2 only (start dates occurring in the period of Day 15 through 22) 
 dose 3 only (start dates occurring in the period of Day 29 through 36) 
AEs beginning after the 1st IP administration on Day 1 and prior to the 2nd IP administration on 
Day 15 will be included in dose 1 summaries.  AEs that begin prior to the 1st IP administration 
will only be included in dose 1 summaries if they worsen after IP administration.  Similarly, AEs 
that start after the 2nd IP administration on Day 15 and prior to the 3rd IP administration will be 
included in dose 2 summaries.  AEs beginning after the 3rd IP administration on Day 29 and prior 
to or on Day 50 will be included in dose 3 summaries. 
For summaries of AEs, the count of events that fit the specified criteria will be presented.   
The number of subjects experiencing at least one event will be described using counts and 
percentages per study group.  Percentages will be based on the number of subjects in the safety 
population within the study group.  For summaries of events associated with dose 2 or dose 3, 
percentages will be based on the number of subjects in the safety population within the study 
group who received the 2nd or 3rd IP administration, respectively. 
The incidence of AEs will be summarized. If a subject experienced more than one episode of an 
AE, the subject is counted once for that PT. If a subject had more than one AE in a SOC (or AE 
type, if applicable), the subject is counted only once in that SOC (or AE type) according to the 
highest severity rating (in order, mild [grade 1], moderate [grade 2], or severe [grades 3, 4 and 
5]).  If the severity of the AE is not reported, then the severity of the AE will be counted as 
unknown.  The summary tables will include incidence estimates for overall SOC (or AE type) as 
well as for PTs within each SOC (or AE type).  Incidence will be presented alphabetically by 
SOC (or AE type) and then by PT within each SOC (or AE type) by decreasing frequency 
overall and then alphabetically. 
The investigator is to record their opinion on the relationship of each AE to IP (“not related”, 
“unlikely related”, “possibly related”, “probably related” and “related”).  If a subject experiences 
the same AE multiple times, the event with the strongest relationship to IP will be counted.  For 
summaries of IP-related AEs, the categories of “possibly related”, “probably related” and 
“related” will be considered IP-related.  If the relationship is missing, it will be counted as 
“related” in summaries. 
Day of onset relative to the most recent IP administration will be dichotomized for summaries as 
≤8 days post IP administration and ≥9 days post IP administration.  If a subject experiences the 


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same AE multiple times for the same IP administration, the event with the closest start date to IP 
administration will be counted. 
Solicited local reactogenicity symptoms and solicited systemic reactogenicity symptoms will be 
summarized by maximum severity with 95% exact (Clopper-Pearson) CIs for dose 1, dose 2, and 
dose 3, separately, and combined dose 1, dose 2 and dose 3.  Solicited local reactogenicity 
symptoms on the contralateral arm will be summarized similarly for dose 2 and dose 3. 
In addition, solicited systemic reactogenicity symptoms will be summarized by the strongest 
relationship to IP in the same method as described above. 
Unsolicited adverse events will be summarized by maximum severity with 95% exact (Clopper-
Pearson) CIs for dose 1, dose 2, and dose 3, separately, and combined dose 1, dose 2, and dose 3. 
In addition, all AEs will be listed by subject in chronological order including ID, age, race, sex, 
and all related event status information (start and stop dates, whether the event was resolved, 
study day of onset, severity, seriousness, relationship to IP, action taken with IP, and outcome). 
Separate flags will be displayed for solicited local reactogenicity symptoms, solicited systemic 
reactogenicity symptoms, SAEs, PIMMCs, MAAEs, unsolicited AEs, deaths, AEs leading to 
treatment discontinuation, and AEs leading to subject study withdrawal.  Additionally, a coding 
list of PTs and the verbatim text associated with them will be produced. 
SAEs, MAAEs and PIMMCs will be summarized in tables and presented in separate listings. 
13.2.2. 
Missing and Partial AE Onset Dates 
The following conventions will be used for imputing missing start dates. 
 For start dates that are missing the day value with non-missing month and year: 
o If the start year is the same as the year of Visit 1 (Day 1), then do the following: 
 If the start month is the same as the month of Visit 1 (Day 1), the start date 
will be imputed as the date of Visit 1 (Day 1). 
 If the start month is not the same as the month of Visit 1 (Day 1), then the 
start date will be imputed as the first day of the non-missing start month. 
o If the start year is not the same as the year of Visit 1 (Day 1), then the start day 
will be imputed as the first day of the start month.  
 For start dates that are missing the day and month values with non-missing year: 
o If the start year is the same as the year of Visit 1 (Day 1), the start date will be 
imputed as the date of Visit 1 (Day 1). 
o If the start year is after the year of Visit 1 (Day 1), the start month and start day 
will be imputed as January 1.  
 Completely missing start dates will be imputed as the date of Visit 1 (Day 1).   
End dates will not be imputed. 


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13.2.3. 
Early Termination of Investigational Product due to Adverse Event, Subject 
Study Withdrawal due to Adverse Event, and Death 
AEs leading to early termination of IP will be summarized in a table by SOC and PT and will be 
presented in listings.  Similar summaries and listings will be provided for AEs leading to subject 
study withdrawal. AEs leading to death and potentially life-threatening (grade 4) AEs will also 
be listed. 
13.3. 
Pregnancy Monitoring and Assessment 
Urine pregnancy assessments will be done at Screening and prior to IP administration on Visit 1 
(Day 1), Visit 4 (Day 15) and Visit 6 (Day 29).  Date, time and result of each pregnancy 
assessment will be listed for all female subjects. 
In the case of one or more pregnancies occurring during study participation, a data listing will be 
prepared to display applicable information, including date of report, method of pregnancy 
confirmation, delivery date (if applicable), pregnancy termination status and week (if applicable), 
and any problems or congenital abnormalities present. 
13.4. 
Safety Endpoint Analyses 
13.4.1. 
General Considerations 
All statistical inferences of safety endpoints are considered exploratory in nature, including 
unadjusted 95% CIs. 
13.4.2. 
Statement of the Null and Alternate Hypotheses 
There are no comparisons or hypotheses involved in the primary or secondary safety objectives. 
13.4.3. 
Subgroup Analyses 
No subgroups will be analyzed.  No by-site analyses are planned. 
13.4.4. 
Analysis of the Primary Safety Endpoint 
The primary safety endpoint for the study is all solicited local and systemic reactogenicity 
symptoms occurring within 8 days of each IP administration, inclusive of the IP administration 
day, excluding reactogenicity symptoms on the contralateral arm. 
For the primary safety endpoint, a solicited local or systemic reactogenicity symptom is defined 
as any of the following occurring within 8 days after each IP administration, inclusive of the IP 
administration day, excluding reactogenicity symptoms on the contralateral arm: 
 Solicited local reactions at the injection site: warmth, tenderness, itching, pain, restriction 
of range of arm motion, erythema/redness, palpable or observable lump, 
induration/swelling, and bruising 
 Solicited systemic reactions: fatigue, myalgia/muscle ache, headache, and fever 
Primary endpoint results will be summarized with frequency, percentage and 95% confidence 
interval, and displayed in tables described in Section 13.2.1. 


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13.4.5. 
Analysis of the Secondary Safety Endpoints 
All secondary safety endpoints are listed below: 

All treatment-emergent unsolicited AEs. Unsolicited AEs are defined as all other than
solicited local and systemic reactogenicity symptoms.

All treatment-emergent SAEs occurring during study participation.  SAEs are defined in
Protocol Section 11.2.1.3.

All treatment-emergent MAAEs occurring during study participation.  MAAEs are
defined as AEs with medically attended visits including hospital, emergency room,
urgent care clinic, or other visits to or from medical personnel for any reason.  AEs (e.g.
abnormal vitals) identified at a routine study visit will not be considered MAAEs.

All treatment-emergent PIMMCs that occur during study participation.  PIMMCs are
defined in Protocol Appendix 3.

All solicited local reactogenicity symptoms on the contralateral arm occurring within
8 days after each vaccination, inclusive of the vaccination day.
Secondary endpoint results will be summarized with frequency and percentage, and displayed in 
tables described in Section 13.2.1. 
13.4.6. 
Summary of Reasons for Safety Non-evaluability/Exclusion from Safety 
Analyses 
All subjects who are randomized and receive at least 1 IP administration will be included in 
safety analyses.  Therefore, a listing of screen failures will be considered the presentation of 
subjects excluded from safety analyses. 
13.5. 
Investigational Product Administration Compliance 
IP administration adherence for dose 1 at Visit 1(Day 1), dose 2 at Visit 4 (Day 15) and dose 3 at 
Visit 6 (Day 29) will be summarized and listed.  Counts and percentages of subjects receiving 
any amount or a full amount of dose 1, dose 2 and dose 3, separately, will be reported in tables; 
the denominator will be the number of subjects within each group as randomized.  For subjects 
who receive all 3 doses of IP, the counts and percentages of subjects receiving 3 doses of IP 
according to the correct study arm will be summarized.  For subjects terminating IP 
administration early, the reasons for terminating IP administration early will also be presented.  
For subjects who received the first IP administration but are found ineligible for the second or 
third IP administration, specific inclusion and exclusion criteria not met at Visit 4 (Day 15) or 
Visit 6 (Day 29) will be listed separately. 
Details of IP administration will be listed for each IP administration, including date of IP 
administration, time IP removed from storage/refrigerator, time of IP preparation, time of 
administration, location of administration and whether a full dose was received. 
13.6. 
Concomitant and Other Medications 
Medications will be coded according to the World Health Organization (WHO) Drug Dictionary 
(refer to the DSMP for the applicable version).  Medications reported on the eCRF will be 


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categorized for analysis as prior or concomitant to IP administration by comparing the 
medication start and stop dates with the first IP administration dates.  Prior medications will have 
a medication start date prior to the first IP administration date.  Concomitant medications will 
have a medication start on or after the first IP administration date or a stop date on or after the 
first IP administration date.  Medications that fit the criteria for both a prior and concomitant 
medication will be indicated as such in data listings. 
The number and percentage of subjects receiving prior or concomitant medications will be 
presented overall and by medication class.  When reporting the number of subjects receiving the 
medication, a subject will only be counted once if they ever received the medication within the 
medication class. 
Medication usage will be listed, including Anatomical Therapeutic Chemical (ATC) level 4 
coding term, verbatim drug name, preferred drug name, start date, end date, dose (with unit), 
frequency, route, ongoing status and indication. 
Non-IP immunizations will be collected post-Screening.  Concomitant immunizations will be 
listed, including immunization type and date. 
13.6.1. 
Missing and Partial Concomitant and Other Medication Start and Stop Dates 
The following conventions will be used for imputing missing start dates.  

For start dates that are missing the day value with non-missing month and year:
o
If the start year is the same as the year of Visit 1 (Day 1), then do the following:

If the start month is the same as the month of Visit 1 (Day 1), the start date
will be imputed as the date of Visit 1 (Day 1).

If the start month is not the same as the month of Visit 1 (Day 1), then the
start date will be imputed as the first day of the non-missing start month.
o
If the start year is not the same as the year of Visit 1 (Day 1), then the start day
will be imputed as the first day of the non-missing start month.

For start dates that are missing the day and month values with non-missing year:
o
If the start year is earlier than the year of Visit 1 (Day 1), the start month and day
will be imputed as July 1.
o
If the start year is the same as the year of Visit 1 (Day 1), the start date will be set
to the date of Visit 1 (Day 1).
o
If the start year is after the year of Visit 1 (Day 1), the start month and start day
will be imputed as January 1.

Completely missing start dates will be imputed as the date of Visit 1 (Day 1).
End dates will not be imputed. 
13.7. 
Investigational Product Administration Site Examination 
Observations from the IP administration site post IP administration will be summarized by visit 
and study group.  IP administration site examinations will be summarized separately for 


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locations of dose 1, dose 2 and dose 3.  Dose 1 site examinations will occur on Visit 1(Day 1), 
Visit 2 (Day 3) (for ≥66 age group), Visit 3 (Day 8) and Visit 4 (Day 15); dose 2 site 
examinations will occur on Visit 4 (Day 15), Visit 5 (Day 22) and Visit 6 (Day 29); dose 3 site 
examinations will occur on Visit 6 (Day 29), Visit 7 (Day 36) and Visit 8 (Day 43).  Counts and 
percentages of subjects experiencing warmth, tenderness, itching, pain, restriction of range of 
arm motion, erythema/redness, palpable or observable lump, induration/swelling, and bruising at 
the injection site will be presented.  Summaries of the largest diameter of erythema/redness, and 
induration/swelling will be presented as well. 
IP administration site examination information will also be listed for each subject, dose and visit.  
Information included will be IP administration date, date of examination, time of examination, 
days since IP administration, whether a photograph was taken of the abnormality, and all 
information summarized in IP administration site examination tables described above in this 
section. 
13.8. 
 Diary Card Measurements 
Participant-reported diary card measurements of vaccinated and contralateral arm (if applicable) 
IP administration site erythema/redness and induration/swelling will be listed for each subject, 
dose and study day for 8 days post-IP administration. 
13.9. 
Clinical Laboratory Data 
Clinical laboratory measurements of serum chemistry, hematology and urinalysis will be 
performed at a central laboratory.  All clinical laboratory data will be reported using the 
International System of Units (SI).  If SI units are not available, laboratory-reported units will be 
used.  Descriptive statistics of laboratory values will be presented by visit.  Summaries of actual 
values and change from baseline values by visit will be presented for quantitative laboratory 
parameters (e.g., white blood cells, lymphocytes).  Baseline is defined as the last lab value prior 
to IP administration. 
If two or more evaluations occur in the same visit window, the latest evaluation will be selected 
for inclusion in the analysis.   
Clinical laboratory results will receive a toxicity grade according to Protocol Appendix 2.  
Clinical laboratory results of grade 1 through 3 that are deemed by the investigator as being 
clinically significant will be recorded as AEs with a corresponding toxicity grade as described 
above and will be presented with the AE displays.  All grade 4 laboratory values will be 
considered AEs.   
Shift tables will be prepared to display cross-tabulations of the number of subjects experiencing 
each toxicity grade at baseline compared to other visits by clinical laboratory test. 
All clinical laboratory values will be presented in a listing. 
13.10. 
Vital Signs 
Vital signs parameters of blood pressure (systolic and diastolic) (mmHg), pulse rate 
(beats/minute), respiratory rate (breaths/minute), oral temperature (°F), and oxygen saturation by 
pulse oximeter (%) will be summarized and listed for all visits with applicable data.  For all 


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results collected post-baseline, change from baseline will be displayed.  Visit 1 (Day 1) pre-IP 
administration vital signs results will be considered baseline for summaries of vital signs data.  If 
the Visit 1 (Day 1) pre-IP administration result is missing, screening results will be considered 
baseline. 
Toxicity grading of vital signs results according to Protocol Appendix 2 will be presented with 
vital signs displays.  Vital signs results that are deemed by the investigator as being clinically 
significant will be recorded as AEs with a corresponding toxicity grade as described above and 
will be presented with the AE displays.   
Shift tables will be prepared to display cross-tabulations of the number of subjects experiencing 
each toxicity grade at baseline compared to other visits by vital sign parameter. 
All vital signs will be listed in by-subject listings including visit and collection date. 
13.11. 
Physical Examination 
Physical examinations will be performed, but only abnormal results will be recorded as either a 
medical history item at screening, or as an adverse event.  Physical exam results will not be 
reported otherwise. 
13.12. 
Other Safety Assessments 
ECG test results will be collected at Screening, Visit 7 (Day 36) and Visit 13 (Day 394).  Results 
will be reported in data listings, including visit and collection date. 
High-sensitivity C-reactive protein (hs-CRP) assay results will be collected at Visit 1 (Day 1) 
and Visit 2 (Day 3) for subjects ≥66 years of age.  Results will be reported in data listings, 
including visit and collection date. 
Blood samples for autoantibody assays will be collected and frozen for potential testing at Visit 1 
(Day 1), Visit 10 (Day 64) and at the early termination visit (if applicable) for subjects ≥66 years 
of age.  If the samples are analyzed, results will be reported in data listings, including visit and 
collection date. 
13.13. 
Subject Study Withdrawal Status 
Reasons for subject study withdrawal will be included in the study disposition displays described 
in Section 10. 


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14. 
PROTOCOL DEVIATIONS 
Protocol deviations captured in the eCRF, including site-level protocol deviations, will be listed 
by site with information such as type of deviation, severity of the deviation (major or 
non-major), date of occurrence, and the reason for the deviation.  Protocol deviations will be 
summarized in tabular format by type of deviation. 


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15. 
MAINTAINING THE BLIND 
For all analyses requiring unblinded data from study start through the Day 394 analysis for the 
final CSR, a blinded programming team consisting of programmers and statisticians will perform 
all programming tasks (including SDTM datasets, ADaM datasets, tables, listings, and figures) 
and all associated validation tasks using dummy study groups, which will be randomly assigned.  
After validation of datasets and displays using dummy study groups, an unblinded team of a 
statistician and a programmer will generate, interpret and report each analysis using appropriate 
study groups and will not modify any programs used to perform analyses.   
Any necessary modification of programs due to incorrect coding will be communicated from the 
unblinded team to the blinded team so that the blinded team can modify the coding while being 
blinded to study groups, after which the unblinded team will then rerun analyses using unblinded 
data.  This process is continued until the unblinded team ensures all data issues have been 
resolved. 
15.1. 
Immunogenicity Data 
Immunogenicity data of TNA NF50, TNA ED50 and ELISA anti-PA IgG antibody levels may 
potentially be unblinding to study group, as a higher antibody level would be expected from 
subjects receiving active IP compared to placebo.  To ensure that no blinded individual may be 
unblinded by viewing the immunogenicity data, the unblinded statistician will randomly reassign 
the IDs in the file so that antibody levels will be assigned to different subjects than those subjects 
to which they actually correspond.  Blinded programming tasks will be done only on the 
reassigned file.  The file with correct ID assignments will be used for all unblinded analyses and 
will only be viewable by unblinded individuals. 


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16. 
INTERIM ANALYSES 
An interim analysis will be performed based on cumulative immunogenicity and safety data 
through Visit 10 (Day 64) for all subjects.  At the interim analysis, the study database (all data 
through Visit 10 [Day 64]) will be monitored and cleaned per the Data Management Plan.  
The blinding at the subject level will be maintained for those outside of the unblinded team until 
database lock of all data through Day 394 for the clinical study report.  Blinding at the subject 
level will be maintained for the interim analysis as specified in Section 15. 
All primary and secondary endpoint analyses will be performed for the interim analysis as 
specified in Sections 12.6 and 12.7 (for immunogenicity analyses) and Sections 13.4.4 and 
13.4.5 (for safety analyses).  Additional analyses included in the interim analysis, such as subject 
disposition and demographics, will be performed based on Sections 10 and 11.  Exploratory 
immunogenicity analyses will also be included in the interim analysis.  
In order to prevent unblinding of any individual subjects, tabular summaries of data will exclude 
extreme values (minimum and maximum).  Listings will not be included in the interim analysis 
package. Immunogenicity tables and figures will report study group and pooled group statistics 
and counts. AE tables will not report study group specific counts, but will instead report the 
overall totals and totals by age group. As such AE tables will remain blinded, even at the group 
level. All remaining tables included in the interim analysis that may have small counts will not 
report study group specific counts for applicable variables.   
The unblinded statistician will be responsible for reporting interim results to Biomedical 
Advanced Research and Development Authority (BARDA). 
Since all active subjects will have completed Visit 10 (Day 64) and this timepoint is of primary 
interest, there will be no penalty for an early look at the data.  In addition, no decisions regarding 
the status of the study will be made as a result of the interim analysis. 
The interim analysis tables and figures will be a subset of the final tables and figures included in 
the CSR. At the time of the final analysis for the CSR, all tables and figures generated as part of 
the interim analysis will be regenerated to include data through the end of the study. 


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17. 
SAFETY MONITORING COMMITTEE MEETINGS 
The Safety Monitoring Committee (SMC) will perform a planned review of interim safety data 
after 40 subjects ≥66 years of age have completed Visit 7 (Day 36).  Enrollment and dosing will 
continue during this planned SMC review.  In addition, ad hoc reviews will occur in the event 
that pausing/stopping rules are met or a review is deemed necessary by the SMC chair. 
Following the planned interim analysis (described in Section 16), a final set of SMC data 
displays will be provided to the SMC members.  These displays will be of the same format as 
provided for the planned SMC data review but will be run on the clean and frozen data from the 
interim analysis. 
The blind will be maintained for all blinded individuals according to Section 15.  The unblinded 
statistician will be responsible for presenting data to the SMC.  Safety analyses for SMC review 
will be completed using the safety population.   
Refer to the SMC Charter for more details of the SMC procedures and reporting. 


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18. 
CHANGES TO COMPLETED REPORTS 
The study database will be monitored and cleaned per the Data Management Plan for all data 
through Visit 10 (Day 64) for the interim analysis and Visit 13 (Day 394) for the final CSR.  In 
the event of any changes in the clinical database at the time of final database lock that affect 
information reported in the interim analysis, these changes will be noted in the CSR. 


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19. 
REFERENCES 
1. BioThrax® (Anthrax Vaccine Adsorbed); Suspension for Intramuscular or Subcutaneous 
Injection [package insert]. Lansing, MI: Emergent BioDefense Operations Lansing LLC, 
2015. 


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20. 
APPENDIX 
20.1. 
Table of Contents for Data Display Specifications 
Tables  
Table 
Number 
Table Title 
Applicable 
Reports 
(I=Interim, 
C=Final 
CSR) 
Applicable 
Populations 
(R=Randomized, 
S=Safety, 
F=IFAP,     
P=IPPP 
M=MIPPP) 
Table 
14.1.1.1 
Subject Disposition by Study Group 
I, C 
R 
Table 
14.1.1.2 
Visit Completion by Study Group 
I, C 
R 
Table 
14.1.1.3 
Analysis Populations by Study Group 
I, C 
R 
Table 
14.1.2 
Protocol Deviations by Study Group 
C 
R 
Table 
14.1.3.1 
Demographics and Baseline Physical 
Characteristics by Study Group 
I, C 
S, F, P, M 
Table 
14.1.3.2 
Demographics and Baseline Physical 
Characteristics by Site and Study Group 
C 
S, F, P, M 
Table 
14.1.4 
Medical History by Study Group 
C 
S 
Table 
14.1.5 
Concomitant Medications by System Organ 
Class, Preferred Term and Study Group 
C 
S 
Table 
14.1.6 
Investigational Product Administration 
Adherence by Study Group 
I, C 
S 
Table 
14.2.1.1 
Seroprotection by TNA NF50 Antibody Levels 
Summary by Study Group   
I, C 
F, P, M 
Table 
14.2.1.2 
Exploratory Seroprotection by TNA NF50 
Antibody Levels Summary Comparisons 
I, C 
P, M 
Table 
14.2.1.3 
TNA NF50 Antibody Levels Summary by 
Study Group   
I, C 
P, M 
Table 
14.2.1.4 
Exploratory TNA NF50 Antibody Level 
Summary Comparisons 
I, C 
P, M 
Table 
14.2.1.5 
Seroconversion by TNA NF50 Antibody 
Levels Summary by Study Group   
I, C 
P, M 
Table 
14.2.2.1 
Seroconversion by TNA ED50 Antibody 
Levels Summary by Study Group   
I, C 
P, M 
Table 
14.2.2.2 
TNA ED50 Antibody Levels Summary by 
Study Group   
I, C 
P, M 


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Table 
14.2.3.1 
Seroconversion by ELISA anti-PA IgG 
Antibody Levels Summary by Study Group   
I, C 
P, M 
Table 
14.2.3.2 
ELISA anti-PA IgG Antibody Levels 
Summary by Study Group   
I, C 
P, M 
Table 
14.3.1.1.1 
Summary of Adverse Events by Study Group 
I, C 
S 
Table 
14.3.1.1.2 
Summary of Adverse Events for Dose 1 by 
Study Group 
I, C 
S 
Table 
14.3.1.1.3 
Summary of Adverse Events for Dose 2 by 
Study Group 
I, C 
S 
Table 
14.3.1.1.4 
Summary of Adverse Events for Dose 3 by 
Study Group 
I, C 
S 
Table 
14.3.1.1.5 
Summary of Adverse Events by Study Group 
and Dose 
I, C 
S 
Table 
14.3.1.2.1 
All Adverse Events by System Organ Class, 
Preferred Term and Study Group  
I, C 
S 
Table 
14.3.1.2.2 
All Adverse Events by System Organ Class, 
Preferred Term and Study Group for Dose 1 
I, C 
S 
Table 
14.3.1.2.3 
All Adverse Events by System Organ Class, 
Preferred Term and Study Group for Dose 2 
I, C 
S 
Table 
14.3.1.2.4 
All Adverse Events by System Organ Class, 
Preferred Term and Study Group for Dose 3 
I, C 
S 
Table 
14.3.1.2.5 
All Adverse Events by System Organ Class, 
Preferred Term, Study Group and Dose 
I, C 
S 
Table 
14.3.1.3.1 
All Adverse Events by Type, Preferred Term 
and Study Group 
I, C 
S 
Table 
14.3.1.3.2 
All Adverse Events by Type, Preferred Term 
and Study Group for Dose 1 
I, C 
S 
Table 
14.3.1.3.3 
All Adverse Events by Type, Preferred Term 
and Study Group for Dose 2 
I, C 
S 
Table 
14.3.1.3.4 
All Adverse Events by Type, Preferred Term 
and Study Group for Dose 3 
I, C 
S 
Table 
14.3.1.4.1 
All Adverse Events by System Organ Class, 
Preferred Term, Maximum Severity and Study 
Group 
I, C 
S 
Table 
14.3.1.4.2 
All Adverse Events by System Organ Class, 
Preferred Term, Maximum Severity and Study 
Group for Dose 1 
I, C 
S 
Table 
14.3.1.4.3 
All Adverse Events by System Organ Class, 
Preferred Term, Maximum Severity Study 
Group for Dose 2 
I, C 
S 
Table 
14.3.1.4.4 
All Adverse Events by System Organ Class, 
Preferred Term, Maximum Severity and Study 
Group for Dose 3 
I, C 
S 


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Table 
14.3.1.5.1 
All Adverse Events by System Organ Class, 
Preferred Term, Strongest Relationship to 
Investigational Product and Study Group 
I, C 
S 
Table 
14.3.1.5.2 
All Adverse Events by System Organ Class, 
Preferred Term, Strongest Relationship to 
Investigational Product and Study Group for 
Dose 1 
I, C 
S 
Table 
14.3.1.5.3 
All Adverse Events by System Organ Class, 
Preferred Term, Strongest Relationship to 
Investigational Product and Study Group for 
Dose 2 
I, C 
S 
Table 
14.3.1.5.4 
All Adverse Events by System Organ Class, 
Preferred Term, Strongest Relationship to 
Investigational Product and Study Group for 
Dose 3 
I, C 
S 
Table 
14.3.1.6.1 
All Adverse Events by System Organ Class, 
Preferred Term, Earliest Day of Onset and 
Study Group 
I, C 
S 
Table 
14.3.1.6.2 
All Adverse Events by System Organ Class, 
Preferred Term, Earliest Day of Onset and 
Study Group for Dose 1 
I, C 
S 
Table 
14.3.1.6.3 
All Adverse Events by System Organ Class, 
Preferred Term, Earliest Day of Onset and 
Study Group for Dose 2  
I, C 
S 
Table 
14.3.1.6.4 
All Adverse Events by System Organ Class, 
Preferred Term, Earliest Day of Onset and 
Study Group for Dose 3  
I, C 
S 
Table 
14.3.1.7.1 
Solicited Local Reactogenicity Symptoms by 
Maximum Severity and Study Group for 
Doses 1, 2 and 3 
I, C 
S 
Table 
14.3.1.7.2 
Solicited Local Reactogenicity Symptoms by 
Maximum Severity and Study Group for Dose 
1 
I, C 
S 
Table 
14.3.1.7.3 
Solicited Local Reactogenicity Symptoms by 
Maximum Severity and Study Group for Dose 
2 
I, C 
S 
Table 
14.3.1.7.4 
Solicited Local Reactogenicity Symptoms by 
Maximum Severity and Study Group for Dose 
3 
I, C 
S 
Table 
14.3.1.7.5 
Solicited Local Reactogenicity Symptoms by 
Maximum Severity, Study Group and Dose 
I, C 
S 
Table 
14.3.1.8.1 
Solicited Systemic Reactogenicity Symptoms 
by Maximum Severity and Study Group for 
Doses 1, 2 and 3 
I, C 
S 


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Table 
14.3.1.8.2 
Solicited Systemic Reactogenicity Symptoms 
by Maximum Severity and Study Group for 
Dose 1 
I, C 
S 
Table 
14.3.1.8.3 
Solicited Systemic Reactogenicity Symptoms 
by Maximum Severity and Study Group for 
Dose 2 
I, C 
S 
Table 
14.3.1.8.4 
Solicited Systemic Reactogenicity Symptoms 
by Maximum Severity and Study Group for 
Dose 3 
I, C 
S 
Table 
14.3.1.8.5 
Solicited Systemic Reactogenicity Symptoms 
by Maximum Severity, Study Group and Dose 
I, C 
S 
Table 
14.3.1.8.6 
Solicited Systemic Reactogenicity Symptoms 
by Strongest Relationship to Investigational 
Product and Study Group for Doses 1, 2 and 3 
I, C 
S 
Table 
14.3.1.8.7 
Solicited Systemic Reactogenicity Symptoms 
by Strongest Relationship to Investigational 
Product and Study Group for Dose 1 
I, C 
S 
Table 
14.3.1.8.8 
Solicited Systemic Reactogenicity Symptoms 
by Strongest Relationship to Investigational 
Product and Study Group for Dose 2 
I, C 
S 
Table 
14.3.1.8.9 
Solicited Systemic Reactogenicity Symptoms 
by Strongest Relationship to Investigational 
Product and Study Group for Dose 3 
I, C 
S 
Table 
14.3.1.9.1 
Unsolicited Adverse Events by System Organ 
Class, Preferred Term and Study Group 
I, C 
 
S 
Table 
14.3.1.9.2 
Unsolicited Adverse Events by System Organ 
Class, Preferred Term and Study Group for 
Dose 1 
I, C 
 
S 
Table 
14.3.1.9.3 
Unsolicited Adverse Events by System Organ 
Class, Preferred Term and Study Group for 
Dose 2 
I, C 
 
S 
Table 
14.3.1.9.4 
Unsolicited Adverse Events by System Organ 
Class, Preferred Term and Study Group for 
Dose 3 
I, C 
 
S 
Table 
14.3.2.1.1 
Serious Adverse Events by System Organ 
Class, Preferred Term and Study Group 
I, C 
S 
Table 
14.3.2.1.2 
Medically Attended Adverse Events by 
System Organ Class, Preferred Term and 
Study Group 
I, C 
S 
Table 
14.3.2.1.3 
Potentially Immune-Mediated Medical 
Conditions by System Organ Class, Preferred 
Term and Study Group 
I, C 
S 
Table 
14.3.2.1.4 
All Adverse Events by System Organ Class, 
Preferred Term and Study Group Leading to 
Death 
I, C 
S 


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Note: Each table will be created once per applicable population.  In addition, each table will be 
created once to show summaries by study group, and once to show summaries by pooled age or 
arm groups. 
 
 
 
Table 
14.3.2.2.1 
All Adverse Events by System Organ Class, 
Preferred Term and Study Group Leading to 
Early Termination of Investigational Product 
I, C 
S 
Table 
14.3.2.2.2 
All Adverse Events by System Organ Class, 
Preferred Term and Study Group Leading to 
Study Withdrawal 
I, C 
S 
Table 
14.3.3.1 
Investigational Product Site Examination by 
Study Group for Dose 1 
C 
S 
Table 
14.3.3.2 
Investigational Product Site Examination by 
Study Group for Dose 2 
C 
S 
Table 
14.3.3.3 
Investigational Product Site Examination by 
Study Group for Dose 3 
C 
S 
Table 
14.3.4.1 
Chemistry, Hematology and Urinalysis 
Clinical Laboratory Results by Study Group 
C 
S 
Table 
14.3.4.2 
Shift from Baseline in Grading of  Chemistry, 
Hematology and Urinalysis Clinical 
Laboratory Results by Study Group 
C 
S 
Table 
14.3.5.1 
Vital Sign Parameters by Study Group  
C 
S 
Table 
14.3.5.2 
Shift from Baseline in Grading of Vital Sign 
Parameters by Study Group 
C 
S 


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Listings 
Listing 
Number 
Listing Title 
Applicable 
Reports 
(C=Final 
CSR) 
Applicable 
Populations 
(NR=Not 
Randomized, 
R=Randomized, 
S=Safety, 
F=IFAP,     
P=IPPP 
M=MIPPP) 
Listing 
16.2.1.1 
Disposition 
C 
R 
Listing 
16.2.1.2 
Visit Completion 
C 
R 
Listing 
16.2.1.3 
Analysis Populations 
C 
R 
Listing 
16.2.1.4  
Reasons for Subject Ineligibility for 
Enrollment 
C 
NR 
Listing 
16.2.1.5 
Reasons for Subject Ineligibility for 2nd 
Investigational Product Administration 
C 
S 
Listing 
16.2.1.6 
Reasons for Subject Ineligibility for 3rd 
Investigational Product Administration 
C 
S 
Listing 
16.2.2.1 
Protocol Deviations 
C 
R 
Listing 
16.2.4.1 
Demographics and Baseline Physical 
Characteristics 
C 
S 
Listing 
16.2.4.2 
Medical History 
C 
S 
Listing 
16.2.4.3 
Immunization History 
C 
S 
Listing 
16.2.4.4 
Prior and Concomitant Medications 
C 
S 
Listing 
16.2.4.5 
Concomitant Immunizations 
C 
S 
Listing 
16.2.5 
Investigational Product Administration 
Adherence 
C 
S 
Listing 
16.2.6 
Serum TNA NF50, TNA ED50 and ELISA anti-
PA IgG Antibody Levels 
C 
F 
Listing 
16.2.7.1 
Adverse Events 
C 
S 
Listing 
16.2.7.2 
Serious Adverse Events 
C 
S 
Listing 
16.2.7.3 
Medically Attended Adverse Events 
C 
S 


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Listing 
16.2.7.4 
Potentially Immune-Mediated Medical 
Conditions 
C 
S 
Listing 
16.2.7.5 
Adverse Events Leading to Death 
C 
S 
Listing 
16.2.7.6 
Potentially Life-Threatening (Grade 4) Adverse 
Events 
C 
S 
Listing 
16.2.7.7 
Adverse Events Leading to Early Termination 
of Investigational Product 
C 
S 
Listing 
16.2.7.8 
Adverse Leading to Study Withdrawal 
C 
S 
Listing 
16.2.7.9 
Adverse Event Verbatim Text Coding List to 
Preferred Term 
C 
N/A 
Listing 
16.2.7.10 
Investigational Product Site Examination 
C 
S 
Listing 
16.2.7.11 
Participant-reported Diary Card Measurements 
of Investigational Product Site 
Erythema/Redness and Induration/Swelling 
C 
S 
Listing 
16.2.8.4 
Chemistry, Hematology and Urinalysis Clinical 
Laboratory Results 
C 
S 
Listing 
16.2.9.1 
Vital Signs 
C 
S 
Listing 
16.2.9.2 
Electrocardiogram Results 
C 
S 
Listing 
16.2.9.3 
High-Sensitivity C-Reactive Protein Assay 
Results for Subjects ≥66 Years 
C 
S 
Listing 
16.2.9.4 
Screening HIV Antibody, Hepatitis B Surface 
Antigen and Hepatitis C Antibody Results  
C 
S 
Listing 
16.2.9.5 
Screening Hemoglobin A1C Results 
C 
S 
Listing 
16.2.9.6 
Screening Urine Drug Test Results 
C 
S 
Listing 
16.2.9.7 
Autoantibody Assay Results 
C 
S 
Listing 
16.2.9.8 
Urine Pregnancy Assessment 
C 
S 
Listing 
16.2.9.9 
Pregnancies 
C 
S 
Note: Additional listings may be produced based on actual study results. 
 
 
 
 
 
 
 


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Figures 
Note: Each figure will be created once per applicable population.  In addition, each figure will be 
created once to show data by study group, and once to show data by pooled age or arm groups. 
 
 
 
Figure 
Number 
Figure Title 
Applicable 
Reports 
(I=Interim, 
C=Final CSR) 
Applicable 
Populations 
(R=Randomized, 
S=Safety, 
F=IFAP,  
P=IPPP 
M=MIPPP) 
Figure 
14.2.1.1 
TNA NF50 Antibody Levels Plot of 
Geometric Mean Levels and 95% CI Over 
Time 
I, C 
P, M 
Figure 
14.2.1.2 
Seroprotection by TNA NF50 Antibody 
Levels at Visit 10 (Day 64)  
I, C 
F, P, M 
Figure 
14.2.1.3 
TNA NF50 Antibody Levels Reverse 
Cumulative Distribution Plot at Visit 10 
(Day 64) 
I, C 
P, M 
Figure 
14.2.2.1 
TNA ED50 Antibody Levels Plot of 
Geometric Mean Levels and 95% CI Over 
Time 
I, C 
P, M 
Figure 
14.2.2.2 
TNA ED50 Antibody Levels Reverse 
Cumulative Distribution Plot at Visit 10 
(Day 64) 
I, C 
P, M 
Figure 
14.2.3.1 
ELISA anti-PA IgG Antibody Levels Plot 
of Geometric Mean Levels and 95% CI 
Over Time 
I, C 
P, M 
Figure 
14.2.3.2 
ELISA anti-PA IgG  Antibody Levels 
Reverse Cumulative Distribution Plot at 
Visit 10 (Day 64) 
I, C 
P, M 
Figure 
14.2.4.1 
TNA NF50 and  ELISA anti-PA IgG 
Antibody Titer Scatter Plot at Visit 10 
(Day 64) 
C 
P, M 
Figure 
14.2.4.2 
TNA ED50 and  ELISA anti-PA IgG 
Antibody Titer Scatter Plot at Visit 10 
(Day 64) 
C 
P, M