Clinical trial NCT04971109
Conditions: Smallpox
Sponsor: SIGA Technologies
Start date: 2022-03-29; Completion date: 2023-05-12
Enrollment: 467 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a study to assess the safety, tolerability, and PK of oral TPOXX 600 mg when administered twice daily (BID) for 28 days in adult subjects.

Detailed description:
This is a Phase 3, multicenter, double-blind, randomized, placebo-controlled study to assess the safety, tolerability, and PK of oral TPOXX 600 mg when administered BID for 28 days in adult subjects.

Arms: arm 1: Treatment Group 1: An oral dose of 600 mg (3 x 200 mg capsules)TPOXX arm 2: Treatment Group 2: An oral dose of placebo (3 capsules identical to TPOXX)
Interventions: intervention 1: TPOXX intervention 2: TPOXX Placebo
Intervention descriptions: intervention 1: Study is based on Animal Regulatory Rule intervention 2: Does not apply

Protocol documents:
Prot_SAP_002.pdf: 
A DOUBLE-BLIND, RANDOMIZED, PLACEBO-CONTROLLED, 
MULTICENTER STUDY TO ASSESS THE SAFETY, TOLERABILITY, 
AND PHARMACOKINETICS OF TPOXX® WHEN ADMINISTERED 
ORALLY FOR 28 DAYS IN ADULT SUBJECTS 
 
 
 
NCT: 04971109 
 
PROTOCOL: 01AUG2022 
 
SAP: 16APR2023 






SIGA Technologies, Inc. 
TPOXX 
Protocol No. SIGA-246-024 
Clinical Study Protocol Amendment 1 
 
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INVESTIGATOR PROTOCOL AGREEMENT PAGE 
 
I agree to conduct the study as outlined in the protocol titled “A Double-Blind, Randomized, 
Placebo-Controlled, Multicenter Study to Assess the Safety, Tolerability, and 
Pharmacokinetics of TPOXX® When Administered Orally for 28 Days in Adult Subjects” in 
accordance with the guidelines and all applicable government regulations, including US 
Title 21 of the Code of Federal Regulations Part 54. I have read and understand all sections 
of the protocol. 
 
 
 
 
Date 
 
 
 


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TABLE OF CONTENTS 
TITLE PAGE .......................................................................................................................... 1 
SIGNATURE PAGE ............................................................................................................... 2 
INVESTIGATOR PROTOCOL AGREEMENT PAGE ..................................................... 3 
PROTOCOL SYNOPSIS ....................................................................................................... 6 
1. 
INTRODUCTION ............................................................................................. 18 
1.1 
BACKGROUND ..............................................................................................18 
1.2 
RATIONALE FOR STUDY ............................................................................18 
1.3 
RATIONALE FOR DOSE SELECTION.........................................................18 
1.4 
POTENTIAL RISKS AND BENEFITS ...........................................................19 
1.4.1 
Potential Risks ..............................................................................................19 
1.4.2 
Known Potential Benefits .............................................................................20 
2. 
STUDY OBJECTIVES ...................................................................................... 20 
2.1 
PRIMARY OBJECTIVE ..................................................................................20 
2.2 
SECONDARY OBJECTIVE ............................................................................20 
3. 
STUDY DESIGN ................................................................................................ 20 
4. 
STUDY POPULATION..................................................................................... 23 
4.1 
INCLUSION CRITERIA .................................................................................23 
4.2 
EXCLUSION CRITERIA ................................................................................25 
4.3 
OTHER SCREENING CONSIDERATIONS ..................................................29 
4.4 
WITHDRAWAL OF SUBJECTS FROM THE STUDY .................................30 
4.4.1 
Reasons for Withdrawal................................................................................30 
4.4.2 
Handling of Withdrawals ..............................................................................31 
4.4.3 
Halting Rules ................................................................................................31 
4.4.4 
Replacements ................................................................................................33 
5. 
STUDY TREATMENTS ................................................................................... 33 
5.1 
TREATMENTS ADMINISTERED .................................................................33 
5.2 
STUDY DRUG ................................................................................................33 
5.2.1 
Study Drug Packaging, Preparation, Administration, and Storage...............34 
5.2.2 
Study Drug Accountability ...........................................................................36 
5.3 
METHOD OF ASSIGNING SUBJECTS TO TREATMENT GROUPS .........36 
5.4 
BLINDING .......................................................................................................37 
5.4.1 
Blinding Procedures .....................................................................................37 
5.4.2 
Breaking the Blind ........................................................................................37 
5.5 
TREATMENT COMPLIANCE .......................................................................38 
5.5.1 
Subject Diary ................................................................................................38 
5.5.2 
Prior and Concomitant Medications .............................................................39 
6. 
STUDY PROCEDURES ................................................................................... 39 


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6.1 
PHARMACOKINETIC SUBSET ASSESSMENTS AND ENDPOINTS ......40 
6.1.1 
Pharmacokinetic Sample Collection .............................................................41 
6.1.2 
Pharmacokinetic Sample Analysis................................................................42 
6.2 
SAFETY ASSESSMENTS AND ENDPOINTS ..............................................42 
6.2.1 
Adverse Events .............................................................................................43 
6.2.2 
Clinical Laboratory Testing ..........................................................................50 
6.2.3 
Medical History ............................................................................................52 
6.2.4 
Vital Sign Measurements ..............................................................................52 
6.2.5 
Electrocardiograms .......................................................................................52 
6.2.6 
Physical Examinations ..................................................................................52 
6.2.7 
Unscheduled Visits .......................................................................................53 
7. 
STATISTICAL ANALYSIS PLANS ................................................................ 53 
7.1 
SAMPLE SIZE CALCULATIONS..................................................................53 
7.2 
ANALYSIS SETS ............................................................................................53 
7.3 
STATISTICAL ANALYSIS .............................................................................54 
7.3.1 
Pharmacokinetic Analyses ............................................................................54 
7.3.2 
Safety Analyses ............................................................................................55 
7.4 
HANDLING OF MISSING DATA ..................................................................56 
7.5 
INTERIM ANALYSES ....................................................................................57 
8. 
REFERENCE LIST........................................................................................... 58 
9. 
APPENDICES .................................................................................................... 59 
9.1 
APPENDIX 1: LIST OF ABBREVIATIONS ..................................................59 
9.2 
APPENDIX 2: SCHEDULE OF EVENTS ......................................................61 
9.3 
APPENDIX 3: STUDY GOVERNANCE .......................................................68 
9.3.1 
Data Quality Assurance ................................................................................68 
9.3.2 
Investigator Obligations ...............................................................................69 
9.3.3 
Study Management .......................................................................................74 
9.4 
APPENDIX 4: DIVISION OF ACQUIRED IMMUNE DEFICIENCY 
SYNDROME (DAIDS) ....................................................................................81 
9.5 
APPENDIX 5: CHANGE HISTORY ............................................................101 
9.5.1 
Protocol Amendment 1 ...............................................................................101 
 
 
 


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PROTOCOL SYNOPSIS 
PROTOCOL NO.: SIGA-246-024 
TITLE: A Double-Blind, Randomized, Placebo-Controlled, Multicenter Study to Assess the 
Safety, Tolerability, and Pharmacokinetics of TPOXX® When Administered Orally for 
28 Days in Adult Subjects 
STUDY PHASE: 3 
STUDY SITES: 
 
OBJECTIVES: 
Primary: 
The primary objective of this study is to determine the safety and tolerability of TPOXX 
when administered orally for 28 days in adult subjects. 
Secondary: 
The secondary objective of this study is to describe the pharmacokinetic (PK) profile of 
TPOXX when administered orally for 28 days in adult subjects. 
STUDY DESIGN AND METHODOLOGY: 
This is a Phase 3, multicenter, double-blind, randomized, placebo-controlled study to assess 
the safety, tolerability, and PK of oral TPOXX 600 mg when administered orally for 28 days 
in adult subjects. 
A total of at least 445 subjects (includes a PK subset of 40 subjects), ages 18 to 80, inclusive, 
will be enrolled and randomly assigned within stratified age groups (18 to 30 years, 31 to 
45 years, 46 to 64 years, and 65 to 80 years) to 1 of 2 treatment groups in an overall 
randomization of 4:1 (approximately 356 subjects will receive TPOXX and 89 subjects will 
receive TPOXX matching placebo). There will be 2 dosing regimens based on the subject’s 
body weight: subjects with a body weight of 120 kg or less will be administered either 
TPOXX 600 mg or placebo two times a day (BID), 12 hours apart (±30 minutes); and 
subjects with a body weight more than 120 kg will be administered either TPOXX 600 mg or 
placebo three times a day (TID), 8 hours apart (±30 minutes). The enrollment goal for the 
study is to randomly assign a sufficient number of subjects to ensure that at least 300 subjects 
receive at least 92% of the oral TPOXX 600 mg BID or TID dosing regimen over the 28-day 
treatment period. Overall, across all clinical investigative sites, a goal of approximately 20% 
of subjects (i.e., 89 subjects) or more will be enrolled and randomly assigned in each age 
group to ensure a respective investigation of TPOXX safety and PK across age groups. The 
treatment groups will be as follows: 
• Treatment Group 1: An oral dose of 600 mg (3 × 200-mg capsules) TPOXX BID (every 
12 hours [±30 minutes]) for subjects with a body weight of 120 kg or less or TID (every 
8 hours [±30 minutes]) for subjects with a body weight more than 120 kg for 28 days 
(Day 1 to Day 28). 


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• Treatment Group 2: An oral dose of placebo (3 capsules identical to TPOXX) BID (every 
12 hours [±30 minutes]) for subjects with a body weight of 120 kg or less or TID (every 
8 hours [±30 minutes]) for subjects with a body weight more than 120 kg for 28 days 
(Day 1 to Day 28). 
When study drug is administered at the clinical investigative site, all subjects will be 
provided a meal (consisting of approximately 600 calories and 25 g of fat). The meal should 
be consumed within 30 minutes and prior to the administration of study drug (TPOXX or 
matching placebo). Subjects should be administered study drug as soon as possible following 
completion of the meal but no more than 30 minutes should elapse between meal completion 
and administration of study drug. Subjects should take study drug with 8 oz. (240 mL) of 
water. Subjects will be instructed at the screening visit and prior to check-in to the clinical 
investigative site on either Day –1 or Day 1 that other than water, no beverages may be 
ingested within 3 hours before or 3 hours after study drug administration. 
When study drug (TPOXX or matching placebo) is administered at home, subjects will be 
instructed to take it within 30 minutes after the completion of a meal consisting of 
approximately 600 calories and 25 g of fat and with 8 oz. (240 mL) of water. Other than 
water, no beverages may be ingested within 3 hours before or 3 hours after taking study drug, 
excluding a beverage that is being consumed as a part of the required meal. 
Clinical investigative sites will provide subjects with instructions and dietary information in 
order to help them meet the study requirement for eating meals with an appropriate caloric 
and fat content before study drug dosing. 
Clinical investigative sites will provide subjects with a subject diary and instructions to 
record the time that they completed their last meal before taking study drug in the subject 
diary. Subjects will be instructed to record that they have met the required caloric and fat 
intake of eating a meal containing approximately 600 calories and 25 g of fat before each 
dose of study drug. 
Clinical investigative sites will instruct subjects to record the time that they take study drug 
in their subject diary. Subjects will follow a dosing regimen of study drug appropriate for 
their weight for 28 days and will be instructed to take their study drug at the same time of the 
day each day. 
Safety assessments will include clinical laboratory test results (hematology, serum chemistry, 
and urinalysis), monitoring of adverse events (AEs) including serious AEs (SAEs), vital sign 
measurements (systolic and diastolic blood pressures, heart rate, respiratory rate, and body 
temperature), electrocardiogram (ECG) results, and physical examination findings. 
All subjects will have a follow-up telephone call 14 and 30 days after the last dose of study 
drug (Day 42 [+2 days] and Day 58 [+2 days], respectively) to report any AEs and SAEs. All 
AEs, SAEs, and clinically significant laboratory abnormalities will be followed until 
resolution or until stability of the abnormality has been demonstrated as determined by the 
investigator and/or medical monitor. 


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The study will consist of a screening period (Day –28 to Day –2), 1 check-in, on-site visits 
(Day 7, Day 14, and Day 21), a dosing complete/early termination (ET) visit (Day 29), and 
2 follow-up telephone calls (Day 42 [+2 days] and Day 58 [+2 days]). 
The total duration of the study for each subject, including screening, treatment, and follow-up 
telephone calls, will be approximately 86 days. 
Non-PK Study Subjects: 
Those subjects not participating in the PK subset will check into the clinical investigative site 
in the morning of Day 1 and will remain at the clinical investigative site until after the first 
dose on Day 1 and all safety assessments have been completed. 
With the exception of the first dose of study drug administered at the clinical investigative 
site on Day 1, subjects will administer study drug at home for all remaining doses through 
Day 28. 
PK Subset Study Subjects: 
Those subjects participating in the PK subset will follow the same general schedule with the 
addition of several overnight stays. Specifically, the PK subset will consist of a screening 
period (Day –28 to Day –2), 3 check-in and in-house periods (Day –1 to Day 2; Day 13 to 
Day 14; and Day 27 to Day 31), a dosing complete/ET visit (Day 29), and 2 follow-up 
telephone calls (Day 42 [+2 days] and Day 58 [+2 days]). 
Subjects in the PK subset will check into the clinical investigative site on Day –1, Day 13, 
and Day 27 and be discharged from the clinical investigative site on Day 2, Day 14, and 
Day 31. Subjects will check into the clinical investigative site early enough to eat the 
required meal and then be administered the final dose for that day on Day 13 and Day 27. 
When the study drug is not administered at the clinical investigative site, subjects will 
administer study drug at home. 
Serial blood samples for PK analysis of TPOXX will be collected before the first dose of 
study drug (0 hour) on Days 1, 14, and 28 and up to 24 hours after study drug administration 
on Day 1 and up to 72 hours after the first dose of study drug on Day 28. 
STUDY POPULATION: 
Inclusion Criteria: 
Each subject must meet all of the following criteria to be enrolled in this study: 
1. Subject is male or female between 18 and 80 years of age, inclusive. 
2. Subject is available for clinical follow-up for the duration of the study. 
3. Women of childbearing potential have a negative β-human chorionic gonadotropin 
pregnancy test (serum) at the screening visit and a negative urine pregnancy test on Day 1 
or Day –1 (PK subset) before receipt of study drug, and meet one of the following 
criteria: 


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a. Subject or their partner has undergone surgical sterilization. 
b. Male sexual partner who has undergone a vasectomy at least 3 months before 
screening. 
c. 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. 
d. Subject agrees to be abstinent (i.e., heterosexually inactive) for the duration of the 
study. 
e. 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. Male and female condoms should not be used together, as this 
can reduce their effectiveness. 
ii. 
Diaphragm or cervical cap with spermicide 
iii. 
Intrauterine device with spermicide 
iv. 
Oral contraceptives or other hormonal methods 
NOTE: Another nonhormonal method of contraception must be used in 
conjunction with oral contraceptives. 
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. 
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 test results, vital sign measurements, 12-lead ECG results, 
and physical examination findings at screening. 
6. Subject agrees not to use nicotine products, including electronic vapor cigarettes, nicotine 
patches, or nicotine gum, for at least 30 days before the Day 1 randomization visit 
through completion of the Day 29 dosing complete/ET visit. 
7. Subject agrees to comply with the study dietary requirements throughout the study drug 
dosing period. 
8. Subject agrees not to consume caffeine- or xanthine-containing products during all study 
visits, including overnight stays (PK subset); sodas, coffee, and tea designated as 
caffeine-free or noncaffeinated may be consumed on study days; caffeine may be 
consumed while at home and between study visits. 
9. Subject agrees to comply with all protocol requirements. 
10. Subject has adequate venous access if participating in the PK subset. 
11. Subject is able and willing to provide written informed consent. 


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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 
• History of head trauma resulting in a diagnosis of traumatic brain injury other than 
concussion 
• Frequent episodes of headache 
3. Subject has received any vaccination within 28 days prior to Day 1 or plans to receive a 
vaccination at any time during the treatment period or within 28 days after study Day 28. 
4. Subject has received treatment in another clinical study of an investigational drug (or 
medical device) or investigational vaccine within 30 days or 5 half-lives (whichever is 
longer) before the first dose of study drug. 
5. Subject has a history of relevant drug and/or food allergies (i.e., allergy to TPOXX or 
excipients, or any significant food allergy that could preclude a standard diet in the 
clinical investigative site). 
6. Subject has any condition possibly affecting drug absorption (e.g., 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 reaction (excluding 
seasonal allergies); or has evidence or history of clinically significant disease, including 
hematological, endocrine, pulmonary, gastrointestinal, cardiovascular, hepatic, 
psychiatric, or neurological disease. Exceptions to these disease criteria (e.g., stable, mild 
joint disease unassociated with collagen vascular disease) may be made following 
discussions with the medical monitor. 
8. Subject has a history of cardiac disease, symptomatic or asymptomatic arrhythmias, 
syncopal episodes, chest pain (that is diagnosed as cardiac related) or trouble breathing 
on exertion, or risk factors for torsades de pointes (e.g., heart failure, hypokalemia). 
9. Subject has a family history of an immediate family member (father, mother, brother, or 
sister) who has had an onset of ischemic heart disease before the age of 50 years. 
10. Subject is 20 years of age or older and has a ≥30% risk of developing a myocardial 
infarction or coronary death within the next 10 years using the National Cholesterol 
Education Program’s Risk Assessment Tool: https://www.mcw.edu/calculators/ldl-
cholesterol-goal-level. 


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11. 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. 
12. Subject has a history of a peptic ulcer or significant gastrointestinal bleeding. 
13. Subject has a bleeding disorder diagnosed by a doctor (e.g., factor deficiency, 
coagulopathy, or platelet disorder requiring special precautions) or significant bruising or 
bleeding difficulties with blood draws. 
14. 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). 
15. Subject has neutropenia or other blood dyscrasia determined to be clinically significant 
by the investigator. 
16. 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 cytochromes (CYP)2C8 
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. 
17.  Subject has a history of drug or alcohol abuse or dependency within the last year before 
screening. 
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 (e.g., human T cell 
lymphotropic virus I or II). 
21. 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). 
22. 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. 
23. Subject reports participation in strenuous activity or contact sports within 24 hours before 
the first dose of study drug. 


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24. 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. 
25. 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), cotinine, or alcohol at screening or check-in. 
26. 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) <70 mL/min 
• Creatinine in males >1.7 mg/dL and in females >1.4 mg/dL (1.3 times the upper 
laboratory reference range) 
• Hemoglobin ≤10% of the lower laboratory reference range 
• White blood cell counts considered to be clinically significant by the investigator 
• Absolute neutrophil count <1000 cells/mm3 
• Platelets not within ±10% of laboratory reference range 
• Alanine aminotransferase >2 times above the upper laboratory reference range 
• Aspartate aminotransferase >2 times above the upper laboratory reference range 
• Alkaline phosphatase >20% above the upper laboratory reference range 
• Hemoglobin A1c ≥7.0% 
• Cholesterol ≥300 mg/dL and low-density lipoprotein ≥190 mg/dL 
27. Subject has hypertension that is poorly controlled (repeat reading >140 mm Hg systolic 
and/or >90 mm Hg diastolic) or blood pressure considered to be clinically significant by 
the investigator. Blood pressure may be retested twice in the sitting position at 5-minute 
intervals. 
28. Subject has a resting heart rate of <40 beats per minute or >110 beats per minute at 
screening. 
29. Subject has an abnormal ECG at screening that is determined by the investigator to be 
clinically significant. 
30. Male subject has a QT interval corrected using Fridericia’s formula (QTcF) >450 ms or 
female subject has a QTcF >470 ms at screening or Day 1 or Day –1 (PK subset). 
31. Subject has used any prescription antiviral drugs with the intention of coronavirus disease 
(COVID-19) treatment or prophylaxis, including those that are thought to be effective for 
prevention of COVID-19 but have or have not been licensed for this indication, within 
1 month prior to study entry or during the study. 
32. In the opinion of the investigator, the subject is not suitable for entry into the study. 
33. Subject is a member or family member of the investigator or study site personnel. 
34. Subject has previously participated in this clinical trial. 


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EVALUATION CRITERIA: 
Pharmacokinetic Assessments and Endpoints (PK Subset) 
BID Dosing: Subjects weighing 120 kg or less: 
Blood samples for PK analysis of TPOXX in plasma will be collected on Day 1 before the 
first dose (0 hour) and at 2, 4, 6, 8, 10, 12 (before the second dose), 14, 16, 18, 20, 22, and 
24 hours (before the first dose on Day 2); on Day 14 (before the first dose); and on Day 28 
(before the first dose) and at 2, 4, 6, 8, 10, 12 (before the second dose on Day 28), 14, 16, 18, 
20, 22, 24 (Day 29, AM), 48 (Day 30, AM), and 72 (Day 31, AM) hours after the first dose on 
Day 28. 
TID Dosing: Subjects weighing more than 120 kg: 
Blood samples for PK analysis of TPOXX in plasma will be collected on Day 1 before the 
first dose (0 hour) and at 2, 4, 6, 8 (before the second dose), 10, 12, 14, 16 (before the third 
dose), 18, 20, 22, and 24 hours (before the first dose on Day 2); on Day 14 (before the first 
dose); and on Day 28 (before the first dose) and at 2, 4, 6, 8 (before the second dose), 10, 12, 
14, 16 (before the third dose), 18, 20, 22, 24 (Day 29, AM), 48 (Day 30, AM), and 72 (Day 31, 
AM) hours after the first dose on Day 28. 
For PK blood samples, the acceptable window for collection from the scheduled collection 
time point will be as follows: ±15 minutes from 0 to 24 hours (except where samples are 
collected predose) and ±60 minutes from 48 to 72 hours. 
The following plasma PK parameters will be calculated separately for BID and TID dosing 
as endpoints for TPOXX to the extent that data permit using actual sampling times rather 
than scheduled sampling times and will include, but are not limited to the following: 
Day 1: 
• Maximum observed plasma concentration (Cmax), reported separately for each dose 
• Time to reach Cmax (Tmax), reported separately for each dose 
• Area under the plasma concentration-time curve (AUC) from time zero to 24 hours 
(AUC0-24) 
• AUC from time zero to tau where tau is the 8-hour or 12-hour dosing interval following 
the first dose (AUCtau) 
Day 28: 
• Cmax 
• Average steady-state plasma concentration (Cavg) 
• Trough plasma concentration (Ctrough) 
• Minimum observed plasma concentration (Cmin) 
• Tmax 
• AUC0-24 
• AUC from time zero to tau where tau is the 8-hour or 12-hour dosing interval (AUCtau) 
• AUC from time zero to the last measurable sample (AUC0-last) 


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• AUC from time zero to infinity (AUC0-∞) 
• Observed elimination rate constant (λz) 
• Terminal elimination half-life (t1/2) 
• Apparent clearance (CLss/F) 
• Apparent volume of distribution (Vz/F) 
• Accumulation ratio (Rac) 
• %Fluctuation 
Safety Assessments: 
Safety and tolerability will be assessed by the following endpoints: monitoring and recording 
of AEs; clinical laboratory test results (hematology, serum chemistry, and urinalysis); 
pregnancy testing; vital sign measurements (systolic and diastolic blood pressures, heart rate, 
respiratory rate, and body temperature); 12-lead ECG results; and physical examination 
findings. A blood sample will be collected for all subjects who discontinue from the study for 
TPOXX plasma concentration if the ET visit occurs within 30 hours after the subject’s last 
dose of TPOXX/matching placebo in order to collect information about the relationship 
between TPOXX blood level and ET from the study. 
STUDY DRUG, DOSAGE, AND ROUTE OF ADMINISTRATION: 
Subjects Weighing 120 kg or Less: 
• An oral dose of 600 mg (3 × 200-mg capsules) TPOXX BID (every 12 hours 
[±30 minutes]) for 28 days 
• An oral dose of placebo (3 capsules identical to TPOXX) BID (every 12 hours 
[±30 minutes]) for 28 days 
Subjects Weighing More Than 120 kg: 
• An oral dose of 600 mg (3 × 200-mg capsules) TPOXX TID (every 8 hours 
[±30 minutes]) for 28 days 
• An oral dose of placebo (3 capsules identical to TPOXX) TID (every 8 hours 
[±30 minutes]) for 28 days 
STATISTICAL CONSIDERATIONS: 
A summary of statistical considerations is provided below. More specific descriptions of the 
statistical methods to be used will be described in the statistical analysis plan (SAP). 
Sample Size: 
There is no formal sample size calculation for this study. Although the sample size is not 
based on statistical power considerations, administration of TPOXX 600 mg to 300 subjects 
provides approximately 95% probability of observing at least 1 occurrence of any AE if the 
incidence of AEs in the study population is 1% and is considered adequate to provide a 
reasonable assessment of safety and tolerability. A sufficient number of subjects will be 
randomly assigned to ensure that at least 300 subjects receive at least 92% of the doses of the 
BID or TID dosing regimen of oral TPOXX 600 mg over the 28-day treatment period. 


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Study Population: 
Adult subjects from 18 to 80 years old, inclusive, are eligible for this study. A total of at least 
445 subjects will be enrolled and randomly assigned into stratified age groups (18 to 
30 years, 31 to 45 years, 46 to 64 years, and 65 to 80 years). Approximately 356 subjects will 
be randomly assigned to receive active drug (TPOXX 600 mg) and 89 subjects will be 
randomly assigned to receive placebo. Overall, across all clinical investigative sites, a goal of 
approximately 20% of subjects (i.e., 89 subjects) or more will be enrolled and randomly 
assigned in each age group to ensure a representative investigation of the safety and PK 
across age groups. 
Analysis Populations: 
All populations will be identified and finalized before the database lock. All subjects who are 
randomly assigned are considered study subjects. Study populations are defined as the 
following: 
• The Intent-to-Treat Population will include all subjects who were randomly assigned to 
the study (i.e., a randomization number and randomization date are present in the 
database). 
• The Safety Population will include all subjects who received at least 1 dose of study drug 
(TPOXX or matching placebo). 
• The Per-Protocol (PP) Safety Population will include all subjects who received at least 
92% of the 600 mg BID or TID dosing regimen of TPOXX or matching placebo. 
• The PK Population will include all subjects in the PK subset who have taken at least 92% 
of the 600 mg BID or TID dosing regimen of TPOXX, have sufficient drug 
concentrations in plasma, and have no protocol deviations or other circumstances that 
would exclude the subject from analysis. 
Pharmacokinetic Analyses: 
The PK Population will be used for the preparation of PK summaries and analyses. 
Individual plasma concentration and time deviation data will be presented in a data listing. 
Plasma concentration data will be summarized by study day, time point, and study drug 
dosing regimen using the following descriptive statistics: number of subjects, arithmetic 
mean, SD, coefficient of variation (CV), minimum, median, and maximum. Individual and 
mean plasma concentration versus scheduled time profiles will be presented in figures on 
both linear and semilogarithmic scales. Mean concentration versus scheduled time profiles 
will be presented by the study drug dosing regimen. 
The PK parameters of TPOXX will be analyzed using noncompartmental methods based on 
the actual sampling times. The individual PK parameters will be presented in data listings 
and summarized by study day and study drug dosing regimen using the following descriptive 
statistics: number of subjects, arithmetic mean, SD, CV, geometric mean, geometric SD, 
geometric CV, minimum, median, and maximum. 


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Safety Analyses: 
The safety and tolerability data summaries will be presented separately for the Safety 
Population and the PP Safety Population and will also be presented by BID or TID study 
drug dosing regimen. 
Adverse events will be coded by preferred term and system organ class using the latest 
version of the Medical Dictionary for Regulatory Activities. All AE data will be presented in 
a data listing. Treatment-emergent AEs will be summarized by treatment, BID and TID study 
drug dosing regimen, and overall, as well as by severity and relationship to study drug for the 
Safety Population and PP Safety Population. For any subject who discontinues the study for 
any reason, data will be summarized by treatment group, reason for discontinuation, if the 
drug concentration was collected, and the result of the bioanalysis. In addition, SAEs and 
AEs leading to subject study discontinuation will be presented in the data listings and 
summarized by treatment, dosing regimen, and overall. 
The overall AE rate will be defined as the percentage of subjects in the Safety Population and 
PP Safety Population who report at least 1 postdose AE. The overall AE rate will be 
compared between treatment groups using Mantel-Haenszel test stratified for age group (18 
to 30, 31 to 45, 46 to 64, and 65 to 80 years). If expected cell counts are less than 5, then 
Fisher’s exact test will be applied. An exact unadjusted 95% confidence interval (CI), 
calculated using the Clopper-Pearson method, will be presented for each treatment group. For 
the difference in overall AE rates between treatment groups, a continuity corrected exact 95% 
CI around the difference will be calculated. In addition, the Mantel-Haenszel adjusted odds 
ratio and 95% CIs from the stratified analysis will be presented. The relationship of treatment 
group, age, clinical investigative site, and their interactions on overall AE rate will also be 
investigated using a logistic regression model; CIs for the odds ratios associated with each 
factor in the model will be presented. Further details will be included in the SAP. 
Time from the first dose to the first AE or to discontinuation from study for any reason will 
be analyzed using Kaplan-Meier quartile estimates along with 2-sided 95% CIs. Treatment 
groups will be compared using the log rank test stratified by age group and site. If a subject 
does not experience any AE or does not discontinue from study, the time to first AE or time 
to discontinuation will be censored at the date of study completion. 
Toxicity grades for laboratory tests will be determined according to the Division of Acquired 
Immune Deficiency Syndrome (DAIDS) AE Grading Table. The maximum postbaseline 
grade increase from baseline grade will be summarized by treatment group and BID and TID 
study drug dosing regimen and overall for the Safety Population and PP Safety Population 
using frequency and percentage of subjects with increase to grade 1, 2, 3, 4, 1 to 4, 2 to 4, 
and 3 to 4, respectively. 
Actual values and changes from baseline for clinical laboratory test results, vital sign 
measurements, and 12-lead ECG results will be summarized by treatment group and BID and 
TID study drug dosing regimen at each time point using descriptive statistics (number of 
subjects, mean, SD, minimum, median, and maximum). Shift tables will be generated for 
clinical laboratory test results. Physical examination findings will be presented in a data 
listing. 


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Narratives will be presented for all deaths, subjects who reported SAEs, subjects withdrawn 
because of AEs, and grade 3 AEs deemed by the investigator to be possibly, probably, or 
definitely related to study drug. 
DATE OF PROTOCOL:  01 August 2022 


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1. 
INTRODUCTION 
1.1 
BACKGROUND 
Historically, variola virus, 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 Smallpox is defined by 2 clinical forms, variola major 
and variola minor. 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 US Food and Drug Administration (FDA) approved oral TPOXX® for the 
treatment of human smallpox disease in adults and pediatric patients weighing at least 
13 kilograms.  
1.2 
RATIONALE FOR STUDY 
Treatment with TPOXX following exposure to variola virus and prior to the onset of 
clinically diagnosed smallpox disease would constitute postexposure prophylaxis treatment. 
For human smallpox, the asymptomatic incubation period following exposure to the variola 
virus may range from 7 to 19 days (most commonly 12 to 14 days) postexposure. This 
approximately 2-week asymptomatic incubation period (with variability in duration) in 
humans before the development of secondary viremia, symptoms, and the generation of 
neutralizing antibody responses, necessitates the need for a longer treatment duration of 
TPOXX as a prophylactic. Humoral immune responses in the form of hemagglutination 
inhibition, complement fixing, and virus-neutralizing antibodies are detectable within 
approximately 5 days after the appearance of the rash and therefore approximately 12 to 
24 days postexposure. To ensure the proper development of a neutralizing antibody response 
to the variola virus and to avoid a post-treatment virologic rebound, SIGA proposes the 
administration of TPOXX 600 mg for 28 days to support a postexposure prophylaxis 
treatment claim. 
1.3 
RATIONALE FOR DOSE SELECTION 
TPOXX 600 mg (3 × 200-mg capsules) two times a day (BID) is the approved dose of 
TPOXX for the treatment of smallpox in patients weighing between 13 kg and 120 kg, 
inclusive. The FDA and SIGA have agreed that TPOXX dosing for patients weighing 120 kg 


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or more should be adjusted to 600 mg TPOXX three times a day (TID).2 The 28-day TPOXX 
treatment duration, rather than the 14-day duration, was chosen for the postexposure 
prophylaxis indication as a longer treatment period may be necessary to provide protection 
from smallpox from the time of initial exposure to variola virus until the development of 
protective neutralizing antibodies. This accounts for the 7- to 17-day, asymptomatic stage; 
the subsequent 2- to 3-day, prodromal stage; and finally, the development of neutralizing 
antibodies, which are evident from about the sixth day following the onset of clinical 
symptoms and increase in antibody titer thereafter. 
1.4 
POTENTIAL RISKS AND BENEFITS 
1.4.1 
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 signing of the informed consent form (ICF) and continuing 
through 30 days after the last dose of study drug. For all women of childbearing potential, 
serum pregnancy testing will be performed and checked by the investigator to confirm a 
negative test result at the screening visit. For women of childbearing potential in the 
pharmacokinetic (PK) subset, a urine pregnancy test will be performed at check-in on Day –1 
and must be confirmed as negative by the investigator prior to randomization and before 
receipt of the first dose of study drug on Day 1. Additional serum pregnancy testing will be 
performed on Days 7, 13, 21, and on Day 29 dosing complete/early termination (ET) visit. 
For women of childbearing potential not in the PK subset, a urine pregnancy test will be 
performed at check-in on Day 1 and must be verified as negative by the investigator prior to 
randomization and before receipt of the first dose of study drug. Additional serum pregnancy 
testing will be performed on Days 7, 14, 21, and on Day 29 dosing complete/ET visit. 
Women who are pregnant or breastfeeding 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 6.2.1.8). 
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 adverse events (AEs) in clinical studies completed to date. There may be 
other side effects of TPOXX that are not yet known. Full details can be found in the TPOXX 
full prescribing information.2 


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1.4.2 
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, electrocardiograms (ECGs), and physical examinations. Others may benefit from 
knowledge gained in this study that may aid in the use of TPOXX for the treatment of 
smallpox. 
2. 
STUDY OBJECTIVES 
2.1 
PRIMARY OBJECTIVE 
The primary objective of this study is to determine the safety and tolerability of TPOXX 
when administered orally for 28 days in adult subjects. 
2.2 
SECONDARY OBJECTIVE 
The secondary objective of this study is to describe the PK profile of TPOXX when 
administered orally for 28 days in adult subjects. 
3. 
STUDY DESIGN 
This is a Phase 3, multicenter, double-blind, randomized, placebo-controlled study to assess 
the safety, tolerability, and PK of oral TPOXX 600 mg when administered for 28 days in 
adult subjects. 
A total of at least 445 subjects (includes a PK subset of 40 subjects), ages 18 to 80, inclusive, 
will be enrolled and randomly assigned within stratified age groups (18 to 30 years, 31 to 
45 years, 46 to 64 years, and 65 to 80 years) to 1 of 2 treatment groups in an overall 
randomization of 4:1 (approximately 356 subjects will receive TPOXX and 89 subjects will 
receive TPOXX matching placebo). There will be 2 dosing regimens based on the subjects 
body weight: subjects with a body weight of 120 kg or less will be administered either 
TPOXX 600 mg or placebo BID, 12 hours apart (±30 minutes); and subjects with a body 
weight of more than 120 kg will be administered TPOXX 600 mg or placebo TID, 8 hours 
apart (±30 minutes). The enrollment goal for the study is to randomly assign a sufficient 
number of subjects to ensure that at least 300 subjects receive at least 92% of the oral 
TPOXX 600 mg BID or TID dosing regimen over the 28-day treatment period. Overall, 
across all clinical investigative sites, a goal of approximately 20% of subjects (i.e., 
89 subjects) or more will be enrolled and randomly assigned in each age group to ensure a 


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representative investigation of TPOXX safety and PK across age groups. The treatment 
groups will be as follows: 
• Treatment Group 1: An oral dose of 600 mg (3 × 200-mg capsules) TPOXX BID (every 
12 hours [±30 minutes]) for subjects with a body weight of 120 kg or less or TID (every 
8 hours [±30 minutes]) for subjects with a body weight more than 120 kg for 28 days 
(Day 1 to Day 28). 
• Treatment Group 2: An oral dose of placebo (3 capsules identical to TPOXX) BID (every 
12 hours [±30 minutes]) for subjects with a body weight of 120 kg or less or TID (every 
8 hours [±30 minutes]) for subjects with a body weight more than 120 kg for 28 days 
(Day 1 to Day 28). 
When study drug is administered at the clinical investigative site, all subjects will be 
provided a meal (consisting of approximately 600 calories and 25 g of fat). The meal should 
be consumed within 30 minutes and prior to the administration of study drug (TPOXX or 
matching placebo). Subjects should be administered study drug as soon as possible following 
completion of the meal but no more than 30 minutes should elapse between meal completion 
and administration of study drug. Subjects should take study drug with 8 oz. (240 mL) of 
water. Subjects will be instructed at the screening visit and prior to check-in to the clinical 
investigative site on either Day –1 or Day 1 that other than water, no beverages may be 
ingested within 3 hours before or 3 hours after study drug administration. 
When study drug (TPOXX or matching placebo) is administered at home, subjects will be 
instructed to take it within 30 minutes after the completion of a meal consisting of 
approximately 600 calories and 25 g of fat and with 8 oz. (240 mL) of water. Other than 
water, no beverages may be ingested within 3 hours before or 3 hours after taking study drug 
excluding a beverage that is being consumed as a part of the required meal. 
Clinical investigative sites will provide subjects with instructions and dietary information in 
order to help them meet the study requirement for eating meals with an appropriate caloric 
and fat content before study drug dosing. 
Clinical investigative sites will provide subjects with a subject diary and instructions to 
record the time that they completed their last meal before taking study drug in the subject 
diary. Subjects will be instructed to record that they have met the required caloric and fat 
intake of eating a meal containing approximately 600 calories and 25 g of fat before each 
dose of study drug. 


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Clinical investigative sites will instruct subjects to record the time that they take study drug 
in their subject diary. Subjects will follow a dosing regimen of study drug appropriate for 
their weight for 28 days and will be instructed to take their study drug at the same time of the 
day each day. 
Safety assessments will include clinical laboratory test results (hematology, serum chemistry, 
and urinalysis), monitoring of AEs including serious AEs (SAEs), vital sign measurements 
(systolic and diastolic blood pressures, heart rate, respiratory rate, and body temperature), 
ECG results, and physical examination findings. 
All subjects will have a follow-up telephone call 14 and 30 days after the last dose of study 
drug (Day 42 [+2 days] and Day 58 [+2 days], respectively) to report any AEs and SAEs. All 
AEs, SAEs, and clinically significant laboratory abnormalities will be followed until 
resolution or until stability of the abnormality has been demonstrated as determined by the 
investigator and/or medical monitor. 
The study will consist of a screening period (Day –28 to Day –2), 1 check-in, on-site visits 
(Day 7, Day 14, and Day 21), a dosing complete/ET visit (Day 29), and 2 follow-up 
telephone calls (Day 42 [+2 days] and Day 58 [+2 days]). 
The total duration of the study for each subject, including screening, treatment, and follow-up 
telephone calls, will be approximately 86 days. 
Non-PK Study Subjects: 
Those subjects not participating in the PK subset will check into the clinical investigative site 
in the morning of Day 1 and will remain at the clinical investigative site until after the first 
dose on Day 1 and all safety assessments have been completed. 
With the exception of the first dose of study drug administered at the clinical investigative 
site on Day 1, subjects will administer study drug at home for all remaining doses through 
Day 28. 


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PK Subset Safety Subjects: 
Those subjects participating in the PK subset will follow the same general schedule with the 
addition of several overnight stays. Specifically, the PK subset will consist of a screening 
period (Day –28 to Day –2), 3 check-in and in house periods (Day –1 to Day 2; Day 13 to 
Day 14; and Day 27 to Day 31), a dosing complete/ET visit (Day 29), and 2 follow-up 
telephone calls (Day 42 [+2 days] and Day 58 [+2 days]). 
Subjects in the PK subset will check into the clinical investigative site on Day –1, Day 13, 
and Day 27 and be discharged from the clinical investigative site on Day 2, Day 14, and 
Day 31. Subjects will check into the clinical investigative site early enough to eat the 
required meal and then be administered the final dose for that day on Day 13 and Day 27. 
When the study drug is not administered at the clinical investigative site, subjects will 
administer study drug at home. 
Serial blood samples for PK analysis of TPOXX will be collected before the first dose 
(0 hour) on Days 1, 14, and 28 and up to 24 hours after study drug administration on Day 1 
and up to 72 hours after study drug administration on Day 28. 
4. 
STUDY POPULATION 
A total of at least 445 adult male and female subjects will be enrolled at approximately 
12 clinical investigative sites in the United States. 
4.1 
INCLUSION CRITERIA 
Each subject must meet all of the following criteria to be enrolled in this study: 
1. Subject is male or female between 18 and 80 years of age, inclusive. 
2. Subject is available for clinical follow-up for the duration of the study. 
3. Women of childbearing potential have a negative β-human chorionic gonadotropin 
pregnancy test (serum) at the screening visit and a negative urine pregnancy test on Day 1 
or Day –1 (PK subset) before receipt of study drug, and meet one of the following 
criteria: 
a. Subject or their partner has undergone surgical sterilization. 


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b. Male sexual partner who had undergone a vasectomy at least 3 months before 
screening 
c. 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. 
d. Subject agrees to be abstinent (i.e., heterosexually inactive) for the duration of the 
study. 
e. 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: 
 
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. Male and female condoms should not be used together, as this can 
reduce their effectiveness. 
 
Diaphragm or cervical cap with spermicide 
 
Intrauterine device with spermicide 
 
Oral contraceptives or other hormonal methods 
NOTE: Another nonhormonal method of contraception must be used in 
conjunction with oral contraceptives. 
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. 
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 test results, vital sign measurements, 12-lead ECG results, 
and physical examination findings at screening. 
6. Subject agrees not to use nicotine products, including electronic vapor cigarettes, nicotine 
patches, or nicotine gum, for at least 30 days before the Day 1 randomization visit through 
completion of the Day 29 dosing complete/ET visit. 


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7. Subject agrees to comply with the study dietary requirements throughout the study drug 
dosing period. 
8. Subject agrees not to consume caffeine- or xanthine-containing products during all study 
visits, including overnight stays (PK subset); sodas, coffee, and tea designated as 
caffeine-free or noncaffeinated may be consumed on study days; caffeine may be 
consumed while at home and between study visits. 
9. Subject agrees to comply with all protocol requirements. 
10. Subject has adequate venous access if participating in the PK subset. 
11. Subject is able and willing to provide written informed consent. 
4.2 
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 
• History of head trauma resulting in a diagnosis of traumatic brain injury other than 
concussion 
• Frequent episodes of headache 
 Subject has received any vaccination within 28 days prior to Day 1 or plans to receive a 
vaccination at any time during the treatment period or within 28 days after study Day 28. 


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 Subject has received treatment in another clinical study of an investigational drug (or 
medical device) or investigational vaccine within 30 days or 5 half-lives (whichever is 
longer) before the first dose of study drug. 
 Subject has a history of relevant drug and/or food allergies (i.e., allergy to TPOXX or 
excipients, or any significant food allergy that could preclude a standard diet in the 
clinical investigative site). 
 Subject has any condition possibly affecting drug absorption (e.g., 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 reaction(s) (excluding 
seasonal allergies); or has evidence or history of clinically significant disease, including 
hematological, endocrine, pulmonary, gastrointestinal, cardiovascular, hepatic, 
psychiatric, or neurological disease. Exceptions to these disease criteria (e.g., stable, mild 
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, chest pain (that is diagnosed as cardiac related) or trouble breathing 
on exertion, or risk factors for torsades de pointes (e.g., heart failure, hypokalemia). 
 Subject has a family history of an immediate family member (father, mother, brother, or 
sister) who parents and/or siblings) who has had an onset of ischemic heart disease before 
the age of 50 years. 
 Subject is 20 years of age or older and has a ≥30% risk of developing a myocardial 
infarction or coronary death within the next 10 years using the National Cholesterol 
Education Program’s Risk Assessment Tool: https://www.mcw.edu/calculators/ldl-
cholesterol-goal-level. 
 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 bleeding. 


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 Subject has a bleeding disorder diagnosed by a doctor (e.g., 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 breast cancer resistance 
protein transporter including methotrexate, mitoxantrone, imatinib, irinotecan, lapatinib, 
rosuvastatin, sulfasalazine, and topotecan; substrates of cytochromes (CYP)2C8 
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.  
 Subject has a history of drug or alcohol abuse or dependency within the last year before 
screening. 
 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 (e.g., human T cell 
lymphotropic virus I or II). 
 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). 


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 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 reports participation in strenuous activity or contact sports within 24 hours before 
the first dose of study drug. 
 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), cotinine, 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) <70 mL/min 
• Creatinine in males >1.7 mg/dL and in females >1.4 mg/dL (1.3 times the upper 
laboratory reference range) 
• Hemoglobin ≤10% of the lower laboratory reference range 
• White blood cell counts considered to be clinically significant by the investigator 
• Absolute neutrophil count <1000 cells/mm3 
• Platelets not within ±10% of laboratory reference range 
• Alanine aminotransferase >2 times above the upper laboratory reference range 
• Aspartate aminotransferase >2 times above the upper laboratory reference range 
• Alkaline phosphatase >20% above the upper laboratory reference range 
• Hemoglobin A1c ≥7.0% 
• Cholesterol ≥300 mg/dL and low-density lipoprotein ≥190 mg/dL 


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 Subject has hypertension that is poorly controlled (repeat readings >140 mm Hg systolic 
and/or >90 mm Hg diastolic) or 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 >110 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 QT interval corrected using Fridericia’s formula (QTcF) >450 ms or 
female subject has a QTcF >470 ms at screening or Day 1, or Day –1 (PK subset). 
 Subject has used any prescription antiviral drugs with the intention of coronavirus disease 
(COVID-19) treatment or prophylaxis, including those that are thought to be effective for 
prevention of COVID-19 but have or have not been licensed for this indication, within 1 
month prior to study entry or during the study. 
 In the opinion of the investigator, the subject is not suitable for entry into the study. 
 Subject is a member or family member of the investigator or study site personnel. 
 Subject has previously participated in this clinical trial. 
4.3 
OTHER SCREENING CONSIDERATIONS 
• Subjects not enrolled in the PK subset must be willing and agree to return to the clinical 
investigative site for follow-up visits on Day 7, Day 14, and Day 21 (+1 day), a dosing 
complete visit on Day 29 or ET visit, and answer follow-up telephone calls on Day 42 
(+2 days) and on Day 58 (+2 days). 
• Subjects in the PK subset must be willing and agree to return to the clinical investigative 
site for 3 separate dosing and PK periods, for follow-up visits on Day 7 and Day 21, and 
answer follow-up telephone calls on Day 42 (+2 days) and on Day 58 (+2 days). 
• Subjects must be willing to fast for 8 hours prior to specimen collection of the fasting 
lipid panel that will be performed at screening. 


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• Subjects must be willing to take study drug within 30 minutes after eating a meal 
containing approximately 600 calories and 25 g of fat. 
• Subjects must be willing to take study drug at home for 28 days and record the date and 
time in a subject diary. 
• Subjects must be willing to record information related to TPOXX or matching TPOXX 
placebo, concomitant medications, AEs, and meal compliance in their subject diary. 
4.4 
WITHDRAWAL OF SUBJECTS FROM THE STUDY 
4.4.1 
Reasons for Withdrawal 
Under certain circumstances, a subject may be terminated from participating in the study 
based on the opinion of the investigator, SIGA, FDA, and/or the Data Safety Monitoring 
Board (DSMB). Subjects will be withdrawn from the study if they do not meet the study 
inclusion and exclusion criteria before dosing of the study drug. 
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: 
• Subject is in violation of the protocol. 
• Subject experiences a serious or intolerable AE that in the investigator’s opinion requires 
withdrawal from the study. 
• Subject becomes pregnant. 
• Subject is noncompliant. 
• Subject has laboratory abnormalities for assessments listed in Sections 4.1 or Section 4.2 
that meet grade 3 or grade 4 on the Division of Acquired Immune Deficiency Syndrome 
AE Grading Table3; 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. 
• Subject develops, during the course of the study, symptoms or conditions listed in the 
exclusion criteria. 


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• Subject develops during the course of the study, laboratory abnormalities listed in the 
exclusion criteria. 
• Subject requires a medication prohibited by the protocol. 
• Subject requests an early discontinuation for any reason. 
• Subject’s primary care provider requests that the subject be withdrawn. 
• The FDA, SIGA, or the DSMB 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 an SAE or intolerable AE, the investigator will confer with the 
medical monitor and 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. 
4.4.2 
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 ET visit assessments (Table 9-1 
and Table 9-2). A blood sample will be collected for all subjects who discontinue from the 
study for TPOXX plasma concentration analysis if the ET visit occurs within 30 hours after 
the subject’s last dose of TPOXX/matching placebo in order to collect information about the 
relationship between TPOXX blood level and ET from the study. Any subject who fails to 
return for final assessments will be contacted by the site 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. 
4.4.3 
Halting Rules 
Safety evaluations will include: medical history, body weight, physical assessments, vital 
sign measurements, routine laboratory test results, ECG results, and AEs reported by 


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subjects. Symptom-directed or targeted physical examinations may be performed if indicated 
by interim complaints or laboratory findings. 
The medical monitor and investigator will closely monitor and analyze study data as they 
become available and will make determinations regarding the presence and level of AEs. The 
medical monitor will provide an independent review of the AEs that have a bearing on study 
stopping. 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 temporary halting of the study should occur. 
The study will be temporarily halted (no new enrollments and no further study drug dosing) 
by the medical monitor or designee by promptly notifying the investigators and the DSMB 
(as outlined in the DSMB charter) according to the following criteria: 
• One subject experiences a grade 4 AE assessed as possibly, probably, or definitely 
related to study drug. 
• There is a subject death that is assessed as possibly, probably, or definitely related to 
study drug. 
• One subject experiences a seizure that is 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 DAIDS grade 3 or 
above and are possibly, probably, or definitely related to the study drug. 
• Three or more subjects have clinically significant laboratory abnormalities that meet 
DAIDS grade 3 or above criteria. 
Investigators will advise SIGA immediately if any of the halting rules are met and SIGA will 
notify the FDA immediately. 
Study enrollment and study drug dosing 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 DSMB 
and review all AEs that meet the criteria for halting the study. The study would remain 
suspended until the events were reviewed by the DSMB and recommendation was made as to 


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whether the study would 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, indicate a potentially serious safety 
concern. Investigators will advise SIGA immediately if any of the halting rules are met. 
Safety oversight for this study is discussed in Section 9.3.3.1.4. 
4.4.4 
Replacements 
At the discretion of the investigator, and after consultation with the medical monitor and 
SIGA, any subject who withdraws before completing the study may be replaced. Any 
replacement subject will be assigned to the same treatment as the subject they are replacing. 
5. 
STUDY TREATMENTS 
5.1 
TREATMENTS ADMINISTERED 
Subjects will be randomly assigned to 1 of 2 treatment groups. The treatment groups will be 
as follows: 
• Treatment Group 1: An oral dose of 600 mg (3 × 200-mg capsules) TPOXX BID (every 
12 hours [±30 minutes]) for subjects with a body weight of 120 kg or less or TID (every 
8 hours [±30 minutes]) for subjects with a body weight more than 120 kg for 28 days 
(Day 1 to Day 28). 
• Treatment Group 2: An oral dose of placebo (3 capsules identical to TPOXX) BID (every 
12 hours [±30 minutes]) for subjects with a body weight of 120 kg or less or TID (every 
8 hours [±30 minutes]) for subjects with a body weight more than 120 kg for 28 days 
(Day 1 to Day 28). 
5.2 
STUDY DRUG 
TPOXX will be supplied as 200-mg capsules containing tecovirimat monohydrate as the 
active pharmaceutical ingredient. The matching TPOXX placebo will be identical in 
appearance and have the same excipient ingredients but will not include the active 
compound. 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. 


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Table 5-1 
Excipients of TPOXX and Matching TPOXX Placebo Capsules 
Component 
Quality Designation 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abbreviations: EP, European Pharmacopeia; JP, Japanese Pharmacopeia; 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: 
 
 
 
Further information on TPOXX can be found in the TPOXX Investigator Brochure4 and Full 
Prescribing Information.2 
5.2.1 
Study Drug Packaging, Preparation, Administration, and 
Storage 
SIGA will be responsible for providing the investigator and clinical investigative sites with 
adequate quantities of TPOXX and TPOXX matching placebo. 
TPOXX capsules and the matching placebo capsules are packaged, labeled, distributed, and 
placed on stability testing in accordance with Current Good Manufacturing Practice and 
International Council for Harmonisation (ICH) guidelines. 


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Packaging of bulk TPOXX: 
 
 
 
Packaging of bulk matching placebo: 
 
 
 
Labeling, storage, and distribution of TPOXX and matching placebo: 
 
 
 
 
The 28-day supply of 200-mg TPOXX capsules and matching placebo 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 TPOXX and matching placebo will 
contain 42 capsules and will be labeled with at a minimum, the study number, bottle content, 
direction for distribution, storage conditions, and cautionary statement. The study drug will 
be provided to subjects in either 4 bottles (subjects weighing 120 kg or less) or 6 bottles 
(subjects weighing more than 120 kg) containing 42 capsules each. Each daily dose is 
3 capsules taken orally either BID or TID depending on the subject’s weight, for a total of 
6 capsules (1200 mg) or 9 capsules (1800 mg) per day. 
TPOXX and matching placebo must be stored in a secure area (e.g., a locked cabinet), out of 
reach of children and pets, protected from moisture and light, and stored at room temperature 
(15°C to 30°C or 59°F to 86°F). 
TPOXX and matching placebo should not be refrigerated or used beyond the expiration dates 
provided by the manufacturer. 
Clinical investigative sites will be required to keep temperature logs to establish a record of 
compliance for study drug storage conditions for TPOXX and matching TPOXX placebo. 


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5.2.2 
Study Drug Accountability 
The clinical investigative sites will maintain accurate records of receipt of all study drugs, 
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. At the completion of the study, and to 
satisfy regulatory requirements regarding study drug accountability, all study drug will be 
reconciled and returned for destruction according to the instructions provided by SIGA. 
Each clinical investigative site will maintain a study drug accountability log of all study drug 
dispensed and returned. Subjects will be instructed to bring the subject diary and all study 
drug bottles (including empty bottles) and unused study drug (in study drug bottles) with 
them to every study visit. Study drug for each subject will be inventoried and accounted for 
by the designated study personnel throughout the study. Study drug accountability will be 
recorded in the subject’s source documentation, entered in the eCRF, and reviewed by the 
monitor during monitoring visits. On a regular basis and after study completion or 
termination of the study, the monitor will prepare used and unused study drug bottles for 
return and destruction. 
5.3 
METHOD OF ASSIGNING SUBJECTS TO TREATMENT 
GROUPS 
Randomization will be performed using an interactive web response system (IWRS). The 
randomization will be balanced by using permuted blocks of an appropriate size and be 
stratified by age group (18 to 30 years, 31 to 45 years, 46 to 64 years, and 65 to 80 years). In 
the event of the withdrawal of a clinical investigative site, no adjustments to the 
randomization scheme will be implemented because site will not be used as a stratification 
factor. After a randomization number has been assigned, it will not be reused. 
The PK subset of 40 subjects will be enrolled at up to 2 sites with at least 32 subjects who 
will receive TPOXX and at least 8 subjects who will receive placebo. Of the remaining 
subjects who are not enrolled in the PK subset, at least 324 subjects will be randomly 
assigned to receive TPOXX and 81 subjects to receive placebo. The IWRS will facilitate the 
random assignment of treatment for subjects in the study. Randomization will occur before 
study drug administration on Day 1, after it has been confirmed that the subject fulfills all 
eligibility criteria. The IWRS will assign a randomization number that is used to link the 
subject to 1 of the 2 treatment groups using a 4:1 ratio based on a computer-generated central 
randomization schedule prepared before enrollment. The IWRS will also specify the study 


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drug bottle numbers to be assigned to the subject where the study drug bottle numbers match 
the treatment group assigned by the randomization list. The assigned study drug bottles will 
be dispensed to the subject by the clinical investigative site. The randomization code will not 
be broken or made available to study subjects or their families, investigators, clinical 
personnel, or site managers until all subjects have completed the double-blind phase of the 
study and the database has been closed in accordance with the clinical investigative sites 
standard operating procedures (SOPs). 
5.4 
BLINDING 
5.4.1 
Blinding Procedures 
This study will be performed as a double-blind study. All parties involved in the study except 
for the medical monitor (in the event of a suspected unexpected serious adverse reaction) and 
the unblinded statistician for DSMB Closed Session meetings, will remain blinded to the 
treatment until study completion. Under routine circumstances, the blind will not be broken. 
TPOXX and matching placebo capsules are indistinguishable and all study drug bottles will 
be packaged the same way. Study drug bottle labeling will include all required identifying 
information except for the identity of the study treatment. 
5.4.2 
Breaking the Blind 
The medical monitor will be responsible for maintaining the blind throughout the study. If a 
subject becomes seriously ill or pregnant during the study, the blind will be broken only if 
knowledge of the administered study drug will affect that subject’s available treatment 
options. In the event of a medical emergency requiring identification of the study drug 
administered to an individual subject, the investigator will make every attempt to contact the 
medical monitor to explain the need for opening the code within 24 hours of unblinding the 
subject’s randomization assignment. The investigator will be responsible for documenting 
the time, date, reason for the code break, and the names of the personnel involved. All 
unblinding activities will be tracked via an audit trail in IWRS. Requests for unblinding of a 
subject’s randomization assignment will be made through the IWRS after consultation with 
the medical monitor. Subject code breaks by the investigator will result in withdrawal of the 
subject from the study. The date, time, and reason for the unblinding must be documented on 
the appropriate page in the eCRF, and SIGA must be informed as soon as possible. The 
treatment assignment of subjects will remain blinded until all clinical evaluations have been 
completed. Unblinding at the end of the study will occur only by written request from the 


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lead statistician to the unblinded randomization statistician and the unblinded IWRS team 
after database lock and confirmation of protocol deviations. The DSMB may request to 
unblind the treatment assignment of a subject or the study at any time. 
5.5 
TREATMENT COMPLIANCE 
On Day 1, study site personnel will document assessment of subject compliance to include: 
direct observation of TPOXX or matching placebo dosing with 8 oz. (240 mL) of water, time 
of completion of last meal before study drug dosing, and time of study drug 
dosing/observation in the source document and eCRF. 
The date and time of study drug dosing will be recorded on the appropriate pages in the 
eCRF. If a subject is not administered study drug, the reason for the missed dose will be 
recorded. 
5.5.1 
Subject Diary 
Clinical investigative sites will provide subjects with a subject diary and instructions on its 
completion. On days when study drug dosing does not occur at the clinical investigative site, 
subjects will be required to record the following information in their subject diary: the date 
and time they completed their meals (or the last time they ate), whether or not the meal they 
ate was the required meal of approximately 600 calories and 25 g of fat, the date and time of 
their study drug doses, whether or not they took 3 capsules of study drug at dosing, and a 
comments for any missed capsules or dose. Subjects will also enter into the diary any new or 
changed concomitant medications (including over-the-counter medications taken, such as 
vitamin, supplemental, and herbal preparations), with the start and stop date of the 
medication, the reason for use, and any symptoms or problems (illness or injuries) that 
subjects may have experienced. 
Subjects will be instructed to record all AEs in the subject diary. Instructions will be provided 
by the clinical investigative sites advising subjects to record the start and stop dates that they 
experience AEs. Subjects will be instructed to bring the subject diary with them to all study 
visits. The subject diary will be reviewed by study site personnel with the subject at study 
visits. 


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5.5.2 
Prior and Concomitant Medications 
Restrictions for prior and concomitant medications and therapies are provided in Sections 4.1 
and Section 4.2. Prior and concomitant medications and therapies will be coded using the 
latest version of the World Health Organization Drug Dictionary. 
5.5.2.1 
Prior Medications 
Information regarding prior medications taken by the subject within the 30 days before 
signing the ICF will be recorded in the subject’s eCRF. 
5.5.2.2 
Concomitant Medications 
Concomitant medications taken by subjects will be recorded at each study visit up to the 
follow-up telephone call on Day 42. Concomitant medications related to SAEs will be 
collected and recorded at the Day 58 follow-up telephone call. 
Subjects will be instructed to record concomitant medications in the subject diary. 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 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 
schedules of events (Table 9-1 and Table 9-2). 
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 SUBSET ASSESSMENTS AND 
ENDPOINTS 
Blood samples for PK analysis of TPOXX in plasma will be collected at the time points 
specified in the schedule of events (Table 9-1).  
The following plasma PK parameters will be calculated separately for BID or TID dosing as 
endpoints for TPOXX to the extent that data permit using actual sampling times rather than 
scheduled sampling times and will include, but are not limited to the following: 
Day 1: 
• Maximum observed plasma concentration (Cmax), reported separately for each dose 
• Time to reach Cmax (Tmax), reported separately for each dose 
• Area under the plasma concentration-time curve (AUC) from time zero to 24 hours 
(AUC0-24) 
• AUC from time zero to tau where tau is the 8-hour or 12-hour dosing interval following 
the first dose (AUCtau) 
Day 28: 
• Cmax 
• Average steady-state plasma concentration (Cavg) 
• Trough plasma concentration (Ctrough) 
• Minimum observed plasma concentration (Cmin) 
• Tmax 
• AUC0-24h 
• AUC from time zero to tau where tau is the 8-hour or 12-hour dosing interval (AUCtau) 
• AUC from time zero to the last measurable sample (AUC0-last) 
• AUC from time zero to infinity (AUC0-∞) 


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• Observed elimination rate constant (λz) 
• Terminal elimination half-life (t1/2) 
• Apparent clearance (CLss/F) 
• Apparent volume of distribution (Vz/F) 
• Accumulation ratio (Rac) 
• %Fluctuation 
6.1.1 
Pharmacokinetic Sample Collection 
Blood samples (approximately 5 mL) for the determination of plasma concentrations of 
TPOXX will be collected in lavender-topped K3EDTA Vacutainer® tubes using a 20 gauge or 
larger needle, or from an in-dwelling intravenous catheter using a vacutainer tube. 
Note: Refer to the investigative clinical site SOPs regarding flushing of peripherally inserted 
in-dwelling intravenous catheters and/or if a heparin lock is used, 1 cc of blood should be 
withdrawn and discarded before sample collection to assure that the heparin solution used to 
maintain catheter patency does not dilute the sample. 
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 their designee in the subject’s eCRF, on the vacutainer and cryovial labels, 
and the Specimen Shipping Log. In addition, the time of study drug administration before PK 
sampling will be recorded in the subject’s eCRF. Labels will 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.  
Pharmacokinetic Sample Processing 
The blood sample must be centrifuged immediately, if possible, or within less than or equal 
to 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 above and should be capped tightly. The second tube will be a duplicate and 
retained at the site as a back-up plasma sample. If red blood cells are inadvertently drawn 


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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. 
Sample processing and storage should be as follows: 
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 freezer should be equipped with a 
temperature monitor and should be checked on the weekend if it is not equipped with a 
temperature-activated alarm. 
The clinical investigative sites will batch ship sets (primary and back-up plasma samples) of 
frozen plasma samples using frozen shippers and dry ice. A log sheet listing the samples 
being shipped will be included in each shipment. Plasma samples will be shipped on dry ice 
via courier to Alturas Analytics (Moscow, ID USA). Back-up plasma samples will remain at 
the clinical investigative site until further notice from SIGA. Shipments before weekends or 
holidays must be avoided. 
The samples will be shipped for analysis to:  
Alturas Analytics, Inc. 
1917 South Main Street 
Moscow, ID 83843, USA 
Alturas Analytics will store all plasma samples at –70°C until analysis for TPOXX is 
complete. SIGA will advise Alturas Analytics when to destroy any remaining plasma 
samples. 
6.1.2 
Pharmacokinetic Sample Analysis 
Pharmacokinetic samples will be analyzed by Alturas Analytics using a validated 
high-performance liquid chromatography and liquid chromatography-tandem mass 
spectrometry analysis for TPOXX in human plasma method in accordance with the US FDA 
Guidance for Industry on Bioanalytical Method Validation.5 
6.2 
SAFETY ASSESSMENTS AND ENDPOINTS 
Safety and tolerability will be assessed by the following endpoints: monitoring and recording 
of AEs; clinical laboratory test results (hematology, serum chemistry, and urinalysis); 
pregnancy testing; vital sign measurements (systolic and diastolic blood pressures, heart rate, 


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respiratory rate, and body temperature); 12-lead ECG results; and physical examination 
findings. A blood sample will be collected for all subjects who discontinue from the study for 
TPOXX plasma concentration analysis if the ET visit occurs within 30 hours after the 
subject’s last dose of TPOXX/matching placebo in order to collect information about the 
relationship between TPOXX blood level and ET from the study. 
For all safety assessments, the investigator will determine whether results are clinically 
significant, which is defined as any variation in a result that has medical relevance and may 
result in an alteration in medical care (e.g., active observation, diagnostic measures, or 
therapeutic measures). If clinical significance is noted, the result and reason for significance 
will be documented and an AE will be reported on the AE page in the subject’s eCRF. The 
investigator will monitor the subject until the result has reached the reference range or the 
result at screening, or until the investigator determines that follow-up is no longer medically 
necessary. 
6.2.1 
Adverse Events 
Adverse events will be assessed from the time of the first dose of study drug until Day 42. 
Serious AEs will be collected up to Day 58. All AEs, SAEs, and clinically significant 
laboratory abnormalities should be followed until they are resolved or until stability of the 
abnormality has been demonstrated as determined by the investigator and/or the medical 
monitor. 
The investigator is responsible for ensuring that all AEs and SAEs are recorded in the eCRF 
and reported to SIGA, 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. 
6.2.1.1 
Adverse Event Definitions 
An AE is defined as any untoward medical occurrence associated with the use of a drug in 
humans, whether or not considered drug related. Subjects will be instructed to contact the 
investigator at any time after start of study drug dosing if any symptoms develop. 
A treatment-emergent AE 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. 
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 investigational new drug safety reporting, 
“reasonable possibility” means that there is evidence to suggest a causal relationship between 


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the study drug and the AE. A suspected adverse reaction implies a lesser degree of certainty 
about causality than an adverse reaction. 
An adverse reaction is any AE caused by a study drug. Adverse reactions belong to a subset 
of all suspected adverse reactions and indicate that there are reasons to conclude that the 
study drug caused the event. 
An AE or suspected adverse reaction is considered “unexpected” if it is not listed in the Full 
Prescribing Information2 or if it occurs with specificity or severity that has been previously 
observed with the study drug being tested. For example, under this definition, hepatic 
necrosis would be unexpected (by virtue of greater severity) if the 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 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 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, medical monitor, or SIGA, it results in any of the following outcomes: 
• Results in death. 
• Is life-threatening (subject 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. 
• Results in congenital anomaly or birth defect. 
• Results in a persistent or significant disability/incapacity. 
• Any other important medical events that may not result in death, be life-threatening, or 
require hospitalization may be considered an SAE when, based upon 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. 


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Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical judgment, 
they may jeopardize the 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, medical monitor, 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. All AEs, SAEs, and clinically significant 
laboratory abnormalities will be followed until resolution or until stability of the abnormality 
has been demonstrated as determined by the investigator and/or medical monitor. 
6.2.1.2 
Eliciting and Documenting Adverse Events 
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 and AEs recorded in subject diaries, AEs will be 
documented from any data collected on the AE page in the eCRF (e.g., laboratory values, 
physical examination findings, and ECG changes) or other documents that are relevant to 
subject safety. 
6.2.1.3 
Reporting Adverse Events 
All AEs reported, observed, or recorded in the subject diary from the first dose of study drug 
through the follow-up telephone call on Day 42 (+2 days) will be recorded on the AE page in 
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, any required treatment or evaluations, and 
outcome. Any AEs resulting from concurrent illnesses, reactions to concurrent illnesses, 
reactions to concurrent medications, or progression of disease states must also be reported. 
The Medical Dictionary of Regulatory Activities will be used to code all AEs. This 
requirement indicates that for some events, follow-up may be required after the subject has 


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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 following the administration of study drug on Day 1, 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 that is 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 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. 
After notification from the investigator, SIGA will report all study drug-related and 
unexpected SAEs (those not listed in the TPOXX full prescribing information) to the FDA 
within 15 calendar days of first knowledge. Fatalities or life-threatening events assessed as 
related and unexpected will be reported to the FDA within 7 calendar days of first 
knowledge. The DSMB will also receive these reports (refer to Section 9.3.3.1.4). 
For this study, the following contact information will be used for SAE reporting: 
 
 
 
The collection and monitoring period for SAEs is 30 days after administration of the last 
dose of study drug. At the time of discharge or ET from the clinical study, the subject will be 


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instructed to notify the investigator of any SAEs that occur within 30 days after the last dose 
of study drug. 
All subjects will have a follow-up telephone call 30 days after administration of the last dose 
of study drug (Day 58 [+2 days]) to report any SAEs. 
6.2.1.5 
Assessment of Severity 
All AEs will be graded for intensity according to the current DAIDS AE Grading Table.3 
Any laboratory or clinical AE that is not listed on the DAIDS table will be assessed for 
severity and classified into 1 of 5 clearly defined categories as follows: 
• Grade 1 (Mild): These events require minimal or no treatment and do not interfere with 
the subject’s daily activities. 
• Grade 2 (Moderate): These events result in a low level of inconvenience or require minor 
therapeutic measures and may cause some interference with normal functioning. 
• Grade 3 (Severe): These events interrupt a subject’s usual daily activity and may require 
systemic drug therapy or other treatment. Severe events are usually incapacitating. 
• Grade 4 (Life-threatening): Events that, in the opinion of the investigator, place the 
subject at immediate risk of death from the reaction as it occurred (i.e., 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 the 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 study drug and the AE; for example, 
the AE occurred shortly after the subject took the study drug. 


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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 (e.g., 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. 
• 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 (e.g., 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 
(i.e., the possibility cannot be excluded), but the AE is most likely explained by causes 
other than the study drug (e.g., 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 (e.g., 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/source 
document. 


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6.2.1.7 
Follow-Up of Adverse Events 
All AEs must be reported in detail on the appropriate page in the eCRF and followed until 
resolved or stabilized as determined by the investigator and/or the medical monitor. 
6.2.1.8 
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 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 
abortion should always be reported as an SAE. Pregnancy data will be captured and followed 
by PPD. All pregnancies and outcomes will be tracked by PPD Pharmacovigilance. A 
pregnancy case will not be closed until after the child is followed for 3 months. 
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, this will be recorded as an SAE in the data forms for the mother (i.e., 
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. 


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6.2.2 
Clinical Laboratory Testing 
Blood and urine samples will be collected at the time points indicated in the schedules of 
events (Table 9-1 and Table 9-2) and will be prepared using standard procedures. Samples for 
safety testing will be shipped via courier to PPD Central Lab where they will be analyzed. 
The central laboratory for the study will receive, test, and store laboratory safety samples at 
the following location: 
 
 
 
 
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 Lab will provide the reference ranges for all clinical laboratory safety 
parameters. 
The following clinical laboratory assessments will be performed by the PPD Central Lab: 
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, creatinine 
clearance (calculated(a)), gamma-glutamyltransferase, globulin, 
glucose, lactate dehydrogenase, phosphorus, potassium, sodium, 
total protein, and uric acid 
Urinalysis 
Appearance, bilirubin, blood, color, glucose, ketones, leukocyte 
esterase, microscopy (performed if dipstick is ≥1+; includes 
bacteria, casts, crystals, epithelial cells, red blood cells, and white 
blood cells), nitrites, pH, protein, specific gravity, and urobilinogen 
(a) Creatinine clearance will be calculated using the Cockcroft-Gault formula:  
𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶 𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐 (𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚
⁄
) = [140 −𝑎𝑎𝑎𝑎𝑎𝑎(𝑦𝑦𝑦𝑦𝑦𝑦𝑦𝑦𝑦𝑦)] × 𝑤𝑤𝑤𝑤𝑤𝑤𝑤𝑤ℎ𝑡𝑡 (𝑘𝑘𝑘𝑘)
72 × 𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠 𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐 (𝑚𝑚𝑚𝑚𝑑𝑑𝑑𝑑
⁄
) {× 0.85 𝑖𝑖𝑖𝑖 𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓} 
Glycosylated hemoglobin and a fasting lipid panel including cholesterol (total, high-density 
lipoprotein, calculated low-density lipoprotein, and triglycerides) will be performed at 


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screening. Subjects will fast for 8 hours prior to specimen collection of the fasting lipid 
panel. 
For women of childbearing potential, serum pregnancy test will be performed at the 
screening visit and on Days 7, 14, 21, and 29 and analyzed by PPD Central Lab as indicated 
in the schedule of events tables (Table 9-1 and Table 9-2). A urine pregnancy test will be 
performed and read locally at check-in on Day -1 (PK subset) or predose on Day 1 (Non-PK 
subset). All positive urine tests will be verified using a serum β-human chorionic 
gonadotropin test. 
For postmenopausal women, a serum follicle-stimulating hormone test 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.  
Drug/Alcohol/Cotinine Testing 
Screening: 
A urine drug screen for alcohol, cotinine, 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 sent to the central lab. 
Day –1 (Check-in - PK Subset, Table 9-1) or Day 1 (Predose - Non-PK Subset Table 9-2): 
A urine drug screen for cotinine, amphetamines (including methamphetamines and 
ecstasy/methylenedioxymethamphetamine), barbiturates, benzodiazepines, cannabinoids 
(including tetrahydrocannabinol), cocaine metabolites, and opiates (including heroin, 
codeine, and oxycodone) will be performed and read locally. Blood alcohol will be tested 
using a breathalyzer device at the clinical investigative site. 
Abnormal clinical laboratory values will be flagged as either high or low (or normal or 
abnormal) based on the reference range for each laboratory parameter. The investigator will 
determine whether any of the abnormally high or low results are clinically significant or not 
clinically significant.  


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6.2.3 
Medical History 
Review of medical history will be performed prior to the first dose of study drug and if 
determined by the investigator based on medical history/symptomology and will include a 
review of systems; recreational, prescription, and over-the-counter drug use; nicotine and 
alcohol use; and past hospitalizations at the time points indicated in the schedules of events 
(Table 9-1 and Table 9-2). 
6.2.4 
Vital Sign Measurements 
Vital signs will be measured after the subject has been in the seated position for at least 
5 minutes at the time points indicated in the schedules of events (Table 9-1 and Table 9-2). 
Vital sign measurements will include systolic and diastolic blood pressures, heart rate, 
respiratory rate, and body temperature. 
6.2.5 
Electrocardiograms 
A single 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 schedules of events (Table 9-1 and 
Table 9-2). The acceptable window for collection from the scheduled collection time point is 
±15 minutes. 
The investigator will review the 12-lead ECGs and determine if they are normal or abnormal. 
Electrocardiogram assessments will include comments on whether the tracings are normal or 
abnormal (clinically significant or not clinically significant), rhythm, the presence of 
arrhythmia or conduction defects, morphology, any evidence of myocardial infarction, or 
ST-segment, T-wave, and U-wave abnormalities. In addition, measurements of the following 
intervals will be measured and reported: heart rate; PR, RR, and QT interval; QTcF; and QRS 
duration. The investigator will determine if any abnormal 12-lead ECG results are clinically 
significant or not clinically significant prior to study drug dosing and throughout the study to 
confirm that the subject can remain in the study. 
All ECGs must be performed by an experienced ECG technician. 
6.2.6 
Physical Examinations 
Full physical examinations will be performed at the time points indicated in the schedules of 
events (Table 9-1 and Table 9-2) and will include, at minimum, assessment of the following 
body systems: head, ears, eyes, nose, and throat; cardiac (including auscultation of heart); 


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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 on Day 31 (PK subset only) as 
well as unscheduled physical exams at the discretion of the investigator, if necessary, to 
evaluate AEs or clinical laboratory abnormalities. 
Height and weight will be measured at screening only. 
6.2.7 
Unscheduled Visits 
Clinical investigative sites will provide subjects 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 study site personnel in the source document. 
Unscheduled procedures and laboratory tests and results will also be recorded in the eCRF. 
7. 
STATISTICAL ANALYSIS PLANS 
7.1 
SAMPLE SIZE CALCULATIONS 
There is no formal sample size calculation for this study. Although the sample size is not 
based on statistical power considerations, administration of TPOXX 600 mg to 300 subjects 
provides approximately 95% probability of observing at least 1 occurrence of any AE if the 
incidence of AEs in the study population is 1% and is considered adequate to provide a 
reasonable assessment of safety and tolerability. A sufficient number of subjects will be 
randomly assigned to ensure that at least 300 subjects receive at least 92% of the doses of the 
BID or TID dosing regimen of oral TPOXX 600 mg over the 28-day treatment period. 
7.2 
ANALYSIS SETS 
All populations will be identified and finalized before the database lock. All subjects who are 
randomly assigned are considered study subjects. Study populations are defined as the 
following: 
• The Intent-to-Treat (ITT) Population will include all subjects who were randomly 
assigned to the study (i.e., a randomization number and randomization date are present in 
the database). 


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• The Safety Population will include all subjects who received at least 1 dose of TPOXX or 
matching placebo. 
• The Per-Protocol (PP) Safety Population will include all subjects who received at least 
92% of the doses of TPOXX or matching placebo 600 mg BID or TID dosing regimen 
over the 28 day treatment period. 
• The PK Population will include all subjects in the PK subset who have taken at least 92% 
of the doses of the 600 mg BID or TID dosing regimen of TPOXX, have sufficient drug 
concentrations in plasma, and have no protocol deviations or other circumstances that 
would exclude the subject from analysis. 
7.3 
STATISTICAL ANALYSIS 
Details of all statistical analyses will be described in a statistical analysis plan (SAP). 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, 
SD, minimum, and maximum). 
Baseline demographic and background variables will be summarized by treatment for the 
ITT, Safety, PP Safety, and PK Populations. The demographics table will also be summarized 
overall and by age group as per the stratification used in randomization. For treatment-related 
tables and listings, the data will be summarized by BID or TID study drug dosing regimen. 
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. 
7.3.1 
Pharmacokinetic Analyses 
The PK Population will be used for the preparation of PK summaries and analyses. 
Individual plasma concentration and time deviation data will be presented in a data listing. 
Plasma concentration data will be summarized by study day, time point, and study drug 
dosing regimen using the following descriptive statistics: number of subjects, arithmetic 


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mean, SD, coefficient of variation (CV), minimum, median, and maximum. Individual and 
mean plasma concentration versus scheduled time profiles will be presented in figures on 
both linear and semilogarithmic scales. Mean concentration versus scheduled time profiles 
will be presented by study drug dosing regimen. 
The PK parameters of TPOXX will be analyzed using noncompartmental methods based on 
the actual sampling times. The individual PK parameters will be presented in data listings 
and summarized by study day and study drug dosing regimen using the following descriptive 
statistics: number of subjects, arithmetic mean, SD, CV, geometric mean, geometric SD, 
geometric CV, minimum, median, and maximum. 
7.3.2 
Safety Analyses 
The safety and tolerability data summaries will be presented separately for the Safety 
Population and the PP Safety Population and will also be presented by BID and TID 
TPOXX/matching placebo dosing regimen. 
Adverse events will be coded by preferred term and system organ class using the latest 
version of the Medical Dictionary for Regulatory Activities. All AE data will be presented in 
a data listing. Treatment-emergent AEs will be summarized by treatment, BID and TID study 
drug dosing regimen, and overall, as well as by severity and relationship to study drug for the 
Safety Population and the PP Safety Population. For any subject who discontinues the study 
for any reason, data will be summarized by treatment group, reason for discontinuation, if the 
drug concentration was collected, and the result of the bioanalysis. In addition, SAEs and 
AEs leading to subject study discontinuation will be presented in the data listings and 
summarized by treatment, dosing regimen, and overall. 
The overall AE rate will be defined as the percentage of subjects in the Safety Population and 
PP Safety Population who report at least 1 postdose AE. The overall AE rate will be 
compared between treatment groups using Mantel-Haenszel test stratified for age group 
(18 to 30, 31 to 45, 46 to 64, and 65 to 80 years). If expected cell counts are less than 5, then 
Fisher’s exact test will be applied. An exact unadjusted 95% confidence interval (CI), 
calculated using the Clopper-Pearson method, will be presented for each treatment group. For 
the difference in overall AE rates between treatment groups, a continuity corrected exact 95% 
CI around the difference will be calculated. In addition, the Mantel-Haenszel adjusted odds 
ratio and 95% CIs from the stratified analysis will be presented. The relationship of treatment 
group, age, clinical investigative site, and their interactions on overall AE rate will also be 


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investigated using a logistic regression model; CIs for the odds ratios associated with each 
factor in the model will be presented. Further details will be included in the SAP. 
Time from the first dose to the first AE or to discontinuation from study for any reason will 
be analyzed using Kaplan-Meier quartile estimates along with 2-sided 95% CIs. Treatment 
groups will be compared using the log rank test stratified by age group and site. If a subject 
does not experience any AE or does not discontinue from study, the time to first AE or time 
to discontinuation will be censored at the date of study completion. 
Toxicity grades for laboratory tests will be determined according to the DAIDS AE Grading 
Table. The maximum postbaseline grade increase from baseline grade will be summarized by 
treatment group and BID and TID study drug dosing regimen and overall for the Safety 
Population and PP Safety Population using frequency and percentage of subjects with 
increase to grade 1, 2, 3, 4, 1 to 4, 2 to 4, and 3 to 4, respectively. 
Actual values and changes from baseline for clinical laboratory test results, vital sign 
measurements, and 12-lead ECG results will be summarized by treatment group and BID and 
TID study drug dosing regimen 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. Physical examination findings will be presented in a data 
listing. 
Narratives will be presented for all deaths, subjects who reported SAEs, subjects withdrawn 
because of AEs, and grade 3 AEs deemed by the investigator to be possibly, probably, or 
definitely related to study drug.  
7.4 
HANDLING OF MISSING DATA 
Plasma concentrations that are below the limit of quantification (BLQ) will be treated as zero 
for descriptive statistics. 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. 
For the PK analysis, BLQ values will be treated as zero with the exception that a BLQ value 
between 2 quantifiable concentrations will be set as missing. Missing concentrations will be 
treated as missing from the PK parameter calculations. If consecutive BLQ concentrations 
are followed by quantifiable concentrations in the terminal phase, those concentrations after 
BLQ concentrations will be treated as missing. 


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7.5 
INTERIM ANALYSES 
No formal interim analyses are planned for 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); 2022. 
3. Division of AIDS (DAIDS), National Institute of Allergy and Infectious Diseases, 
National Institutes of Health, US Department of Health and Human Services. Division of 
AIDS (DAIDS) table for grading the severity of adult and pediatric adverse events. 
July 2017 [cited 2020 Aug 18]. Available from: 
https://rsc.niaid.nih.gov/sites/default/files/daidsgradingcorrectedv21.pdf. 
4. SIGA Technologies, Inc. TPOXX (tecovirimat). Investigator’s Brochure, 17th ed. 
Corvallis (OR); 2021. 125 p. 
5. Department of Health and Human Services (DHHS), Food and Drug Administration 
Center for Drug Evaluation and Research (US). Guidance for Industry: Bioanalytical 
Method Validation. May 2018 [cited 2020 Aug 18]. Available from: 
https://www.fda.gov/media/70858/download. 


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9. 
APPENDICES 
9.1 
APPENDIX 1: LIST OF ABBREVIATIONS 
Abbreviation 
Term 
λz 
the observed 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 zero to 
24 hours 
AUC0-tau 
area under the plasma concentration-time curve during the first 
dosing interval 
AUC0-∞ 
area under the plasma concentration-time curve from time zero to 
infinity 
BID 
two times a day 
BLQ 
below the limit of quantification 
Cavg 
average steady-state plasma concentration 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
CLss/F 
apparent clearance 
Cmin 
minimum observed plasma concentration 
Cmax 
maximum observed plasma concentration 
CRA 
clinical research associate 
CRF 
case report form 
Ctrough 
trough plasma concentration 
CV 
coefficient of variation 
CYP 
cytochromes 
DAIDS 
Division of Acquired Immune Deficiency Syndrome 
DSMB 
Data Safety Monitoring Board 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
ET 
early termination 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IRB 
institutional review board 
ITT 
intent to treat 
IWRS 
interactive web response system 
PK 
pharmacokinetic(s) 
PP 
per protocol 
QTcF 
QT interval corrected using Fridericia’s formula 
Rac 
accumulation ratio 
SAE 
serious adverse event 


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Abbreviation 
Term 
SAP 
statistical analysis plan 
SOP 
standard operating procedure 
t1/2 
terminal elimination half-life 
TID 
three times a day 
Tmax 
time to reach maximum observed plasma concentration 
Vz/F 
apparent volume of distribution 


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9.2 
APPENDIX 2: SCHEDULE OF EVENTS 
Table 9-1 
Schedule of Events: Pharmacokinetic Subset Study Subjects 
Period Screening Check-in 
Treatment 
PK Sampling 
Follow-up 
Procedure(a) 
Day –28 to –2 
–1 
1 
2 
3 to 
6 
7 
8 to 
12 13 14 
15 to 
20 
21 
22 to 
26 
27 28 
Dosing 
Complete
/ET Visit 
29  
30 31 
Telephone 
Call  
42 
(+2 days) 
SAE 
Telephone 
Call  
58 
(+2 days) 
Admission to clinic 
 
X 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
Discharge from 
clinic(b) 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
criteria 
X 
X(c) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
X(d) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical 
examination(e) 
X 
X 
 
 
 
X 
 
 
X 
 
X 
 
 
 
X 
 
X 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height and weight 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serology (HBsAg, 
HCV, and HIV) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital sign 
measurements(f) 
X 
X 
X(g) 
 
 
X 
 
 
X(g) 
 
X 
 
 
 
X 
 
X 
 
 
Drug/alcohol/cotinine 
screen(h) 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Glycosylated 
hemoglobin (HbA1c) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Fasting lipid panel(i) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical laboratory 
testing(j) 
X 
X 
 
 
 
X 
 
X 
 
 
X 
 
 
 
X 
 
 
 
 
Serum pregnancy 
test(k) 
X 
 
 
 
 
X 
 
X 
 
 
X 
 
 
 
X 
 
 
 
 


SIGA Technologies, Inc. 
TPOXX 
Protocol No. SIGA-246-024 
Clinical Study Protocol Amendment 1 
 
Page 62 
Period Screening Check-in 
Treatment 
PK Sampling 
Follow-up 
Procedure(a) 
Day –28 to –2 
–1 
1 
2 
3 to 
6 
7 
8 to 
12 13 14 
15 to 
20 
21 
22 to 
26 
27 28 
Dosing 
Complete
/ET Visit 
29  
30 31 
Telephone 
Call  
42 
(+2 days) 
SAE 
Telephone 
Call  
58 
(+2 days) 
Urine pregnancy 
test(k) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum follicle-
stimulating hormone(l) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
12-lead ECG(m) 
X 
X 
X 
 
 
X 
 
 
X 
 
X 
 
 
 
X 
 
 
 
 
Randomization 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Meal(n) 
 
 
X 
X 
 
 
 
X 
X 
 
 
 
X 
X 
 
 
 
 
 
Administration of 
study drug(o) 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
Dispense study drug 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Collect study drug 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
Study drug 
instructions 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pharmacokinetic 
sampling(p) 
 
 
X 
X 
 
 
 
 
X 
 
 
 
 
X 
X(q) 
X 
X 
 
 
Subject diary 
dispensing(r) 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Subject diary review 
 
 
 
 
 
X 
 
X 
 
 
X 
 
X 
 
 
 
 
 
 
Subject diary 
collection 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
AEs/SAEs(s) 
 
 
X 
X 
X 
Prior/concomitant 
medications(t) 
X 
X 
X 
X 
Abbreviations: AE, adverse event; ECG, electrocardiogram; ET, early termination; HBsAg, hepatitis B surface antigen; HCV, hepatitis C virus; HIV, human 
immunodeficiency virus; PK, pharmacokinetic; SAE, serious adverse event. 
(a) 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. 
(b) Discharge from the clinical investigative site will follow collection of all safety assessments. 
(c) Review of inclusion/exclusion criteria will be performed prior to the first dose of study drug. 


SIGA Technologies, Inc. 
TPOXX 
Protocol No. SIGA-246-024 
Clinical Study Protocol Amendment 1 
 
Page 63 
(d) Review of medical history will be performed prior to the first dose of study drug and if determined by the investigator based on medical 
history/symptomology and will include a review of systems; recreational, prescription, and over-the-counter drug use; nicotine and alcohol use; and past 
hospitalizations. 
(e) A full physical examination will include, at minimum, 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 on Day 31 at the 
discretion of the investigator, if necessary, to evaluate AEs or clinical laboratory abnormalities. 
(f) Vital signs will be measured after the subject has been in the seated position for at least 5 minutes and will include systolic and diastolic blood pressures, heart 
rate, respiratory rate, and body temperature. Day 31 vital signs only need to be collected in the event that a symptom-directed physical examination is 
performed.  
(g) Vital signs will be measured within 60 minutes prior to the first dose of the day and 4 hours following the first dose of the day. The acceptable window for 
collection is ±15 minutes from the scheduled time point. 
(h) Includes alcohol, cotinine, amphetamines (including methamphetamines and ecstasy/methylenedioxymethamphetamine), barbiturates, benzodiazepines, 
cannabinoids (including tetrahydrocannabinol), cocaine metabolites, and opiates (including heroin, codeine, and oxycodone). A urine drug screen including 
alcohol and cotinine will be collected and sent to the central laboratory at the screening visit. A urine drug screen and alcohol breath test using a breathalyzer 
will be performed and read locally on Day –1. 
(i) Fasting lipid panel will include cholesterol (total, high-density lipoprotein, calculated low-density lipoprotein, and triglycerides). Fasting shall occur for 8 
hours prior specimen collection. 
(j) Clinical laboratory testing will include hematology, serum chemistry, and urinalysis. Clinical laboratory testing from screening will be used to determine 
eligibility. 
(k) Women of childbearing potential only. A urine pregnancy test will be performed and read locally on Day –1.  All other pregnancy tests, including screening, 
are by serum and read by the Central Lab. 
(l) For postmenopausal women. 
(m) A single 12-lead ECG will be obtained after the subject has been in the supine position for at least 10 minutes. On Day 1 and Day 14, an ECG will be 
recorded within 60 minutes prior to the first dose of the day and 4 hours after the first dose of the day. The acceptable window for collection from the 
scheduled collection time point is ±15 minutes. 
(n) When study drug is administered at the clinical investigative site, all subjects will be provided a meal (consisting of approximately 600 calories and 25 g of 
fat). The meal should be consumed within 30 minutes and prior to the administration of study drug (TPOXX or matching placebo). Subjects should be 
administered study drug as soon as possible following completion of the meal but no more than 30 minutes should elapse between meal completion and 
administration of study drug. Subjects should take study drug with 8 oz. (240 mL) of water.  
(o) The time of study drug dosing will be called “0” hour. Study drug will be administered to subjects by study site personnel when subjects are in house and 
subjects will self-administer study drug when at home. 


SIGA Technologies, Inc. 
TPOXX 
Protocol No. SIGA-246-024 
Clinical Study Protocol Amendment 1 
 
Page 64 
(p) Two times a day dosing: Subjects weighing 120 kg or less: 
Blood samples for PK analysis of TPOXX in plasma will be collected on Day 1 before the first dose (0 hour) and at 2, 4, 6, 8, 10, 12 (before the second dose), 
14, 16, 18, 20, 22, and 24 hours (before the first dose on Day 2); on Day 14 (before the first dose); and on Day 28 (before the first dose) and at 2, 4, 6, 8, 10, 
12 (before the second dose on Day 28), 14, 16, 18, 20, 22, 24 (Day 29, AM), 48 (Day 30, AM), and 72 (Day 31, AM) hours after the first dose on Day 28. 
Three times a day dosing: Subjects weighing more than 120 kg: 
Blood samples for PK analysis of TPOXX in plasma will be collected on Day 1 before the first dose (0 hour) and at 2, 4, 6, 8 (before the second dose), 10, 12, 
14, 16 (before the third dose), 18, 20, 22, and 24 hours (before the first dose on Day 2); on Day 14 (before the first dose); and on Day 28 (before the first dose) 
and at 2, 4, 6, 8 (before the second dose), 10, 12, 14, 16 (before the third dose), 18, 20, 22, 24 (Day 29, AM), 48 (Day 30, AM), and 72 (Day 31, AM) hours 
after the first dose on Day 28. 
 For PK blood samples, the acceptable window for collection from the scheduled collection time point will be as follows: ±15 minutes from 0 to 24 hours 
(except where samples are collected predose) and ±60 minutes from 48 to 72 hours.  
(q) If the subject is completing the ET visit, a blood sample for TPOXX concentration analysis should be collected within 30 hours after the last dose of study 
drug from subjects who discontinue. If the visit occurs more than 30 hours following the subject’s last dose of study drug, no sample needs to be collected. 
(r) One diary will be dispensed to record TPOXX or matching placebo administration, completion of required meals before and after dosing, all concomitant 
medications, and all AEs. 
(s) Adverse events will be collected from first dose of study drug until Day 42. Serious AEs will be collected up to Day 58. All AEs, SAEs, and clinically 
significant laboratory abnormalities will be followed until resolution or until stability of the abnormality has been demonstrated as determined by the 
investigator and/or medical monitor. 
(t) Concomitant medication information will only be collected at the Day 58 follow-up telephone call if it is related to an SAE. 
 
 


SIGA Technologies, Inc. 
TPOXX 
Protocol No. SIGA-246-024 
Clinical Study Protocol Amendment 1 
 
Page 65 
Table 9-2 
Schedule of Events: Non-Pharmacokinetic Subset Safety Subjects 
Procedure(a) 
 
Screening 
(Day –28 
to -1) 
Baseline 
Day 1  
Predose 
(AM)  
Day 1 
Postdose 
Day 7 
Follow-
up 
Day 14 
Follow-up 
Day 21 
Follow-up 
Day 29 
Dosing 
Complete/ET 
Visit 
Follow-up 
Telephone 
Call 
Day 42 
(+2 days) 
SAE Follow-up 
Telephone Call 
Day 58 
(+2 days) 
Admission to clinic 
 
X 
 
 
 
 
 
 
 
Discharge from clinic(b) 
 
 
X 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
X(c) 
 
 
 
 
 
 
 
Medical history 
X 
X(d) 
 
 
 
 
 
 
 
Physical examination(e) 
X 
 
 
X 
X 
X 
X 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
Height and weight 
X 
 
 
 
 
 
 
 
 
Serology (HBsAg, HCV, and HIV) 
X 
 
 
 
 
 
 
 
 
Vital sign measurements(f) 
X 
X 
X(g) 
X 
X 
X 
X 
 
 
Urine drug/alcohol/cotinine screen(h) 
X 
X 
 
 
 
 
 
 
 
Glycosylated hemoglobin (HbA1c) 
X 
 
 
 
 
 
 
 
 
Fasting lipid panel(i) 
X 
 
 
 
 
 
 
 
 
Clinical laboratory testing(j) 
X 
X 
 
X 
X 
X 
X 
 
 
Serum pregnancy test(k) 
X 
 
 
X 
X 
X 
X 
 
 
Urine pregnancy test(k) 
 
X 
 
 
 
 
 
 
 
Serum follicle-stimulating 
hormone(l) 
X 
 
 
 
 
 
 
 
 
12-lead ECG(m) 
X 
X 
X 
X 
X 
X 
X 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
Meal(n) 
 
X 
 
 
 
 
 
 
 
Administration of study drug(o) 
 
X 
 
 
 
 
 
 
 
Dispense study drug 
 
 
X 
 
 
 
 
 
 
Collect study drug 
 
 
 
 
 
 
X 
 
 
Study drug instructions 
 
 
X 
 
 
 
 
 
 
Subject diary dispensing(p) 
 
 
X 
 
 
 
 
 
 
Subject diary review 
 
 
 
X 
X 
X 
 
 
 
Subject diary collection 
 
 
 
 
 
 
X 
 
 
TPOXX concentration sampling 
 
 
 
 
 
 
X(q) 
 
 


SIGA Technologies, Inc. 
TPOXX 
Protocol No. SIGA-246-024 
Clinical Study Protocol Amendment 1 
 
Page 66 
Procedure(a) 
 
Screening 
(Day –28 
to -1) 
Baseline 
Day 1  
Predose 
(AM)  
Day 1 
Postdose 
Day 7 
Follow-
up 
Day 14 
Follow-up 
Day 21 
Follow-up 
Day 29 
Dosing 
Complete/ET 
Visit 
Follow-up 
Telephone 
Call 
Day 42 
(+2 days) 
SAE Follow-up 
Telephone Call 
Day 58 
(+2 days) 
AEs/SAEs(r) 
 
 
X 
X 
X 
Prior/concomitant medications(s)  
X 
X 
X 
X 
X 
Abbreviations: AE, adverse events; ECG, electrocardiogram; ET, early termination; HBsAg, hepatitis B surface antigen; HCV, hepatitis C virus; HIV, human 
immunodeficiency virus; SAE, serious adverse event. 
(a) When procedures are overlapping and occurring at the same time point, the order of procedures should be ECG then vital sign measurements unless dictated 
by other study events happening at that time, such as dosing requirements. 
(b) Discharge from the clinical investigative site will follow collection of all safety assessments. 
(c) Review of inclusion/exclusion criteria will be performed prior to the first dose of study drug. 
(d) Review of medical history will be performed prior to the first dose of study drug and if determined by the investigator based on medical 
history/symptomology and will include a review of systems; recreational, prescription, and over-the-counter drug use; nicotine and alcohol use; and past 
hospitalizations. 
(e) A full physical examination will include, at minimum, 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). Interim, unscheduled, symptom-directed physical examination will be performed 
at the discretion of the investigator, if necessary, to evaluate AEs or clinical laboratory abnormalities. 
(f) Vital signs will be measured after the subject has been in the seated position for at least 5 minutes and will include systolic and diastolic blood pressures, heart 
rate, respiratory rate, and body temperature.  
(g) Vital signs will be measured within 60 minutes prior to the first dose of the day and 4 hours following the first dose of the day. The acceptable window for 
collection is ±15 minutes from the scheduled time point 
(h) Includes alcohol, cotinine, amphetamines (including methamphetamines and ecstasy/methylenedioxymethamphetamine), barbiturates, benzodiazepines, 
cannabinoids (including tetrahydrocannabinol), cocaine metabolites, and opiates (including heroin, codeine, and oxycodone). A urine drug screen including 
alcohol and cotinine will be collected and sent to the central laboratory at the screening visit. A urine drug screen and alcohol breath test using a breathalyzer 
will be performed and read locally on Day 1. 
(i) Fasting lipid panel will include cholesterol (total, high-density lipoprotein, calculated low-density lipoprotein, and triglycerides). Fasting shall occur for 8 
hours prior specimen collection. 
(j) Clinical laboratory testing will include hematology, serum chemistry, and urinalysis. Clinical laboratory testing from screening will be used to determine 
eligibility. 
(k) Women of childbearing potential only.. A urine pregnancy test will be performed and read locally on Day 1 Predose.  All other pregnancy tests, including 
screening, are by serum and read by the Central Lab. 
(l) For postmenopausal women. 
(m) A single 12-lead ECG will be obtained after the subject has been in the supine position for at least 10 minutes. On Day 1, an ECG will be recorded prior to the 
first dose of the day and after the first dose of the day.  


SIGA Technologies, Inc. 
TPOXX 
Protocol No. SIGA-246-024 
Clinical Study Protocol Amendment 1 
 
Page 67 
(n) When study drug is administered at the clinical investigative site, all subjects will be provided a meal (consisting of approximately 600 calories and 25 g of 
fat). The meal should be consumed within 30 minutes and prior to the administration of study drug (TPOXX or matching placebo). Subjects should be 
administered study drug as soon as possible following completion of the meal but no more than 30 minutes should elapse between meal completion and 
administration of study drug. Subjects should take study drug with 8 oz. (240 mL) of water.  
(o) The time of study drug dosing will be called “0” hour. Study drug will be administered to subjects by study site personnel for the first dose on Day 1 and 
subjects will self-administer study drug when at home. Subjects will be instructed at the screening visit and prior to check-in to the clinical investigative site 
on Day 1 that other than water, no beverages may be ingested within 3 hours before or 3 hours after study drug administration, excluding a beverage that is 
being consumed as a part of the required meal. 
(p) One diary will be dispensed to record TPOXX or matching placebo administration, completion of required meals before and after dosing, all concomitant 
medications (dose and frequency), and all AEs. 
(q) If the subject is completing the ET visit, a blood sample for TPOXX concentration analysis should be collected within 30 hours after the last dose of study 
drug from subjects who discontinue. If the visit occurs more than 30 hours following the subject’s last dose of study drug, no sample needs to be collected. 
(r) Adverse events will be collected from first dose of study drug until Day 42. Serious AEs will be collected up to Day 58. All AEs, SAEs, and clinically 
significant laboratory abnormalities will be followed until resolution or until stability of the abnormality has been demonstrated as determined by the 
investigator and/or medical monitor. 
(s) Concomitant medication information will only be collected at the Day 58 follow-up telephone call if it is related to an SAE. 
 


SIGA Technologies, Inc. 
TPOXX 
Protocol No. SIGA-246-024 
Clinical Study Protocol Amendment 1 
 
Page 68 
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 (GCP), the protocol, and 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 case report forms (eCRFs) 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 investigators and appropriate clinical investigative sites, protocol 
training and review of protocol procedures with the investigators and study site personnel 
before the start of the study, site initiation and periodic interim monitoring visits by 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 a PPD clinical research associate (CRA) during on-site monitoring visits. Discrepancies 
will be resolved with the investigators or designees, as appropriate. The data will be entered 
into the clinical study database and validated for accuracy. During on-site monitoring visits, 
100% source documentation verification will be performed. SIGA or the Joint Program 
Executive Office for Chemical, Biological, Radiological and Nuclear Defense representatives 
may accompany the PPD CRA on any scheduled site visit. Investigators will be informed in 
advance of any visitors to the clinical investigative 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 


SIGA Technologies, Inc. 
TPOXX 
Protocol No. SIGA-246-024 
Clinical Study Protocol Amendment 1 
 
Page 69 
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. 
Investigators are 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 ICF. 
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 that is to be provided to the subject or the subject’s legal 
guardian must be approved by a central IRB.  


SIGA Technologies, Inc. 
TPOXX 
Protocol No. SIGA-246-024 
Clinical Study Protocol Amendment 1 
 
Page 70 
ADVARRA IRB 
6940 Columbia Gateway Drive, Suite 110 
Columbia, MD 21046 
Telephone: 410-884-2900 
Documentation of all IRB approvals and of the IRB compliance with the ICH harmonised 
tripartite guideline E6(R2): GCP will be maintained by the clinical investigative 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 administrated. 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 their legal guardian will be 
given a full explanation of the study and will be allowed 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 
their 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 80 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 


SIGA Technologies, Inc. 
TPOXX 
Protocol No. SIGA-246-024 
Clinical Study Protocol Amendment 1 
 
Page 71 
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. 
9.3.2.5 
Study Reporting Requirements 
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 the central IRB. 
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 


SIGA Technologies, Inc. 
TPOXX 
Protocol No. SIGA-246-024 
Clinical Study Protocol Amendment 1 
 
Page 72 
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 SIGA a commitment to promptly update this 
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): GCP; the 
protocol; and all national, state, and local laws or regulations. 
9.3.2.9 
Case Report Forms and Source Documents 
Study 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 CRAs. 
Each eCRF is presented as an electronic copy, allowing data entry by study 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 


SIGA Technologies, Inc. 
TPOXX 
Protocol No. SIGA-246-024 
Clinical Study Protocol Amendment 1 
 
Page 73 
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 study site personnel, CRAs, and reviewers with access to 
hardcopy audits, discrepancy reviews, and investigator comment information. 
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 the central IRB. 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. 


SIGA Technologies, Inc. 
TPOXX 
Protocol No. SIGA-246-024 
Clinical Study Protocol Amendment 1 
 
Page 74 
9.3.2.14 
Publications 
All information concerning TPOXX, SIGA operations, patient applications, 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 
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. Clinical research associates 
will conduct site monitoring visits as detailed in the monitoring plan. 
Site investigators will allow the CRA(s), the central IRB, SIGA or its designee, and the FDA 
to review, audit, and inspect study documents (e.g., 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 
clinical investigative site, at intervals determined by SIGA during conduct of the study, and at 
completion of the study. 


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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 clinical 
investigative site electronically.  
9.3.3.1.2 
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/SIGA project team 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. 
9.3.3.1.3 
Medical Monitor 
The medical monitor, or their qualified designee, will receive reports within 24 hours of 
clinical investigative site awareness of all SAEs and within 7 days of clinical investigative 
site awareness of all other AEs. The safety monitors will review all safety data and alert the 
medical monitor of SAEs. 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. 
9.3.3.1.4 
Safety Oversight 
In addition to the investigator’s ongoing review of the safety data, an independent DSMB 
will be established to review the protocol for any major concerns and will be involved in data 
review in coordination with the investigators and the medical monitor. The primary role of 
the committee will be to evaluate the study safety and tolerability data. 


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The 3-member independent DSMB will establish a charter for the committee with procedures 
for reviewing the safety information during the study and intends to meet at least 4 times 
throughout the study as follows: 
• At the beginning of the study (before first subject randomized). 
• At the completion of 112 subjects (approximately 25% of subjects) receiving their first 
dose of study drug. 
• After the last subject receives the final dose of study drug. 
• At the completion of all subjects in the study, including the final follow-up safety visits. 
• At any time during the study as deemed necessary by the committee and/or SIGA. 
Before initiation of the study, the DSMB will review the study design, the methods for safety 
assessments, and the rules for halting this study. As part of their responsibility, DSMB 
members must be satisfied that the timeliness, completeness, and accuracy of the data 
submitted to them for review are sufficient for evaluation of the safety and welfare of study 
subjects. The DSMB will also assess the performance of overall study operations and any 
other relevant issues, as necessary. The DSMB will remain blinded to study treatment 
assignments unless the need to unblind treatment assignment(s) is deemed necessary by the 
committee. PPD will provide access to the randomization codes through the unblinded 
statistician who will be available for DSMB meetings and as requested to provide unblinding 
information when needed. 
Immediate notification will be provided to DSMB of specific events, including the following: 
• All events meeting the criteria for an SAE. 
• Withdrawal of subjects because of an AE possibly, probably, or definitely related to 
study drug. 
• DAIDS grade 4 laboratory abnormalities that are considered clinically significant by the 
investigator (may require additional testing or treatment beyond protocol-specific 
assessments). 
• Any death of a subject. 


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A summary of safety results will be provided to the DSMB for review and discussion at 
scheduled and ad-hoc meetings. The specific reporting requirements will be outlined in the 
DSMB Charter, but are anticipated to be based on data collected up to and including the 
follow-up period and will include the following: demographics, study accountability, subjects 
withdrawn, summaries and listings of SAEs/AEs coded by the Medical Dictionary for 
Regulatory Activities, summary of abnormal clinical laboratory results, summary of ECG 
results, and protocol deviations. Narrative summaries for subjects with withdrawals because 
of AEs determined by the investigator to be possibly, probably, or definitely related to the 
study drug; AEs that are grade 3 and higher; SAEs; or special cases of particular interest will 
be provided to the DSMB per the reporting requirements of the DSMB Charter. 
The study can be temporarily halted in 2 capacities based on the observations in a summary 
review: immediate halt (no new enrollments and no further study drug dosing) or enrollment 
halt (no new enrollments but further study drug dosing of enrolled subjects may continue), 
with PPD providing notification to the investigators. 
9.3.3.1.5 
Inspection of Records 
The investigators and institutions involved in the study will permit study-related monitoring, 
audits, IRB review, and regulatory inspections by providing direct access to all study records. 
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. 
Investigators should promptly notify PPD and SIGA of inspections scheduled by any 
regulatory authorities and promptly forward copies of any inspection forms or other 
documentation received to SIGA. 
9.3.3.1.6 
General COVID-19 Precautions at Clinical Investigative 
Sites 
Clinical investigative sites participating in this study will have processes in place locally for 
following recommendations of the local public health authorities for the management of 
COVID-19. Subjects will be asked to follow good hygiene and safe physical distancing 
measures such as wearing a face mask on-site, frequent hand hygiene, and maintaining a 
physical distance of 2 meters (or 6 feet) from others, except during procedures where staff 
must come into close proximity of subjects (e.g., blood draws, collecting vital sign 
measurements).  


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Staff at the clinical investigative sites will also follow the same good hygiene and safe 
physical distancing measures as the subjects at the clinical investigative site. In addition, the 
study site staff will be responsible for disinfecting materials and/or areas between each use 
by subjects and study site staff. All study site staff involved with on-site procedures will have 
a back-up member who is qualified to perform the same duties/responsibilities in the event 
that a member of the study site staff is infected with SARS-CoV-2 or comes into contact with 
an individual known to have COVID-19 and is restricted to self-isolation and following the 
recommendations of the local public health authorities for the management of COVID-19. 
Subjects will be asked to inform the clinical investigative site if they have tested positive for 
COVID-19 and if they are following the actions (e.g., quarantine, re-testing) recommended 
by local public health authorities. Subjects will be asked to not visit the clinical investigative 
site until after they have fully recovered (i.e., no more clinical symptoms) and have 
completed all of the actions (e.g., quarantine, re-testing) recommended by local public health 
authorities. If the quarantine period for the subject overlaps with clinical investigative site 
visit and the visit window, then the procedures for that particular visit may be performed by 
trained medical staff, using reliable personal protective equipment, and following good 
hygiene, at the subject’s home (or place of quarantine). 
9.3.3.2 
Management of Protocol Amendments and Deviations 
9.3.3.2.1 
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 central IRB and IRB 
approved before subjects are enrolled into an amended protocol. 
9.3.3.2.2 
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. 


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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 major or significant deviation) is a subset of protocol deviations that leads to a subject 
being discontinued from the study, or significantly affects the subject’s rights, safety, or 
well-being and/or completeness, accuracy, and reliability of the study data. 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 and shared with the PPD/SIGA team. 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. 
9.3.3.3 
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 by SIGA, PPD, or the FDA. Reasons for such action include, but are not 
limited to: 
• Clinical investigative 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 FDA has the prerogative to delay or terminate the study. 


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The end of the study is defined as the date on which the last subject completes the last visit 
(including the follow-up telephone calls). 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. 
9.3.3.4 
Final Report 
Regardless of 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. 
Where required by applicable regulatory requirements, an investigator signatory will be 
identified for the approval of the clinical study report. The investigator will be provided 
reasonable access to statistical tables, figures, and relevant reports and will have the 
opportunity to review complete study results. 
Upon completion of the clinical study report, the investigators will be provided with the final 
approved clinical study report, as appropriate. 
 
 


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9.4 
APPENDIX 4: DIVISION OF ACQUIRED IMMUNE 
DEFICIENCY SYNDROME (DAIDS) 
Introduction 
The DAIDS oversees more than 300 clinical trials domestically and internationally, which 
evaluate the safety and efficacy of therapeutic products, vaccines, and other preventive 
modalities. Adverse event data collected during these clinical trials form the basis for 
subsequent safety and efficacy analyses of pharmaceutical products and medical devices. 
Incorrect and inconsistent AE severity grading can lead to inaccurate data analyses and 
interpretation, which in turn can impact the safety and well-being of clinical trial participants 
and future patients using pharmaceutical products. 
Over the years, DAIDS scientific knowledge and experience have expanded, necessitating 
revisions of the DAIDS grading table which serves as a guide for assessing the severity of 
AEs (including clinical and laboratory abnormalities) in participants enrolled in 
DAIDS-sponsored and -supported clinical trials. The Division of AIDS (DAIDS) Table for 
Grading the Severity of Adult and Pediatric Adverse Events, Corrected Version 2.1 
(July 2017) updates and replaces version 2.1 (March 2017). 
DAIDS is grateful to the DAIDS Grading Table Working Group, numerous government and 
non-government affiliated medical subject matter experts and reviewers who were 
instrumental in the revision of the DAIDS grading table. 
Instructions for Use 
General Considerations 
The DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events, 
Version 2.1 consists of parameters, or AEs, with severity grading guidance that are to be used 
in DAIDS clinical trials for safety data reporting to maintain accuracy and consistency in the 
evaluation of AEs. The term “severe” is not the same as the term “serious” in classifying 
AEs. The severity of a specific event describes its intensity, and it is the intensity which is 
graded. Seriousness, which is not graded, relates to an outcome of an AE and is a regulatory 
definition. 
Clinical sites are encouraged to report parameters in the DAIDS grading table as they are 
written to maintain data consistency across clinical trials. However, since some parameters 
can be reported with more specificity, clinical sites are encouraged to report parameters that 
convey additional clinical information. For example, diarrhea could be reported as neonatal 
diarrhea; seizures, as febrile seizures; and pain, as jaw pain. 


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The DAIDS grading table provides an AE severity grading scale ranging from grades 1 to 5 
with descriptions for each AE based on the following general guidelines: 
• Grade 1 indicates a mild event 
• Grade 2 indicates a moderate event 
• Grade 3 indicates a severe event 
• Grade 4 indicates a potentially life-threatening event 
• Grade 5 indicates death (Note: This grade is not specifically listed on each page of the 
grading table). 
Other points to consider include: 
• Use age and sex values as applicable. 
• Unless noted, laboratory values are for term neonates.  
• Where applicable, Standard International (SI) units are included in italics. 
Selecting and Reporting a Primary AE Term 
When selecting a primary AE term to report, sites should select the term that best describes 
what occurred to the participant. For example, a participant may present with itching, 
urticaria, flushing, angioedema of the face, and dyspnea. If the underlying diagnosis is 
determined to be an acute allergic reaction, sites should report “Acute Allergic Reaction” as 
the primary AE term. 
Primary AE terms should be reported using the DAIDS Adverse Experience Reporting 
System (DAERS) only if they meet expedited reporting criteria. However, all primary AE 
terms should be reported using protocol-specific case report forms (CRFs). Because the 
reported information is stored in different databases (i.e., safety and clinical), sites should 
report primary AE terms using the same terminology for data consistency. 
When reporting using DAERS, other clinically significant events associated with a primary 
AE term that more fully describe the nature, severity, or complications of the primary AE 
term should be entered in the “Other Events” section. However, the severity grade for these 
events must be lower than or equal to the severity grade of the primary AE term. In the 


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example above, dyspnea and angioedema of the face may be entered in the “Other Events” 
section, because they are more descriptive and provide additional information on the severity 
of the acute allergic reaction. However, their severity grades must be lower than or equal to 
the severity grade of the primary AE term of “Acute Allergic Reaction”. 
Differences exist in the reporting and recording of information (e.g., signs and symptoms, 
clinically significant events) in DAERS and CRFs. Therefore, sites should refer to their 
protocols and CRF requirements for further instructions. 
Grading Adult and Pediatric Adverse Events 
When a single parameter is not appropriate for grading an AE in both adult and pediatric 
populations, separate parameters with specified age ranges are provided. If no distinction 
between adult and pediatric populations has been made, the listed parameter should be used 
for grading an AE in both populations. 
Reporting Pregnancy Outcomes 
In the Pregnancy, Puerperium, and Perinatal section, all parameters are pregnancy outcomes 
and should be reported using the mother's participant ID. If an infant is not enrolled in the 
same study as the mother, any identified birth defects should be reported using the mother's 
participant ID. However, if an infant is enrolled in the same study as the mother or in another 
study, any identified birth defects should be reported using the infant's participant ID. Sites 
should refer to the applicable network standards for reporting abnormal pregnancy outcomes 
on the CRFs. 
Determining Severity Grade for Parameters between Grades 
If the severity of an AE could fall in either one of two grades (i.e., the severity of an AE 
could be either grade 2 or grade 3), sites should select the higher of the two grades. 
Using Addenda 1-3: Grading Tables Used in Microbicide Studies 
In protocols involving topical application of products to the female and male genital tracts or 
rectum, strong consideration should be given to using Addenda 1 to 3 (see below) as the 
primary grading tables for these areas. Although these grading tables are used specifically in 
microbicide studies, they may be used in other protocols as adjuncts to the main grading table 
(i.e., the DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events, 
Version 2.0). It should be clearly stated in a protocol which addendum is being used as the 


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primary grading table (and thus takes precedence over the main grading table) and which 
addendum is being used in a complementary fashion. 
• Addendum 1 – Female Genital Grading Table for Use in Microbicide Studies 
http://rsc.tech-res.com/clinical-research-sites/safety-reporting/daids-grading-tables 
• Addendum 2 – Male Genital Grading Table for Use in Microbicide Studies 
http://rsc.tech-res.com/clinical-research-sites/safety-reporting/daids-grading-tables 
• Addendum 3 – Rectal Grading Table for Use in Microbicide Studies            
http://rsc.tech-res.com/clinical-research-sites/safety-reporting/daids-grading-tables 
Estimating Severity Grade for Parameters Not Identified in the Grading Table 
The functional table below should be used to grade the severity of an AE that is not 
specifically identified in the grading table. In addition, all deaths related to an AE are to be 
classified as grade 5. 
Table 9-3 
Division of AIDS (DAIDS) Table for Grading the Severity of Adult 
and Pediatric Adverse Events 
PARAMETER 
GRADE 1 MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING 
Clinical adverse event 
NOT identified 
elsewhere in the grading 
table 
Mild symptoms 
causing no or minimal 
interference with 
usual social & 
functional activities 
with intervention not 
indicated 
Moderate 
symptoms causing 
greater than 
minimal 
interference with 
usual social & 
functional 
activities with 
intervention 
indicated 
Severe symptoms 
causing inability to 
perform usual 
social & functional 
activities with 
intervention or 
hospitalization 
indicated 
Potentially life-
threatening 
symptoms causing 
inability to perform 
basic self-care 
functions with 
intervention 
indicated to prevent 
permanent 
impairment, 
persistent disability, 
or death 
Cardiovascular 
Arrhythmia 
(by ECG or physical 
examination) Specify 
type, if applicable 
No symptoms AND 
No intervention 
indicated 
No symptoms 
AND Non-urgent 
intervention 
indicated 
Non-life-
threatening 
symptoms AND 
Non-urgent 
intervention 
indicated 
Life-threatening 
arrhythmia OR 
Urgent intervention 
indicated 


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PARAMETER 
GRADE 1 MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING 
Blood Pressure 
Abnormalities 
Hypertension (with the 
lowest reading taken 
after repeat testing 
during a visit) ≥ 18 
years of age 
140 to < 160 mmHg 
systolic OR 90 to 
< 100 mmHg diastolic 
≥ 160 to < 180 
mmHg systolic OR 
≥ 100 to < 
110 mmHg 
diastolic 
≥ 180 mmHg 
systolic OR ≥ 110 
mmHg diastolic 
Life-threatening 
consequences in a 
participant not 
previously diagnosed 
with hypertension 
(e.g., malignant 
hypertension) OR 
Hospitalization 
indicated 
< 18 years of age  
> 120/80 mmHg 
≥ 95th to < 99th 
percentile + 
5 mmHg adjusted 
for age, height, and 
gender (systolic 
and/or diastolic) 
≥ 99th percentile 
+ 5 mmHg adjusted 
for age, height, and 
gender (systolic 
and/or diastolic) 
Life-threatening 
consequences in a 
participant not 
previously diagnosed 
with hypertension 
(e.g., malignant 
hypertension) OR 
Hospitalization 
indicated 
Hypotension 
No symptoms  
Symptoms 
corrected with oral 
fluid replacement 
Symptoms AND IV 
fluids indicated 
Shock requiring use 
of vasopressors or 
mechanical 
assistance to 
maintain blood 
pressure 
Cardiac Ischemia or 
Infarction 
Report only one 
NA 
NA 
New symptoms 
with ischemia 
(stable angina) OR 
New testing 
consistent with 
ischemia 
Unstable angina OR 
Acute myocardial 
infarction 
Heart Failure 
No symptoms AND 
Laboratory or cardiac 
imaging abnormalities 
Symptoms with 
mild to moderate 
activity or exertion 
Symptoms at rest or 
with minimal 
activity or exertion 
(e.g., hypoxemia) 
OR Intervention 
indicated (e.g., 
oxygen) 
Life-threatening 
consequences OR 
Urgent intervention 
indicated (e.g., 
vasoactive 
medications, 
ventricular assist 
device, heart 
transplant) 
Hemorrhage 
(with significant acute 
blood loss) 
NA 
Symptoms AND 
No transfusion 
indicated 
Symptoms AND 
Transfusion of 
≤ 2 units packed 
RBCs indicated 
Life-threatening 
hypotension OR 
Transfusion of 
> 2 units packed 
RBCs (for children, 
packed RBCs 
> 10 cc/kg) indicated 
Prolonged PR Interval 
or AV Block Report 
only one > 16 years of 
age 
PR interval 0.21 to 
< 0.25 seconds 
PR interval ≥ 0.25 
seconds OR Type I 
2nd degree AV 
block 
Type II 2nd degree 
AV block OR 
Ventricular pause 
≥ 3.0 seconds 
Complete AV block 
Prolonged QTc 
Intervala 
0.45 to 0.47 seconds 
> 0.47 to 0.50 
seconds 
> 0.50 seconds OR 
≥ 0.06 seconds 
above baseline 
dysrhythmia) 
Life-threatening 
consequences (e.g., 
Torsade de pointes, 
other associated 
serious ventricular 


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PARAMETER 
GRADE 1 MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING 
Thrombosis or 
Embolism Report only 
one 
NA 
Symptoms AND 
No intervention 
indicated 
Symptoms AND 
Intervention 
indicated  
Life-threatening 
embolic event (e.g., 
pulmonary 
embolism, thrombus) 
Dermatologic 
Alopecia (scalp only)  
Detectable by study 
participant, caregiver, 
or physician AND 
causing no or minimal 
interference with 
usual social & 
functional activities 
Obvious on visual 
inspection AND 
causing greater 
than minimal 
interference with 
usual social & 
functional 
activities 
NA 
NA 
Bruising 
Localized to one area 
Localized to more 
than one area 
Generalized 
NA 
Cellulitis 
NA 
Non-parenteral 
treatment indicated 
(e.g., oral 
antibiotics, 
antifungals, 
antivirals) 
IV treatment 
indicated (e.g., IV 
antibiotics, 
antifungals, 
antivirals) 
Life-threatening 
consequences (e.g., 
sepsis, tissue 
necrosis) 
Hyperpigmentation 
Slight or localized 
causing no or minimal 
interference with 
usual social & 
functional activities 
Marked or 
generalized 
causing greater 
than minimal 
interference with 
usual social & 
functional 
activities 
NA 
NA 
Hypopigmentation 
Slight or localized 
causing no or minimal 
interference with 
usual social & 
functional activities 
Marked or 
generalized 
causing greater 
than minimal 
interference with 
usual social & 
functional 
activities 
NA 
NA 
Petechiae 
Localized to one area 
Localized to more 
than one area 
Generalized 
NA 
Pruritusb 
(without skin lesions) 
Itching causing no or 
minimal interference 
with usual social & 
functional activities 
Itching causing 
greater than 
minimal 
interference with 
usual social & 
functional 
activities 
Itching causing 
inability to perform 
usual social & 
functional activities 
NA 


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PARAMETER 
GRADE 1 MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING 
Rash 
Specify type, if 
applicable 
Localized rash 
Diffuse rash OR 
Target lesions 
Diffuse rash AND 
Vesicles or limited 
number of bullae or 
superficial 
ulcerations of 
mucous membrane 
limited to one site 
Extensive or 
generalized bullous 
lesions OR 
Ulceration of 
mucous membrane 
involving two or 
more distinct 
mucosal sites OR 
Stevens-Johnson 
syndrome OR Toxic 
epidermal necrolysis 
Diabetes Mellitus 
Controlled without 
medication 
Controlled with 
medication OR 
Modification of 
current medication 
regimen 
Uncontrolled 
despite treatment 
modification OR 
Hospitalization for 
immediate glucose 
control indicated 
Life-threatening 
consequences (e.g., 
ketoacidosis, 
hyperosmolar 
nonketotic coma, end 
organ failure) 
Gynecomastia 
Detectable by study 
participant, caregiver, 
or physician AND 
Causing no or 
minimal interference 
with usual social & 
functional activities 
Obvious on visual 
inspection AND 
Causing pain with 
greater than 
minimal 
interference with 
usual social & 
functional 
activities 
Disfiguring 
changes AND 
Symptoms 
requiring 
intervention or 
causing inability to 
perform usual 
social & functional 
activities 
NA 
Hyperthyroidism 
No symptoms AND 
Abnormal laboratory 
value 
Symptoms causing 
greater than 
minimal 
interference with 
usual social & 
functional 
activities OR 
Thyroid 
suppression 
therapy indicated 
Symptoms causing 
inability to perform 
usual social & 
functional activities 
OR Uncontrolled 
despite treatment 
modification 
Life-threatening 
consequences (e.g., 
thyroid storm) 
Hypothyroidism 
No symptoms AND 
Abnormal laboratory 
value 
Symptoms causing 
greater than 
minimal 
interference with 
usual social & 
functional 
activities OR 
Thyroid 
replacement 
therapy indicated 
Symptoms causing 
inability to perform 
usual social & 
functional activities 
OR Uncontrolled 
despite treatment 
modification 
Life-threatening 
consequences (e.g., 
myxedema coma) 
Lipoatrophy (a disorder 
characterized by fat loss 
in the face, extremities, 
and buttocks) 
Detectable by study 
participant, caregiver, 
or physician AND 
Causing no or 
minimal interference 
with usual social & 
functional activities 
Obvious on visual 
inspection AND 
Causing greater 
than minimal 
interference with 
usual social & 
functional 
activities 
Disfiguring 
changes 
NA 


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PARAMETER 
GRADE 1 MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING 
Endocrine and Metabolic 
Lipohypertrophy 
(characterized by 
abnormal fat 
accumulation on the back 
of the neck, breasts, and 
abdomen) 
Detectable by study 
participant, caregiver, 
or physician AND 
Causing no or 
minimal interference 
with usual social & 
functional activities 
Obvious on visual 
inspection AND 
Causing greater 
than minimal 
interference with 
usual social & 
functional 
activities 
Disfiguring 
changes 
NA 
 
 
 
 
 
Gastrointestinal 
Anorexia  
Loss of appetite 
without decreased oral 
intake 
Loss of appetite 
associated with 
decreased oral 
intake without 
significant weight 
loss 
Loss of appetite 
associated with 
significant weight 
loss 
Life-threatening 
consequences OR 
aggressive 
intervention 
indicated (e.g., tube 
feeding, total 
parenteral nutrition) 
Ascites 
No symptoms 
Symptoms AND 
Intervention 
indicated (e.g., 
diuretics, 
therapeutic 
paracentesis) 
Symptoms recur or 
persist despite 
intervention 
Life-threatening 
consequences 
Bloating or Distension 
Report only one 
 
Symptoms causing no 
or minimal 
interference with 
usual social & 
functional activities 
Symptoms causing 
greater than 
minimal 
interference with 
usual social & 
functional 
activities 
Symptoms causing 
inability to perform 
usual social & 
functional activities 
NA 
Cholecystitis 
NA 
Symptoms AND 
Medical 
intervention 
indicated 
Radiologic, 
endoscopic, or 
operative 
intervention 
indicated 
Life-threatening 
consequences (e.g., 
sepsis, perforation) 
Constipation 
NA 
Persistent 
constipation 
requiring regular 
use of dietary 
modifications, 
laxatives, or 
enemas 
Obstipation with 
manual evacuation 
indicated 
Life-threatening 
consequences (e.g., 
obstruction) 
Diarrhea 
≥ 1 year of age  
Transient or 
intermittent episodes 
of unformed stools 
OR Increase of 
≤ 3 stools over 
baseline per 24-hour 
period 
Persistent episodes 
of unformed to 
watery stools OR 
Increase of 4 to 
6 stools over 
baseline per 
24-hour period 
Increase of 
≥ 7 stools per 
24-hour period OR 
IV fluid 
replacement 
indicated 
Life-threatening 
consequences (e.g., 
hypotensive shock) 
< 1 year of age  
Liquid stools (more 
unformed than usual) 
but usual number of 
stools 
Liquid stools with 
increased number 
of stools OR Mild 
dehydration 
Liquid stools with 
moderate 
dehydration 
Life-threatening 
consequences (e.g., 
liquid stools 
resulting in severe 
dehydration, 
hypotensive shock) 


SIGA Technologies, Inc. 
TPOXX 
Protocol No. SIGA-246-024 
Clinical Study Protocol Amendment 1 
 
Page 89 
PARAMETER 
GRADE 1 MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING 
Dysphagia or 
Odynophagia 
Report only one and 
specify location 
Symptoms but able to 
eat usual diet 
Symptoms causing 
altered dietary 
intake with no 
intervention 
indicated 
Symptoms causing 
severely altered 
dietary intake with 
intervention 
indicated 
Life-threatening 
reduction in oral 
intake 
Gastrointestinal 
Bleeding 
Not requiring 
intervention other than 
iron supplement 
Endoscopic 
intervention 
indicated 
Transfusion 
indicated 
Life-threatening 
consequences (e.g., 
hypotensive shock) 
Mucositis or Stomatitis 
Report only one and 
specify location 
Mucosal erythema 
Patchy 
pseudomembranes 
or ulcerations 
Confluent 
pseudomembranes 
or ulcerations OR 
Mucosal bleeding 
with minor trauma 
Life-threatening 
consequences (e.g., 
aspiration, choking) 
OR Tissue necrosis 
OR Diffuse 
spontaneous mucosal 
bleeding 
Nausea  
Transient (< 24 hours) 
or intermittent AND 
No or minimal 
interference with oral 
intake 
Persistent nausea 
resulting in 
decreased oral 
intake for 24 to 
48 hours 
Persistent nausea 
resulting in 
minimal oral intake 
for > 48 hours OR 
Rehydration 
indicated (e.g., IV 
fluids) 
Life-threatening 
consequences (e.g., 
hypotensive shock) 
Pancreatitis 
NA 
Symptoms with 
hospitalization not 
indicated 
Symptoms with 
hospitalization 
indicated 
Life-threatening 
consequences (e.g., 
circulatory failure, 
hemorrhage, sepsis) 
Perforation 
(colon or rectum) 
NA 
NA 
Intervention 
indicated 
Life-threatening 
consequences 
Proctitis  
Rectal discomfort 
with no intervention 
indicated 
Symptoms causing 
greater than 
minimal 
interference with 
usual social & 
functional 
activities OR 
Medical 
intervention 
indicated 
Symptoms causing 
inability to perform 
usual social & 
functional activities 
OR Operative 
intervention 
indicated 
Life-threatening 
consequences (e.g., 
perforation) 
Rectal Discharge 
Visible discharge 
Discharge 
requiring the use of 
pads 
NA 
NA 
Vomiting  
Transient or 
intermittent AND No 
or minimal 
interference with oral 
intake 
Frequent episodes 
with no or mild 
dehydration 
Persistent vomiting 
resulting in 
orthostatic 
hypotension OR 
Aggressive 
rehydration 
indicated (e.g., IV 
fluids) 
Life-threatening 
consequences (e.g., 
hypotensive shock) 
Musculoskeletal 
Arthralgia  
Joint pain causing no 
or minimal 
interference with 
usual social & 
functional activities 
Joint pain causing 
greater than 
minimal 
interference with 
usual social & 
Joint pain causing 
inability to perform 
usual social & 
functional activities 
Disabling joint pain 
causing inability to 
perform basic 
self-care functions 


SIGA Technologies, Inc. 
TPOXX 
Protocol No. SIGA-246-024 
Clinical Study Protocol Amendment 1 
 
Page 90 
PARAMETER 
GRADE 1 MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING 
functional 
activities 
Arthritis 
Stiffness or joint 
swelling causing no or 
minimal interference 
with usual social & 
functional activities 
Stiffness or joint 
swelling causing 
greater than 
minimal 
interference with 
usual social & 
functional 
activities 
Stiffness or joint 
swelling causing 
inability to perform 
usual social & 
functional activities 
Disabling joint 
stiffness or swelling 
causing inability to 
perform basic 
self-care functions 
Myalgia (generalized)  
Muscle pain causing 
no or minimal 
interference with 
usual social & 
functional activities 
Muscle pain 
causing greater 
than minimal 
interference with 
usual social & 
functional 
activities 
Muscle pain 
causing inability to 
perform usual 
social & functional 
activities 
Disabling muscle 
pain causing inability 
to perform basic 
self-care functions 
Osteonecrosis 
NA 
No symptoms but 
with radiographic 
findings AND No 
operative 
intervention 
indicated 
Bone pain with 
radiographic 
findings OR 
Operative 
intervention 
indicated 
Disabling bone pain 
with radiographic 
findings causing 
inability to perform 
basic self-care 
functions 
Osteopeniac 
≥ 30 years of age  
BMD t-score -2.5 to -
1 
NA 
NA 
NA 
< 30 years of age  
BMD z-score -2 to -1 
NA 
NA 
NA 
Osteoporosisc 
≥ 30 years of age 
NA 
BMD t-score < -2.5 
Pathologic fracture 
(e.g., compression 
fracture causing 
loss of vertebral 
height) 
Pathologic fracture 
causing 
life-threatening 
consequences 
< 30 years of age NA  
NA 
BMD z-score < -2 
Pathologic fracture 
(e.g., compression 
fracture causing 
loss of vertebral 
height) 
Pathologic fracture 
causing 
life-threatening 
consequences 
Neurologic 
Acute CNS Ischemia 
NA 
NA 
Transient ischemic 
attack 
Cerebral vascular 
accident (e.g., stroke 
with neurological 
deficit) 
Altered Mental Status 
(for Dementia, see 
Cognitive, Behavioral, or 
Attentional Disturbance 
below) 
Changes causing no or 
minimal interference 
with usual social & 
functional activities 
Mild lethargy or 
somnolence 
causing greater 
than minimal 
interference with 
usual social & 
functional 
activities 
Confusion, memory 
impairment, 
lethargy, or 
somnolence 
causing inability to 
perform usual 
social & functional 
activities 
Delirium OR 
Obtundation OR 
Coma 
Ataxia 
Symptoms causing no 
or minimal 
interference with 
usual social & 
functional activities 
OR No symptoms 
Symptoms causing 
greater than 
minimal 
interference with 
usual social & 
functional 
activities 
Symptoms causing 
inability to perform 
usual social & 
functional activities 
Disabling symptoms 
causing inability to 
perform basic 
self-care functions 


SIGA Technologies, Inc. 
TPOXX 
Protocol No. SIGA-246-024 
Clinical Study Protocol Amendment 1 
 
Page 91 
PARAMETER 
GRADE 1 MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING 
with ataxia detected 
on examination 
Cognitive, Behavioral, 
or Attentional 
Disturbance (includes 
dementia and attention 
deficit disorder) Specify 
type, if applicable 
Disability causing no 
or minimal 
interference with 
usual social & 
functional activities 
OR Specialized 
resources not 
indicated 
Disability causing 
greater than 
minimal 
interference with 
usual social & 
functional 
activities OR 
Specialized 
resources on 
parttime basis 
indicated 
Disability causing 
inability to perform 
usual social & 
functional activities 
OR Specialized 
resources on a 
fulltime basis 
indicated 
Disability causing 
inability to perform 
basic self-care 
functions OR 
Institutionalization 
indicated 
Developmental Delay 
< 18 years of age 
Specify type, if 
applicable 
Mild developmental 
delay, either motor or 
cognitive, as 
determined by 
comparison with a 
developmental 
screening tool 
appropriate for the 
setting 
Moderate 
developmental 
delay, either motor 
or cognitive, as 
determined by 
comparison with a 
developmental 
screening tool 
appropriate for the 
setting 
Severe 
developmental 
delay, either motor 
or cognitive, as 
determined by 
comparison with a 
developmental 
screening tool 
appropriate for the 
setting 
Developmental 
regression, either 
motor or cognitive, 
as determined by 
comparison with a 
developmental 
screening tool 
appropriate for the 
setting 
Headache 
Symptoms causing no 
or minimal 
interference with 
usual social & 
functional activities 
Symptoms causing 
greater than 
minimal 
interference with 
usual social & 
functional 
activities 
Symptoms causing 
inability to perform 
usual social & 
functional activities 
Symptoms causing 
inability to perform 
basic self-care 
functions OR 
Hospitalization 
indicated OR 
Headache with 
significant 
impairment of 
alertness or other 
neurologic function 
Neuromuscular 
Weakness (includes 
myopathy and 
neuropathy) 
Specify type, if 
applicable 
Minimal muscle 
weakness causing no 
or minimal 
interference with 
usual social & 
functional activities 
OR No symptoms 
with decreased 
strength on 
examination 
Muscle weakness 
causing greater 
than minimal 
interference with 
usual social & 
functional 
activities 
Muscle weakness 
causing inability to 
perform usual 
social & functional 
activities 
Disabling muscle 
weakness causing 
inability to perform 
basic self-care 
functions OR 
Respiratory muscle 
weakness impairing 
ventilation 
Neurosensory 
Alteration (includes 
paresthesia and painful 
neuropathy) 
Specify type, if 
applicable 
Minimal paresthesia 
causing no or minimal 
interference with 
usual social & 
functional activities 
OR No symptoms 
with sensory alteration 
on examination 
Sensory alteration 
or paresthesia 
causing greater 
than minimal 
interference with 
usual social & 
functional 
activities 
Sensory alteration 
or paresthesia 
causing inability to 
perform usual 
social & functional 
activities 
Disabling sensory 
alteration or 
paresthesia causing 
inability to perform 
basic self-care 
functions 


SIGA Technologies, Inc. 
TPOXX 
Protocol No. SIGA-246-024 
Clinical Study Protocol Amendment 1 
 
Page 92 
PARAMETER 
GRADE 1 MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING 
Seizures New Onset 
Seizure 
≥ 18 years of age 
NA 
NA 
1 to 3 seizures 
Prolonged and 
repetitive seizures 
(e.g., status 
epilepticus) OR 
Difficult to control 
(e.g., refractory 
epilepsy) 
< 18 years of age 
(includes new or 
preexisting febrile 
seizures) 
Seizure lasting 
< 5 minutes with 
< 24 hours postictal 
state 
Seizure lasting 5 to 
< 20 minutes with 
< 24 hours 
postictal state 
Seizure lasting 
≥ 20 minutes OR 
> 24 hours postictal 
state 
Prolonged and 
repetitive seizures 
(e.g., status 
epilepticus) OR 
Difficult to control 
(e.g., refractory 
epilepsy) 
Pre-existing Seizure 
NA 
Increased 
frequency from 
previous level of 
control without 
change in seizure 
character 
Change in seizure 
character either in 
duration or quality 
(e.g., severity or 
focality) 
Prolonged and 
repetitive seizures 
(e.g., status 
epilepticus) OR 
Difficult to control 
(e.g., refractory 
epilepsy) 
Syncope 
Near syncope without 
loss of consciousness 
(e.g., pre-syncope) 
Loss of 
consciousness with 
no intervention 
indicated 
Loss of 
consciousness 
AND 
Hospitalization or 
intervention 
required 
NA 
Pregnancy, Puerperium, and Perinatal 
Stillbirth (report using 
mother’s participant ID) 
Report only one 
NA 
NA 
Fetal death 
occurring at 
≥ 20 weeks 
gestation 
NA 
Preterm Birth (report 
using mother’s 
participant ID) 
Live birth at 34 to 
< 37 weeks 
gestational age 
Live birth at 28 to 
< 34 weeks 
gestational age 
Live birth at 24 to 
< 28 weeks 
gestational age 
Live birth at 
< 24 weeks 
gestational age 
Spontaneous Abortion 
or Miscarriaged (report 
using mother’s 
participant ID) 
Report only one 
Chemical pregnancy 
Uncomplicated 
spontaneous 
abortion or 
miscarriage 
Complicated 
spontaneous 
abortion or 
miscarriage 
NA 
Psychiatric 
Insomnia 
Mild difficulty falling 
asleep, staying asleep, 
or waking up early 
causing no or minimal 
interference with 
usual social & 
functional activities 
Moderate difficulty 
falling asleep, 
staying asleep, or 
waking up early 
causing more than 
minimal 
interference with 
usual social & 
functional 
activities 
Severe difficulty 
falling asleep, 
staying asleep, or 
waking up early 
causing inability to 
perform usual 
social & functional 
activities requiring 
intervention or 
hospitalization 
NA 


SIGA Technologies, Inc. 
TPOXX 
Protocol No. SIGA-246-024 
Clinical Study Protocol Amendment 1 
 
Page 93 
PARAMETER 
GRADE 1 MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING 
Psychiatric Disorders 
(includes anxiety, 
depression, mania, and 
psychosis) 
Specify disorder 
Symptoms with 
intervention not 
indicated OR 
Behavior causing no 
or minimal 
interference with 
usual social & 
functional activities 
Symptoms with 
intervention 
indicated OR 
Behavior causing 
greater than 
minimal 
interference with 
usual social & 
functional 
activities 
Symptoms with 
hospitalization 
indicated OR 
Behavior causing 
inability to perform 
usual social & 
functional activities 
Threatens harm to 
self or others OR 
Acute psychosis OR 
Behavior causing 
inability to perform 
basic self-care 
functions 
Suicidal Ideation or 
Attempt 
Report only one 
Preoccupied with 
thoughts of death 
AND No wish to kill 
oneself 
Preoccupied with 
thoughts of death 
AND Wish to kill 
oneself with no 
specific plan or 
intent 
Thoughts of killing 
oneself with partial 
or complete plans 
but no attempt to 
do so OR 
Hospitalization 
Indicated 
Suicide attempted 
Respiratory 
Acute Bronchospasm 
Forced expiratory 
volume in 1 second or 
peak flow reduced to 
≥ 70 to < 80% OR 
Mild symptoms with 
intervention not 
indicated 
Forced expiratory 
volume in 1 second 
or peak flow 50 to 
< 70% OR 
Symptoms with 
intervention 
indicated OR 
Symptoms causing 
greater than 
minimal 
interference with 
usual social & 
functional 
activities 
Forced expiratory 
volume in 1 second 
or peak flow 25 to 
< 50% OR 
Symptoms causing 
inability to perform 
usual social & 
functional activities 
Forced expiratory 
volume in 1 second 
or peak flow < 25% 
OR Life-threatening 
respiratory or 
hemodynamic 
compromise OR 
Intubation 
Dyspnea or Respiratory 
Distress 
Report only one 
Dyspnea on exertion 
with no or minimal 
interference with 
usual social & 
functional activities 
OR Wheezing OR 
Minimal increase in 
respiratory rate for 
age 
Dyspnea on 
exertion causing 
greater than 
minimal 
interference with 
usual social & 
functional 
activities OR Nasal 
flaring OR 
Intercostal 
retractions OR 
Pulse oximetry 
90 to < 95% 
Dyspnea at rest 
causing inability to 
perform usual 
social & functional 
activities OR Pulse 
oximetry < 90% 
Respiratory failure 
with ventilator 
support indicated 
(e.g., CPAP, BPAP, 
intubation) 
Sensory 
Hearing Loss 
≥ 12 years of age 
NA 
Hearing aid or 
intervention not 
indicated 
Hearing aid or 
intervention 
indicated 
Profound bilateral 
hearing loss 
(> 80 dB at 2 kHz 
and above) OR 
Non-serviceable 
hearing (i.e., >50 dB 
audiogram and 
<50% speech 
discrimination) 


SIGA Technologies, Inc. 
TPOXX 
Protocol No. SIGA-246-024 
Clinical Study Protocol Amendment 1 
 
Page 94 
PARAMETER 
GRADE 1 MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING 
< 12 years of age 
(based on a 1, 2, 3, 
4,6 and 8 kHz 
audiogram) 
> 20 dB hearing loss 
at ≤ 4 kHz 
> 20 dB hearing 
loss at > 4 kHz 
> 20 dB hearing 
loss at ≥ 3 kHz in 
one ear with 
additional speech 
language related 
services indicated 
(where available) 
OR Hearing loss 
sufficient to 
indicate therapeutic 
intervention, 
including hearing 
aids 
Audiologic 
indication for 
cochlear implant and 
additional speech 
language related 
services indicated 
(where available) 
Tinnitus 
Symptoms causing no 
or minimal 
interference with 
usual social & 
functional activities 
with intervention not 
indicated 
Symptoms causing 
greater than 
minimal 
interference with 
usual social & 
functional 
activities with 
intervention 
indicated 
Symptoms causing 
inability to perform 
usual social & 
functional activities 
NA 
Uveitis 
No symptoms AND 
Detectable on 
examination 
Anterior uveitis 
with symptoms OR 
Medical 
intervention 
indicated 
Posterior or 
panuveitis OR 
Operative 
intervention 
indicated 
Disabling visual loss 
in affected eye(s) 
Vertigo 
Vertigo causing no or 
minimal interference 
with usual social & 
functional activities 
Vertigo causing 
greater than 
minimal 
interference with 
usual social & 
functional 
activities 
Vertigo causing 
inability to perform 
usual social & 
functional activities 
Disabling vertigo 
causing inability to 
perform basic 
self-care functions 
Visual Changes 
(assessed from baseline) 
Visual changes 
causing no or minimal 
interference with 
usual social & 
functional activities 
Visual changes 
causing greater 
than minimal 
interference with 
usual social & 
functional 
activities 
Visual changes 
causing inability to 
perform usual 
social & functional 
activities 
Disabling visual loss 
in affected eye(s) 
Systemic 
Acute Allergic Reaction 
Localized urticaria 
(wheals) with no 
medical intervention 
indicated 
Localized urticaria 
with intervention 
indicated OR Mild 
angioedema with 
no intervention 
indicated 
Generalized 
urticaria OR 
Angioedema with 
intervention 
indicated OR 
Symptoms of mild 
bronchospasm 
Acute anaphylaxis 
OR Life-threatening 
bronchospasm OR 
Laryngeal edema 
Chills 
Symptoms causing no 
or minimal 
interference with 
usual social & 
functional activities 
Symptoms causing 
greater than 
minimal 
interference with 
usual social & 
functional 
activities 
Symptoms causing 
inability to perform 
usual social & 
functional activities  
NA 


SIGA Technologies, Inc. 
TPOXX 
Protocol No. SIGA-246-024 
Clinical Study Protocol Amendment 1 
 
Page 95 
PARAMETER 
GRADE 1 MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING 
Cytokine Release 
Syndromee 
Mild signs and 
symptoms AND 
Therapy (i.e., 
antibody infusion) 
interruption not 
indicated 
Therapy (i.e., 
antibody infusion) 
interruption 
indicated AND 
Responds promptly 
to symptomatic 
treatment OR 
Prophylactic 
medications 
indicated for 
≤ 24 hours 
Prolonged severe 
signs and 
symptoms OR 
Recurrence of 
symptoms 
following initial 
improvement 
Life-threatening 
consequences (e.g., 
requiring pressor or 
ventilator support) 
Fatigue or Malaise 
Report only one 
Symptoms causing no 
or minimal 
interference with 
usual social & 
functional activities 
Symptoms causing 
greater than 
Minimal 
interference with 
usual social & 
functional 
activities 
Symptoms causing 
inability to perform 
usual social & 
functional activities 
Incapacitating 
symptoms of fatigue 
or malaise causing 
inability to perform 
basic self-care 
functions 
Fever (non-axillary 
temperatures only) 
38.0 to < 38.6°C or 
100.4 to < 101.5°F 
≥ 38.6 to < 39.3°C 
or ≥ 101.5 to 
< 102.7°F 
≥ 39.3 to < 40.0°C 
or ≥ 102.7 to 
< 104.0°F 
≥ 40.0°C or ≥ 
104.0°F 
Painf (not associated 
with study agent 
injections and not 
specified elsewhere) 
Specify location 
Pain causing no or 
minimal interference 
with usual social & 
functional activities 
Pain causing 
greater than 
minimal 
interference with 
usual social & 
functional 
activities 
Pain causing 
inability to perform 
usual social & 
functional activities 
Disabling pain 
causing inability to 
perform basic 
self-care functions 
OR Hospitalization 
indicated 
Serum Sicknessg 
Mild signs and 
symptoms 
Moderate signs and 
symptoms AND 
Intervention 
indicated (e.g., 
antihistamines) 
Severe signs and 
symptoms AND 
Higher level 
intervention 
indicated (e.g., 
steroids or IV 
fluids) 
Life-threatening 
consequences (e.g., 
requiring pressor or 
ventilator support) 
Underweighth 
> 5 to 19 years of age 
WHO BMI z-score < -
1 to -2 
WHO BMI z-score 
< -2 to -3 
WHO BMI z-score 
< -3 
WHO BMI z-score 
< -3 with 
life-threatening 
consequences 
2 to 5 years of age  
WHO 
Weight-for-height 
z-score < -1 to -2 
WHO Weight-
for-height z-score 
< -2 to -3 
WHO Weight-
for-height z-score 
< -3 
WHO Weight-for-
height z-score < -3 
with life threatening 
consequences 
< 2 years of age WHO  
Weight-for-length 
z-score < -1 to -2 
WHO Weight-
for-length z-score 
< -2 to -3 
WHO Weight-
for-length z-score 
< -3 
WHO Weight-for-
length z-score < -3 
with life threatening 
consequences 
Unintentional Weight 
Loss (excludes 
postpartum weight loss) 
NA 
5 to < 9% loss in 
body weight from 
baseline 
≥ 9 to < 20% loss 
in body weight 
from baseline 
≥ 20% loss in body 
weight from baseline 
OR Aggressive 
intervention 
indicated (e.g., tube 
feeding, total 
parenteral nutrition) 


SIGA Technologies, Inc. 
TPOXX 
Protocol No. SIGA-246-024 
Clinical Study Protocol Amendment 1 
 
Page 96 
PARAMETER 
GRADE 1 MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING 
Urinary  
Urinary Tract 
Obstruction 
NA 
Signs or symptoms 
of urinary tract 
obstruction without 
hydronephrosis or 
renal dysfunction 
Signs or symptoms 
of urinary tract 
obstruction with 
hydronephrosis or 
renal dysfunction 
Obstruction causing 
life-threatening 
consequences 
Site Reactions to Injections and Infusions 
Injection Site Erythema 
or Rednessi 
Report only one 
> 15 years of age 
2.5 to < 5 cm in 
diameter OR 6.25 to < 
25 cm2 surface area 
AND Symptoms 
causing no or minimal 
interference with 
usual social & 
functional activities 
≥ 5 to < 10 cm in 
diameter OR ≥ 
25 to < 100 cm2 
surface area OR 
Symptoms causing 
greater than 
minimal 
interference with 
usual social & 
functional 
activities 
≥ 10 cm in 
diameter OR 
≥ 100 cm2 surface 
area OR Ulceration 
OR Secondary 
infection OR 
Phlebitis OR Sterile 
abscess OR 
Drainage OR 
Symptoms causing 
inability to perform 
usual social & 
functional activities 
Potentially life 
threatening 
consequences (e.g., 
abscess, exfoliative 
dermatitis, necrosis 
involving dermis or 
deeper tissue) 
≤ 15 years of age 
≤ 2.5 cm in diameter 
> 2.5 cm in 
diameter with 
< 50% surface area 
of the extremity 
segment involved 
(e.g., upper arm or 
thigh) 
≥ 50% surface area 
of the extremity 
segment involved 
(e.g., upper arm or 
thigh) OR 
Ulceration OR 
Secondary infection 
OR Phlebitis OR 
Sterile abscess OR 
Drainage 
Potentially life 
threatening 
consequences (e.g., 
abscess, exfoliative 
dermatitis, necrosis 
involving dermis or 
deeper tissue) 
Injection Site 
Induration or Swelling 
Report only one 
> 15 years of age 
Same as for Injection 
Site Erythema or 
Redness, > 15 years 
of age 
Same as for 
Injection Site 
Erythema or 
Redness, 
> 15 years of age 
Same as for 
Injection Site 
Erythema or 
Redness, 
> 15 years of age 
Same as for 
Injection Site 
Erythema or 
Redness, > 15 years 
of age 
≤ 15 years of age  
Same as for Injection 
Site Erythema or 
Redness, ≤ 15 years 
of age 
Same as for 
Injection Site 
Erythema or 
Redness, 
≤ 15 years of age 
Same as for 
Injection Site 
Erythema or 
Redness, 
≤ 15 years of age 
Same as for 
Injection Site 
Erythema or 
Redness, ≤ 15 years 
of age 
Injection Site Pruritus 
Itching localized to 
the injection site that 
is relieved 
spontaneously or in 
< 48 hours of 
treatment 
Itching beyond the 
injection site that is 
not generalized OR 
Itching localized to 
the injection site 
requiring 
≥ 48 hours 
treatment 
Generalized itching 
causing inability to 
perform usual 
social & functional 
activities 
NA 
Laboratory Values - Chemistry 
Acidosis 
NA 
pH ≥ 7.3 to < LLN 
pH < 7.3 without 
life threatening 
consequences 
pH < 7.3 with life 
threatening 
consequences 
Albumin, Low 
(g/dL; g/L) 
3.0 to < LLN 
30 to < LLN 
≥ 2.0 to < 3.0 
≥ 20 to < 30 
< 2.0 
< 20 
NA 
Alkaline Phosphatase, 
High 
1.25 to < 2.5 x ULN 
2.5 to < 5.0 x ULN  
5.0 to < 10.0 x 
ULN 
≥ 10.0 x ULN 


SIGA Technologies, Inc. 
TPOXX 
Protocol No. SIGA-246-024 
Clinical Study Protocol Amendment 1 
 
Page 97 
PARAMETER 
GRADE 1 MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING 
Alkalosis  
NA 
pH > ULN to ≤ 7.5 
pH > 7.5 without 
life threatening 
consequences 
 
pH > 7.5 with life 
threatening 
consequences 
 
ALT or SGPT, High 
Report only one 
1.25 to < 2.5 × ULN 
2.5 to < 5.0 × ULN 
5.0 to < 10.0 × 
ULN 
≥ 10.0 x ULN 
Amylase (Pancreatic) 
or Amylase (Total), 
High Report only one 
1.1 to < 1.5 × ULN 
1.5 to < 3.0 × ULN 
3.0 to < 5.0 × ULN 
≥ 5.0 × ULN 
AST or SGOT, High 
Report only one 
1.25 to < 2.5 × ULN 
2.5 to < 5.0 × ULN 
5.0 to < 10.0 × 
ULN 
≥ 10.0 × ULN 
Bicarbonate, Low 
(mEq/L; mmol/L) 
16.0 to < LLN 
16.0 to < LLN 
11.0 to < 16.0 
11.0 to < 16.0 
8.0 to < 11.0 
8.0 to < 11.0 
< 8.0 
< 8.0 
Bilirubin Direct 
Bilirubinj, 
High 
> 28 days of age 
NA 
NA 
> ULN with other 
signs and 
symptoms of 
hepatotoxicity 
> ULN with life 
threatening 
consequences (e.g., 
signs and symptoms 
of liver failure) 
≤ 28 days of age  
ULN to ≤ 1 mg/dL 
> 1 to ≤ 1.5 mg/dL 
> 1.5 to ≤ 2 mg/dL 
> 2 mg/dL 
Total Bilirubin, High 
> 28 days of age 
1.1 to < 1.6 × ULN 
1.6 to < 2.6 × ULN 
2.6 to < 5.0 × ULN 
≥ 5.0 × ULN 
Calcium, High 
(mg/dL; mmol/L) 
≥ 7 days of age 
10.6 to < 11.5 
2.65 to < 2.88 
11.5 to < 12.5 
2.88 to < 3.13 
12.5 to < 13.5 
3.13 to < 3.38 
≥ 13.5 
≥ 3.38 
< 7 days of age  
11.5 to < 12.4 
2.88 to < 3.10 
12.4 to < 12.9 
3.10 to < 3.23 
12.9 to < 13.5 
3.23 to < 3.38 
≥ 13.5 
≥ 3.38 
Calcium (Ionized), 
High (mg/dL; mmol/L) 
> ULN to < 6.0 
> ULN to < 1.5 
6.0 to < 6.4 
1.5 to < 1.6 
6.4 to < 7.2 
1.6 to < 1.8 
≥ 7.2 
≥ 1.8 
Calcium, Low 
(mg/dL; mmol/L) 
≥ 7 days of age  
7.8 to < 8.4 
1.95 to < 2.10 
7.0 to < 7.8 
1.75 to < 1.95 
6.1 to < 7.0 
1.53 to < 1.75 
< 6.1 
< 1.53 
< 7 days of age  
6.5 to < 7.5 
1.63 to < 1.88 
6.0 to < 6.5 
1.50 to < 1.63 
5.50 to < 6.0 
1.38 to < 1.50 
< 5.50 
< 1.38 
Calcium (Ionized), Low 
(mg/dL; mmol/L) 
< LLN to 4.0 
< LLN to 1.0 
3.6 to < 4.0 
0.9 to < 1.0 
3.2 to < 3.6 
0.8 to < 0.9 
< 3.2 
< 0.8 
Cardiac Troponin I, 
High 
NA 
NA 
NA 
Levels consistent 
with myocardial 
infarction or unstable 
angina as defined by 
the local laboratory 
Creatine Kinase, High 
3 to < 6 × ULN 
6 to < 10 × ULN 
10 to < 20 x ULN 
≥ 20 x ULN 
Creatinine, High 
*Report only one 
(Choose the method that 
selects for the higher 
grade) 
1.1 to 1.3 × ULN 
> 1.3 to 1.8 × ULN 
OR Increase to 1.3 
to < 1.5 × 
participant’s 
baseline 
> 1.8 to < 3.5 × 
ULN OR Increase 
to 1.5 to < 2.0 × 
participant’s 
baseline 
≥ 3.5 × ULN OR 
Increase of ≥ 2.0 × 
participant’s baseline 
Creatinine Clearancek 
or eGFR, Low 
*Report only one 
(Choose the method that 
selects for the higher 
grade) 
NA 
< 90 to 60 ml/min 
or mL/min/1.73 m2 
OR 10 to < 30% 
decrease from 
participant’s 
baseline 
< 60 to 30 ml/min 
or mL/min/1.73 m2 
OR 30 to < 50% 
decrease from 
participant’s 
baseline 
< 30 ml/min or 
mL/min/1.73 m2  OR 
≥ 50% decrease from 
participant’s baseline 
or dialysis needed 


SIGA Technologies, Inc. 
TPOXX 
Protocol No. SIGA-246-024 
Clinical Study Protocol Amendment 1 
 
Page 98 
PARAMETER 
GRADE 1 MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING 
Glucose 
(mg/dL; mmol/L) 
Fasting, High 
110 to 125 
6.11 to < 6.95 
> 125 to 250 
6.95 to < 13.89 
> 250 to 500 
13.89 to < 27.75 
≥ 500 
≥ 27.75 
Nonfasting, High 
116 to 160 
6.44 to < 8.89 
> 160 to 250 
8.89 to < 13.89 
> 250 to 500 
13.89 to < 27.75 
≥ 500 
≥ 27.75 
Glucose, Low 
(mg/dL; mmol/L) 
≥ 1 month of age 
55 to 64 
3.05 to <3.55 
40 to < 55 
2.22 to < 3.05 
30 to < 40 
1.67 to < 2.22 
< 30 
< 1.67 
< 1 month of age  
50 to 54 
2.78 to < 3.00 
40 to < 50 
2.22 to < 2.78 
30 to < 40 
1.67 to < 2.22 
< 30 
< 1.67 
Lactate, High 
ULN to < 2.0 × ULN 
without acidosis 
≥ 2.0 × ULN 
without acidosis 
Increased lactate 
with pH < 7.3 
without life 
threatening 
consequences 
Increased lactate 
with pH < 7.3 with 
life threatening 
consequences 
Lipase, High 
1.1 to < 1.5 × ULN 
1.5 to < 3.0 × ULN 
3.0 to < 5.0 × ULN 
≥ 5.0 × ULN 
Lipid Disorders 
(mg/dL; mmol/L) 
Cholesterol, Fasting, 
High 
≥ 18 years of age 
200 to < 240 
5.18 to < 6.19 
240 to < 300 
6.19 to < 7.77 
≥ 300 
≥ 7.77 
NA 
< 18 years of age  
170 to < 200 
4.40 to < 5.15 
200 to < 300 
5.15 to < 7.77 
≥ 300 
≥ 7.77 
NA 
LDL, Fasting, High 
≥ 18 years of age 
130 to < 160 
3.37 to < 4.12 
160 to < 190 
4.12 to < 4.90 
≥ 190 
≥ 4.90 
NA 
> 2 to < 18 years of age 
110 to < 130 
2.85 to < 3.34 
130 to < 190 
3.34 to < 4.90 
≥ 190 
≥ 4.90 
NA 
Triglycerides, Fasting, 
High 
150 to 300 
1.71 to 3.42 
>300 to 500 
>3.42 to 5.7 
>500 to < 1,000 
>5.7 to 11.4 
> 1,000 
> 11.4 
Magnesiuml, Low 
(mEq/L; mmol/L) 
1.2 to < 1.4 
0.60 to < 0.70 
0.9 to < 1.2 
0.45 to < 0.60 
0.6 to < 0.9 
0.30 to < 0.45 
< 0.6 
< 0.30 
Phosphate, Low 
(mg/dL; mmol/L) 
> 14 years of age  
2.0 to < LLN 
0.65 to < LLN 
1.4 to < 2.0 
0.45 to < 0.65 
1.0 to < 1.4 
0.32 to < 0.45 
< 1.0 
< 0.32 
1 to 14 years of age 
3.0 to < 3.5 
0.97 to < 1.13 
2.5 to < 3.0 
0.81 to < 0.97 
1.5 to < 2.5 
0.48 to < 0.81 
< 1.5 
< 0.48 
< 1 year of age  
3.5 to < 4.5 
1.13 to < 1.45 
2.5 to < 3.5 
0.81 to < 1.13 
1.5 to < 2.5 
0.48 to < 0.81 
< 1.5 
< 0.48 
Potassium, High 
(mEq/L; mmol/L) 
5.6 to < 6.0 
5.6 to < 6.0 
6.0 to < 6.5 
6.0 to < 6.5 
6.5 to < 7.0 
6.5 to < 7.0 
≥ 7.0 
≥ 7.0 
Potassium, Low 
(mEq/L; mmol/L) 
3.0 to < 3.4 
3.0 to < 3.4 
2.5 to < 3.0 
2.5 to < 3.0 
2.0 to < 2.5 
2.0 to < 2.5 
< 2.0 
< 2.0 
Sodium, High 
(mEq/L; mmol/L) 
146 to < 150 
146 to < 150 
150 to < 154 
150 to < 154 
154 to < 160 
154 to < 160 
≥ 160 
≥ 160 
Sodium, Low 
(mEq/L; mmol/L) 
130 to < 135 
130 to < 135 
125 to < 130 
125 to < 130 
121 to < 125 
121 to < 125 
≤ 120 
≤ 120 
Uric Acid, High 
(mg/dL; mmol/L) 
7.5 to < 10.0 
0.45 to < 0.59 
10.0 to < 12.0 
0.59 to < 0.71 
12.0 to < 15.0 
0.71 to < 0.89 
≥ 15.0 
≥ 0.89 
Laboratory Values - Hematology 
Absolute CD4+ Count, 
Low (cell/mm3; cells/L) 
> 5 years of age 
(not HIV infected) 
300 to < 400 
300 to < 400 
200 to < 300 
200 to < 300 
100 to < 200 
100 to < 200 
< 100 
< 100 


SIGA Technologies, Inc. 
TPOXX 
Protocol No. SIGA-246-024 
Clinical Study Protocol Amendment 1 
 
Page 99 
PARAMETER 
GRADE 1 MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING 
Absolute Lymphocyte 
Count, Low 
(cell/mm3; cells/L) 
> 5 years of age 
(not HIV infected) 
600 to < 650 
0.600 × 109 to 
< 0.650 × 109 
500 to < 600 
0.500 × 109 to 
< 0.600 × 109 
350 to < 500 
0.350 × 109 to 
< 0.500 × 109 
< 350 
< 0.350 x 109 
Absolute Neutrophil 
Count, Low 
(cells/mm3; cells/L) 
> 7 days of age 
800 to 1,000 
0.800 × 109 to 
1.000 × 109 
600 to 799 
0.600 × 109 to 
0.799 × 109 
400 to 599 
0.400 × 109 to 
0.599 × 109 
< 400 
< 0.400 × 109 
2 to 7 days of age  
1,250 to 1,500 
1.250 × 109 to 
1.500 × 109 
1,000 to 1,249 
1.000 × 109 to 
1.249 × 109 
750 to 999 
0.750 × 109 to 
0.999 × 109 
< 750 
< 0.750 × 109 
≤ 1 day of age  
4,000 to 5,000 
4.000 × 109to 
5.000 × 109 
3,000 to 3,999 
3.000 × 109 to 
3.999 × 109 
1,500 to 2,999 
1.500 × 109 to 
2.999 × 109 
< 1,500 
< 1.500 × 109 
Fibrinogen, Decreased 
(mg/dL; g/L) 
100 to < 200 
1.00 to < 2.00 OR 
0.75 to < 1.00 × LLN 
75 to < 100 
0.75 to < 1.00 OR 
≥ 0.50 to 
< 0.75 × LLN 
50 to < 75 
0.50 to < 0.75 OR 
0.25 to 
< 0.50 × LLN 
< 50  
< 0.50 OR 
< 0.25 × LLN OR 
Associated with 
gross bleeding 
Hemoglobinm, Low 
(g/dL; mmol/L)n  
≥ 13 years of age 
(male only) 
10.0 to 10.9 
6.19 to 6.76 
9.0 to < 10.0 
5.57 to < 6.19 
7.0 to < 9.0 
4.34 to < 5.57 
< 7.0 
< 4.34 
≥ 13 years of age 
(female only) 
9.5 to 10.4 
5.88 to 6.48 
8.5 to < 9.5 
5.25 to < 5.88 
6.5 to < 8.5 
4.03 to < 5.25 
< 6.5 
< 4.03 
57 days of age to 
< 13 years of age 
(male and female) 
9.5 to 10.4 
5.88 to 6.48 
8.5 to < 9.5 
5.25 to < 5.88 
6.5 to < 8.5 
4.03 to < 5.25 
< 6.5 
< 4.03 
36 to 56 days of age 
(male and female) 
8.5 to 9.6 
5.26 to 5.99 
7.0 to < 8.5 
4.32 to < 5.26 
6.0 to < 7.0 
3.72 to < 4.32 
< 6.0 
< 3.72 
22 to 35 days of age 
(male and female) 
9.5 to 11.0 
5.88 to 6.86 
8.0 to < 9.5 
4.94 to < 5.88 
6.7 to < 8.0 
4.15 to < 4.94 
< 6.7 
< 4.15 
8 to ≤ 21 days of age 
(male and female) 
11.0 to 13.0 
6.81 to 8.10 
9.0 to < 11.0 
5.57 to < 6.81 
8.0 to < 9.0 
4.96 to < 5.57 
< 8.0 
< 4.96 
≤ 7 days of age 
(male and female) 
13.0 to 14.0 
8.05 to 8.72 
10.0 to < 13.0 
6.19 to < 8.05 
9.0 to < 10.0 
5.59 to < 6.19 
< 9.0 
< 5.59 
INR, High 
(not on anticoagulation 
therapy) 
1.1 to < 1.5 × ULN 
1.5 to < 2.0 × ULN 
2.0 to < 3.0 × ULN 
≥ 3.0 × ULN 
Methemoglobin 
(% hemoglobin) 
5.0 to < 10.0% 
10.0 to < 15.0% 
15.0 to < 20.0% 
≥ 20.0% 
PTT, High 
(not on anticoagulation 
therapy) 
1.1 to < 1.66 × ULN 
1.66 to < 2.33 × 
ULN 
2.33 to < 3.00 × 
ULN 
≥ 3.00 × ULN 
Platelets, Decreased 
(cells/mm3; cells/L) 
100,000 to < 125,000 
100.000 x 109 to 
< 125.000 × 109 
50,000 to 
< 100,000  
50.000 × 109 to 
< 100.000 × 109 
25,000 to < 50,000 
25.000 × 109 to 
< 50.000 × 109 
< 25,000 
< 25.000 × 109 
PT, High 
(not on anticoagulation 
therapy 
1.1 to < 1.25 × ULN 
1.25 to < 1.50 × 
ULN 
1.50 to < 3.00 × 
ULN 
≥ 3.00 × ULN 
WBC, Decreased 
(cells/mm3; cells/L) 
> 7 days of age 
2,000 to 2,499 
2.000 × 109 to 
2.499 × 109 
1,500 to 1,999 
1.500 × 109 to 
1.999 × 109 
1,000 to 1,499 
1.000 × 109 to 
1.499 × 109 
< 1,000 
< 1.000 × 109 


SIGA Technologies, Inc. 
TPOXX 
Protocol No. SIGA-246-024 
Clinical Study Protocol Amendment 1 
 
Page 100 
PARAMETER 
GRADE 1 MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING 
≤ 7 days of age  
5,500 to 6,999  
5.500 × 109 to 
6.999 × 109 
4,000 to 5,499 
4.000 × 109 to 
5.499 × 109 
2,500 to 3,999 
2.500 × 109 to 
3.999 × 109 
< 2,500 
< 2.500 × 109 
Urinalysis 
Glycosuria (random 
collection tested by 
dipstick) 
Trace to 1+ or 
≤ 250 mg 
2+ or ˃ 250 to 
≤ 500 mg 
> 2+ or > 500 mg 
NA 
Hematuria (not to be 
reported based on 
dipstick findings or on 
blood believed to be of 
menstrual origin) 
6 to < 10 RBCs per 
high power field 
≥ 10 RBCs per 
high power field 
Gross, with or 
without clots OR 
With RBC casts 
OR Intervention 
indicated 
Life-threatening 
consequences 
Proteinuria (random 
collection tested by 
dipstick) 
1+ 
2+ 
3+ or higher 
NA 
a. 
As per Bazett’s formula. 
b. 
For pruritus associated with injections or infusions, see the Site Reactions to Injections and Infusions section. 
c. 
BMD t and z scores can be found in: Kanis JA on behalf of the World Health Organization Scientific Group (2007). 
Assessment of osteoporosis at the primary health-care level. Technical Report. World Health Organization 
Collaborating Centre for Metabolic Bone Diseases, University of Sheffield, UK. 2007: Printed by the University of 
Sheffield. 
d. 
A pregnancy loss occurring at < 20 weeks gestational age. 
e. 
Definition: A disorder characterized by nausea, headache, tachycardia, hypotension, rash, and/or shortness of breath. 
f. 
For pain associated with injections or infusions, see the Site Reactions to Injections and Infusions section. 
g. 
Definition: A disorder characterized by fever, arthralgia, myalgia, skin eruptions, lymphadenopathy, marked 
discomfort, and/or dyspnea. 
h. 
WHO reference tables may be accessed by clicking the desired age range or by accessing the following URLs: 
http://www.who.int/growthref/who2007_bmi_for_age/en/ for participants > 5 to 19 years of age and 
http://www.who.int/childgrowth/standards/chart_catalogue/en/ for those ≤ 5 years of age. 
i. 
Injection Site Erythema or Redness should be evaluated and graded using the greatest single diameter or measured 
surface area. 
j. 
Direct bilirubin > 1.5 mg/dL in a participant < 28 days of age should be graded as grade 2, if < 10% of the total 
bilirubin. 
k. 
Use the applicable formula (i.e., Cockcroft-Gault in mL/min or Schwartz, MDRD, CKD-Epi in mL/min/1.73m2). Sites 
should choose the method defined in their study and when not specified, use the method most relevant to the study 
population. 
l. 
To convert a magnesium value from mg/dL to mmol/L, laboratories should multiply by 0.4114. 
m. 
Male and female sex are defined as sex at birth. For transgender participants ≥13 years of age who have been on 
hormone therapy for more than 6 consecutive months, grade hemoglobin based on the gender with which they identify 
(i.e., a transgender female should be graded using the female sex at birth hemoglobin laboratory values). 
n. 
The most commonly used conversion factor to convert g/dL to mmol/L is 0.6206. For grading hemoglobin results 
obtained by an analytic method with a conversion factor other than 0.6206, the result must be converted to g/dL using 
appropriate conversion factor for the particular laboratory. 
Source: DAIDS 2017. 
 
 


SIGA Technologies, Inc. 
TPOXX 
Protocol No. SIGA-246-024 
Clinical Study Protocol Amendment 1 
 
Page 101 
 
9.5 
APPENDIX 5: CHANGE HISTORY 
9.5.1 
Protocol Amendment 1 
Protocol Amendment 1 was issued in order to make administrative changes, update exclusion 
criteria noted in the table, update references, remove preterm and term neonate information, 
and to provide clarification regarding meal consumption, fasting, vital signs collection, and 
pregnancy testing.  
Protocol 
Section 
Change 
Rationale 
Throughout 
the protocol 
Minor administrative changes were made. 
 
Synopsis 
Study Design, 
3. Study 
Design and  
9.2 Appendix 
2: Schedule of 
events 
Clarification regarding beverage ingestion: 
…no beverages may be ingested within 3 hours 
before or 3 hours after study drug 
administration; excluding a beverage that is 
being consumed as a part of the required meal. 
Clarification added 
that beverages other 
than water may be 
ingested during 
3 hours before or 
3 hours after taking 
study drug so long as 
they are being 
consumed as part of 
the required meal. 
Synopsis 
Exclusion 
Criteria and 
4.2 Exclusion 
Criteria 
Amended Exclusion Criteria #7: 
Subject has evidence or history of clinically 
significant allergic reaction (excluding seasonal 
allergies); or has evidence or history of 
clinically significant disease, including 
hematological, endocrine, pulmonary, 
gastrointestinal, cardiovascular, hepatic, 
psychiatric, or neurological disease. Exceptions 
to these disease criteria (e.g., stable, mild joint 
disease unassociated with collagen vascular 
disease) may be made following discussions 
with the medical monitor. 
Clarification added to 
allow for subject 
inclusion for those that 
have evidence or 
history of seasonal 
allergies. 


SIGA Technologies, Inc. 
TPOXX 
Protocol No. SIGA-246-024 
Clinical Study Protocol Amendment 1 
 
Page 102 
Protocol 
Section 
Change 
Rationale 
Synopsis 
Exclusion 
Criteria and 
4.2 Exclusion 
Criteria 
Amended Exclusion Criteria #10: 
Subject is 20 years of age or older and has a 
≥30% risk of developing a myocardial 
infarction or coronary death within the next 10 
years using the National Cholesterol Education 
Program’s Risk Assessment Tool: 
https://www.mcw.edu/calculators/ldl-
cholesterol-goal-level. 
The risk calculator was 
updated in order to 
prevent automatic 
elimination of males 
aged 70+ years with 
no other risk 
indicators. Cardiac and 
pulmonary function is 
adequately monitored 
using additional 
inclusion/exclusion 
criteria.  Therefore, 
this criteria was 
amended from ≥10% 
risk to ≥30% risk. 
Synopsis 
Exclusion 
Criteria and 
4.2 Exclusion 
Criteria 
Removed Exclusion Criteria #32: 
Subject is at a high risk of contracting SARS-
CoV-2/COVID-19 infection, including, but not 
limited to, individuals with known close contact 
with: 
a. Anyone residing in, visiting, or working 
at a health care or long-term care 
institution (i.e., long-term care facilities, 
acute care hospitals, rehabilitation 
hospitals, mental health hospitals, 
emergency departments). 
b. Anyone with a known history of 
COVID-19 within 2 weeks prior to study 
entry. 
c. Anyone who traveled outside the United 
States or has recently traveled outside of 
the state in which they will be enrolled 
in the study and has returned from a 
state that is listed on a travel advisory 
list requiring quarantine for any duration 
within 30 days before study entry. 
 
Because the majority 
of the population has 
been vaccinated for 
COVID-19 and the 
sites have their own 
guidelines in place 
regarding COVID-19, 
this exclusion criteria 
was removed. 


SIGA Technologies, Inc. 
TPOXX 
Protocol No. SIGA-246-024 
Clinical Study Protocol Amendment 1 
 
Page 103 
Protocol 
Section 
Change 
Rationale 
Synopsis 
Exclusion 
Criteria and 
4.2 Exclusion 
Criteria 
Amended Exclusion Criteria #34: 
Subject has previously participated in this 
clinical trial.   
Clarification added to 
only prevent subject 
inclusion for those that 
have previously 
participated in this 
study. Other 
tecovirimat study 
enrollment is 
allowable so long as 
all other 
Inclusion/Exclusion 
criteria are met. 
Section 4.3, 
Section 6.2.2 
Clinical 
Laboratory 
Testing and  
9.2 Appendix 
2: Schedule of 
events 
Clarification regarding fasting for fasting lipid 
panel: 
Fasting shall occur for 8 hours prior specimen 
collection. 
Clarify amount of time 
subjects are required to 
fast prior to screening. 
Section 5.2.2 
Study Drug 
Accountability 
Clarification regarding study visit requirements 
for study drug accountability: 
Subjects will be instructed to bring the subject 
diary and all study drug bottles (including 
empty bottles) and unused study drug (in study 
drug bottles) with them to every study visit. 
Clarification for 
subjects to bring all 
bottles (including 
empty) and study drug 
to every study visit.  
Section 6.2 
Clinical 
Laboratory 
Testing 
Clarification regarding clinical laboratory 
testing performed at the Central Laboratory: 
The following clinical laboratory assessments 
will be performed by the PPD Central Lab 
Clarification added to 
clinical laboratory 
testing.   
Section 6.2.2 
Clinical 
Laboratory 
Testing 
Clarification regarding pregnancy testing: 
All positive urine tests will be verified using a 
serum β-human chorionic gonadotropin test. 
Clarification added to 
pregnancy serum and 
urine testing type. 
Section 8 
Reference List 
Reference updated for the TPOXX full 
prescribing information.  
TPOXX prescribing 
information was 
updated. 
Section 8 
Reference List 
Reference updated for the TPOXX investigator 
brochure. 
TPOXX investigator 
brochure was updated. 


SIGA Technologies, Inc. 
TPOXX 
Protocol No. SIGA-246-024 
Clinical Study Protocol Amendment 1 
 
Page 104 
Protocol 
Section 
Change 
Rationale 
9.2 Appendix 
2: Schedule of 
events 
Clarification regarding vital signs testing: 
Vital signs will be measured within 60 minutes 
prior to the first dose of the day and 4 hours 
following the first dose of the day. 
Clarification added for 
predose vital signs.  
9.2 Appendix 
2: Schedule of 
events 
Clarification regarding pregnancy testing: 
A urine pregnancy test will be performed and 
read locally on Day –1 (PK subset) or Day 1 
Predose (Non-PK subset). All other pregnancy 
tests, including screening, are by serum and read 
by the Central Lab. 
Clarification added to 
pregnancy serum and 
urine testing. 
9.4 Appendix 
4: Division of 
Acquired 
Immune 
Deficiency 
Syndrome 
(DAIDS) 
Remove preterm and term neonate DAIDS 
information: 
- 
Preterm neonates should be assessed 
using local laboratory normal ranges. 
- 
Appendix A takes priority over the main 
grading table in all assessments of total 
bilirubin for term and preterm neonates. 
- 
See Appendix A. Total Bilirubin for Term 
and Preterm Neonates6 
Reference to neonate 
grading and Appendix 
A is not applicable to 
this study and has 
therefore been 
removed.  
Appendix 5 
Added Protocol Change History. 
First amendment. 
 




 
 
 
TABLE OF CONTENTS 
 
 
1. 
INTRODUCTION ............................................................................................................ 6 
2. 
STUDY OBJECTIVES..................................................................................................... 6 
2.1. 
PRIMARY OBJECTIVE ........................................................................................ 6 
2.2. 
SECONDARY OBJECTIVE ................................................................................... 6 
3. 
STUDY DESIGN AND DESCRIPTION ........................................................................ 6 
3.1. 
SUBJECT SELECTION ......................................................................................... 8 
3.1.1 
Inclusion Criteria ............................................................................................. 8 
3.1.2 
Exclusion Criteria ............................................................................................ 8 
4. 
GENERAL STATISTICAL CONSIDERATIONS ....................................................... 8 
4.1. 
GENERAL DEFINITIONS ..................................................................................... 9 
4.2. 
SAMPLE SIZE .................................................................................................... 9 
4.3. 
RANDOMIZATION, STRATIFICATION, AND BLINDING ........................................ 9 
4.4. 
ADMINISTRATION OF STUDY MEDICATION ..................................................... 10 
4.5. 
ENDPOINTS ..................................................................................................... 11 
4.5.1 
Safety Endpoints ............................................................................................ 11 
4.5.2 
Pharmacokinetic Endpoints ........................................................................... 11 
4.6. 
ANALYSIS SETS .............................................................................................. 11 
4.5.3 
Intent to Treat (ITT) Population .................................................................... 11 
4.5.4 
Safety Population ........................................................................................... 11 
4.5.5 
Per-Protocol Safety Population ..................................................................... 11 
4.5.6 
Pharmacokinetic (PK) Population ................................................................ 12 
5. 
SUBJECT DISPOSITION ............................................................................................. 12 
5.1. 
DISPOSITION ................................................................................................... 12 
5.2. 
PROTOCOL DEVIATIONS .................................................................................. 13 
5.3. 
INCLUSION AND EXCLUSION CRITERIA ........................................................... 13 
6. 
DEMOGRAPHICS AND OTHER BASELINE CHARACTERISTICS ................... 13 
6.1. 
DEMOGRAPHICS .............................................................................................. 13 
6.2. 
MEDICAL HISTORY ......................................................................................... 13 
7. 
TREATMENTS AND MEDICATIONS ....................................................................... 14 
7.1. 
PRIOR AND CONCOMITANT MEDICATIONS ...................................................... 14 
7.2. 
MEDICAL OR SURGICAL TREATMENT PROCEDURES ........................................ 14 
7.3. 
STUDY TREATMENT ........................................................................................ 14 
7.4. 
MEALS ............................................................................................................ 15 
8. 
ANALYSIS OF PHARMACOKINETICS ................................................................... 15 
8.1. 
COLLECTION SCHEDULE ................................................................................. 15 
8.2. 
DATA HANDLING ............................................................................................ 16 
8.3. 
PLASMA PHARMACOKINETIC PARAMETERS AND DEFINITIONS ....................... 16 
9. 
SAFETY ANALYSIS ..................................................................................................... 18 


 
 
9.1. 
EXTENT OF EXPOSURE .................................................................................... 18 
9.2. 
TREATMENT COMPLIANCE .............................................................................. 18 
9.3. 
ADVERSE EVENTS ........................................................................................... 18 
10.3.1 
Time to First Adverse Event .......................................................................... 18 
10.3.2 
Time to Withdrawal for Any Reason .............................................................. 19 
10.3.3 
Adverse Event Summaries .............................................................................. 19 
9.4. 
CLINICAL LABORATORY EVALUATIONS ......................................................... 20 
9.5. 
VITAL SIGN MEASUREMENTS ......................................................................... 22 
9.6. 
PHYSICAL EXAMINATION ................................................................................ 22 
9.7. 
ELECTROCARDIOGRAMS ................................................................................. 23 
9.8. 
UNSCHEDULED VISITS .................................................................................... 23 
10. 
TIMING OF ANALYSES .............................................................................................. 24 
10.1. 
FINAL ANALYSIS ............................................................................................ 24 
10.2. 
DATA SAFETY MONITORING BOARD (DSMB) ANALYSIS .............................. 24 
11. 
CHANGES IN THE PLANNED ANALYSIS .............................................................. 24 
12. 
REFERENCES ................................................................................................................ 24 
13. 
SCHEDULE OF ASSESSMENTS ................................................................................ 25 
14. 
INDEX OF TABLES AND FIGURES .......................................................................... 32 
15. 
INDEX OF LISTINGS ................................................................................................... 33 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
List of Abbreviations 
λz 
the observed 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 zero to 24 hours 
AUC0-tau 
area under the plasma concentration-time curve during the first dosing interval 
BID 
two times a day 
BLQ 
below the limit of quantification 
Cavg 
average steady-state plasma concentration 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
CLss/F 
apparent clearance; total systemic clearance not corrected for bioavailability (F) 
after multiple dosing at steady state 
Cmin 
minimum observed drug concentration in plasma  
Cmax 
maximum observed drug concentration in plasma  
CRA 
clinical research associate 
CRF 
case report form 
Ctrough 
trough plasma concentration 
CV 
coefficient of variation 
CYP 
cytochromes 
DAIDS 
Division of Acquired Immune Deficiency Syndrome 
DSMB 
Data Safety Monitoring Board 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
ET 
early termination 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IRB 
institutional review board 
ITT 
Intent-to treat 
IWRS 
interactive web response system 
PK 
pharmacokinetic(s) 
PP 
per protocol 
PT 
preferred term 
QTcF 
Fridericia-corrected QT interval  


 
 
Rac 
accumulation ratio 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SOC 
system organ class 
SOP 
standard operating procedure 
TLFs 
tables, listings and figures 
t1/2 
terminal elimination half-life 
TID 
three times a day 
Tmax 
time to maximum observed plasma concentration 
Vz/F 
volume of distribution in the terminal elimination phase not corrected for 
bioavailability (F) after multiple dosing (D28) 
 
 


 
 
1. Introduction 
The purpose of this statistical analysis plan (SAP) is to define and ensure that the data listings, 
summary tables and figures that will be produced, and the statistical methods that will be used are 
complete and appropriate to allow valid conclusions consistent with the study objectives. This SAP 
V2 dated March XX, 2023 is written based on SIGA Protocol: SIGA-246-024, version 2.0, dated 
01 August 2022. 
TPOXX 600 mg (3 × 200-mg capsules) two times a day (BID) for 14 days is the approved dose of 
TPOXX for the treatment of smallpox in patients weighing between 13 kg and less than 120 kg,. 
TPOXX dosing for patients weighing 120 kg or more should be adjusted to 600 mg TPOXX three 
times a day (TID).1 The 28-day TPOXX treatment duration, rather than the 14-day duration, was 
chosen for the postexposure prophylaxis indication as a longer treatment period may be necessary 
to provide protection from smallpox from the time of initial exposure to variola virus until the 
development of protective neutralizing antibodies. This accounts for the 7- to 17-day, 
asymptomatic stage; the subsequent 2- to 3-day, prodromal stage; and finally, the development of 
neutralizing antibodies, which are evident from about the sixth day following the onset of clinical 
symptoms and increase in antibody titer thereafter.  
2. Study Objectives 
2.1. 
Primary Objective 
The primary objective of this study is to determine the safety and tolerability of TPOXX when 
administered orally for 28 days in adult subjects. 
2.2. 
Secondary Objective 
The secondary objective of this study is to describe the PK profile of TPOXX when administered 
orally for 28 days in adult subjects. 
3. Study Design and Description 
 
This is a Phase 3, multicenter, double-blind, randomized, placebo-controlled study to assess the 
safety, tolerability, and PK of oral TPOXX 600 mg when administered for 28 days in adult subjects.  
A total of at least 445 subjects (includes a PK subset of 40 subjects), ages 18 to 80, inclusive, will 
be enrolled and randomly assigned within stratified age groups (18 to 30 years, 31 to 45 years, 
46 to 64 years, and 65 to 80 years) to 1 of 2 treatment groups in an overall randomization of 4:1 
(approximately 356 subjects will receive TPOXX and 89 subjects will receive TPOXX matching 
placebo). There will be 2 dosing regimens based on the subject’s body weight: subjects with a body 
weight of 120 kg or less will be administered either TPOXX 600 mg or placebo two times a day 
(BID), 12 hours apart (±30 minutes); and subjects with a body weight of more than 120 kg will be 
administered TPOXX 600 mg or placebo three times a day (TID), 8 hours apart (±30 minutes). 
The study will consist of a screening period (Day –28 to Day –2), 1 check-in, on-site visits (Day 7, 
Day 14, and Day 21), a dosing complete/ET visit (Day 29), and 2 follow-up telephone calls (Day 42 
[+2 days] and Day 58 [+2 days]). The total duration of the study for each subject, including 
screening, treatment, and follow-up telephone calls will be approximately 86 days,  


 
 
The enrollment goal for the study is to randomly assign a sufficient number of subjects to ensure 
that at least 300 subjects receive at least 92% of the oral TPOXX 600 mg BID or TID dosing 
regimen over the 28-day treatment period. Overall, across all clinical investigative sites, a goal of 
approximately 20% of subjects (i.e., 89 subjects) or more will be enrolled and randomly assigned 
in each age group to ensure a representative investigation of TPOXX safety and PK across age 
groups. The treatment groups will be as follows:  
• Treatment Group 1: An oral dose of 600 mg (3 × 200-mg capsules) TPOXX BID (every 
12 hours [±30 minutes]) for subjects with a body weight of 120 kg or less or TID (every 
8 hours [±30 minutes]) for subjects with a body weight more than 120 kg for 28 days 
(Day 1 to Day 28). 
• Treatment Group 2: An oral dose of placebo (3 capsules identical to TPOXX) BID (every 
12 hours [±30 minutes]) for subjects with a body weight of 120 kg or less or TID (every 
8 hours [±30 minutes]) for subjects with a body weight more than 120 kg for 28 days (Day 
1 to Day 28). 
Subjects that fail to meet any inclusion or meet one or more exclusion criteria prior to study drug 
administration will not be randomized into the study. Under certain circumstances, a subject may 
be terminated from participating in the study based on the opinion of the investigator, the medical 
monitor, the sponsor, the Food and Drug Administration (FDA), and/or the Data Safety Monitoring 
Board (DSMB). 
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: 
 
• Subject is in violation of the protocol. 
• Subject experiences a serious or intolerable AE that in the investigator’s opinion requires 
withdrawal from the study. 
• Subject becomes pregnant. 
• Subject is noncompliant. 
• Subject has laboratory abnormalities for assessments listed in Sections 4.1 or Section 4.2 
that meet grade 3 or grade 4 on the Division of Acquired Immune Deficiency Syndrome 
(DAIDS) AE Grading Table; 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.  
• Subject develops, during the course of the study, symptoms or conditions listed in the 
exclusion criteria.  
• Subject develops laboratory abnormalities listed in the exclusion criteria during the 
course of the study.  
• Subject requires a medication prohibited by the protocol.  
• Subject requests an early discontinuation for any reason.  
• Subject’s primary care provider requests that the subject be withdrawn.  
 
The FDA, SIGA, or the DSMB may request 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 an SAE or intolerable AE, the investigator will confer with the 
medical monitor and 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.  
 
3.1. 
Subject Selection 
The study population will consist of male and female volunteers, aged 18 to 80 years inclusive. 
3.1.1 Inclusion Criteria 
As stated in Protocol Section 4.1. 
3.1.2 Exclusion Criteria 
As stated in Protocol Section 4.2. 
4. General Statistical Considerations 
All statistical analyses will be conducted using statistical analysis system SAS® Version 9.4 or 
higher (SAS Institute, Cary, NC). 
Descriptive statistics for continuous variables will include number of subjects, mean, standard 
deviation (SD), median, minimum, and maximum, unless otherwise noted. For categorical 
variables, frequencies and percentages will be presented.  
All tables, listings, and figures will be presented by treatment and weight. The treatments below 
will be used for presentations: 
• TPOXX 600mg 
• Matching TPOXX Placebo 
 
Unless otherwise indicated, outputs which are summarized by treatment and weight will be 
summarized for each dose level for subjects on active study drug. 
All data listings will be sorted by treatment (TPOXX or placebo), by treatment regimen (BID or 
TID dosing), and subject number. 
Visit Windows 
There are no plans to derive visit windows; visits will be used in the analyses as reported on the 
eCRF. 
Pooling of Sites 
Up to 10 sites in the USA will be used in this study. The PK subset will be enrolled at 1 Phase 1 
unit.  For the remaining sites, a maximum number of subjects will be agreed upon and enrollment 


 
 
will be competitive. Thus major differences in subject enrollment numbers per site are not 
expected, and therefore there will be no inter-subject pooling of data. 
Subgroups 
The effects of age group (18 to 30 years, 31 to 45 years, 46 to 64 years, and 65 to 80 years) used 
for stratification at randomization and site will be investigated for AE and severe AE rates. Time 
to first AE or severe AE and time to withdrawal for any reason will be calculated. 
Study day is relative to first dose of study drug. Study days are calculated with respect to the first 
dose date as below: 
• If the assessment/observation date is on or after the first dose date, then Study 
Day = Assessment/Observation Date – First Dose Date + 1; 
• Otherwise, Study Day = Assessment/Observation Date – First Dose Date. 
Baseline will be defined as the last non-missing assessment (including repeated and unscheduled 
assessments) before the first dose of study drug administration, unless otherwise specified. 
For summary of safety assessments, if there are repeated measurements at a time point, the first 
non-missing assessment at that time point will be used in the summary tables.  
Unscheduled results will not be included in the summary tables, except for determining Baseline, 
but will be presented in data listings. 
The methodology and data handling specifications for PK data are detailed in Section 8. 
4.1. 
General Definitions 
 
Age: Will be calculated as the integer part of the difference between birth date and the date of 
informed consent divided by 365.25. Birth date with missing day will be imputed as day 15 and 
birth data with missing day and month will be imputed as 30-June. 
 
Adverse Event: any newly occurring event or previous condition that has increased in severity 
or frequency since administration of the first dose of study drug. 
4.2. 
Sample Size 
There is no formal sample size calculation for this study. Although the sample size is not based on 
statistical power considerations, administration of TPOXX 600 mg to 300 subjects provides 
approximately 95% probability of observing at least 1 occurrence of any AE if the incidence of 
AEs in the study population is 1% and is considered adequate to provide a reasonable assessment 
of safety and tolerability. A sufficient number of subjects will be randomly assigned to ensure that 
at least 300 subjects receive at least 92% of the doses of the BID or TID dosing regimen of oral 
TPOXX 600 mg over the 28-day treatment period. 
4.3. 
Randomization, Stratification, and Blinding 
Healthy subjects will be randomized to receive:  


 
 
• Treatment Group 1: An oral dose of 600 mg (3 × 200-mg capsules) TPOXX BID (every 
12 hours [±30 minutes]) for subjects with a body weight of 120 kg or less or TID (every 
8 hours [±30 minutes]) for subjects with a body weight more than 120 kg for 28 days 
(Day 1 to Day 28). 
• Treatment Group 2: An oral dose of placebo (3 capsules identical to TPOXX) BID (every 
12 hours [±30 minutes]) for subjects with a body weight of 120 kg or less or TID (every 
8 hours [±30 minutes]) for subjects with a body weight more than 120 kg for 28 days (Day 
1 to Day 28). 
Randomization will occur according to the randomization schedule and will happen before the 
study drug administration on Day 1 after informed consent has been obtained and after it has been 
confirmed that the subject fulfills all eligibility criteria. Subjects will be randomly assigned to 1 of 
2 treatment groups using a 4:1 ratio so that 4 subjects will receive TPOXX and 1 subject will 
receive placebo. This will be based on a randomization schedule prepared by a PPD biostatistician 
before the study. The groups will be stratified by age groups (18 to 30 years, 31 to 45 years, 46 to 
64 years, and 65 to 80 years). 
This study will employ a double-blind study design. Treatment assignment will not be known to 
the subjects, the Sponsor, the investigator, or the staff who are involved in the clinical evaluation 
of the subjects and the analysis of data. The randomization schedule will be generated by an 
unblinded randomization statistician at PPD according to PPD’s standard operating procedures. 
The medical monitor will be responsible for maintaining the blind throughout the study. If a subject 
becomes seriously ill or pregnant during the study, the blind will be broken only if knowledge of 
the administered study drug will affect that subject’s available treatment options. In the event of a 
medical emergency requiring identification of the study drug administered to an individual subject, 
the investigator will make every attempt to contact the medical monitor to explain the need for 
opening the code within 24 hours of unblinding the subject’s randomization assignment. The 
investigator will be responsible for documenting the time, date, reason for the code break, and the 
names of the personnel involved. All unblinding activities will be tracked via an audit trail in 
IWRS. Requests for unblinding of a subject’s randomization assignment will be made through the 
IWRS after consultation with the medical monitor. Subject code breaks by the investigator will 
result in withdrawal of the subject from the study. The date, time, and reason for the unblinding 
must be documented on the appropriate page in the eCRF, and SIGA must be informed as soon as 
possible. The treatment assignment of subjects will remain blinded until all clinical evaluations 
have been completed. Unblinding at the end of the study will occur only by written request from 
the lead statistician to the unblinded randomization statistician and the unblinded IWRS team after 
database lock and confirmation of protocol deviations. The DSMB may request to unblind the 
treatment assignment of a subject or the study at any time. 
4.4. 
Administration of Study Medication 
Study Medication will be provided to subjects in 4 or 6 bottles (depending on weight which 
determines BID or TID daily dosing regimen), which is equivalent to 56 or 84 doses.  Subjects 
will be randomly assigned to receive 4 or 6 bottles each containing 42 capsules of 200 mg 
TPOXX capsules or matching placebo.  Each daily dose will be 3 capsules taken orally twice or 
three times a day for a total of 6 or 9 capsules per day depending upon subject weight.   


 
 
4.5. 
Endpoints 
4.5.1 Safety Endpoints 
The primary outcome measure is the evaluation of the safety and tolerability of twice or three times 
daily oral dosing of TPOXX 600 mg for 28 days through adverse event (AE) findings, clinical 
laboratory tests, vital sign measurements, electrocardiogram (ECG) tests, and physical 
examinations.  The primary endpoint is the AE rate.  Other endpoints include severe AE rate, time 
to first AE and time to withdrawal for any reason. 
4.5.2 Pharmacokinetic Endpoints 
The plasma samples will be collected at specific time points before and after dosing to evaluate 
the appropriate pharmacokinetic (PK) endpoints for TPOXX after treatment with oral TPOXX 600 
mg twice daily or three times daily in the PK subset.  A validated bioanalytical method will be 
used to analyze plasma samples for quantification of TPOXX. For relevant PK timepoints, please 
refer to Section 8.2. 
4.6. 
Analysis Sets 
All populations will be identified and finalized before the database lock. All subjects who are 
randomly assigned are considered study subjects.   
4.6.1 Intent to Treat (ITT) Population 
The Intent-to-Treat (ITT) Population will include all subjects who were randomly assigned to the 
study (i.e., a randomization number and randomization date are present in the database).  
 This population will be used for summaries of subject disposition. 
4.6.2 Safety Population 
 
The Safety Population is defined as all subjects who received at least 1 dose of study drug (TPOXX 
or matching placebo). 
The Safety Population will be used for all summary and analysis of safety endpoints. 
4.6.3 Per-Protocol Safety Population 
 
The Per-Protocol (PP) Safety Population will include all subjects who received at least 92% of the 
600 mg BID or TID dosing regimen of TPOXX or matching placebo. 
If a subject takes less than 92% of study drug, then they will be considered ‘Course Too Short’ but 
will be included in the safety analysis. 
The Per-Protocol Safety Population will also be used for all summary and analyses of safety 
endpoints. 
 


 
 
4.6.4 Pharmacokinetic (PK) Population 
 
The PK Population will include all subjects in the Per-Protocol Safety Population who have taken 
at least 2 doses of study drug in sequence, have sufficient TPOXX plasma concentrations, and who 
have no protocol deviations or other circumstances that would exclude the subject from analysis.   
Potential subject exclusions will be determined on a case-by-case basis before unblinding. For 
example, where subjects experience issues, which may affect exposure to study drug (e.g., emesis, 
dosing errors, etc.), data will be reviewed by the study pharmacokineticist and evaluated for 
exclusion from the PK population on a case-by-case basis. All subjects excluded from the PK 
population will be documented in the data listings. 
All plasma drug concentrations by time profiles will be reviewed by the pharmacokineticist.  
The PK Population will be used for the preparation of PK summaries and analysis.   
5. Subject Disposition 
5.1. 
Disposition 
A disposition table will be provided by treatment for the number and percentage of subjects 
enrolled/randomized, completed, and discontinued together with the reasons for discontinuation.  
This table will also include the number and percentage of subjects recruited into each age group 
(randomization strata) and the number and percentage of subjects included in each analysis 
population will also be presented.   
Informed consent, eligibility, and randomization details and protocol details will be listed for all 
enrolled subjects.   
The following will be summarized for the overall population and by treatment for all subjects. 
• The number of subjects who were enrolled 
• The number of subjects who were randomized 
• The number of subjects who received each treatment 
• The number of subjects who completed the study treatment 
• The number of subjects who did not complete the study treatment 
• The number of subjects who completed the study 
• The number of subjects who did not complete the study (both overall and according to 
reasons for discontinuation from the study) 
• The number of subjects in each analysis population 
 
Subject disposition will be summarized by dose level and overall based on ITT population using 
frequency distribution or descriptive statistics. Subjects who complete, withdraw consent, or are 
terminated early from the study and the associated reasons will be summarized using frequency 
distribution. 
Baseline demographic and background variables will be summarized by treatment for the ITT, 
Safety, PP Safety, and PK Populations. The demographics table will also be summarized overall 


 
 
and by age group as per the stratification used in randomization. For treatment-related tables and 
listings, the data will be summarized by BID or TID study drug dosing regimen. 
5.2. 
Protocol Deviations 
Protocol deviations will be collected during monitoring visits. All protocol deviations are to be 
recorded in the Clinical Trial Management System (CTMS) with the indication of whether these 
are major.  These data will be listed including the assignment of minor or major.  Major deviations 
are defined as those that may have an impact on subject safety or the validity of the study data (this 
should be noted in the Clinical Monitoring Plan).  The assignment is finalized prior to unblinding.   
Major protocol deviations will be summarized overall. All protocol deviations will be presented in 
a data listing, including the categorization of the deviation as major or minor. 
5.3. 
Inclusion and Exclusion Criteria 
All inclusion/exclusion criteria deviations recorded in the electronic case report form (eCRF) will 
be presented in a data listing. 
6. Demographics and Other Baseline Characteristics 
6.1. 
Demographics 
The descriptive summaries of demographic and baseline characteristics will be presented for the 
Safety, PP Safety and PK Populations.  The demographics table will also be summarized overall 
and by age category as per the stratification used in randomization. 
For all ITT subjects, demographic data to be summarized include: age (years), gender, race, height 
(cm), and weight (kg) at screening, and ethnicity. A subject’s age in years is calculated using the 
date of the informed consent and date of birth. Age (years) and baseline weight (kg) will be 
summarized using descriptive statistics. The number and percentage of subjects by race (American 
Indian or Alaska Native, Asian, Black or African American, Native Hawaiian or Other Pacific 
Islander, and White), ethnicity (Hispanic or Latino, Not Hispanic or Latino). Percentages will be 
based on the total number of subjects in the Safety Population. 
Subject demographic and baseline characteristics will be presented in a data listing. 
6.2. 
Medical History 
Previous and concurrent diseases/conditions will be listed for all ITT subjects sorted by treatment 
group, subject, and start date.  A complete medical history will be obtained, including recreational, 
prescription drug use, over-the-counter drug use, nicotine and alcohol use, and past 
hospitalizations.  
Medical history will be coded using the Medical Dictionary for Regulatory Activities (MedDRA, 
version to be delineated in the clinical study report [CSR]). 
Medical history will be presented in a data listing. 


 
 
7. Treatments and Medications 
7.1. 
Prior and Concomitant Medications 
Medications taken are to be recorded for each subject from screening through day 42 or Day 58 
for subjects with any SAEs.  Medications that stop within 30 days of the first dose of study drug 
will be classified as prior medication. Medications that start on or after the first dose of study 
drug will be classified as concomitant. If a medication starts before the first dose of study drug 
and stops on or after the first dose of study drug, then the medication will be classified as both 
prior and concomitant. 
Concomitant medications taken by subjects will be recorded at each study visit up to the follow-
up telephone call on Day 42. Concomitant medications related to SAEs will be collected and 
recorded at the Day 58 follow-up telephone call. Subjects will be instructed to record 
concomitant medications in the subject diary. 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 that meets exclusion criteria is taken during the study, 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. 
All medications will be listed for all safety subjects by treatment group and dosing regimen, subject 
and start date, and those taken between Day 1 post-dose through to Day 28, i.e., concomitant will 
be indicated.  See SAP Section 4.0 which describes how to deal with partial dates when 
determining whether a medication is concomitant or prior.  Any prior medication will be flagged 
in the listings.  Prohibited medication are indicated in section 4.2 of the protocol.  Any subject 
taking a prohibited medication will be considered a protocol deviator. Prohibited medications will 
also be flagged in the data listing.  
Prior and concomitant medications will be summarized overall for all subjects by treatment. 
Prior and concomitant medications and therapies will be coded using the latest version of the World 
Health Organization Drug Dictionary. 
All prior and concomitant medications will be presented in a data listing. 
7.2. 
Medical or Surgical Treatment Procedures 
Medical or surgical treatment procedures will be presented in a data listing. 
7.3. 
Study Treatment 
The investigational drug administration and drug accountability data will be summarized by 
treatment and treatment regimen and presented in the data listings.  Visit name, study treatment, 
date and time of administration, route of administration, actual dose, amount of drug dispensed 
and adjusted, as well as reason for adjustment, and TPOXX concentration will be recorded. 
 


 
 
7.4. 
Meals 
Subjects will receive a subject diary where they’ll keep track of meal consumption. Meal data, 
which includes time of meal and whether or not the required meal was eaten will be summarized 
by treatment arm.  
 
Meal data will be presented in a data listing.  
 
8. Analysis of Pharmacokinetics 
The ITT Population will be used for the presentation of subjects in all subject listings. The PK 
population will be used for the pharmacokinetic analysis. Pharmacokinetic tables, mean figures, 
and all statistical analyses will be presented using data from the PK population. 
8.1. 
Collection Schedule 
Serial blood samples will be collected at the following time points for PK assessment:  
• BID Dosing (Subjects weighing 120 kg or less) 
o Day 1: Before the first dose (0 hour) and at 2, 4, 6, 8, 10, 12 (before the second 
dose), 14, 16, 18, 20, 22, and 24 hours (before the first dose on Day 2)  
o Day 14: Before the first dose (0 hour) 
o Day 28: Before the first dose (0 hour) and at 2, 4, 6, 8, 10, 12 (before the second 
dose on Day 28), 14, 16, 18, 20, 22, 24 (Day 29, AM), 48 (Day 30, AM), and 72 
(Day 31, AM) hours after the first dose on Day 28 
• TID Dosing (Subjects weighing more than 120 kg) 
o Day 1: Before the first dose (0 hour) and at 2, 4, 6, 8 (before the second dose), 10, 
12, 14, 16 (before the third dose), 18, 20, 22, and 24 hours (before the first dose 
on Day 2) 
o Day 14: Before the first dose (0 hour) 
o Day 28: Before the first dose (0 hour) and at 2, 4, 6, 8 (before the second dose), 
10, 12, 14, 16 (before the third dose), 18, 20, 22, 24 (Day 29, AM), 48 (Day 30, 
AM), and 72 (Day 31, AM) hours after the first dose on Day 28 
For PK blood samples, the acceptable window for collection from the scheduled collection time 
point will be as follows: ±15 minutes from 0 to 24 hours (except where samples are collected 
predose) and ±60 minutes from 48 to 72 hours. 
Individual plasma concentrations and time deviation data will be presented in data listings.  
Plasma concentration data will be summarized using descriptive statistics (number of 
observations, arithmetic mean, SD, CV, median, minimum, and maximum) by study day, time 
point, and study drug dosing regimen.   
Individual plasma concentrations versus nominal time will be plotted on both linear and semi-
logarithmic scales. Mean plasma concentrations versus scheduled time will be plotted by study 
day and study drug dosing regimen on both linear and semi-logarithmic scales.  


 
 
8.2. 
Data Handling 
Data rounding specifications for PK data are documented in the PK table, listing, and figure 
shells.  
Plasma concentrations that are below the limit of quantification (BLQ) will be replaced by zero 
for calculation of concentration descriptive statistics. Mean BLQ concentrations will be 
presented as BLQ, and the SD and coefficient of variation (CV) will be reported as not 
applicable. Missing concentrations will be excluded from the calculations. 
Non-compartmental PK parameters for TPOXX will be calculated. Actual sampling times will 
be used in the determination of the individual PK parameters. 
Handling of Dropouts or Missing Data 
Missing concentration data for all subjects who take scheduled study drug treatment will be 
considered as non-informative missing and will not be imputed. 
The following rules will apply for the derivation of all kinds of AUCs: 
• Concentration values that are BLQ for pre-dose samples will be treated as zero. 
• The sampling time relative to dosing for pre-dose samples will also be treated as zero. 
• Concentration values that are BLQ before the first quantifiable concentration will be 
treated as zero. 
• Post-dose BLQ values after the first quantifiable time point that are flanked or followed 
by measurable concentrations will be set to half the value of BLQ. 
• Post-dose BLQ value after first quantifiable time point that are not followed by 
measurable concentrations will be replaced by zero. 
If the actual time of sampling is missing, the nominal time may be used. 
No further imputation will be applied to any missing values. 
8.3. 
Plasma Pharmacokinetic Parameters and Definitions 
Plasma concentration-time data will be analyzed by non-compartmental analysis using Phoenix® 
WinNonlin® Version 8.0 or higher (Certara USA, Inc., Princeton, NJ). The following PK 
parameters will be calculated for TPOXX, where data permit: 
Cmax 
Maximum observed drug concentration in plasma, reported separately 
for each dose. 
Cavg 
Average steady-state drug concentration in plasma, calculated as: AUCtau 
/ tau (Day 28 only) 
Ctrough 
Trough plasma concentration (Day 28 only). 
Cmin 
Minimum observed drug concentration in plasma (Day 28 only). 
Tmax 
Time of maximum observed drug concentration in plasma. 
AUC0-24 
Area under the plasma concentration-time curve (AUC) from time 0 to 
24 hours, calculated using the linear trapezoidal rule. 


 
 
AUCtau 
AUC from time zero to tau where tau is the 8-hour or 12-hour dosing 
interval following the first dose, calculated using the linear trapezoidal 
rule 
AUC(0-last) 
AUC from time 0 to the last measurable observed concentration (Ct), 
calculated using the linear trapezoidal rule (Day 28 only). 
λz 
Observed elimination rate constant, where λz is the magnitude of the 
slope of the linear regression of the log concentration versus time profile 
during the terminal phase. (Day 28 only). 
t1/2 
Apparent terminal elimination half-life, calculated as: ln (2) / λz. (Day 28 
only). 
CLss/F 
Apparent total body clearance, calculated as: Dose / AUCtau (Day 28 
only). 
Vz/F 
Apparent volume of distribution during the terminal phase, calculated as: 
Dose / [λz * AUCtau] (Day 28 only). 
RacCmax 
Accumulation ratio based on Cmax, calculated as: Cmax (following first 
dose on Day 28) / Cmax (following first daily dose on Day 1). 
RacAUC 
Accumulation ratio based on AUC, calculated as: AUCtau (following first 
dose on Day 28) / AUCtau (following first daily dose on Day 1). 
Fluctuation 
Calculated as: (Cmax – Ctau) / Ctau * 100 (Day 28 only). 
In addition to the above PK parameters, which will be listed and summarized, the following 
parameters will also be listed to document the selection of data points used to estimate t1/2 using 
non-compartmental procedures: 
Number 
points 
Number of data points used to estimate λz; a minimum of 3 data points 
must be used, and Cmax must not be included (Day 28 only). 
λz lower 
Lower bound used for the estimation of λz (Day 28 only). 
λz upper 
Upper bound used for the estimation of λz (Day 28 only). 
Span 
Number of elapsed half-lives over which λz is estimated, calculated as 
(λz upper – λz lower) / t½. (Day 28 only) 
Rsq 
r2, the coefficient of determination (goodness of fit statistic); λz and all 
associated parameters will only be reported where r2 ≥ 0.80. (Day 28 
only) 
Actual sampling times will be used for the estimation of all matrix PK parameters, and all 
concentrations will be included in the analysis (including concentrations collected outside 
predefined collection windows).  
Plasma PK parameters will be presented in data listings and summarized separately using 
descriptive statistics (number of observations, arithmetic mean, SD, CV, geometric mean, 


 
 
geometric SD, geometric CV, median, minimum, and maximum) by study day and study drug 
dosing regimen. Tmax will be summarized using number of observations, median, minimum, and 
maximum only. 
9. Safety Analysis 
The Safety Population and the Per-Protocol Safety Population will be used for the safety data 
summaries and analysis. All safety data collected will be listed. The safety and tolerability data 
summaries will be presented separately for the Safety Population and the PP Safety Population and 
will also be presented by BID and TID TPOXX/matching placebo dosing regimen.  Safety will be 
assessed on the basis of AE reports, clinical laboratory data, vital signs, ECG parameters and 
physical examinations. 
For all subjects that discontinued, data will be summarized by treatment group and dosing regimen, 
and reason for discontinuation. 
9.1. 
Extent of Exposure 
All derived exposure variables and variables recorded on the eCRF will be listed by subject 
number. 
9.2. 
Treatment Compliance 
Compliance will be derived for each subject and listed with exposure data.   
% Compliance= (Number of capsules dispensed- Sum of number of capsules returned and lost) 
/(Number of capsules dispensed)X 100 
Percentage compliance will be summarized by treatment group and dosing regimen using statistics 
for continuous variables, and the number of percentages of subjects achieving at least 92% 
compliance will be summarized by treatment group and dosing regimen. 
9.3. 
Adverse Events 
The primary objective of this study is to determine the safety and tolerability of TPOXX when 
administered orally for 28 days in adult subjects. The overall AE rate in the Safety Population and 
the Per-Protocol Safety Population will be compared between treatment groups using a stratified 
Mantel-Haenszel test accounting for age (18 to 30 years, 31 to 45 years, 46 to 64 years, and 65 to 
80 years).  If expected cell counts are less than 5, then Fisher’s extract test will be applied.  The 
AE rate is the number of subjects who report at least 1 post-dose AE expressed as a proportion of 
the number of subjects in the Safety Population and the Per-Protocol Safety Population.  An exact 
unadjusted 95% confidence interval (CI), calculated using the Clopper-Pearson method, will be 
given for each treatment group.  For the difference in AE rates between the treatment groups, a 
continually corrected exact 95% CI around the difference will be calculated.  In addition, the 
Mantel-Haenszel adjusted odds ratio and 95% Cis from the stratified analysis will be presented. 
9.3.1 Time to First Adverse Event 
Time to first AE is defined as the duration from start of the treatment to the first recorded post-dose 
AE.  If the subject does not have an AE, time to first event will be censored at the date of the last 
adequate assessment; this is expected to be on the Day 42 (+2 day) Follow-up Telephone Call.   


 
 
Time to First AE (days) = (Date of first AE – Date of first dose) +1 
Time to first AE will be analyzed using Kaplan Meier (KM) quartile estimates along with 2 sided 95% 
CIs.  Treatment groups will be compared using the log rank test stratified by age group and clinical 
investigative site. Statistical significance will be assessed at the 0.5 level.  A summary table will be 
produced.   
If a subject does not experience any AE during the study, the time to first AE will be censored at the 
date of study completion. 
9.3.2 Time to Withdrawal for Any Reason 
Time to Withdrawal for Any Reason is defined as the duration from start of treatment to study 
withdrawal for any reason. If the subject does not discontinue from the study, time to withdrawal for 
any reason will be censored at the date of study completion; this is expected to be the Day 42 (+ 2 
days) Follow-up Telephone Call.   
Time to Withdrawal for Any Reason (days) = (Date of study withdrawal – Date of first dose) + 1 
Time to Withdrawal for Any Reason will be analyzed as described above for the time to first AE. 
If a subject does not discontinue or withdraw from the study, the time to discontinuation will be 
censored at the date of study completion. 
9.3.3 Adverse Event Summaries 
An adverse event (AEs) will include any newly occurring event or previous condition that has 
increased in severity or frequency since administration of the first dose of study drug.  If there are 
partial AE start date and times, an AE will be date/time of onset on or after the time of first dose 
of study medication on Day 1 to Day 42 (+2 day) Follow-up Telephone Call. 
Adverse events will be coded by preferred term (PT) and system organ class (SOC) using 
MedDRA (version to be delineated in the CSR). 
Each AE will be graded for severity and classified into one of five categories according to Division 
of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric AEs (protocol Appendix 
4):  Grade 1 (mild), Grade 2 (moderate), Grade 3 (severe), Grade 4 (life threatening), and Grade 5 
(death).   
Each AE is assessed for relationship to study drug. Terms to describe the degree of causality 
between a study drug and an event are definitely, probably, possibly, unlikely related or not related. 
If relationship to study drug is missing, it will be regarded as definitely related for the purposes of 
data summaries.   
Frequency of AEs will be calculated for each system organ class, by preferred term and treatment 
group for the number of subjects reporting the event for the Safety Population and the Per-Protocol 
Safety Population. 
Each AE will be counted only once per subject at the preferred term level. 


 
 
For summaries of AEs by system organ class, preferred term, maximum severity and treatment the 
rule is as follows:  if a subject experiences more than one episode of an AE, the subject is counted 
only once by the maximum severity of the episode (preferred term).  If a subject has more than 
one AE within a system organ class, the subject is counted only once in that system organ class.  
Similarly, when study drug relationship is presented, the strongest relationship to study drug is 
used for AEs mapping to the same preferred term, or within a system organ class. 
Summaries will be ordered by descending frequency of SOC and then, within a SOC, by overall 
descending frequency of PT for the TPOXX group. 
The following AE tables will be produced: 
• An Overall summary of the number of events and number and percentage of subjects 
reporting the following: 
o All AES 
o Serious AEs 
o Treatment-related AEs 
o AEs leading to early study discontinuation and  
o AEs leading to death 
• AEs overall by system organ class and preferred term 
• AEs by maximum severity, overall and by system organ class and preferred term 
• AEs by maximum relationship to study treatment, overall and by system organ class and 
preferred term 
• Treatment-related AEs, overall and by system organ class and preferred term 
• Serious AEs, overall and by system organ class and preferred term. 
 
In general, all AE tables will show the number and percentage of subjects with an event. The 
number of events overall by treatment group and dosing regimen will also be included. 
A listing of all AEs will provide details including system organ class, preferred term, verbatim 
term, whether treatment was emergent or not, severity, relationship to treatment, onset and 
resolution date and time, duration (in days for any AEs lasting longer than 24 hours, in hours 
otherwise, derived as stop date and time – start date and time), action and outcome.  Similar listings 
will be presented for SAEs, AEs with Grade 3 or higher, AEs with a fatal outcome (or Grade 5) 
and AEs leading to early withdrawal.   
Toxicity grades for laboratory tests will be determined according to the DAIDS AE Grading Table2. 
The maximum post-baseline grade increase from baseline grade will be summarized by treatment 
group and dosing regimen and overall for the safety population and PP safety population using 
frequency and percentage of subjects with increase to grade 1, 2, 3, 4, 1 to 4, 2 to 4, and 3 to 4, 
respectively. 
All AEs will be presented in a data listing. 
9.4. 
Clinical Laboratory Evaluations 
The following laboratory tests 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, creatinine clearance 
(calculated(a)), gamma-glutamyltransferase, globulin, glucose, lactate 
dehydrogenase, phosphorus, potassium, sodium, total protein, and 
uric acid 
Urinalysis 
Appearance, bilirubin, blood, color, glucose, ketones, leukocyte 
esterase, microscopy (performed if dipstick is ≥1+; includes bacteria, 
casts, crystals, epithelial cells, red blood cells, and white blood 
cells), nitrites, pH, protein, specific gravity, and urobilinogen. 
 
(a) Creatinine clearance will be calculated using the Cockcroft-Gault formula:  
Creatinine clearance (mLmin ⁄) = [140 −𝑎𝑔𝑒(𝑦𝑒𝑎𝑟𝑠] 𝑥 𝑤𝑒𝑖𝑔ℎ𝑡(𝑘𝑔)
72 𝑥 𝑠𝑒𝑟𝑢𝑚 𝑐𝑟𝑒𝑎𝑡𝑖𝑛𝑒 (𝑚𝑔
𝑑𝐿)
{𝑥 0.85 𝑖𝑓 𝑓𝑒𝑚𝑎𝑙𝑒} 
The hematology, serum chemistry, and urinalysis tests will be performed at the time points 
indicated in the schedule of assessments (schedules of assessments can be found in Section 13. 
Glycosylated hemoglobin and a fasting lipid panel including cholesterol (total, high-density 
lipoprotein, calculated low-density lipoprotein, and triglycerides) will be performed at screening. 
For women of childbearing potential, serum pregnancy test will be performed at the screening visit 
and analysed by PPD Central Lab. A urine pregnancy test will be performed and read locally at 
check-in on Day -1 (PK subset) or predose on Day 1 (Non-PK subset). Serum pregnancy tests will 
be read by PPD Central Lab at the time points indicated in the schedules of events (Section 13). 
All positive urine pregnancy tests will be verified using the ß-human chorionic gonadotropin test. 
For postmenopausal women, a serum follicle-stimulating hormone test will be performed at 
screening.  
All clinical laboratory test results will be presented in the data listings. Laboratory values that are 
outside of the normal reference range will be flagged in the data listings. 
Actual results and change from baseline for hematology, serum chemistry and urinalysis at each 
time point will be summarized for the Safety and PP Safety Populations by treatment group and 
dosing regimen at each time point using descriptive statistics. Shift from baseline in terms of 
low/normal/high for hematology and serum chemistry tests, and in terms of normal/abnormal for 
urinalysis tests will be summarized for the safety population.  
A urine drug screen for alcohol, cotinine, 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 sent to the central lab. 
Day –1 (Check-in - PK Subset or Day 1 (Predose - Non-PK Subset) (Section 13): 
A urine drug screen for cotinine, amphetamines (including methamphetamines and 
ecstasy/methylenedioxymethamphetamine), 
barbiturates, 
benzodiazepines, 
cannabinoids 
(including tetrahydrocannabinol), cocaine metabolites, and opiates (including heroin, codeine, and 
oxycodone) will be performed and read locally. Blood alcohol will be tested using a breathalyzer 
device at the clinical investigative site.  
Abnormal clinical laboratory values will be flagged as either high or low (or normal or abnormal) 
based on the reference range for each laboratory parameter. The investigator will determine 
whether any of the abnormally high or low results are clinically significant or not clinically 
significant. 
Toxicity grades for laboratory tests will be determined according to the DAIDS AE Grading Table2. 
Actual values and changes from baseline for clinical laboratory test results, will be summarized 
for Safety and PP Safety Populations and by treatment group and dosing regimen at each time 
point using descriptive statistics. 
9.5. 
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 (Section 13). 
Vital sign measurements will include systolic and diastolic blood pressures, heart rate, respiratory 
rate, and body temperature.   
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 (e.g., 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.  
Summary tables presenting observed values and changes from baseline will be summarized for 
Safety and PP Safety populations and by treatment group and dosing regimen at each time point 
using descriptive statistics. 
All vital sign data will be presented in a data listing. All vital signs, body weight, and height 
measurements will be presented in a data listing.  
9.6. 
Physical Examination 
Full physical examinations will be performed at the time points indicated in the schedules of events 
(Section 13) and will include, at minimum, 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 on Day 31 (PK subset only) as well 
as unscheduled physical examinations at the discretion of the investigator, if necessary, to evaluate 
AEs or clinical laboratory abnormalities.  
Height and weight will be measured at screening only. 
Physical examination results will be presented in a data listing. 
9.7. 
Electrocardiograms 
A standard 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 (Section 13).  
Electrocardiogram assessments will include comments on whether the tracings are normal, 
abnormal, indeterminate, not evaluable and unknown. The following parameters will be measured 
and reported: heart rate; PR interval, QT intervals; QT interval corrected using Fridericia’s 
formula; QRS duration and RR interval. 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 (e.g., 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. 
Summaries will be presented separately for the Safety Population and the PP Safety Population 
and will also be presented by treatment and dosing regimen. ECG tables presenting observed 
values and changes from baseline will be presented for numeric results. Changes from baseline to 
each scheduled post baseline visit will be presented. 
All ECG data will be presented in a data listing. 
9.8. 
Unscheduled Visits 
Clinical investigative sites will provide subjects with the contact information for the study site 
personnel. Subjects are free to contact study site personnel at any time, and the clinical 
investigative site may require an unscheduled visit for the purpose of physical examinations, 
laboratory tests, etc. Unscheduled visits will be documented by study site personnel in the source 
document. Unscheduled procedures and laboratory tests and results will also be recorded in the 
eCRF. 


 
 
10. Timing of Analyses 
10.1. Final Analysis 
 
The primary analysis of safety and pharmacokinetics is planned after all subjects complete the 
final study visit or terminate early from the study and the data base has been hard locked. 
10.2. Data Safety Monitoring Board (DSMB) Analysis 
 
An independent DSMB will review descriptive summaries of accumulating safety data at least 4 
times during the course of the study as described in Protocol Section 9.3.3.1.4.  Further 
description of the DSMB analyses can be found in the DSMB Charter. Data summaries for the 
DSMB will have dummy treatment and/or subject codes assigned to maintain the study blind.   
 
Interim Analysis:  No formal interim analysis is planned for this study.  
 
11. Changes in the Planned Analysis 
Protocol version 1.0, dated 04 NOV 2021, states that “the relationship of treatment group, age, 
clinical investigative site, and their interactions on overall AE rate will also be investigated using 
a logistic regression model…”. This is an outcome that will not be presented in the TLFs.  
Any further changes from this SAP and the protocol will be documented in the CSR for this 
study. 
12. References 
 
1. TPOXX (tecovirimat) capsules for oral use [full prescribing information]. SIGA 
Technologies, Inc. Corvallis (OR); 2022, 24 p.  
2. Division of AIDS (DAIDS), National Institute of Allergy and Infectious Diseases, 
National Institutes of Health, US Department of Health and Human Services. Division of 
AIDS (DAIDS) table for grading the severity of adult and pediatric adverse events. July 
2017 [cited 2020 Aug 18]. Available from: 
https://rsc.niaid.nih.gov/sites/default/files/daidsgradingcorrectedv21.pdf.  
3. SIGA Technologies, Inc. TPOXX (tecovirimat). Investigator’s brochure, 18th ed. 
Corvallis (OR); 2022. 112 p.  
4. Department of Health and Human Services (DHHS), Food and Drug Administration 
Center for Drug Evaluation and Research (US). Guidance for Industry: Bioanalytical 
Method Validation. May 2018 [cited 2020 Aug 18]. Available from: 
https://www.fda.gov/media/70858/download.  


 
SIGA Technologies, Inc. 
Statistical Analysis Plan, Version 2.0 
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Date Issued: 13 APR 2023 
 
 
 
13. Schedule of Assessments 
Table 13-1 Schedule of Events: Pharmacokinetic Subset Study Subjects 
Period 
Screenin
g 
Check-
in 
Treatment 
PK Sampling 
Follow-up 
Procedure(a) 
Day –28 to –2 
–1 
1 
2 
3 to 
6 
7 
8 to 
12 13 14 
15 
to 
20 
21 
22 to 
26 
27 28 
Dosing 
Complet
e/ET 
Visit 29  30 31 
Telephone 
Call  
42 
(+2 days) 
SAE 
Telephone 
Call  
58 
(+2 days) 
Admission to clinic 
 
X 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
Discharge from 
clinic(a) 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
criteria 
X 
X(b) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
X(c) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical 
examination(d) 
X 
X 
 
 
 
X 
 
 
X 
 
X 
 
 
 
X 
 
X 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height and weight 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serology (HBsAg, 
HCV, and HIV) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital sign 
measurements(e) 
X 
X 
X(f) 
 
 
X 
 
 
X(f) 
 
X 
 
 
 
X 
 
X 
 
 
Drug/alcohol/cotinin
e screen(g) 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Glycosylated 
hemoglobin 
(HbA1c) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Fasting lipid panel(h) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical laboratory 
testing(i) 
X 
X 
 
 
 
X 
 
X 
 
 
X 
 
 
 
X 
 
 
 
 
Serum or urine 
pregnancy test(j) 
X 
X 
 
 
 
X 
 
X 
 
 
X 
 
 
 
X 
 
 
 
 


 
SIGA Technologies, Inc. 
Statistical Analysis Plan, Version 2.0 
Protocol: SIGA-246-024 
Date Issued: 13 APR 2023 
 
 
 
Period 
Screenin
g 
Check-
in 
Treatment 
PK Sampling 
Follow-up 
Procedure(a) 
Day –28 to –2 
–1 
1 
2 
3 to 
6 
7 
8 to 
12 13 14 
15 
to 
20 
21 
22 to 
26 
27 28 
Dosing 
Complet
e/ET 
Visit 29  30 31 
Telephone 
Call  
42 
(+2 days) 
SAE 
Telephone 
Call  
58 
(+2 days) 
Serum follicle-
stimulating 
hormone(k) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
12-lead ECG(l) 
X 
X 
X 
 
 
X 
 
 
X 
 
X 
 
 
 
X 
 
 
 
 
Randomization 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Meal(m) 
 
 
X 
X 
 
 
 
X 
X 
 
 
 
X 
X 
 
 
 
 
 
Administration of 
study drug(n) 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
Dispense study drug 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Collect study drug 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
Study drug 
instructions 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pharmacokinetic 
sampling(o) 
 
 
X 
X 
 
 
 
 
X 
 
 
 
 
X 
X(p) 
X X 
 
 
Subject diary 
dispensing(q) 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Subject diary review 
 
 
 
 
 
X 
 
X 
 
 
X 
 
X 
 
 
 
 
 
 
Subject diary 
collection 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
AEs/SAEs(r) 
 
 
X 
X 
X 
Prior/concomitant 
medications(s) 
X 
X 
X 
X 
Abbreviations: AE, adverse event; ECG, electrocardiogram; ET, early termination; HBsAg, hepatitis B surface antigen; HCV, hepatitis C virus; HIV, 
human immunodeficiency virus; PK, pharmacokinetic; SAE, serious adverse event. 
(a) 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. 
(a) Discharge from the clinical investigative site will follow collection of all safety assessments. 
(b) Review of inclusion/exclusion criteria will be performed prior to the first dose of study drug. 


 
SIGA Technologies, Inc. 
Statistical Analysis Plan, Version 2.0 
Protocol: SIGA-246-024 
Date Issued: 13 APR 2023 
 
 
 
(c) Review of medical history will be performed prior to the first dose of study drug and if determined by the investigator based on medical 
history/symptomology and will include a review of systems; recreational, prescription, and over-the-counter drug use; nicotine and alcohol use; and 
past hospitalizations. 
(d) A full physical examination will include, at minimum, 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 on Day 31 at the discretion of the investigator, if necessary, to evaluate AEs or clinical laboratory abnormalities. 
(e) Vital signs will be measured after the subject has been in the seated position for at least 5 minutes and will include systolic and diastolic blood 
pressures, heart rate, respiratory rate, and body temperature. Day 31 vital signs only need to be collected in the event that a symptom-directed 
physical examination is performed.  
(f) Vital signs will be measured within 60 minutes of the first dose of the day and 4 hours following the first dose of the day. The acceptable window 
for collection is ±15 minutes from the scheduled time point. 
(g) Includes alcohol, cotinine, amphetamines (including methamphetamines and ecstasy/methylenedioxymethamphetamine), barbiturates, 
benzodiazepines, cannabinoids (including tetrahydrocannabinol), cocaine metabolites, and opiates (including heroin, codeine, and oxycodone). A 
urine drug screen including alcohol and cotinine will be collected and sent to the central laboratory at the screening visit. A urine drug screen and 
alcohol breath test using a breathalyzer will be performed and read locally on Day –1. 
(h) Fasting lipid panel will include cholesterol (total, high-density lipoprotein, calculated low-density lipoprotein, and triglycerides). 
(i) Clinical laboratory testing will include hematology, serum chemistry, and urinalysis. Clinical laboratory testing from screening will be used to 
determine eligibility. 
(j) Women of childbearing potential only. A urine pregnancy test will be performed and read locally on Day –1. 
(k) For postmenopausal women. 
(l) A single 12-lead ECG will be obtained after the subject has been in the supine position for at least 10 minutes. On Day 1 and Day 14, an ECG will 
be recorded within 60 minutes prior to the first dose of the day and 4 hours after the first dose of the day. The acceptable window for collection 
from the scheduled collection time point is ±15 minutes. 
(m) When study drug is administered at the clinical investigative site, all subjects will be provided a meal (consisting of approximately 600 calories and 
25 g of fat). The meal should be consumed within 30 minutes and prior to the administration of study drug (TPOXX or matching placebo). Subjects 
should be administered study drug as soon as possible following completion of the meal but no more than 30 minutes should elapse between meal 
completion and administration of study drug. Subjects should take study drug with 8 oz (240 mL) of water.  
(n) The time of study drug dosing will be called “0” hour. Study drug will be administered to subjects by study site personnel when subjects are in 
house and subjects will self-administer study drug when at home. 


 
SIGA Technologies, Inc. 
Statistical Analysis Plan, Version 2.0 
Protocol: SIGA-246-024 
Date Issued: 13 APR 2023 
 
 
 
(o) Two times a day dosing: Subjects weighing 120 kg or less: 
Blood samples for PK analysis of TPOXX in plasma will be collected on Day 1 before the first dose (0 hour) and at 2, 4, 6, 8, 10, 12 (before the 
second dose), 14, 16, 18, 20, 22, and 24 hours (before the first dose on Day 2); on Day 14 (before the first dose); and on Day 28 (before the first 
dose) and at 2, 4, 6, 8, 10, 12 (before the second dose on Day 28), 14, 16, 18, 20, 22, 24 (Day 29, AM), 48 (Day 30, AM), and 72 (Day 31, AM) 
hours after the first dose on Day 28. 
Three times a day dosing: Subjects weighing more than 120 kg: 
Blood samples for PK analysis of TPOXX in plasma will be collected on Day 1 before the first dose (0 hour) and at 2, 4, 6, 8 (before the second 
dose), 10, 12, 14, 16 (before the third dose), 18, 20, 22, and 24 hours (before the first dose on Day 2); on Day 14 (before the first dose); and on 
Day 28 (before the first dose) and at 2, 4, 6, 8 (before the second dose), 10, 12, 14, 16 (before the third dose), 18, 20, 22, 24 (Day 29, AM), 48 (Day 
30, AM), and 72 (Day 31, AM) hours after the first dose on Day 28. 
 For PK blood samples, the acceptable window for collection from the scheduled collection time point will be as follows: ±15 minutes from 0 to 24 
hours (except where samples are collected predose) and ±60 minutes from 48 to 72 hours.  
(p) If the subject is completing the ET visit, a blood sample for TPOXX concentration analysis should be collected within 30 hours after the last dose 
of study drug from subjects who discontinue. If the visit occurs more than 30 hours following the subject’s last dose of study drug, no sample needs 
to be collected. 
(q) One diary will be dispensed to record TPOXX or matching placebo administration, completion of required meals before and after dosing, all 
concomitant medications, and all AEs. 
(r) Adverse events will be collected from first dose of study drug until Day 42. Serious AEs will be collected up to Day 58. All AEs, SAEs, and 
clinically significant laboratory abnormalities will be followed until resolution or until stability of the abnormality has been demonstrated as 
determined by the investigator and/or medical monitor. 
(s) Concomitant medication information will only be collected at the Day 58 follow-up telephone call if it is related to an SAE. 
 
 


 
SIGA Technologies, Inc. 
Statistical Analysis Plan, Version 2.0 
Protocol: SIGA-246-024 
Date Issued: 13 APR 2023 
 
 
 
Table 13-2 
Schedule of Events: Non-Pharmacokinetic Subset Safety Subjects 
Procedure(a) 
 
Screening 
(Day –28 
to -1) 
Baseline 
Day 1  
Predose 
(AM)  
Day 1 
Postdose 
Day 7 
Follow-
up 
Day 14 
Follow-
up 
Day 21 
Follow-
up 
Day 29 
Dosing 
Complete/ET 
Visit 
Follow-up 
Telephone 
Call 
Day 42 
(+2 days) 
SAE 
Follow-up 
Telephone Call 
Day 58 
(+2 days) 
Admission to clinic 
 
X 
 
 
 
 
 
 
 
Discharge from clinic(b) 
 
 
X 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
X(b) 
 
 
 
 
 
 
 
Medical history 
X 
X(c) 
 
 
 
 
 
 
 
Physical examination(d) 
X 
 
 
X 
X 
X 
X 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
Height and weight 
X 
 
 
 
 
 
 
 
 
Serology (HBsAg, HCV, and 
HIV) 
X 
 
 
 
 
 
 
 
 
Vital sign measurements(f) 
X 
X 
X(g) 
X 
X 
X 
X 
 
 
Urine drug/alcohol/cotinine 
screen(g) 
X 
X 
 
 
 
 
 
 
 
Glycosylated hemoglobin 
(HbA1c) 
X 
 
 
 
 
 
 
 
 
Fasting lipid panel(i) 
X 
 
 
 
 
 
 
 
 
Clinical laboratory testing(i) 
X 
X 
 
X 
X 
X 
X 
 
 
Serum or urine pregnancy test(j) 
X 
X 
 
X 
X 
X 
X 
 
 
Serum follicle-stimulating 
hormone(l) 
X 
 
 
 
 
 
 
 
 
12-lead ECG(l) 
X 
X 
X 
X 
X 
X 
X 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
Meal(n) 
 
X 
 
 
 
 
 
 
 
Administration of study drug(n) 
 
X 
 
 
 
 
 
 
 
Dispense study drug 
 
 
X 
 
 
 
 
 
 
Collect study drug 
 
 
 
 
 
 
X 
 
 
Study drug instructions 
 
 
X 
 
 
 
 
 
 
Subject diary dispensing(p) 
 
 
X 
 
 
 
 
 
 
Subject diary review 
 
 
 
X 
X 
X 
 
 
 


 
SIGA Technologies, Inc. 
Statistical Analysis Plan, Version 2.0 
Protocol: SIGA-246-024 
Date Issued: 13 APR 2023 
 
 
 
Procedure(a) 
 
Screening 
(Day –28 
to -1) 
Baseline 
Day 1  
Predose 
(AM)  
Day 1 
Postdose 
Day 7 
Follow-
up 
Day 14 
Follow-
up 
Day 21 
Follow-
up 
Day 29 
Dosing 
Complete/ET 
Visit 
Follow-up 
Telephone 
Call 
Day 42 
(+2 days) 
SAE 
Follow-up 
Telephone Call 
Day 58 
(+2 days) 
Subject diary collection 
 
 
 
 
 
 
X 
 
 
TPOXX concentration sampling 
 
 
 
 
 
 
X(q) 
 
 
AEs/SAEs(r) 
 
 
X 
X 
X 
Prior/concomitant medications0  
X 
X 
X 
X 
X 
Abbreviations: AE, adverse events; ECG, electrocardiogram; ET, early termination; HBsAg, hepatitis B surface antigen; HCV, hepatitis C virus; HIV, 
human immunodeficiency virus; SAE, serious adverse event. 
(a) When procedures are overlapping and occurring at the same time point, the order of procedures should be ECG then vital sign measurements unless 
dictated by other study events happening at that time, such as dosing requirements. 
(b) Discharge from the clinical investigative site will follow collection of all safety assessments. 
(c) Review of inclusion/exclusion criteria will be performed prior to the first dose of study drug. 
(d) Review of medical history will be performed prior to the first dose of study drug and if determined by the investigator based on medical 
history/symptomology and will include a review of systems; recreational, prescription, and over-the-counter drug use; nicotine and alcohol use; and 
past hospitalizations. 
(e) A full physical examination will include, at minimum, 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). Interim, unscheduled, symptom-directed 
physical examination will be performed at the discretion of the investigator, if necessary, to evaluate AEs or clinical laboratory abnormalities. 
(f) Vital signs will be measured after the subject has been in the seated position for at least 5 minutes and will include systolic and diastolic blood 
pressures, heart rate, respiratory rate, and body temperature.  
(g) Vital signs will be measured within 60 minutes of the first dose of the day and 4 hours following the first dose of the day. The acceptable window 
for collection is ±15 minutes from the scheduled time point 
(h) Includes alcohol, cotinine, amphetamines (including methamphetamines and ecstasy/methylenedioxymethamphetamine), barbiturates, 
benzodiazepines, cannabinoids (including tetrahydrocannabinol), cocaine metabolites, and opiates (including heroin, codeine, and oxycodone). A 
urine drug screen including alcohol and cotinine will be collected and sent to the central laboratory at the screening visit. A urine drug screen and 
alcohol breath test using a breathalyzer will be performed and read locally on Day 1. 
(i) Fasting lipid panel will include cholesterol (total, high-density lipoprotein, calculated low-density lipoprotein, and triglycerides). 
(j) Clinical laboratory testing will include hematology, serum chemistry, and urinalysis. Clinical laboratory testing from screening will be used to 
determine eligibility. 
(k) Women of childbearing potential only. A urine pregnancy test will be performed and read locally on Day 1 Predose. 
(l) For postmenopausal women. 
(m) A single 12-lead ECG will be obtained after the subject has been in the supine position for at least 10 minutes. On Day 1, an ECG will be recorded 
prior to the first dose of the day and after the first dose of the day.  


 
SIGA Technologies, Inc. 
Statistical Analysis Plan, Version 2.0 
Protocol: SIGA-246-024 
Date Issued: 13 APR 2023 
 
 
 
(n) When study drug is administered at the clinical investigative site, all subjects will be provided a meal (consisting of approximately 600 calories and 
25 g of fat). The meal should be consumed within 30 minutes and prior to the administration of study drug (TPOXX or matching placebo). Subjects 
should be administered study drug as soon as possible following completion of the meal but no more than 30 minutes should elapse between meal 
completion and administration of study drug. Subjects should take study drug with 8 oz (240 mL) of water.  
(o) The time of study drug dosing will be called “0” hour. Study drug will be administered to subjects by study site personnel for the first dose on Day 
1 and subjects will self-administer study drug when at home. Subjects will be instructed at the screening visit and prior to check-in to the clinical 
investigative site on Day 1 that other than water, no beverages may be ingested within 3 hours before or 3 hours after study drug administration. 
(p) One diary will be dispensed to record TPOXX or matching placebo administration, completion of required meals before and after dosing, all 
concomitant medications (dose and frequency), and all AEs. 
(q) If the subject is completing the ET visit, a blood sample for TPOXX concentration analysis should be collected within 30 hours after the last dose 
of study drug from subjects who discontinue. If the visit occurs more than 30 hours following the subject’s last dose of study drug, no sample needs 
to be collected. 
(r) Adverse events will be collected from first dose of study drug until Day 42. Serious AEs will be collected up to Day 58. All AEs, SAEs, and 
clinically significant laboratory abnormalities will be followed until resolution or until stability of the abnormality has been demonstrated as 
determined by the investigator and/or medical monitor. 
Concomitant medication information will only be collected at the Day 58 follow-up telephone call if it is related to an SAE. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
SIGA Technologies, Inc. 
Statistical Analysis Plan, Version 2.0 
Protocol: SIGA-246-024 
Date Issued: 13 APR 2023 
 
 
 
14. Index of Tables and Figures  
Table/Figure Number Name 
Population 
Table 14.1.1 
Subject Disposition 
ITT Population 
Table 14.1.2.1.1 
Demographic and Baseline Characteristics 
Safety Population 
Table 14.1.2.1.2 
Demographic and Baseline Characteristics by Age Group 
Safety Population 
Table 14.1.2.3.1 
Demographic and Baseline Characteristics 
PP Safety Population 
Table 14.1.2.3.2 
Demographic and Baseline Characteristics by Age Group 
PP Safety Population 
Table 14.1.2.4.1 
Demographic and Baseline Characteristics 
PK Population 
Table 14.1.2.4.2 
Demographic and Baseline Characteristics by Age Group 
PK Population 
Table 14.1.3 
Major Protocol Deviations 
Safety Population 
Table 14.1.4.2 
Concomitant Medications 
Safety Population 
Table 14.1.5.1.1 
Treatment Compliance 
Safety Population 
Table 14.1.5.1.2 
Treatment Compliance 
PP Safety Population 
Table 14.2.1 
Summary of Plasma Concentrations of TPOXX 
PK Population 
Table 14.2.2 
Summary of Plasma Pharmacokinetic Parameters of TPOXX 
PK Population 
Table 14.3.1.1.1 
Overall Summary of Adverse Events 
Safety Population 
Table 14.3.1.2.1 
Summary of AEs by Preferred Term and System Organ Class 
Safety Population 
Table 14.3.1.4.1 
Adverse Events by Severity 
Safety Population 
Table 14.3.1.5.1 
Adverse Events by Relationship to Study Drug 
Safety Population 
Table 14.3.1.7.1 
Comparison of AE Rates between Treatment Groups Stratified by Age 
Safety Population 
Table 14.3.4.1.1 
Summary and Change from Baseline in Hematology 
Safety Population 
Table 14.3.4.1.2 
Summary and Change from Baseline in Hematology 
PP Safety Population 
Table 14.3.4.1.2.1 
Shift from Baseline in Hematology 
Safety Population 
Table 14.3.4.1.2.2 
Shift from Baseline in Hematology 
PP Safety Population 
Table 14.3.4.2.1.1 
Summary and Change from Baseline in Chemistry 
Safety Population 
Table 14.3.4.2.1.2 
Summary and Change from Baseline in Chemistry 
PP Safety Population 
Table 14.3.4.2.2.1 
Shift from Baseline in Chemistry 
Safety Population 
Table 14.3.4.2.2.2 
Shift from Baseline in Chemistry 
PP Safety Population 
Table 14.3.4.3.1.1 
Summary and Change from Baseline in Urinalysis 
Safety Population 
Table 14.3.4.3.1.2 
Summary and Change from Baseline in Urinalysis 
PP Safety Population 
Table 14.3.4.3.2.1 
Shift from Baseline in Urinalysis 
Safety Population 
Table 14.3.4.3.2.2 
Shift from Baseline in Urinalysis 
PP Safety Population 
Table 14.3.5.1 
Summary and Change from Baseline in Vital Sign Measurements 
Safety Population 
Table 14.3.5.2 
Summary and Change from Baseline in Vital Sign Measurements 
PP Safety Population 
Figure 14.2.1 
Mean Plasma Concentration versus Time Profiles for TPOXX 
PK Population 
Figure 14.2.2 
Individual Plasma Concentration versus Time Profiles for TPOXX 
PK Population 
 


 
SIGA Technologies, Inc. 
Statistical Analysis Plan, Version 2.0 
Protocol: SIGA-246-024 
Date Issued: 13 APR 2023 
 
 
 
15. Index of Listings 
 
Listing Number Name 
16.1.7 
Randomization 
16.2.1 
Subject Disposition 
16.2.2.1 
Inclusion/Exclusion Criteria Deviations 
16.2.2.2 
Protocol Deviations 
16.2.3 
Subjects Excluded from Analysis Populations 
16.2.4.1 
Demographic and Baseline Characteristics 
16.2.4.2 
Medical History 
16.2.4.3 
Prior and Concomitant Medications 
16.2.4.4 
Medical or Surgical Treatment Procedures 
16.2.5.1 
Extent of Exposure 
16.2.5.2 
TPOXX Concentration Data 
16.2.5.3 
Meal Consumption 
16.2.6.1 
Individual Plasma Concentrations of TPOXX 
16.2.6.2 
Individual Plasma Pharmacokinetic Parameters of TPOXX: BID Dosing 
16.2.6.3 
Individual Plasma Pharmacokinetic Parameters of TPOXX: TID Dosing 
16.2.7.1 
Overall Adverse Events 
16.2.7.2 
Treatment-Related Adverse Events 
14.2.3.1 
Serious Adverse Events 
14.3.2.2 
Adverse Events Leading to Early Study Discontinuation 
16.2.8.1 
Hematology Laboratory Test Results 
16.2.8.2 
Abnormal Laboratory Results (Toxicity Grade of at least 1) in Hematology 
16.2.8.3 
Serum Chemistry Laboratory Test Results 
16.2.8.4 
Abnormal Laboratory Results (Toxicity Grade of at least 1) in Chemistry 
16.2.8.5 
Urinalysis Laboratory Test Results 
16.2.8.6 
Abnormal Laboratory Results (Toxicity Grade of at least 1) in Urinalysis 
16.2.9.1 
Vital Sign Measurements 
16.2.9.2 
Electrocardiograms 
16.2.9.3 
Physical Examinations 
16.2.9.4 
Follow-Up AE Call 
16.2.9.5 
Follow-Up SAE Call