A Post Marketing Study of the Safety, Tolerability, and Pharmacokinetics of TPOXX In Adult Subjects Weighing More Than 120 KG
Phase: PHASE4
Conditions: Smallpox
Sponsor: SIGA Technologies



SIGA Technologies, Inc. 
TPOXX 
Protocol No. SIGA-246-022 
Clinical Study Protocol 
 
 
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SIGNATURE PAGE 
 
PROTOCOL TITLE: 
A Post Marketing Study of the Safety, Tolerability, and 
Pharmacokinetics of TPOXX® in Adult Subjects Weighing 
More Than 120 kg 
PROTOCOL NUMBER: 
SIGA-246-022 
 
Dennis E. Hruby, PhD 
Chief Scientific Officer 
SIGA Technologies, Inc. 
 
Date 
 

SIGA Technologies, Inc. 
TPOXX 
Protocol No. SIGA-246-022 
Clinical Study Protocol 
 
 
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TABLE OF CONTENTS 
TITLE PAGE .......................................................................................................................... 1 
SIGNATURE PAGE ............................................................................................................... 2 
INVESTIGATOR PROTOCOL AGREEMENT PAGE ..................................................... 3 
TABLE OF CONTENTS ........................................................................................................ 4 
LIST OF TABLES ................................................................................................................... 6 
PROTOCOL SYNOPSIS ....................................................................................................... 7 
1. 
INTRODUCTION ............................................................................................. 15 
1.1 
BACKGROUND ..............................................................................................15 
1.2 
RATIONALE FOR STUDY ............................................................................15 
1.3 
POTENTIAL RISKS AND BENEFITS ...........................................................15 
1.3.1 
Potential Risks ..............................................................................................15 
1.3.2 
Known Potential Benefits .............................................................................16 
2. 
STUDY OBJECTIVES ...................................................................................... 16 
2.1 
PRIMARY OBJECTIVE ..................................................................................16 
2.2 
SECONDARY OBJECTIVE ............................................................................16 
3. 
STUDY POPULATION..................................................................................... 16 
3.1 
INCLUSION CRITERIA .................................................................................16 
3.2 
EXCLUSION CRITERIA ................................................................................18 
3.3 
OTHER SCREENING CONSIDERATIONS ..................................................22 
3.3.1 
Subject Restrictions During the Study .........................................................22 
3.4 
WITHDRAWAL OF SUBJECTS FROM THE STUDY .................................22 
3.4.1 
Reasons for Withdrawal................................................................................22 
3.4.2 
Handling of Withdrawals ..............................................................................23 
3.4.3 
Halting Rules ................................................................................................23 
4. 
STUDY DESIGN ................................................................................................ 24 
4.1.1 
Replacements ................................................................................................25 
5. 
STUDY TREATMENT ..................................................................................... 25 
5.1 
TREATMENT ADMINISTERED....................................................................25 
5.2 
STUDY DRUG ................................................................................................26 
5.2.1 
Study Drug Packaging and Storage ..............................................................27 
5.2.2 
Study Drug Accountability ...........................................................................27 
5.3 
TREATMENT COMPLIANCE .......................................................................27 
5.3.1 
Prior and Concomitant Medications .............................................................28 
5.3.1.1 
Prior Medications ..................................................................................... 28 
5.3.1.2 
Concomitant Medications ........................................................................ 28 
6. 
STUDY PROCEDURES ................................................................................... 28 

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6.1 
PHARMACOKINETIC ASSESSMENTS AND ENDPOINTS ......................29 
6.1.1 
Pharmacokinetic Sample Collection, Shipping, and Storage .......................30 
6.1.2 
Pharmacokinetic Sample Analysis................................................................31 
6.2 
SAFETY ASSESSMENTS AND ENDPOINTS ..............................................31 
6.2.1 
Adverse Events .............................................................................................31 
6.2.1.1 
Adverse Event Definitions ....................................................................... 31 
6.2.1.2 
Eliciting and Documenting Adverse Events ............................................ 33 
6.2.1.3 
Reporting Adverse Events ....................................................................... 34 
6.2.1.4 
Reporting of Serious Adverse Events ...................................................... 34 
6.2.1.5 
Assessment of Severity ............................................................................ 35 
6.2.1.6 
Assessment of Causality .......................................................................... 36 
6.2.1.7 
Follow-up of Adverse Events .................................................................. 37 
6.2.1.8 
Reactogenicity ......................................................................................... 37 
6.2.1.9 
Reporting of Pregnancy ........................................................................... 37 
6.2.2 
Clinical Laboratory Testing ..........................................................................38 
6.2.3 
Medical History ............................................................................................40 
6.2.4 
Vital Sign Measurements ..............................................................................40 
6.2.5 
Electrocardiograms .......................................................................................40 
6.2.6 
Physical Examinations ..................................................................................41 
6.2.7 
Unscheduled Visits .......................................................................................42 
7. 
STATISTICAL ANALYSIS PLANS ................................................................ 42 
7.1 
SAMPLE SIZE CALCULATIONS..................................................................42 
7.2 
ANALYSIS POPULATIONS ...........................................................................42 
7.3 
STATISTICAL ANALYSIS .............................................................................42 
7.3.1 
Pharmacokinetic Analyses ............................................................................43 
7.3.2 
Safety Analyses ............................................................................................43 
7.4 
HANDLING OF BELOW THE LIMIT OF QUANTIFICATION AND 
MISSING DATA ..............................................................................................44 
7.5 
INTERIM ANALYSES ....................................................................................44 
8. 
REFERENCE LIST........................................................................................... 45 
9. 
APPENDICES .................................................................................................... 46 
9.1 
APPENDIX 1: LIST OF ABBREVIATIONS ..................................................46 
9.2 
APPENDIX 2: SCHEDULE OF EVENTS ......................................................48 
9.3 
APPENDIX 3: STUDY GOVERNANCE .......................................................50 
9.3.1 
Data Quality Assurance ................................................................................50 
9.3.2 
Investigator Obligations ...............................................................................51 
9.3.2.1 
Confidentiality ......................................................................................... 51 
9.3.2.2 
Institutional Review ................................................................................. 51 

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9.3.2.3 
Subject Consent ....................................................................................... 52 
9.3.2.4 
Exclusion of Children .............................................................................. 52 
9.3.2.5 
Study Reporting Requirements ................................................................ 53 
9.3.2.6 
Financial Disclosure and Obligations ...................................................... 53 
9.3.2.7 
Investigator Documentation ..................................................................... 53 
9.3.2.8 
Study Conduct ......................................................................................... 54 
9.3.2.9 
Case Report Forms and Source Documents ............................................ 54 
9.3.2.10 
Adherence to Protocol ............................................................................. 55 
9.3.2.11 
Reporting Adverse Events ....................................................................... 55 
9.3.2.12 
Investigator’s Final Report ...................................................................... 55 
9.3.2.13 
Records Retention .................................................................................... 55 
9.3.2.14 
Publications .............................................................................................. 55 
9.3.3 
Study Management .......................................................................................56 
9.3.3.1 
Monitoring ............................................................................................... 56 
9.3.4 
Safety Monitoring Plan .................................................................................57 
9.3.5 
Medical Monitor ...........................................................................................57 
9.3.6 
Safety Oversite (Independent Safety Monitor) .............................................57 
9.3.6.1 
Inspection of Records .............................................................................. 57 
9.3.6.2 
Management of Protocol Amendments and Deviations .......................... 58 
9.3.6.3 
Study Termination .................................................................................... 59 
9.3.6.4 
Final Report ............................................................................................. 59 
9.4 
APPENDIX 4: CHANGE HISTORY ..............................................................60 
9.4.1 
Protocol Amendment 1 .................................................................................60 
9.4.2 
Protocol Amendment 2 .................................................................................61 
LIST OF TABLES 
Table 5-1 
Excipients of TPOXX Capsules ...................................................................... 26 
Table 9-1 
Schedule of Events .......................................................................................... 48 

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Protocol No. SIGA-246-022 
Clinical Study Protocol 
 
 
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PROTOCOL SYNOPSIS 
PROTOCOL NO.: SIGA-246-022 
TITLE: A Post Marketing Study of the Safety, Tolerability, and Pharmacokinetics of 
TPOXX® in Adult Subjects Weighing More Than 120 kg 
STUDY PHASE: 4 Post Marketing Study 
STUDY SITE: PPD Phase I Clinic, 7551 Metro Center Drive, Suite 200, Austin, TX 78744, 
USA. 
OBJECTIVES: 
Primary: 
The primary objective of this study is to determine the pharmacokinetic (PK) profile of 
600 mg oral TPOXX (3 × 200-mg capsules) administered twice daily (BID) for 7 days in 
adult subjects weighing more than 120 kg to determine if a change in dosing regimen would 
be needed in these patients. 
Secondary: 
The secondary objective of this study is to evaluate the safety and tolerability of 600 mg oral 
TPOXX administered BID for 7 days in healthy adult subjects weighing more than 120 kg. 
STUDY DESIGN AND METHODOLOGY: 
This is an open-label, multiple-dose study to assess the safety, tolerability, and PK of TPOXX 
600 mg BID when administered orally for 7 days to adult subjects weighing more than 
120 kg. A total of 36 subjects, ages 18 to 50, inclusive, will be enrolled. The study will 
consist of a screening period (Day –28 to Day –2), a treatment and confinement period 
(Days –1 to 9), a follow-up telephone call or visit (Day 14 [+2 days]), and a follow-up 
telephone call (Day 37 [+2 days]).  
Subjects will undergo screening evaluations to determine eligibility within 28 days before 
study drug administration. Subjects will be admitted to the study site on Day –1 to complete 
baseline assessments; results of these assessments must be reviewed by the investigator 
before dosing. Starting in the morning of Day 1, subjects will receive 600 mg oral TPOXX 
BID for 7 days (Days 1 through 7). 
All subjects will be provided meals (consisting of approximately 600 calories and 25 g fat) 
30 minutes prior to study drug administration and subjects must fast for 2 hours after taking 
study drug. Subjects should eat this meal within 30 minutes or less of taking study drug. 
Study drug and meals must be taken with water only, and no other beverage except water 
should be ingested within 3 hours before or 3 hours after study drug administration. 
Subjects will remain confined to the study site for collection of PK samples and will be 
carefully monitored for safety and tolerability until discharge on Day 9. Subjects who have 
abnormal physical examination findings or an ongoing adverse event (AE)/serious adverse 
event (SAE) on Day 9 that is deemed related to study drug or per investigator or SIGA 
discretion will return to the study site on Day 14 (+2 days) for a follow-up visit. All other 
subjects will have the Day 14 (+2 days) follow-up via telephone. All subjects will have a 

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Protocol No. SIGA-246-022 
Clinical Study Protocol 
 
 
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follow-up telephone call 30 days after administration of the last dose of study drug 
(Day 37 [+2 days]) to report any SAEs. At the time of discharge from the clinical research 
unit, subjects will be instructed to notify the investigator of any SAEs that occur within 
30 days after administration of the last dose of study drug. Serious AEs will be followed until 
the SAE is stable or until resolution as determined by the investigator and/or medical 
monitor. 
The total duration of the study for each subject, including the screening period, treatment 
period, and the Day 37 (+2 days) follow-up telephone call, will be approximately 65 days. 
STUDY POPULATION: 
Inclusion Criteria: 
Each subject must meet all the following criteria to be enrolled in this study: 
1. Subject is male or female between 18 and 50 years of age, inclusive. 
2. Subject has a body weight >120 kg at screening, at check-in on Day -1, and prior to 
dosing on Day 1. 
3. Women of childbearing potential, have a negative β human chorionic gonadotropin 
pregnancy test (serum) at the screening visit and a confirmatory negative serum 
pregnancy test on Day –1 before receipt of study drug, and meet 1 of the following 
criteria: 
a. The subject or their partner has undergone surgical sterilization 
b. The subject is postmenopausal, defined as 12 consecutive months with no menses 
without an alternative medical cause and has a documented plasma 
follicle-stimulating hormone level >40 IU/mL 
c. The subject agrees to be abstinent (ie, heterosexually inactive or women in a religious 
order) 
d. The subject agrees to consistently use 1 of the following methods of contraception 
from the beginning of screening (which they had been consistently using for at least 
30 days before the first dose of study drug) through 30 days after the last dose of 
study drug: 
i. 
Condoms, male or female, with a spermicide 
NOTE: For male subjects, condoms must be used for 90 days after the last dose 
of study drug. 
ii. 
Diaphragm or cervical cap with spermicide 
iii. 
Intrauterine device with spermicide 
iv. 
Oral contraceptives or other hormonal methods 
NOTE: Subject must agree to use an additional nonhormonal method of 
contraception in conjunction with oral contraceptives. 
v. 
Male sexual partner who had undergone a vasectomy at least 3 months before 
screening 
4. Male subjects must agree to not donate sperm from the first dose of study drug through 
90 days after the last dose of study drug. 

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Protocol No. SIGA-246-022 
Clinical Study Protocol 
 
 
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5. Subject is considered by the investigator to be in good general health as determined by 
medical history (no hospitalizations for chronic medical conditions in the previous 
2 years), clinical laboratory results, vital sign measurements, 12-lead electrocardiogram 
(ECG) results, and physical examination findings at screening. 
6. Subject agrees to comply with all protocol requirements. 
7. Subject is able to provide written informed consent. 
8. Subject agrees to comply with the dietary requirements. 
9. Subject does not intend to lose weight (diet or weight loss) from the screening visit and 
throughout the study. 
EXCLUSION CRITERIA: 
Subjects meeting any of the following criteria will be excluded from the study: 
1. Subject is a female who is pregnant or breastfeeding or planning to become pregnant 
within 3 months after the last dose of study drug. 
2. Subject has a history of any clinically significant conditions including: 
• Asthma treated with oral systemic steroids within the past 6 months 
• Diabetes mellitus (type 1 or 2), with the exception of gestational diabetes 
• Thyroidectomy or thyroid disease that required medication within the past 12 months 
• Serious angioedema episodes within the previous 3 years or requiring medication in 
the previous 2 years 
• Head trauma resulting in a diagnosis of traumatic brain injury other than concussion 
• Frequent episodes of headache. 
3. Subject has received treatment in another clinical study of an investigational drug (or 
medical device) within 30 days or 5 half-lives (whichever is longer) before the first dose 
of study drug. 
4. Subject has been previously enrolled in any clinical study involving TPOXX 
(tecovirimat). 
5. Subject has a history of relevant drug and/or food allergies (ie, allergy to tecovirimat or 
excipients, or any significant food allergy that could preclude a standard diet in the study 
site). 
6. Subject has any condition possibly affecting drug absorption (eg, previous surgery on the 
gastrointestinal tract, including removal of parts of the stomach, bowel, liver, gallbladder, 
or pancreas, with the exception of appendectomy). 
7. Subject has evidence or history of clinically significant allergic (except for untreated, 
asymptomatic, seasonal allergies at time of the first dose of study drug), hematological, 
endocrine, pulmonary, gastrointestinal, cardiovascular, hepatic, psychiatric, or 
neurological disease. Exceptions to these criteria (eg, stable, mild joint disease 
unassociated with collagen vascular disease) may be made following discussions with the 
medical monitor. 

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Clinical Study Protocol 
 
 
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8. Subject has a history of cardiac disease, symptomatic or asymptomatic arrhythmias, 
syncopal episodes, or risk factors for torsades de pointes (eg, heart failure, hypokalemia). 
9. Subject has a family history of sudden cardiac death, not clearly due to acute myocardial 
infarction. 
10. Subject has a seizure disorder or history of seizures (does not include childhood febrile 
seizures) or a past history that increases seizure risks such as significant head injury that 
caused loss of consciousness or other changes in the subject’s daily function, concussion, 
stroke, central nervous system infection or disease, or alcohol or drug abuse or family 
history of idiopathic seizures. 
11. Subject has a history of a peptic ulcer or significant gastrointestinal bleed. 
12. Subject has a bleeding disorder diagnosed by a doctor (eg, factor deficiency, 
coagulopathy, or platelet disorder requiring special precautions) or significant bruising or 
bleeding difficulties with blood draws. 
13. Subject has a malignancy that is active, or treated malignancy for which there is not 
reasonable assurance of sustained cure, or malignancy that is likely to recur during the 
period of the study (subject should be in complete remission for at least 5 years). 
14. Subject has neutropenia or other blood dyscrasia determined to be clinically significant 
by the investigator. 
15. Subject has used any of the following prohibited medications from within 7 days (or 
5 half-lives, whichever is longer) before the first dose of study drug: antidiabetic 
medication; anticoagulants; anticonvulsants; substrates of the breast cancer resistance 
protein transporter including methotrexate, mitoxantrone, imatinib, irinotecan, lapatinib, 
rosuvastatin, sulfasalazine, and topotecan; substrates of CYP2C8 including repaglinide, 
paclitaxel, Montelukast, pioglitazone, rosiglitazone; and substrates of CYP2C19 
including S-mephenytoin, clobazam, diazepam, rabeprazole, voriconazole, lansoprazole, 
and omeprazole. Medications not listed here that are known (or thought) to be CYP3A4 
substrates may be allowed at the investigator’s discretion, after consultation with the 
medical monitor, if administration poses little to no risk to the subject. 
16. Subject has a history of drug or alcohol abuse or dependency within the last year before 
screening. 
17. Subject has a history of an eating disorder. 
18. Subject has a current or recent (<30 days before screening) history of clinically 
significant bacterial, fungal, or mycobacterial infection. 
19. Subject has a current clinically significant viral infection. 
20. Subject has a known clinically significant chronic viral infection (eg, human T cell 
lymphotropic virus I or II). 
21. Subject has consumed grapefruit or grapefruit juice, Seville orange or Seville 
orange-containing products (eg, marmalade), or caffeine- or xanthine-containing products 
within 48 hours before the first dose of study drug or throughout the study. 
22. Subject has used any prescription (excluding hormonal birth control) or over-the-counter 
medication (including herbal or nutritional supplements) within 14 days before the first 
dose of study drug. 

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23. Subject demonstrates long-term use (≥14 consecutive days) of glucocorticoids including 
oral or parenteral prednisone or equivalent (>20 mg total dose per day) or high-dose 
inhaled steroids (>800 mcg/day of beclomethasone dipropionate or equivalent) within the 
preceding 1 month (low-dose [≤800 mcg/day of beclomethasone dipropionate or 
equivalent] inhaled and topical steroids are allowed). 
24. Subject has donated >450 mL blood or blood components within 30 days before the first 
dose of study drug. The investigator should instruct subjects who participate in this study 
to not donate blood or blood components for 4 weeks after the completion of the study. 
25. Subject is a smoker or has used nicotine or nicotine-containing products (eg, cigarettes, 
electronic vapor cigarettes, cigars, chewing tobacco, snuff, nicotine patches, or nicotine 
gum) within 6 months before the first dose of study drug. 
26. Subject has consumed pomegranate or pomegranate juice, pomelo fruits or pomelo juice, 
or alcohol within 72 hours before the first dose of study drug. 
27. Subject reports participation in strenuous activity or contact sports within 24 hours before 
the first dose of study drug. 
28. Subject has known hepatitis B or C infection or positive test for hepatitis B surface 
antigen, hepatitis C virus antibody, or human immunodeficiency virus type 1 or 2 
antibodies at screening. 
29. Subject has a positive test result for amphetamines (including methamphetamines and 
ecstasy/methylenedioxymethamphetamine), barbiturates, benzodiazepines, cannabinoids 
(including tetrahydrocannabinol), cocaine metabolites, opiates (including heroin, codeine, 
and oxycodone), or alcohol at screening or check-in. 
30. Subject has any of the following laboratory test results within 28 days before the first 
dose of study drug: 
• Estimated serum creatinine clearance (Cockcroft-Gault) <90 mL/min 
• Creatinine in males >1.7 mg/dL and in females >1.4 mg/dL (1.3 times the upper 
central laboratory reference range) 
• Hemoglobin ≤10% of the lower central laboratory reference range 
• White blood cell count not within the central laboratory reference range 
• Absolute neutrophil count <1000 cells/mm3 
• Platelets not within ±10% of central laboratory reference range 
• Alanine aminotransferase >1.5 times above the upper central laboratory reference 
range 
• Aspartate aminotransferase >1.5 times above the upper central laboratory reference 
range 
• Alkaline phosphatase >20% above the upper central laboratory reference range 
• Hemoglobin A1c ≥7.0% 
• Cholesterol ≥300 mg/dL and low-density lipoprotein ≥190 mg/dL. 
31. Subject has a blood pressure considered to be clinically significant by the investigator. 
Blood pressure may be retested twice in the sitting position at 5-minute intervals. 

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32. Subject has a resting heart rate of <40 beats per minute or >100 beats per minute at 
screening. 
33. Subject has an abnormal ECG at screening that is determined by the investigator to be 
clinically significant. 
34. Male subject has a QTcF >450 ms or female subject has a QTcF >470 ms at screening or 
Day –1. 
35. In the opinion of the investigator, the subject is not suitable for entry into the study. 
EVALUATION PROCEDURES: 
Pharmacokinetic Assessments: 
Blood samples for PK analysis of TPOXX will be collected from all subjects on Day 1 before 
study drug administration (0 hour), at 0.5, 1, 2, 4, 6, 8, 12 (before the PM dose), 14, 16, 18, 
20, and 24 hours (before the AM dose on Day 2), on Day 6 (before the AM dose and 4 hours 
after the AM dose), on Day 7 before the AM dose (0 hour), at 0.5, 1, 2, 4, 6, 8, 12 (before the 
PM dose), 14, 16, 18, 20, and 24 hours (Day 8, 24 hours after the AM dose on Day 7), and on 
Day 9 (48 hours after the AM dose on Day 7). 
For PK samples, the acceptable window for collection from the scheduled collection time 
point will be as follows: ±5 minutes for the time points from 1 to 8 hours and ±15 minutes 
for the 12- to 48-hour time points. 
The following plasma PK parameters will be calculated for TPOXX using actual sampling 
times rather than scheduled sampling times and will include but are not limited to:  
• Area under the plasma concentration-time curve (AUC) from time 0 to the last 
quantifiable measurement (AUC0-t) 
• AUC from time 0 extrapolated to infinity (AUC0-∞) 
• AUC from time 0 to 24 hours (AUC0-24) 
• AUC during the first dosing interval (tau = 12 hours) (AUC0-tau) 
• Maximum drug concentration in plasma (Cmax) 
• Time to Cmax (Tmax) 
• Apparent volume of distribution (Vd/F) 
• Apparent total body clearance (CL/F) 
• Concentration observed prior to the next dose administration (Ctrough) 
• Terminal elimination half-life (t1/2) 
• Terminal elimination rate constant (λz) 
• Percentage of AUC0-∞ extrapolated from the last quantifiable measurement to infinity 
(%AUCextrap). 

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Safety Assessments: 
Safety and tolerability will be assessed by monitoring and recording of AEs, clinical 
laboratory test results (hematology, serum chemistry, pregnancy, and urinalysis), vital sign 
measurements (systolic and diastolic blood pressures, heart rate, respiratory rate, and body 
temperature), 12-lead ECG results, and physical examination findings. 
STUDY DRUG, DOSAGE, AND ROUTE OF ADMINISTRATION: 
TPOXX, 600 mg (3 × 200-mg capsules), will be administered orally twice daily, 
approximately 12 hours (±30 minutes) apart, on Days 1 through 7. 
STATISTICAL METHODS: 
Complete, detailed statistical methods will be described in the statistical analysis plan. 
Sample Size: 
The sample size (N = 36 [to allow at least 32 enrolled subjects to complete]) for this study is 
based on clinical and practical considerations and not on a formal statistical power 
calculation. The sample size is considered sufficient to effectively assess the PK and safety 
profiles of TPOXX. 
Analysis Populations: 
• The Safety Population will include all subjects who receive at least 1 dose of study drug. 
• The PK Population will include subjects who receive study drug and have sufficient 
concentration data to facilitate the calculation of PK variables. 
Pharmacokinetic Analyses: 
Individual plasma concentration and time deviation data will be presented in a data listing. 
Plasma concentration data will be listed and summarized using the following descriptive 
statistics: number of subjects, arithmetic mean, standard deviation (SD), coefficient of 
variation (CV), geometric mean, geometric CV, median, minimum, and maximum. Individual 
and mean plasma concentration versus time profiles will be presented in figures on both 
linear and semilogarithmic scales. 
The PK parameters of TPOXX will be analyzed based on the actual sampling times. All 
parameters will be determined using noncompartmental methods using Phoenix® 
WinNonlin® Version 8.0 or higher (Certara, L.P., Princeton, New Jersey) or SAS® Version 9.4 
or higher (SAS Institute Inc., Cary, North Carolina). 
The individual PK parameters and weight-normalized PK parameters will be presented in 
data listings and summarized using the following descriptive statistics: number of subjects, 
arithmetic mean, SD, CV, median, minimum, maximum, geometric mean, geometric SD, and 
geometric CV. 
Safety Analyses: 
Adverse events will be coded by preferred term and system organ class using the latest 
version of the Medical Dictionary for Regulatory Activities and summarized overall. All AE 
data will be presented in a data listing. Treatment-emergent AEs will be summarized overall, 
as well as by severity and relationship to study drug. Serious AEs and AEs leading to 

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discontinuation of study drug will also be presented in the data listings and summarized 
overall. 
Actual values and changes from baseline for clinical laboratory test results, vital sign 
measurements, and 12-lead ECG results will be summarized at each time point using 
descriptive statistics (number of subjects, mean, SD, median, minimum, and maximum). 
Shift tables will be generated for clinical laboratory test results. Clinical laboratory data, vital 
sign measurements, 12-lead ECG results, and physical examination findings will be 
presented in data listings. 
DATE OF PROTOCOL: 02 August 2019 

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1. 
INTRODUCTION 
1.1 
BACKGROUND 
Historically, variola virus (VARV), the etiologic agent of smallpox, has been one of the more 
important human pathogens. Smallpox is highly communicable and carries exceptionally 
high morbidity. Secondary attack rates from 30% to 80% have been reported among 
unvaccinated members of households.1 Mortality rates range from 1% for variola minor to 
30% for variola major.1 With the advent of biowarfare as an instrument of terrorism, 
smallpox can no longer be thought of as a disease only of historic impact.  
In July 2018, the FDA approved the oral formulation of TPOXX for the treatment of patients 
with human smallpox disease caused by VARV.  
1.2 
RATIONALE FOR STUDY 
This study is being conducted as an FDA post marketing commitment to the approved New 
Drug Application for TPOXX. SIGA is required to conduct a study to determine the 
pharmacokinetic (PK) profile of TPOXX in subjects with a body weight greater than 
120 kilograms (>120 kg) to determine if a change in dosing regimen would be needed in 
these patients. 
1.3 
POTENTIAL RISKS AND BENEFITS 
1.3.1 
Potential Risks 
The effect of TPOXX on a fetus or nursing baby is not yet known; therefore, women of 
childbearing potential participating in this study will be required to agree to use an acceptable 
means of birth control from 30 days before the first dose of study drug and continuing 
through 30 days after the last dose of study drug. Pregnancy testing will be performed at the 
screening visit and checked by the investigator for negative pregnancy before administration 
of study drug on Day –1. Women who are pregnant or lactating or plan to become pregnant 
within 3 months after study drug administration will be excluded from the study; if a female 
subject becomes pregnant during study participation, study drug dosing will be discontinued, 
and the subject will be withdrawn from the study (Section 6.2.1.9). 
As with all drugs, there is potential risk of an allergic reaction. At this time, there is no 
definitive information on the allergic activity of TPOXX. Headache and nausea have been 
the most common AEs in clinical studies completed to date. There may be other side effects 

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of TPOXX that are not yet known. Full details can be found in the TPOXX full prescribing 
information.2 
1.3.2 
Known Potential Benefits 
As this study will be conducted in subjects free from smallpox, no direct health benefits from 
taking the study drug are expected. Study subjects may benefit from receiving the laboratory 
testing, ECGs, and physical examinations. Others may benefit from knowledge gained in this 
study that may aid in the development of a drug for the treatment of smallpox.  
2. 
STUDY OBJECTIVES 
2.1 
PRIMARY OBJECTIVE 
The primary objective of this study is to determine the PK profile of 600 mg oral TPOXX 
(3 × 200-mg capsules) administered twice daily (BID) for 7 days in adult subjects weighing 
more than 120 kg to determine if a change in dosing regimen would be needed in these 
patients. 
2.2 
SECONDARY OBJECTIVE 
The secondary objective of this study is to evaluate the safety and tolerability of 600 mg oral 
TPOXX administered BID for 7 days in adult subjects weighing more than 120 kg. 
3. 
STUDY POPULATION 
Approximately 36 male and female subjects will be enrolled at a single center in the United 
States to achieve at least 32 evaluable enrolled subjects. 
3.1 
INCLUSION CRITERIA 
Each subject must meet all the following criteria to be enrolled in this study: 
 Subject is male or female between 18 and 50 years of age, inclusive. 
 Subject has a body weight >120 kg at screening, at check-in on Day -1, and prior to 
dosing on Day 1. 
 Women of childbearing potential, have a negative β human chorionic gonadotropin 
pregnancy test (serum) at the screening visit and a confirmatory negative serum 

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pregnancy test on Day –1 before receipt of study drug, and meet 1 of the following 
criteria: 
 The subject or their partner has undergone surgical sterilization 
 The subject is postmenopausal, defined as 12 consecutive months with no menses 
without an alternative medical cause and has a documented plasma 
follicle-stimulating hormone level >40 IU/mL 
 The subject agrees to be abstinent (ie, heterosexually inactive or women in a 
religious order) 
 The subject agrees to consistently use 1 of the following methods of contraception 
from the beginning of screening (which they had been consistently using for at 
least 30 days before the first dose of study drug) through 30 days after the last 
dose of study drug: 
i. 
Condoms, male or female, with a spermicide 
NOTE: For male subjects, condoms must be used for 90 days after the last 
dose of study drug. 
ii. 
Diaphragm or cervical cap with spermicide 
iii. 
Intrauterine device with spermicide 
iv. 
Oral contraceptives or other hormonal methods 
NOTE: Subject must agree to use an additional nonhormonal method of 
contraception in conjunction with oral contraceptives. 
v. 
Male sexual partner who had undergone a vasectomy at least 3 months before 
screening. 
 Male subjects must agree to not donate sperm from the first dose of study drug 
through 90 days after the last dose of study drug. 
 Subject is considered by the investigator to be in good general health as determined 
by medical history (no hospitalizations for chronic medical conditions in the 
previous 2 years), clinical laboratory results, vital sign measurements, 12-lead ECG 
results, and physical examination findings at screening. 
 Subject agrees to comply with all protocol requirements. 
 Subject is able to provide written informed consent. 
 Subject agrees to comply with the dietary requirements. 

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 Subject does not intend to lose weight (diet or weight loss) from the screening visit 
and throughout the study. 
3.2 
EXCLUSION CRITERIA 
Subjects meeting any of the following criteria will be excluded from the study: 
 Subject is a female who is pregnant or breastfeeding or planning to become 
pregnant within 3 months after the last dose of study drug. 
 Subject has a history of any clinically significant conditions including: 
• Asthma treated with oral systemic steroids within the past 6 months 
• Diabetes mellitus (type 1 or 2), with the exception of gestational diabetes 
• Thyroidectomy or thyroid disease that required medication within the past 
12 months 
• Serious angioedema episodes within the previous 3 years or requiring medication 
in the previous 2 years 
• Head trauma resulting in a diagnosis of traumatic brain injury other than 
concussion 
• Frequent episodes of headache. 
 Subject has received treatment in another clinical study of an investigational drug 
(or medical device) within 30 days or 5 half-lives (whichever is longer) before the 
first dose of study drug. 
 Subject has been previously enrolled in any clinical study involving TPOXX 
(tecovirimat). 
 Subject has a history of relevant drug and/or food allergies (ie, allergy to 
tecovirimat or excipients, or any significant food allergy that could preclude a 
standard diet in the study site). 
 Subject has any condition possibly affecting drug absorption (eg, previous surgery 
on the gastrointestinal tract, including removal of parts of the stomach, bowel, liver, 
gallbladder, or pancreas, with the exception of appendectomy). 
 Subject has evidence or history of clinically significant allergic (except for 
untreated, asymptomatic, seasonal allergies at time of the first dose of study drug), 
hematological, endocrine, pulmonary, gastrointestinal, cardiovascular, hepatic, 
psychiatric, or neurological disease. Exceptions to these criteria (eg, stable, mild 

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joint disease unassociated with collagen vascular disease) may be made following 
discussions with the medical monitor. 
 Subject has a history of cardiac disease, symptomatic or asymptomatic arrhythmias, 
syncopal episodes, or risk factors for torsades de pointes (eg, heart failure, 
hypokalemia). 
 Subject has a family history of sudden cardiac death not clearly due to acute 
myocardial infarction. 
 Subject has a seizure disorder or history of seizures (does not include childhood 
febrile seizures) or a past history that increases seizure risks such as significant 
head injury that caused loss of consciousness or other changes in the subject’s daily 
function, concussion, stroke, central nervous system infection or disease, or alcohol 
or drug abuse or family history of idiopathic seizures. 
 Subject has a history of a peptic ulcer or significant gastrointestinal bleed. 
 Subject has a bleeding disorder diagnosed by a doctor (eg, factor deficiency, 
coagulopathy, or platelet disorder requiring special precautions) or significant 
bruising or bleeding difficulties with blood draws. 
 Subject has a malignancy that is active, or treated malignancy for which there is not 
reasonable assurance of sustained cure, or malignancy that is likely to recur during 
the period of the study (subject should be in complete remission for at least 
5 years). 
 Subject has neutropenia or other blood dyscrasia determined to be clinically 
significant by the investigator. 
 Subject has used any of the following prohibited medications from within 7 days 
(or 5 half-lives, whichever is longer) before the first dose of study drug: 
antidiabetic medication; anticoagulants; anticonvulsants; substrates of the BCRP 
transporter including methotrexate, mitoxantrone, imatinib, irinotecan, lapatinib, 
rosuvastatin, sulfasalazine, and topotecan; substrates of CYP2C8 including 
repaglinide, paclitaxel, Montelukast, pioglitazone, rosiglitazone; and substrates of 
CYP2C19 including S-mephenytoin, clobazam, diazepam, rabeprazole, 
voriconazole, lansoprazole, and omeprazole. Medications not listed here that are 
known (or thought) to be CYP3A4 substrates may be allowed at the investigator’s 
discretion, after consultation with the medical monitor, if administration poses little 
to no risk to the subject. 

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 Subject has a history of drug or alcohol abuse or dependency within the last year 
before screening. 
 Subject has a history of an eating disorder. 
 Subject has a current or recent (<30 days before screening) history of clinically 
significant bacterial, fungal, or mycobacterial infection. 
 Subject has a current clinically significant viral infection. 
 Subject has a known clinically significant chronic viral infection (eg, human T cell 
lymphotropic virus I or II). 
 Subject has consumed grapefruit or grapefruit juice, Seville orange or Seville 
orange-containing products (eg, marmalade), or caffeine- or xanthine-containing 
products within 48 hours before the first dose of study drug or throughout the study. 
 Subject has used any prescription (excluding hormonal birth control) or 
over-the-counter medication (including herbal or nutritional supplements) within 
14 days before the first dose of study drug. 
 Subject demonstrates long-term use (≥14 consecutive days) of glucocorticoids 
including oral or parenteral prednisone or equivalent (>20 mg total dose per day) or 
high-dose inhaled steroids (>800 mcg/day of beclomethasone dipropionate or 
equivalent) within the preceding 1 month (low-dose [≤800 mcg/day of 
beclomethasone dipropionate or equivalent] inhaled and topical steroids are 
allowed). 
 Subject has donated >450 mL blood or blood components within 30 days before the 
first dose of study drug. The investigator should instruct subjects who participate in 
this study to not donate blood or blood components for 4 weeks after the 
completion of the study. 
 Subject is a smoker or has used nicotine or nicotine-containing products (eg, 
cigarettes, electronic vapor cigarettes, cigars, chewing tobacco, snuff, nicotine 
patches, or nicotine gum) within 6 months before the first dose of study drug. 
 Subject has consumed pomegranate or pomegranate juice, pomelo fruits or pomelo 
juice, or alcohol within 72 hours before the first dose of study drug. 
 Subject reports participation in strenuous activity or contact sports within 24 hours 
before the first dose of study drug. 

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 Subject has known hepatitis B or C infection or positive test for hepatitis B surface 
antigen, hepatitis C virus antibody, or human immunodeficiency virus type 1 or 2 
antibodies at screening. 
 Subject has a positive test result for amphetamines (including methamphetamines 
and ecstasy/methylenedioxymethamphetamine), barbiturates, benzodiazepines, 
cannabinoids (including tetrahydrocannabinol), cocaine metabolites, opiates 
(including heroin, codeine, and oxycodone), or alcohol at screening or check-in. 
 Subject has any of the following laboratory test results within 28 days before the 
first dose of study drug: 
• Estimated serum creatinine clearance (Cockcroft-Gault) <90 mL/min 
• Creatinine in males >1.7 mg/dL and in females >1.4 mg/dL (1.3 times the upper 
central laboratory reference range) 
• Hemoglobin ≤10% of the lower central laboratory reference range 
• White blood cell count not within the central laboratory reference range 
• Absolute neutrophil count <1000 cells/mm3 
• Platelets not within ±10% of central laboratory reference range 
• Alanine aminotransferase >1.5 times above the upper central laboratory reference 
range 
• Aspartate aminotransferase >1.5 times above the upper central laboratory 
reference range 
• Alkaline phosphatase >20% above the upper central laboratory reference range 
• Hemoglobin A1c ≥7.0% 
• Cholesterol ≥300 mg/dL and low-density lipoprotein ≥190 mg/dL. 
 Subject has a blood pressure considered to be clinically significant by the 
investigator. Blood pressure may be retested twice in the sitting position at 5-
minute intervals. 
 Subject has a resting heart rate of <40 beats per minute or >100 beats per minute at 
screening. 
 Subject has an abnormal ECG at screening that is determined by the investigator to 
be clinically significant. 
 Male subject has a QTcF >450 ms or female subject has a QTcF >470 ms at 
screening or Day –1. 
 In the opinion of the investigator, the subject is not suitable for entry into the study. 

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3.3 
OTHER SCREENING CONSIDERATIONS 
3.3.1 
Subject Restrictions During the Study 
• Subjects must be willing to remain confined at the study site from check-in (Day –1) until 
safety assessments are completed on Day 9. 
• Subjects who have abnormal physical examination findings or an ongoing AE/SAE on 
Day 9 that is deemed related to study drug or per investigator or SIGA discretion will 
return to the study site on Day 14 (+2 days) for a follow-up visit. 
3.4 
WITHDRAWAL OF SUBJECTS FROM THE STUDY 
3.4.1 
Reasons for Withdrawal 
Subjects can withdraw consent and discontinue from the study at any time, for any reason, 
without prejudice to further treatment. 
The investigator may withdraw a subject from the study for any of the following: 
• The subject is in violation of the protocol. 
• The subject experiences a serious or intolerable AE. 
• The subject becomes pregnant. 
• The subject is noncompliant. 
• The subject has laboratory abnormalities for assessments listed in 
Sections 4.1 or 4.2 that meet Grade 3 or Grade 4 on the Division of 
Acquired Immune Deficiency Syndrome (DAIDS) AE Grading Table 
Version 2.1 July 2017, any other Grade 3 or Grade 4 AE; or a Grade 2 or 
higher rash considered by the investigator to be possibly, probably, or 
definitely related to study drug. 
• The subject develops, during the course of the study, symptoms or conditions listed in 
the exclusion criteria. 
• The subject requires a medication prohibited by the protocol. 
• The subject requests an early discontinuation for any reason. 
• The subject’s primary care provider requests that the subject be withdrawn. 

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• The independent safety monitor (ISM), SIGA, or the FDA requests subject 
withdrawal based on study safety findings. 
The investigator can also withdraw a subject upon the request of SIGA or if SIGA terminates 
the study. Upon occurrence of a SAE or intolerable AE, the investigator will confer with 
SIGA. If a subject is discontinued because of an AE, the event will be followed until it is 
resolved or stabilized as determined by the investigator and/or the medical monitor. 
3.4.2 
Handling of Withdrawals 
Subjects are free to withdraw from the study at any time upon request. Subject participation 
in the study may be stopped at any time at the discretion of the investigator or at the request 
of SIGA. 
When a subject withdraws from the study, the reason(s) for withdrawal will be recorded by 
the investigator in the electronic case report form (eCRF). Whenever possible, any subject 
who withdraws from the study prematurely will undergo all Day 9/early discontinuation 
assessments (Table 9-1). Any subject who fails to return for final assessments will be 
contacted by the study site personnel in an attempt to have them comply with the protocol. 
The status of subjects who fail to complete final assessments will be documented in the 
eCRF. 
3.4.3 
Halting Rules 
The medical monitor, investigator, SIGA, and ISM will review all AEs. All AEs determined 
by the investigator to be severe and possibly, probably, or definitely related to study drug, as 
well as all clinical assessments, laboratory test results, ECG results, or vital sign 
measurements that meet Grade 3 criteria on the DAIDS AE Grading Table will be assessed 
by the medical monitor, who will make a recommendation as to whether or not halting of the 
study should occur. At the discretion of the medical monitor, depending on the assessment of 
the severity of the event, the recommendation to halt the study may be made after 
consultation with the investigator, SIGA, and the ISM. 
The study will be temporarily halted (no new enrollments and no further study drug 
administration) by the investigator and the medical monitor, SIGA, and the ISM will be 
promptly notified according to the following criteria: 
• One subject experiences a Grade 4 AE assessed as possibly, probably, or definitely 
related to study drug. 

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• There is a subject death assessed as possibly, probably, or definitely related to study 
drug. 
• One subject experiences a seizure assessed as possibly, probably, or definitely 
related to study drug. 
• Two or more subjects experience the same or similar SAEs that are possibly, 
probably, or definitely related to the study drug. 
• Three or more subjects experience the same or similar AEs that are Grade 3 or 
above and are possibly, probably, or definitely related to the study drug. 
Study enrollment and study drug administration would resume if review of the AEs that 
caused the halt resulted in a recommendation to permit further continuation. In such an 
instance, SIGA, with participation by the investigator and the medical monitor, would consult 
with the ISM to conduct the review of all AEs that meet the criteria for halting the study. The 
study would remain suspended until the events were reviewed by the ISM and a 
recommendation was made as to whether the study should be continued or stopped. This 
constitutes a minimum criterion, and the decision to halt the study may be made based on any 
other criteria that, in the judgment of the investigator, with agreement of the medical monitor 
and ISM, indicate a potentially serious safety concern. The investigator will advise SIGA 
immediately if any of the halting rules are met. 
4. 
STUDY DESIGN 
This is an open-label, multiple-dose study to assess the safety, tolerability, and PK of TPOXX 
600 mg BID when administered orally for 7 days to adult subjects weighing more than 
120 kg. A total of 36 subjects, ages 18 to 50, inclusive, will be enrolled. The study will 
consist of a screening period (Day –28 to Day –2), a treatment and confinement period 
(Days –1 to 9), a follow-up telephone call or visit (Day 14 [+2 days]), and a follow-up 
telephone call (Day 37 [+2 days]).  
Subjects will undergo screening evaluations to determine eligibility within 28 days before 
study drug administration. Subjects will be admitted to the study site on Day –1 to complete 
baseline assessments; results of these assessments must be reviewed by the investigator 
before dosing. Starting in the morning of Day 1, subjects will receive 600 mg oral TPOXX 
BID for 7 days (Days 1 through 7). 
All subjects will be provided meals (consisting of approximately 600 calories and 25 g fat) 
30 minutes prior to study drug administration and subjects must fast for 2 hours after taking 

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study drug. Subjects should eat this meal within 30 minutes or less of taking study drug. 
Study drug and meals must be taken with water only, and no other beverage except water 
should be ingested within 3 hours before or 3 hours after study drug administration. 
Subjects will remain confined to the study site for collection of PK samples and will be 
carefully monitored for safety and tolerability until discharge on Day 9. Subjects who have 
abnormal physical examination findings or an ongoing adverse event (AE)/serious adverse 
event (SAE) on Day 9 that is deemed related to study drug or per investigator or SIGA 
discretion will return to the study site on Day 14 (+2 days) for a follow-up visit. All other 
subjects will have the Day 14 (+2 days) follow-up via telephone. All subjects will have a 
follow-up telephone call 30 days after administration of the last dose of study drug 
(Day 37 [+2 days]) to report any SAEs. At the time of discharge from the clinical research 
unit, subjects will be instructed to notify the investigator of any SAEs that occur within 30 
days after administration of the last dose of study drug. Serious AEs will be followed until 
the SAE is stable or until resolution as determined by the investigator and/or medical 
monitor. 
The total duration of the study for each subject, including the screening period, treatment 
period, and the Day 37 (+2 days) follow-up telephone call, will be approximately 65 days. 
4.1.1 
Replacements 
At the discretion of the investigator, and after consultation with the medical monitor, any 
subject who withdraws before completing the study may be replaced to retain the target of 
32 evaluable enrolled subjects. 
5. 
STUDY TREATMENT 
5.1 
TREATMENT ADMINISTERED 
On Days 1 to 7, all subjects will receive an oral dose of TPOXX 600 mg (3 × 200-mg 
capsules) BID, approximately 12 hours (±30 minutes) apart, for 7 days. 
All subjects will be provided meals consisting of approximately 600 calories and 25 g fat, 
30 minutes before study drug administration. Subjects should eat this meal within 30 minutes 
or less of taking study drug. Study drug will be administered approximately 30 minutes after 
the start of the meal. All doses of study drug will be administered to subjects by study site 
personnel with approximately 240 mL of water. Subjects must fast 2 hours after taking study 

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drug. Study drug and meals must be taken with water only, and no other beverage except 
water should be ingested within 3 hours before or 3 hours after study drug administration. 
5.2 
STUDY DRUG 
TPOXX will be supplied as 200-mg capsules containing tecovirimat monohydrate as the 
active pharmaceutical ingredient. The TPOXX capsules are immediate release, size 0, orange 
and black, hard gelatin capsules containing white to off white powder. All inactive 
ingredients/excipients are generally recognized as safe and are United States 
Pharmacopeia/National Formulary grade. The TPOXX excipients are shown in Table 5-1. 
Table 5-1 
Excipients of TPOXX Capsules 
Component 
Quality Designation 
Microcrystalline cellulose 
NFa 
Lactose monohydrate 
NF 
Croscarmellose sodium 
NFa 
Colloidal silicon dioxide 
NF 
Hydroxypropyl methylcellulose 
USP 
Sodium lauryl sulfate 
NF 
Purified waterb 
USP 
Magnesium stearate 
NF 
Abbreviations: NF, National Formulary; USP, United States Pharmacopeia. 
a Microcrystalline cellulose and croscarmellose sodium are added as intragranular and extragranular excipients. 
b Removed during processing. 
Compendial components are tested and released in accordance with full compendial methods 
and specifications before their use in clinical formulations. TPOXX 200-mg capsules are 
manufactured and analyzed for clinical use in accordance with Current Good Manufacturing 
Practices. 
TPOXX capsules are manufactured by: 
Catalent Pharma Solutions 
1100 Enterprise Drive 
Winchester, KY 40391. 
Further information on TPOXX can be found in the TPOXX full prescribing information.2 

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5.2.1 
Study Drug Packaging and Storage 
TPOXX capsules are packaged, labeled, distributed, and placed on stability testing in 
accordance with Current Good Manufacturing Practice and International Council for 
Harmonisation (ICH) guidelines. 
The 200-mg TPOXX capsules are supplied in 75-mL high density polyethylene bottles fitted 
with a heat induction seal and child-resistant screw cap closure system. Each bottle of study 
drug will contain 42 capsules and will be labeled with the drug name, SIGA’s name, a space 
to fill in the protocol number, and a space to fill in the bottle number. 
SIGA (or designee) will provide the investigator and study site with adequate quantities of 
TPOXX.  
All study drug must be stored in a secure area (eg, a locked cabinet), protected from moisture 
and light, and stored at 15°C to 30°C (59°F to 86°F). Study drug should not be refrigerated or 
used beyond the expiration dates provided by the manufacturer. The study site will be 
required to keep a temperature log to establish a record of compliance with these study drug 
storage conditions. All study drug will be kept in a secure cabinet or room with access 
restricted to necessary study site personnel. 
5.2.2 
Study Drug Accountability 
The investigator will maintain accurate records of receipt of all study drug, including dates of 
receipt. Accurate records will be kept regarding when and how much study drug is dispensed 
and used by each subject in the study. Reasons for departure from the expected dispensing 
regimen must also be recorded. Study drug accountability will be recorded in the subject 
source documentation, entered into the eCRF, and should be reviewed by the monitor during 
each monitoring visit. On a regular basis and at the completion of the study, to satisfy 
regulatory requirements regarding drug accountability, all study drug will be reconciled and 
retained or destroyed according to applicable regulations. 
5.3 
TREATMENT COMPLIANCE 
All doses of the study drug will be administered in the study site under direct observation of 
study site personnel and recorded in the eCRF. Per standard clinic procedure, study site 
personnel will perform a mouth check and inspect all dose containers to ensure that the entire 
dose was administered. Following completion of dosing procedures and return of dosing 
containers to the pharmacy by team members, pharmacy staff will follow standard clinic 

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procedures for study drug reconciliation. SIGA will provide information to PPD for 
destruction of returned used and unused study drug and study drug bottles. 
The date and time of study drug dosing will be captured and recorded on the appropriate page 
of the eCRF. If a subject is not administered study drug, the reason for the missed dose will 
be recorded. 
5.3.1 
Prior and Concomitant Medications 
Restrictions for prior and concomitant medications and therapies are provided in Sections 4.1 
and 4.2. Prior and concomitant medications and therapies will be coded using the latest 
version of the World Health Organization Drug Dictionary. 
5.3.1.1 
Prior Medications 
Information regarding prior medications taken by the subject within the 30 days before 
signing the informed consent form (ICF) will be recorded in the subject’s eCRF. 
5.3.1.2 
Concomitant Medications 
Any concomitant medication deemed necessary for the welfare of the subject during the 
study may be given at the discretion of the investigator. If a concomitant medication listed in 
Section 4.2 is taken it will be documented as a protocol deviation and a joint decision will be 
made by the investigator and SIGA to continue or discontinue the subject based on the time 
the medication was administered, its pharmacology and PK, and whether the use of the 
medication will compromise the safety of the subject or the interpretation of the data. The 
investigator is responsible for ensuring that details regarding the medication are adequately 
recorded in both the subject’s source document and the eCRF. 
6. 
STUDY PROCEDURES 
Before performing any study procedures, all potential subjects will sign an ICF as outlined in 
Section 9.3.2.3. Subjects will undergo study procedures at the time points specified in the 
schedule of events (Table 9-1). 
The total amount of blood collected from each subject over the duration of the study, 
including any extra assessments that may be required, will not exceed 500 mL. 

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6.1 
PHARMACOKINETIC ASSESSMENTS AND ENDPOINTS 
Blood samples for PK analysis of TPOXX will be collected from all subjects Day 1 before 
study drug administration (0 hour), at 0.5, 1, 2, 4, 6, 8, 12 (before the PM dose), 14, 16, 18, 
20, and 24 hours (before the AM dose on Day 2), on Day 6 (before the AM dose and 4 hours 
after the AM dose), on Day 7 before the AM dose (0 hour), at 0.5, 1, 2, 4, 6, 8, 12 (before the 
PM dose), 14, 16, 18, 20, and 24 hours (Day 8, 24 hours after the AM dose on Day 7), and on 
Day 9 (48 hours after the AM dose on Day 7). 
For PK samples, the acceptable window for collection from the scheduled collection time 
point will be as follows: ±5 minutes for the time points from 1 to 8 hours and ±15 minutes 
for the 12- to 48-hour time points. 
The following plasma PK parameters will be calculated for TPOXX using actual sampling 
times rather than scheduled sampling times and will include but are not limited to:  
• Area under the plasma concentration-time curve (AUC) from time 0 to the last 
quantifiable measurement (AUC0-t) 
• AUC from time 0 extrapolated to infinity (AUC0-∞) 
• AUC from time 0 to 24 hour (AUC0-24) 
• AUC during the first dosing interval (tau = 12 hours) (AUC0-tau) 
• Maximum drug concentration in plasma (Cmax) 
• Time to Cmax (Tmax) 
• Apparent volume of distribution (Vd/F) 
• Apparent total body clearance (CL/F) 
• Concentration observed prior to the next dose administration (Ctrough) 
• Terminal elimination half-life (t1/2) 
• Terminal elimination rate constant (λz) 
• Percentage of AUC0-∞ extrapolated from the last quantifiable measurement to infinity 
(%AUCextrap). 

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6.1.1 
Pharmacokinetic Sample Collection, Shipping, and Storage 
Blood samples (approximately 5 mL) for the determination of plasma concentrations of 
TPOXX will be collected in 5-mL lavender-topped K3EDTA Vacutainer® tubes using a 
21 gauge or larger needle, or from an indwelling intravenous catheter using a vacutainer tube. 
Blood samples should be placed on wet ice or equivalent (approximately 4°C to 8°C) and 
kept at this temperature until processed to separate plasma.  
The exact time and date of sample collection will be recorded for each sample by the 
investigator or designee on the subject’s eCRF, the vacutainer and cryovial labels, and the 
specimen shipping log. In addition, the time of study drug administration before PK sampling 
will be recorded on the subject’s eCRF. Labels will be created by the site and should contain 
the protocol number, matrix (plasma), subject number, date, and time drawn. For information 
that is not preprinted on the label, a fine tipped indelible marking pen is to be used to 
complete the entry. 
The 5-mL blood sample will be centrifuged in a refrigerated centrifuge immediately, if 
possible, or within 60 minutes of collection at 1000 to 1200 × g (2000 to 3000 rpm) for 
10 minutes to separate plasma. Each plasma sample should be transferred via pipette into 
2 cryovials labeled as described previously and should be capped tightly. The second tube 
will be a duplicate and retained at the site as a backup sample. If red blood cells are 
inadvertently drawn into the plasma, the sample should be re-centrifuged as soon as possible. 
Adequate space between the solution and the tube cap should be allowed for expansion 
during freezing.  
Cryovial tubes containing plasma samples must be frozen at –70°C or below until shipment 
in a freezer equipped with a temperature monitor and temperature-activated alarm. 
Uncentrifuged specimens should not be frozen. 
The study site will batch ship sets of frozen plasma samples. A log sheet listing the samples 
being shipped will be included in each shipment. The samples will be sent on dry ice via 
courier to Alturas Analytics (Moscow, ID). The back-up sets will remain at the site until 
confirmation that the first sets have been received. After receipt confirmation is received 
from Alturas Analytics, the back-up sets should be shipped. The site will contact Alturas 
Analytics and coordinate the shipment prior to sending the samples. Shipments before 
weekends or holidays must be avoided. 

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The samples will be shipped for analysis to:  
Alturas Analytics 
1324 Alturas Drive 
Moscow, ID 83843 
The bioanalytical laboratory will store all plasma samples at –70°C until analysis for 
tecovirimat is complete. SIGA will advise Alturas to destroy any remaining plasma samples 
after regulatory review is complete or the samples have met their applicable length of 
stability, whichever comes sooner. 
6.1.2 
Pharmacokinetic Sample Analysis 
Pharmacokinetic samples will be analyzed by Alturas Analytics using a validated liquid 
chromatography coupled with tandem mass spectrometry assay for tecovirimat in human 
plasma method in accordance with the US FDA Guidance for Industry on Bioanalytical 
Method Validation.3 
6.2 
SAFETY ASSESSMENTS AND ENDPOINTS 
Safety and tolerability will be assessed by monitoring and recording of AEs, clinical 
laboratory test results (hematology, serum chemistry, pregnancy, and urinalysis), vital sign 
measurements (systolic and diastolic blood pressures, heart rate, respiratory rate, and body 
temperature), 12-lead ECG results, and physical examination findings. Adverse events will 
be assessed from the time of the first dose of study drug until the follow-up telephone call on 
Day 37 (+2 days). 
6.2.1 
Adverse Events 
6.2.1.1 
Adverse Event Definitions 
The investigator is responsible for reporting all AEs that are observed or reported during the 
study, regardless of their relationship to study drug or clinical significance. If there is any 
doubt as to whether a clinical observation is an AE, the event should be reported. 
An AE is any event or other untoward medical occurrence, including those AEs that result 
from dosing errors, which may present during administration of a study drug or during a 
reasonable follow-up period and which does not necessarily have a causal relationship with 
this treatment. An AE is any unfavorable and unintended sign (eg, a clinically significant 

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abnormal laboratory finding), symptom, or disease temporally associated with the use of a 
medicinal product, whether or not considered to be related to the medicinal product. All AEs 
will be followed until the AE is resolved or stabilized as determined by the investigator 
and/or the medical monitor. 
A treatment-emergent AE (TEAE) is defined as any event not present before exposure to 
study drug or any event already present that worsens in intensity or frequency after exposure 
to study drug. 
An adverse reaction is any AE caused by a drug. Adverse reactions are a subset of all 
suspected adverse reactions for which there are reasons to conclude that the drug caused the 
event. 
A suspected adverse reaction is any AE for which there is a reasonable possibility that the 
study drug caused the AE. For the purposes of IND safety reporting, “reasonable possibility” 
means that there is evidence to suggest a causal relationship between the drug and the AE. A 
suspected adverse reaction implies a lesser degree of certainty about causality than adverse 
reaction, which means any AE caused by a study drug. 
An AE or suspected adverse reaction is considered “unexpected” if it is not listed in the 
TPOXX full prescribing information or at the specificity or severity that has been observed 
with the study drug being tested. For example, under this definition, hepatic necrosis would 
be unexpected (by virtue of greater severity) if the TPOXX full prescribing information 
referred only to elevated hepatic enzymes or hepatitis. Similarly, cerebral thromboembolism 
and cerebral vasculitis would be unexpected (by virtue of greater specificity) if the TPOXX 
full prescribing information listed only cerebral vascular accidents. “Unexpected,” as used in 
this definition, also refers to AEs or suspected adverse reactions that are mentioned in the 
TPOXX full prescribing information as occurring with a class of drugs or as anticipated from 
the pharmacological properties of the drug, but are not specifically mentioned as occurring 
with the particular drug under investigation. 
An AE or suspected adverse reaction is considered an SAE if, in the view of either the 
investigator or SIGA, it results in any of the following outcomes: 
• Results in death. 
• Is life threatening (subject is at immediate risk of death at the time of the event). 
• Requires inpatient hospitalization or prolongation of existing hospitalization, other than 
elective hospitalization, during the period of protocol defined surveillance. 

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• Results in congenital anomaly or birth defect. 
• Results in a persistent or significant disability/incapacity. 
• Any other important medical event that may not result in death, be life threatening, or 
requires hospitalization may be considered an SAE when, based on appropriate medical 
judgment, the event may jeopardize the subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition or is otherwise 
considered to be medically significant. 
Important medical events that may not result in death, be life threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical judgement, 
they may jeopardize the subject and may require medical or surgical intervention to prevent 
one of the outcomes listed in this definition. Examples of such medical events include 
allergic bronchospasm requiring intensive treatment in an emergency room or at home, blood 
dyscrasias or convulsions that do not result in inpatient hospitalization, or the development of 
drug dependency or drug abuse. 
An AE or suspected adverse reaction is considered “life-threatening” if, in the view of either 
the investigator or SIGA, its occurrence places the subject at immediate risk of death. It does 
not include an AE or suspected adverse reaction that, had it occurred in a more severe form, 
might have caused death. 
Serious AEs will be followed until the SAE is stable or until resolution as determined by the 
investigator and/or the medical monitor. 
6.2.1.2 
Eliciting and Documenting Adverse Events 
The investigator is responsible for ensuring that all AEs and SAEs are recorded in the eCRF 
and reported to SIGA by PPD. Adverse events and SAEs will be assessed from the first dose 
of study drug through the telephone call on Day 37 (+2 days).  
At every study visit or assessment, subjects will be asked a standard question to elicit any 
medically related changes in their well-being. They will also be asked if they have been 
hospitalized, had any accidents, used any new medications, or changed concomitant 
medication regimens (both prescription and over-the-counter medications). 
In addition to subject observations, AEs will be documented from any data collected on the 
AE page of the eCRF (eg, laboratory values, physical examination findings, and ECG 
changes) or other documents that are relevant to subject safety. 

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6.2.1.3 
Reporting Adverse Events 
All AEs reported or observed from the first dose of study drug through the follow-up 
telephone call on Day 37 (+2 days) will be recorded on the AE page of the eCRF. 
Information to be collected includes drug treatment, type of event, date and time of onset, 
investigator-specified assessment of severity and relationship to study drug, date and time of 
resolution of the event, seriousness, as well as any required treatment or evaluations, and 
outcome. Adverse events resulting from concurrent illnesses, reactions to concurrent 
illnesses, reactions to concurrent medications, or progression of disease states must also be 
reported. 
All AEs will be followed until they are resolved or stabilized as determined by the 
investigator and/or medical monitor. These data will be reviewed on an ongoing basis by the 
study coordinator, the investigator, the medical monitor, and the ISM. This requirement 
indicates that for some events, follow-up may be required after the subject has completed 
study participation. These events will be reported by SIGA, as required, to the FDA. 
Any medical condition that is present at the time that the subject is screened but does not 
deteriorate should not be reported as an AE. However, if it deteriorates at any time during the 
study, it should be recorded as an AE. Prior to this, medical conditions reported by subjects 
are considered medical history. 
6.2.1.4 
Reporting of Serious Adverse Events 
Any AE considered serious by the investigator or which meets SAE criteria (Section 6.2.1.1), 
or any other event or condition regardless of grade, which in their judgment represents a 
reportable event, must be reported to the medical monitor and SIGA as soon as the 
investigator becomes aware of the event. In addition, the event must be reported to PPD via 
the SAE hotline. The PPD SAE Report Form must be submitted within 24 hours of 
knowledge of the event. SIGA (or designee) will be responsible for notifying the relevant 
regulatory authorities of any SAE as outlined in US Title 21 Code of Federal Regulations 
(CFR) Parts 312 and 320. The investigator is responsible for notifying the institutional 
review board (IRB) directly. 
In addition, the investigator (or designee) must report any Grade 3 (severe) AE that they 
deem possibly, probably, or definitely related to study drug to the medical monitor and SIGA 
within 24 hours after becoming aware of the event. 

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• Grade 3 (Severe): Events interrupt a subject’s usual daily activity, may require systemic 
drug therapy or other treatment, and are usually incapacitating. 
• Grade 4 (Life-threatening): Event that, in the opinion of the investigator, places the 
subject at immediate risk of death from the reaction as it occurred (ie, it does not include 
a reaction that, had it occurred in a more severe form, might have caused death). 
• Grade 5 (Death). 
Changes in the severity of an AE should be documented to allow an assessment of the 
duration of the event at each level of intensity to be performed. An AE characterized as 
intermittent requires documentation of onset and duration of each episode.  
6.2.1.6 
Assessment of Causality 
Any occurrence of an AE will be assessed for relationship to the study drug. A causal 
relationship means that the study drug caused (or is reasonably likely to have caused) the AE. 
This usually implies a relationship in time between the drug and the AE; for example, the AE 
occurred shortly after the subject received the study drug. 
The investigator who examines and evaluates the subject will determine AE causality based 
on the temporal relationship to administration of the study drug, the pharmacology of the 
study drug, and their clinical judgment. Terms used to describe the degree of causality 
between a study drug and an AE are definitely related, probably related, possibly related, 
unlikely related, or not related. 
The best estimate at the time of reporting of an event and the degree of certainty about the 
causal relationship between the study drug administration and the AE will be graded as 
follows: 
Associated 
• Definitely Related: The AE and administration of study drug are related in time, and a 
direct association can be demonstrated (eg, the event disappears or decreases with 
reduction in dose or cessation of study drug and recurs with re-exposure). 
• Probably Related: The AE and administration of study drug are reasonably related in time 
and/or follow a known pattern of response, and the AE is more likely explained by study 
drug than other causes. 

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• Possibly Related: The AE and administration of study drug are reasonably related in time 
and/or follow a known pattern of response, but the AE can be explained equally well by 
causes other than study drug (eg, could readily have been produced by the subject’s 
clinical state or could have been due to environmental or other interventions). 
Not Associated 
• Unlikely Related: A potential relationship between study drug and the AE could exist 
(ie, the possibility cannot be excluded), but the AE is most likely explained by causes 
other than the study drug (eg, could readily have been produced by the subject’s clinical 
state or could have been due to environmental or other interventions). 
• Not Related: The AE is clearly due to extraneous causes (eg, underlying disease, 
environment) or exposure to the study drug has not occurred. Such events MUST have an 
alternative, definitive etiology documented in the subject’s medical record. 
6.2.1.7 
Follow-up of Adverse Events 
All AEs must be reported in detail on the appropriate page of the eCRF and followed until 
they are resolved or stabilized as determined by the investigator and/or medical monitor. 
6.2.1.8 
Reactogenicity 
At this time, there is no definitive information on allergic activity of TPOXX. Reactogenicity 
will be monitored in subjects during the study treatment period. 
6.2.1.9 
Reporting of Pregnancy 
Pregnant women are not eligible to participate in the study. Subjects must be counseled 
regarding prevention of pregnancy and encouraged to make every effort to avoid pregnancy 
during study participation. If a female subject becomes pregnant during study participation, 
study drug dosing will be discontinued, and the subject will be withdrawn from the study. 
The pregnancy itself is not considered an SAE. However, the investigator must complete the 
pregnancy report form and fax it to PPD Pharmacovigilance within 24 hours of knowledge of 
the pregnancy. After delivery or termination of pregnancy, the follow-up pregnancy report 
form should be completed and submitted via fax to PPD Pharmacovigilance. Spontaneous 
abortions should always be reported as SAEs. Pregnancy data will be captured and followed 
by PPD. All pregnancies and outcomes will be tracked. The case will not be closed until after 
the child is followed for 3 months. 

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If there are complications during the pregnancy, the complications will be recorded as AEs in 
the usual manner. The subject will be asked to report the outcome of the pregnancy. If there is 
a congenital anomaly in the infant, this will be recorded as an SAE in the data forms for the 
mother (ie, the study subject). 
If a subject becomes pregnant during the study after receiving the study drug, all safety 
evaluations will be collected as per protocol. In addition, at the time that the pregnancy is 
reported, consent will be requested to contact the subject and her physician in the postpartum 
period to assess delivery and health status of the neonate. 
If the partner of a male subject becomes pregnant, the partner will be asked for consent to 
allow her treating physician to provide SIGA or its designee with follow-up information 
regarding the pregnancy and its outcome. 
6.2.2 
Clinical Laboratory Testing 
Clinical laboratory tests will be performed by the PPD Central Laboratory. Blood samples 
will be collected at the time points indicated in the schedule of events (Table 9-1) and will be 
prepared using standard procedures.  
Repeat clinical laboratory tests may be performed at the discretion of the investigator, if 
necessary, to evaluate inclusion and exclusion criteria or clinical laboratory abnormalities. 
PPD central laboratory will provide the reference ranges for all clinical laboratory safety 
parameters. 
The following clinical laboratory assessments will be performed: 
Hematology 
Hematocrit, hemoglobin, mean corpuscular hemoglobin, mean 
corpuscular hemoglobin concentration, total and differential 
leukocyte count (basophils, eosinophils, lymphocytes, monocytes, 
neutrophils), mean corpuscular volume, platelet count, red blood 
cell count, and red cell distribution width 
Serum Chemistry 
Alanine aminotransferase, albumin, alkaline phosphatase, anion 
gap, aspartate aminotransferase, bilirubin (total), blood urea 
nitrogen, calcium, carbon dioxide, chloride, creatinine clearance 
(calculateda), gamma-glutamyltransferase, globulin, glucose, lactate 
dehydrogenase, phosphorus, potassium, sodium, total protein, and 
uric acid 

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Urinalysis 
Appearance, bilirubin, blood, color, glucose, ketones, leukocytes, 
microscopy (performed if dipstick is ≥1+; includes bacteria, cast, 
crystals, epithelial cells, red blood cells, and white blood cells), 
nitrates, pH, protein, specific gravity, turbidity, and urobilinogen  
a Creatinine clearance (CLcr) will be calculated using the Cockcroft-Gault formula:  
𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶 (𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚
⁄
) = [140 −𝑎𝑎𝑎𝑎𝑎𝑎(𝑦𝑦𝑦𝑦𝑦𝑦𝑦𝑦𝑦𝑦)] × 𝑤𝑤𝑤𝑤𝑤𝑤𝑤𝑤ℎ𝑡𝑡 (𝑘𝑘𝑘𝑘)
72 × 𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠 𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐 (𝑚𝑚𝑚𝑚𝑑𝑑𝑑𝑑
⁄
) {× 0.85 𝑖𝑖𝑖𝑖 𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓} 
Glycosylated hemoglobin A1c and a fasting lipid panel including cholesterol (total, 
high-density lipoprotein, calculated low-density lipoprotein, and triglycerides) will be 
performed at screening. 
Serum pregnancy test (β human chorionic gonadotropin) for women of childbearing potential 
will be performed at screening and on Day –1. 
A serum follicle-stimulating hormone test for postmenopausal women will be performed at 
screening.  
Human immunodeficiency virus (type 1 and 2) antibodies, hepatitis B surface antigen, and 
hepatitis C virus antibody will be assessed at screening only.  
A urine drug screen for alcohol, amphetamines (including methamphetamines and 
ecstasy/methylenedioxymethamphetamine), barbiturates, benzodiazepines, cannabinoids 
(including tetrahydrocannabinol), cocaine metabolites, and opiates (including heroin, 
codeine, and oxycodone) will be performed at screening and on Day –1. 
Abnormal clinical laboratory values will be flagged as either high or low (or normal or 
abnormal) based on the reference ranges for each laboratory parameter. The investigator will 
determine whether any of the abnormally high or low results are clinically significant or not 
clinically significant. Clinical significance is defined as any variation in results that has 
medical relevance and may result in an alteration in medical care (eg, active observation, 
diagnostic measures, or therapeutic measures). If a clinically significant change from the 
screening value is noted, the clinically significant value and reason for clinical significance 
will be documented on the AE page of the eCRF. The investigator will continue to monitor 
the subject with additional assessments until the values have reached the reference range or 
the values at screening or until the investigator determines that follow-up is no longer 
medically necessary. 

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6.2.3 
Medical History 
A complete medical history will be obtained, including a review of systems, recreational and 
prescription drug use, over-the-counter drug use, nicotine and alcohol use, and past 
hospitalizations.  
6.2.4 
Vital Sign Measurements 
Vital signs will be measured after the subject has been seated for at least 5 minutes at the 
time points indicated in the schedule of events (Table 9-1). 
Vital sign measurements will include systolic and diastolic blood pressures, heart rate, 
respiratory rate, and body temperature.  
When procedures are overlapping and occurring at the same time point, the order of 
procedures should be ECG, vital sign measurements, and then blood collection, with the 
blood collection scheduled to occur at the nominal time point, unless dictated by other study 
events happening at that time, such as dosing requirements. 
The investigator will determine whether any of the vital sign measurements are clinically 
significant or not clinically significant. Clinical significance is defined as any variation in 
results that has medical relevance and may result in an alteration in medical care (eg, active 
observation, diagnostic measures, or therapeutic measures). If a clinically significant change 
from the screening values is noted, the clinically significant value and reason for clinical 
significance will be documented on the AE page of the subject’s eCRF. The investigator will 
continue to monitor the subject with additional assessments until the value has reached the 
reference range or the value at screening or until the investigator determines that follow up is 
no longer medically necessary. 
6.2.5 
Electrocardiograms 
A 12-lead ECG will be obtained after the subject has been in the supine position for at least 
10 minutes at the time points indicated in the schedule of events (Table 9-1). On Days 1, 4, 
and 7, an ECG will be recorded 4 hours after the AM study drug administration. The 
acceptable window for collection from the scheduled collection time point will ±15 minutes. 
Electrocardiogram assessments will include comments on whether the tracings are normal or 
abnormal, rhythm, presence of arrhythmia or conduction defects, morphology, any evidence 
of myocardial infarction, or ST segment, T wave, and U wave abnormalities. In addition, the 

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following parameters will be measured and reported: heart rate; PR, RR, and QT intervals; 
QTcF; QT interval corrected using Bazett’s formula; and QRS duration. All ECGs must be 
performed by an experienced ECG technician. 
The investigator will determine whether any of the 12-lead ECG results are clinically 
significant or not clinically significant. Clinical significance is defined as any variation in 
results that has medical relevance and may result in an alteration in medical care (eg, active 
observation, diagnostic measures, or therapeutic measures). If a clinically significant change 
from screening is noted, the clinically significant value and reason for clinical significance 
will be documented on the AE page of the subject’s eCRF. The investigator will continue to 
monitor the subject with additional assessments until either the values have reached reference 
range or the values at screening or until the investigator determines that follow-up is no 
longer medically necessary. 
6.2.6 
Physical Examinations 
A full physical examination will be performed at the time points indicated in the schedule of 
events (Table 9-1) and will include assessment of the following body systems: head, ears, 
eyes, nose, and throat; cardiac (including auscultation of heart); pulmonary (chest) 
auscultation of lungs; abdomen; skin; musculoskeletal system; lymphatic system; and 
neurologic system (cranial nerves, sensation, motor function, coordination, reflexes, and 
mental status). 
A symptom-directed physical examination will be performed at the time points indicated in 
the schedule of events (Table 9-1) (for those subjects who require it), and at unscheduled 
visits as necessary. This examination will include an assessment of the heart, lungs, abdomen, 
a neurologic review, and a review of symptoms for assessments and/or follow-up of reported 
or potential AEs. 
Weight will be measured without shoes and in light clothing at screening and without shoes 
and in hospital gowns at all other time points indicated in the schedule of events (Table 9-1). 
The scales should be calibrated, and the same weight scale should be used throughout the 
study starting with Screening through Day 9.  Weight measurements will be rounded to one 
decimal place. 
Height will be measured at Check-in on Day -1.  

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6.2.7 
Unscheduled Visits 
Subjects will be provided with the contact information for the study site personnel. Subjects 
are free to contact study site personnel at any time, and the site may require an unscheduled 
visit for the purpose of physical examinations, laboratory tests, etc. Unscheduled visits will 
be documented by the site personnel in the source documents. Unscheduled procedures and 
laboratory tests and results will also be recorded in the eCRF. 
7. 
STATISTICAL ANALYSIS PLANS 
7.1 
SAMPLE SIZE CALCULATIONS 
The sample size (N = 36 [to allow at least 32 enrolled subjects to complete]) for this study is 
based on clinical and practical considerations and not on a formal statistical power 
calculation. The sample size is considered sufficient to effectively assess the PK and safety 
profiles of TPOXX. 
7.2 
ANALYSIS POPULATIONS 
The Safety Population will include all subjects who receive at least 1 dose of study drug. 
The PK Population will include subjects who receive study drug and have sufficient 
concentration data to facilitate the calculation of PK variables. 
7.3 
STATISTICAL ANALYSIS 
Details of all statistical analyses will be described in a statistical analysis plan. All data 
collected will be presented in data listings. Data from subjects excluded from an analysis 
population will be presented in the data listings, but not included in the calculation of 
summary statistics. 
For categorical variables, frequencies and percentages will be presented. Continuous 
variables will be summarized using descriptive statistics (number of subjects, mean, median, 
standard deviation [SD], minimum, and maximum). 
Baseline demographic and background variables will be summarized overall for all subjects. 
The number of subjects who enroll in the study and the number and percentage of subjects 
who complete the study will be presented. Frequency and percentage of subjects who 
withdraw or discontinue from the study, and the reason for withdrawal or discontinuation, 
will also be summarized. 

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7.3.1 
Pharmacokinetic Analyses 
Individual plasma concentration and time deviation data will be presented in a data listing. 
Plasma concentration data will be listed and summarized using the following descriptive 
statistics: number of subjects, arithmetic mean, SD, coefficient of variation (CV), geometric 
mean, geometric CV, median, minimum, and maximum. Individual and mean plasma 
concentration versus time profiles will be presented in figures on both linear and 
semilogarithmic scales. 
The PK parameters of TPOXX will be analyzed based on the actual sampling times. All 
parameters will be determined using noncompartmental methods using Phoenix® 
WinNonlin® Version 8.0 or higher (Certara, L.P., Princeton, New Jersey) or SAS® Version 9.4 
or higher (SAS Institute Inc., Cary, North Carolina). 
The individual PK parameters and body weight-normalized PK parameters will be presented 
in data listings and summarized using the following descriptive statistics: number of subjects, 
arithmetic mean, SD, CV, median, minimum, maximum, geometric mean, geometric SD, and 
geometric CV. 
7.3.2 
Safety Analyses 
Adverse events will be coded by preferred term and system organ class using the latest 
version of the Medical Dictionary for Regulatory Activities and summarized overall. All AE 
data will be presented in a data listing. Treatment-emergent AEs will be summarized overall, 
as well as by severity and relationship to study drug. Serious AEs and AEs leading to 
discontinuation of study drug will also be presented in the data listings and summarized 
overall. 
Actual values and changes from baseline for clinical laboratory test results, vital sign 
measurements, and 12-lead ECG results will be summarized at each time point using 
descriptive statistics (number of subjects, mean, SD, median, minimum, and maximum). 
Shift tables will be generated for clinical laboratory test results. Clinical laboratory data, vital 
sign measurements, 12-lead ECG results, and physical examination findings will be 
presented in data listings. 

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7.4 
HANDLING OF BELOW THE LIMIT OF 
QUANTIFICATION AND MISSING DATA 
Plasma concentrations that are below the limit of quantification (BLQ) will be treated as zero 
for descriptive statistics. Geometric mean values will not be calculated or displayed when 
zero is the minimal value. Mean BLQ concentrations will be presented as BLQ, and the SD 
and CV will be reported as not applicable. Missing concentrations will be excluded from the 
calculations. 
7.5 
INTERIM ANALYSES 
No formal interim safety analyses will be performed in this study. 

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8. 
REFERENCE LIST 
1. Breman JG, Henderson DA. Diagnosis and management of smallpox. N Engl J Med. 
2002;346(17):1300-8.  
2. TPOXX (tecovirimat) [full prescribing information]. SIGA Technologies, Inc. Corvallis 
(OR); 2018. 18 p. 
3. Department of Health and Human Services, Food and Drug Administration (US). 
Guidance for Industry. Bioanalytical Method Validation. May 2018. Available from: 
https://www.fda.gov/files/drugs/published/Bioanalytical-Method-Validation-Guidance-
for-Industry.pdf. 

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9. 
APPENDICES 
9.1 
APPENDIX 1: LIST OF ABBREVIATIONS 
Abbreviation 
Term 
%AUCextrap 
percentage of AUC0-∞ extrapolated from the last quantifiable 
measurement to infinity 
λz 
terminal elimination rate constant 
AE 
adverse event 
AUC 
area under the plasma concentration-time curve 
AUC0-24 
area under the plasma concentration-time curve from time 0 to 
24 hours 
AUC0-∞ 
area under the plasma concentration-time curve from time 0 
extrapolated to infinity 
AUC0-t 
area under the plasma concentration-time curve from time 0 to the 
last quantifiable measurement 
AUC0-tau 
area under the plasma concentration-time curve during the first 
dosing interval 
BCRP 
breast cancer resistance protein 
BID 
twice daily 
BLQ 
below the limit of quantification 
CFR 
Code of Federal Regulations 
CL/F 
apparent total body clearance 
Cmax 
maximum drug concentration in plasma 
Ctrough 
concentration observed prior to the next dose administration 
CRA 
clinical research associate 
CV 
coefficient of variation 
CYP 
cytochrome P450 
DAIDS 
Division of Acquired Immune Deficiency Syndrome 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
FDA 
Food and Drug Administration 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IRB 
institutional review board 
ISM 
independent safety monitor  
MedDRA 
Medical Dictionary for Regulatory Activities 
PK 
pharmacokinetic(s) 
QTcF 
QT interval corrected using Fridericia’s formula 
SAE 
serious adverse event 
SD 
standard deviation 
SOP 
standard operating procedures 
t1/2 
terminal elimination half-life 
TEAE 
treatment-emergent adverse event 

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Abbreviation 
Term 
Tmax 
time to maximum drug concentration in plasma 
UGT 
uridine diphosphate-glucuronosyltransferase 
VARV 
variola virus 
Vd/F 
apparent volume of distribution 

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9.2 
APPENDIX 2: SCHEDULE OF EVENTS 
Table 9-1 
Schedule of Events 
 Screening Check-in 
Treatment Period 
Telephone Call 
or Follow-up 
Visit(a) 
Follow-up 
Telephone 
Call(b) 
Procedure(c) 
Day –28 to –2 
–1 
1 
2 
3 
4 
5 
6 
7 
8 
9 or Early 
Discontinuation  
14 (+2) 
  
37 (+2) 
Admission to clinic 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Discharge from clinic(d) 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Medical history(e) 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Complete physical examination(f) 
X 
X 
 
 
 
 
 
 
X 
 
X 
 
 
Weight(g) 
X 
X 
X(h) 
 
 
 
 
 
 
 
X 
 
 
Height 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Vital sign measurements(i) 
X 
X 
X(j) 
 
 
X(j) 
 
 
X(j) 
X 
X 
X(k) 
 
Glycosylated hemoglobin (HbA1c) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Fasting lipid panel(l) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical laboratory testing(m) 
X(n) 
X 
 
 
 
X 
 
 
 
X(o) 
X(n) 
 
 
Serum follicle-stimulating 
hormone(p) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Serum pregnancy test(q) 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Urine drug/alcohol screen(r) 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Serology (HBsAg, HCV, and HIV) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
12-Lead ECG(s) 
X 
X 
X 
 
 
X 
 
 
X 
 
X 
 
 
TPOXX administration(t) 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Pharmacokinetic sampling(u) 
 
 
X 
X 
 
 
 
X 
X 
X 
X 
 
 
Symptom-directed physical 
examination(v) 
 
 
 
X 
X 
X 
X 
X 
 
 
 
X(k) 
 
Adverse events 
 
 
X 
Prior/concomitant medications 
X 
Abbreviations: AE, adverse event; ECG, electrocardiogram; HBsAg, hepatitis B surface antigen; HCV, hepatitis C virus; HIV, human immunodeficiency virus; 
PK, pharmacokinetic; SAE, serious adverse event. 

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Notes: 
(a) The follow-up visit or telephone call will occur on Day 14 (+2 days), 7 days after the last dose of study drug. Subjects who have abnormal physical examination findings or an 
ongoing AE/SAE on Day 9 that is deemed related to study drug or per investigator or SIGA discretion will return to the study site on Day 14 (+2 days) for a follow-up visit. All 
other subjects will have the Day 14 (+2 days) follow-up via telephone.  
(b) The follow-up telephone call will be made 30 days after the last dose of study drug (Day 37 [+2 days]). 
(c) When procedures are overlapping and occurring at the same time point, the order of procedures should be ECG, vital sign measurements, and then blood collection, with the 
blood collection scheduled to occur at the nominal time point, unless dictated by other study events happening at that time, such as dosing requirements. 
(d) Discharge following collection of all safety assessments. 
(e) Including a review of systems; recreational, prescription, and over-the-counter drug use; nicotine and alcohol use; and past hospitalizations. 
(f) Including assessment of the following body systems: head, ears, eyes, nose, and throat; cardiac (including auscultation of heart); pulmonary (chest) auscultation of lungs; 
abdomen; skin; musculoskeletal system; lymphatic system; and neurologic system (cranial nerves, sensation, motor function, coordination, reflexes, and mental status). 
(g) Weight will be measured without shoes and in light clothing at screening and without shoes and in hospital gowns at all other time points. The scales should 
be calibrated and the same weight scale should be used throughout the study starting with Screening through Day 9.  Weight measurements will be rounded to 
one decimal place. 
(h) Weight will be collected prior to dosing. 
(i) Vital sign measurements will include systolic and diastolic blood pressures, heart rate, respiratory rate, and body temperature. Vital signs will be measured after the subject has 
been seated for at least 5 minutes.  
(j) Vital sign measurements will be performed before dosing and 4 hours after the AM study drug administration on Days 1 and 7 and 4 hours after the AM study drug 
administration on Day 4. The acceptable window for collection from the scheduled collection time point is ±15 minutes. 
(k) Collected only if subjects are required to return to the study site on Day 14 (+2 days) for a follow-up visit. 
(l) Including cholesterol (total, high-density lipoprotein, calculated low-density lipoprotein, and triglycerides). 
(m) Clinical laboratory testing will include hematology and serum chemistry.  
(n) Clinical laboratory testing at screening and at Day 9 or early discontinuation will include hematology, serum chemistry, and urinalysis. 
(o) Collect 12 hours after the PM study drug administration on Day 7.  
(p) For postmenopausal women, a serum follicle-stimulating hormone test will be performed at screening. 
(q) Women of childbearing potential only. 
(r) Includes alcohol, amphetamines (including methamphetamines and ecstasy/methylenedioxymethamphetamine), barbiturates, benzodiazepines, cannabinoids (including 
tetrahydrocannabinol), cocaine metabolites, and opiates (including heroin, codeine, and oxycodone). 
(s) A 12-lead ECG will be collected after the subject has been in the supine position for at least 10 minutes. On Days 1, 4, and 7, an ECG will be recorded 4 hours after the AM 
study drug administration. The acceptable window for collection from the scheduled collection time point is ±15 minutes. 
(t) TPOXX, 600 mg (3 × 200-mg capsules) will be administered orally twice daily, approximately 12 hours (± 30 minutes) apart on Days 1 through 7. All subjects will be 
provided meals consisting of approximately 600 calories and 25 g fat, which will start 30 minutes before study drug administration. Subjects should eat this meal within 30 
minutes or less of taking study drug. Study drug will be administered approximately 30 minutes after the start of the meal. All doses of study drug will be administered to 
subjects by study site personnel with approximately 240 mL of water. Subjects must fast 2 hours after taking study drug. Study drug and meals must be taken with water only, 
and no other beverage except water should be ingested within 3 hours before or 3 hours after study drug administration. 
(u) Blood samples for PK analysis of TPOXX will be collected from all subjects at the following tome points: on Day 1 before study drug administration (0 hour), at 0.5, 1, 2, 4, 6, 
8, 12 (before the PM dose), 14, 16, 18, 20, and 24 hours (before the AM dose on Day 2), on Day 6 (before the AM dose and 4 hours after the AM dose), on Day 7 before the 
AM dose (0 hour), at 0.5, 1, 2, 4, 6, 8, 12 (before the PM dose), 14, 16, 18, 20, and 24 hours (Day 8, 24 hours after the AM dose on Day 7), and on Day 9 (48 hours after the 
AM dose on Day 7). For PK blood samples, the acceptable window for collection from the scheduled collection time point will be as follows: ±5 minutes for the time points 
from 1 to 8 hours and ±15 minutes for the 12- to 48-hour time points. 
(v) Including assessment of heart, lungs, abdomen, a neurologic review, and a review of symptoms for assessment and/or follow-up of reported or potential adverse events. 

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9.3 
APPENDIX 3: STUDY GOVERNANCE 
9.3.1 
Data Quality Assurance 
This study will be conducted using the quality processes described in applicable procedural 
documents. The quality management approach to be implemented will be documented and 
will comply with current ICH guidance on quality and risk management. All aspects of the 
study will be monitored for compliance with applicable government regulatory requirements, 
current Good Clinical Practice, the protocol, and standard operating procedures (SOPs). The 
monitor will maintain current personal knowledge of the study through observation, review 
of study records and source documentation, and discussion of the conduct of the study with 
the investigator and staff. Electronic CRFs and electronic data capture will be utilized. The 
electronic data capture system is validated and compliant with US Title 21 CFR Part 11. Each 
person involved with the study will have an individual identification code and password that 
allows for record traceability. There may be an internal quality review audit of the data and 
additional reviews by the clinical monitor. 
Steps to be taken to ensure the accuracy and reliability of data include, but are not limited to: 
selection of qualified investigator and appropriate study center, protocol training and review 
of protocol procedures with the investigator and study site personnel before the start of the 
study, site initiation and periodic interim monitoring visits by SIGA or PPD, and direct 
transmission of safety laboratory data into the PPD study database for all clinical safety 
laboratory tests performed. The eCRF will be reviewed for accuracy and completeness by 
PPD Clinical research associate (CRA) remotely and during on-site monitoring visits. 
Discrepancies will be resolved with the investigator or designees, as appropriate. The data 
will be entered into the clinical study database and validated for accuracy. During on-site 
monitoring visits, 100% of the data will be verified using source documentation. SIGA or 
Biomedical Advanced Research and Development Authority representatives may accompany 
the PPD CRA on any scheduled site visit. The investigator will be informed in advance of 
any visitors to the study site in addition to the PPD CRA.  
Representatives of SIGA’s Quality Assurance department (or designee) may visit the site to 
carry out an audit of the study in compliance with regulatory guidelines and PPD policy. 
Such audits will require access to all study records, including source documents, for 
inspection and source document verification with the eCRF. Subject privacy must, however, 
be respected. Sufficient prior notice will be provided to allow the investigator to prepare 
properly for the audit. Similar auditing procedures may also be conducted by any regulatory 
body reviewing the results of this study in support of a Licensing Application. The 

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investigator will immediately notify SIGA if they are contacted by a regulatory agency 
requesting a site inspection. 
9.3.2 
Investigator Obligations 
The following administrative items are meant to guide the investigator in the conduct of the 
study and may be subject to change based on industry and government SOPs, working 
practice documents, or guidelines. Changes will be reported to the IRB but will not result in 
protocol amendments. 
9.3.2.1 
Confidentiality 
All laboratory specimens, evaluation forms, reports, and other records will be identified in a 
manner designed to maintain subject confidentiality. All records will be kept in a secure 
storage area with limited access. Subjects will not be identified by name in any reports in this 
study. All records will be kept confidential to the extent provided by federal, state, and local 
law. Medical records are made available for review when required by the FDA or other 
authorized users only under the guidelines set by the Federal Privacy Act. Direct access, as 
defined in the Federal Privacy Act, includes examining, analyzing, verifying, and 
reproducing any records and reports that are important to the evaluation of the study. The 
investigator is obligated to inform the subjects that these representatives may review their 
study-related records without violating the confidentiality of the subjects. The requirement to 
maintain subject confidentiality is included in the study informed consent document. 
The investigator and all employees and coworkers involved with this study may not disclose 
or use for any purpose other than performance of the study, any data, record, or other 
unpublished, confidential information disclosed to those individuals for the purpose of the 
study. Prior written agreement from SIGA or its designee must be obtained for the disclosure 
of any said confidential information to other parties. 
9.3.2.2 
Institutional Review 
Federal regulations and ICH guidelines require that approval be obtained from an IRB before 
participation of human subjects in research studies. Before study onset, the protocol, ICF, 
advertisements to be used for the recruitment of study subjects, and any other written 
information regarding this study to be provided to the subject or the subject’s legal guardian 
must be approved by the IRB. Documentation of all IRB approvals and of the IRB 

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compliance with the ICH harmonised tripartite guideline E6(R2): Good Clinical Practice will 
be maintained by the site and will be available for review by SIGA or its designee. 
All IRB approvals should be signed by the IRB chairman or designee and must identify the 
IRB name and address, the clinical protocol by title or protocol number or both, and the date 
approval or a favorable opinion was granted. 
9.3.2.3 
Subject Consent 
Written documentation of informed consent in compliance with US Title 21 CFR Part 50 
shall be obtained from each subject before any study-related procedures are performed and 
study drug is administered. If any institution-specific modifications to study-related 
procedures are proposed or made by the site, the consent should be reviewed by SIGA or its 
designee or both before IRB submission. Once reviewed, the investigator will submit the ICF 
to the IRB for review and approval before the start of the study. If the ICF is revised during 
the course of the study, all active participating subjects must sign the revised ICF. 
Before recruitment and enrollment, each prospective subject or his/her legal guardian will be 
given a full explanation of the study and will be asked to read and review the approved ICF. 
Once the investigator is assured that the subject/legal guardian understands the implications 
of participating in the study, the subject/legal guardian will be asked to give his or her 
consent to participate in the study by signing the ICF. A copy of the ICF will be provided to 
the subject/legal guardian. 
9.3.2.4 
Exclusion of Children 
Effort will be made to include women and minorities in proportions similar to that of the 
community from which they are recruited. Because this study is designed to establish safety 
of the study drug in adults, enrollment will be limited to persons at least 18 years of age, and 
no older than 50 years. Children are excluded from participation in this clinical study because 
it does not meet the Department of Health and Human Services’ guidelines (45 CFR 46, 
Subpart D, 401-409) for inclusion of children in research. These guidelines provide guidance 
for the protection of children in research. Generally, healthy children can be studied when the 
research is considered as “not greater than minimal risk.” Children can be involved in 
research with greater than minimal risk only when it presents the prospect of direct benefit to 
the individual child or is likely to yield generalizable knowledge about the child’s disorder or 
condition. 

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9.3.2.5 
Study Reporting Requirements 
By participating in this study, the investigator agrees to submit reports of SAEs according to 
the time line and method outlined in this protocol. In addition, the investigator agrees to 
submit annual reports to his or her IRB as appropriate. 
9.3.2.6 
Financial Disclosure and Obligations 
The investigator is required to provide financial disclosure information to allow SIGA to 
submit the complete and accurate certification or disclosure statements required under US 
Title 21 CFR Part 54. In addition, the investigator must provide to SIGA a commitment to 
promptly update this information if any relevant changes occur during the course of the 
investigation and for 1 year following the completion of the study. 
Neither SIGA nor PPD is financially responsible for further testing or treatment of any 
medical condition that may be detected during the screening process. In addition, in the 
absence of specific arrangements, neither SIGA nor PPD is financially responsible for further 
treatment of the disease under study. 
9.3.2.7 
Investigator Documentation 
Prior to beginning the study, the investigator will be asked to comply with ICH 
E6(R2) Section 8.2 and US Title 21 of the CFR by providing essential documents, including 
but not limited to, the following: 
• IRB approval. 
• An original investigator-signed investigator agreement page of the protocol. 
• Form FDA 1572, fully executed, and all updates on a new fully executed 
Form FDA 1572. 
• Curriculum vitae for the principal investigator and each subinvestigator listed on Form 
FDA 1572. Current licensure must be noted on the curriculum vitae. Curriculum vitae 
will be signed and dated by the principal investigators and subinvestigators at study 
start-up, indicating that they are accurate and current. 
• Financial disclosure information to allow SIGA to submit complete and accurate 
certification or disclosure statements required under US Title 21 CFR Part 54. In 
addition, the investigators must provide to SIGA a commitment to promptly update this 

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information if any relevant changes occur during the course of the investigation and for 
1 year after the completion of the study. 
• An IRB-approved ICF, samples of site advertisements for recruitment for this study, and 
any other written information about this study that is to be provided to the subject or legal 
guardians. 
• Laboratory certifications and reference ranges for any local laboratories used by the site, 
in accordance with US Title 42 CFR Part 493. 
9.3.2.8 
Study Conduct 
The investigator agrees to perform all aspects of this study in accordance with the ethical 
principles that have their origin in the Declaration of Helsinki, ICH E6(R2): Good Clinical 
Practice; the protocol; and all national, state, and local laws or regulations. 
9.3.2.9 
Case Report Forms and Source Documents 
Site personnel will maintain source documentation, enter subject data into the eCRF as 
accurately as possible, and will rapidly respond to any reported discrepancies. 
Electronic CRFs and electronic data capture will be utilized. The electronic data capture 
system is validated and compliant with US Title 21 CFR Part 11. Each person involved with 
the study will have an individual identification code and password that allows for record 
traceability. Thus, the system, and any subsequent investigative reviews, can identify 
coordinators, investigators, and individuals who have entered or modified records, as well as 
the time and date of any modifications. There may be an internal quality review audit of the 
data and additional reviews by PPD’s CRA. 
Each eCRF is presented as an electronic copy, allowing data entry by site personnel, who can 
add and edit data, add new subjects, identify and resolve discrepancies, and view records. 
This system provides immediate direct data transfer to the database, as well as immediate 
detection of discrepancies, enabling site coordinators to resolve and manage discrepancies in 
a timely manner. 
Paper copies of the eCRFs and other database reports may be printed and signed by the 
investigator. This system provides site personnel, PPD CRAs, and reviewers with access to 
hardcopy audits, discrepancy reviews, and investigator comment information. 

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9.3.2.10 
Adherence to Protocol 
The investigator agrees to conduct the study as outlined in this protocol, in accordance with 
ICH E6(R2) and all applicable guidelines and regulations. 
9.3.2.11 
Reporting Adverse Events 
By participating in this study, the investigator agrees to submit reports of SAEs according to 
the timeline and method outlined in this protocol. In addition, the investigator agrees to 
submit annual reports to his or her IRB as appropriate. The investigator also agrees to 
provide SIGA with an adequate report, if applicable, shortly after completion of the 
investigator’s participation in the study. 
9.3.2.12 
Investigator’s Final Report 
Upon completion of the study, the investigator, where applicable, should inform the 
institution; the investigator/institution should provide the IRB with a summary of the study’s 
outcome and SIGA and regulatory authorities with any reports required. 
9.3.2.13 
Records Retention 
Essential documents should be retained until at least 2 years after the last approval of a 
marketing application in an ICH region and until there are no pending or contemplated 
marketing applications in an ICH region or until at least 2 years have elapsed since the 
formal discontinuation of clinical development of the study drug. These documents should be 
retained for a longer period, however, if required by applicable regulatory requirements or by 
an agreement with SIGA. SIGA is responsible for informing the investigator/institution when 
these documents no longer need to be retained. 
9.3.2.14 
Publications 
All information concerning TPOXX, SIGA operations, patent application, formulas, 
manufacturing processes, basic scientific data, and formula information, supplied by SIGA to 
the investigator and not previously published, is considered confidential and remains the sole 
property of SIGA. The investigator agrees to use this information only to accomplish this 
study and will not use it for other purposes without SIGA’s written consent. The investigator 
understands that the information developed in the clinical study will be used by SIGA, in 
connection with the continued development of TPOXX, and thus may be disclosed as 
required to other clinical investigators or government regulatory agencies. To permit the 

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information derived from the clinical studies to be used, the investigator is obligated to 
provide SIGA with all data obtained in the study. Any publication or other public 
presentation of results from this study, including manuscripts and materials for presentation 
at scientific meetings, should be provided to SIGA at least 30 working days before abstract or 
other relevant submission deadlines. Authorship of publications resulting from this study will 
be determined at the discretion of SIGA. 
9.3.3 
Study Management 
9.3.3.1 
Monitoring 
9.3.3.1.1 
Monitoring of the Study 
Site monitoring for safety is conducted to ensure that human subject protection, study 
procedures, and laboratory, study drug dosing, and data collection processes are of high 
quality and meet SIGA, GCP/ICH, and regulatory guidelines. PPD CRA(s) will conduct site 
monitoring visits as detailed in the monitoring plan. 
Site investigators will allow the CRA(s), the designated IRB, SIGA or its designee and the 
FDA to review, audit, and inspect study documents (eg, ICFs, drug accountability and 
distribution forms, eCRF), pertinent hospital and site records, and source documentation for 
verification of the study data.  
Clinical research associates will conduct site visits in accordance with PPD SOPs to monitor 
the following: study operations, the quality of data collected in the research records, the 
accuracy and timeliness of data entered in the database, and to determine that all process and 
regulatory requirements are met. Study monitoring visits will occur at initiation of the study 
site, at intervals determined by SIGA during conduct of the study, and at completion of the 
study.  
The CRA will maintain current personal knowledge of the study through observation, review 
of study records and source documentation, and discussion of the conduct of the study with 
the investigator and staff. During the routine monitoring visits, the CRA will perform a 100% 
source document verification of all subject data entered into the eCRF. Discrepancies, if any, 
will be clarified with the study site coordinator and investigator, and corrected at the site by 
the study coordinator. Any questions or required data clarifications will be sent to the study 
site electronically.  

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9.3.4 
Safety Monitoring Plan 
Close cooperation between the designated members of the study team will occur to evaluate 
and respond to individual AEs in a timely manner. Designated team members (investigator, 
subinvestigators, study coordinator, and other designated study clinicians) will review the 
subject safety information and data (laboratory test results, ECGs, AEs, and concomitant 
medications) and update the PPD project team and the ISM on the status of all enrolled 
subjects at their site on a weekly basis (or more frequently if required because of an 
unexpected safety issue) through completion of each subject’s final study visit. 
9.3.5 
Medical Monitor 
The medical monitor, or their qualified designee, will receive reports within 24 hours of 
study site awareness of all SAEs and within 7 days of study site awareness of all other AEs. 
The safety monitors will review all safety data and alert the medical monitor of SAEs and 
AEs of interest. The medical monitor may make a request for data to the investigator as 
necessary for safety evaluations.  
The medical monitor will review each significant AE in a timely fashion and ensure that 
appropriate management is initiated and completed. Drug safety representatives and the 
medical monitor will have direct contact with the investigators and follow all significant 
events as needed. 
9.3.6 
Safety Oversite (Independent Safety Monitor) 
In addition to the investigator’s ongoing review of the safety data, the ISM will review the 
protocol for any major concerns and will be involved in data review in coordination with the 
investigator. The primary role of the ISM will be to evaluate the study safety and tolerability 
data. The ISM will provide independent safety monitoring in a timely fashion, which will 
include reviewing individual SAE reports and a review of periodic cumulative AE reports. 
Clinical safety and laboratory data, clinical records, and other safety study-related records 
will be made available for the ISM to review. Based on review of this data, the ISM may 
make recommendations regarding the safe continuation of the study. Specific details will be 
outlined in the Safety and Medical Management Plan. 
9.3.6.1 
Inspection of Records 
The investigator and study site involved in the study will permit study-related monitoring, 
audits, IRB review, and regulatory inspections by providing direct access to all study records. 

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In the event of an audit, the investigator agrees to allow SIGA, their representatives, the 
FDA, or other regulatory agencies access to all study records. 
The investigator should promptly notify SIGA and study site of any audits scheduled by any 
regulatory authorities and promptly forward copies of any audit reports received to SIGA. 
9.3.6.2 
Management of Protocol Amendments and Deviations 
9.3.6.2.1 
Modification of the Protocol 
Any changes in this research activity, except those necessary to remove an apparent 
immediate hazard to the subject, must be reviewed and approved by SIGA or designee. 
Amendments to the protocol must be submitted in writing to the IRB for approval before 
subjects are enrolled into an amended protocol. 
9.3.6.2.2 
Protocol Deviations 
The investigator or designee must document and explain in the subject’s source 
documentation any deviation from the approved protocol. The investigator may implement a 
deviation from, or a change to, the protocol to eliminate an immediate hazard to study 
subjects without prior IRB approval. As soon as possible after such an occurrence, the 
implemented deviation or change, the reasons for it, and any proposed protocol amendments 
should be submitted to the IRB for review and approval, to SIGA for agreement, and to the 
regulatory authorities, if required. 
A protocol deviation is any change, divergence, or departure from the study design or 
procedures defined in the protocol. An important protocol deviation (sometimes referred to 
as a protocol violation or a major protocol deviation) is a subset of protocol deviations that 
might significantly affect the reliability of the study data or that might significantly affect a 
subject's safety. An important deviation can include nonadherence to inclusion or exclusion 
criteria or nonadherence to FDA regulations or ICH E6(R2) guidelines. 
Protocol deviations will be documented by the clinical monitor throughout the course of 
monitoring visits. The investigator will be notified in writing by the monitor of deviations. 
The IRB should be notified of all protocol deviations, if appropriate, in a timely manner. 

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9.3.6.3 
Study Termination 
Although SIGA has every intention of completing the study, they reserve the right to 
discontinue it at any time for clinical or administrative reasons. 
An initiative for closure of the clinical investigative site or termination of the study can be 
taken at any time either by SIGA, PPD, or the investigator provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. Reasons for such action 
include, but are not limited to: 
• Study site closure 
o Inadequate site recruitment/enrollment of subjects 
o Failure of an investigator to comply with the protocol, PPD SOPs, GCP guidelines, or 
applicable federal regulations 
• Termination of enrollment 
o Enrollment of the required estimated number of subjects for the study 
• Study termination 
o Completion of the study 
o Safety concerns 
In addition, the ISM and FDA have the prerogative to delay or terminate the study. 
The end of the study is defined as the date on which the last subject completes the last visit 
(includes the follow-up visit and the follow-up telephone call). Any additional long-term 
follow-up that is required for monitoring of the resolution of an AE or finding may be 
reported through an amendment to the clinical study report. 
9.3.6.4 
Final Report 
Whether the study is completed or prematurely terminated, SIGA will ensure that clinical 
study reports are prepared and provided to regulatory agency(ies) as required by the 
applicable regulatory requirement(s). SIGA will also ensure that clinical study reports in 
marketing applications meet the standards of the ICH harmonised tripartite guideline E3: 
Structure and content of clinical study reports. 

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Upon completion of the clinical study report, the investigator will be provided with the final 
approved clinical study report, as appropriate. 
9.4 
APPENDIX 4: CHANGE HISTORY 
9.4.1 
Protocol Amendment 1 
Protocol Amendment 1 was issued to clarify the weight requirements for qualified subjects 
on Day -1 and Day 1, clarify that the same scale will be used in Screening and how rounding 
procedures will be used, update Reference 3 to cite the current FDA Guidance, remove the 
±2 day window for the Day 9 / Early Discontinuation visit, and remove symptom-directed 
physical examination from Day 7.  The changes to Protocol Amendment 1 are outlined as 
follows: 
Protocol Section 
Change 
Rationale 
Synopsis and Section 
3.1 Inclusion Criteria 
Clarified subjects need to weigh 
>120 kg at check-in on Day -1, 
and prior to dosing on Day 1, in 
addition to weighing >120 kg at 
Screening. 
In order to obtain accurate 
pharmacokinetic data in 
subjects weighing >120 kg, 
subjects participating in this 
study need to meet the weight 
requirement during dosing. 
Section 6.2.6 
Physical 
Examinations and 
Section 9.2 Appendix 
2:  Schedule of 
Events 
Clarified the scale should be 
used throughout the entire study 
including Screening.  Clarified 
rounding should occur by adding 
the following text:  Weight 
measurements will be rounded to 
one decimal place. 
The same scale should be used 
for the screening of subjects as 
will be used in the study to 
ensure weight measurement 
consistency.  Scales at the site 
measure weight to two decimal 
places.   
Section 8 Reference 
List 
Updated reference 3 to cite the 
May 2018 Bioanalytical Method 
Validation Guidance for Industry 
An updated Guidance was 
published in May of 2018. 
Section 9.2 Appendix 
2:  Schedule of 
Events 
Removal of (±2) from Day 9 or 
Early Discontinuation visit 
header 
The ±2 day visit window was 
included in error.  Subjects will 
check out on day 9 or will 
undergo Early Discontinuation 
Procedures on the day they 
discontinue.  There is no 
window for these visits. 
Section 9.2 Appendix 
2:  Schedule of 
Events 
Removal of Day 7 symptom-
directed physical examination 
from schedule. 
A complete physical exam is 
already being conducted on 
Day 7. 

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9.4.2 
Protocol Amendment 2 
Protocol Amendment 2 was issued to revise Exclusion Criteria 31; to remove redundant 
Exclusion Criteria; to add the measurement of height to the Day -1 Check-in procedures; and 
to remove the one hour observation period for allergic reaction following dosing.  The 
changes to Protocol Amendment 2 are outlined as follows: 
Protocol Section 
Change 
Rationale 
Synopsis and 
Section 3.2 
Exclusion Criteria 
Removed bullet point 3 from Exclusion 
Criteria 2, which stated: Hypertension that 
is poorly controlled (repeat readings >140 
mm Hg systolic and/or >90 mm Hg 
diastolic) and revised Exclusion Criteria 
31 from Subject has a sustained sitting 
systolic blood pressure >140 mm Hg or 
<100 mm Hg or a diastolic blood pressure 
>90 mm Hg at screening. Blood pressure 
may be retested twice in the sitting 
position at 5-minute intervals. The 
pressure elevation is considered sustained 
if either the systolic or the diastolic 
pressure exceeds the stated limits on all 3 
assessments to Subject has a blood 
pressure considered to be clinically 
significant by the investigator. Blood 
pressure may be retested twice in the 
sitting position at 5-minute intervals.  
Bullet point 3 was 
removed as it was 
redundant with 
Exclusion Criteria 31.  
Exclusion Criteria 31 
was revised to allow 
the investigator to 
determine clinical 
significance of blood 
pressure for study 
inclusion or exclusion. 
Section 6.2.6 
Physical 
Examinations and 
Section 9.2 
Appendix 2:  
Schedule of Events 
Added height to Day -1 Check-in 
procedures 
This measurement was 
previously 
unintentionally 
omitted from the study 
assessments.   
Section 6.2.1.8 
Reactogenicity and 
Section 9.2 
Appendix 2:  
Schedule of Events 
Removed specific mention of a one hour 
observation period for allergic reaction 
following dosing from Section 6.2.1.8 and 
removed reactogenicity from the Schedule 
of Events. 
Subjects are  required 
to stay at the clinical 
site throughout the 
entire dosing period 
and are continually 
under observation by 
site staff.