Clinical trial NCT04485039
Conditions: Smallpox
Sponsor: SIGA Technologies
Start date: 2022-06-08; Completion date: 2023-04-23
Enrollment: 44 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
An open-label, drug-drug interaction study with TPOXX and phosphate binders.

Detailed description:
A postmarketing open-label, 5 period crossover, drug-drug interaction study of orally administered TPOXX when coadministered with 4 different phosphate binders in healthy adult subjects.

Arms: arm 1: Single oral dose of TPOXX 600 mg arm 2: Single oral dose of TPOXX 600 mg co-administered with single oral dose of 1600 mg sevelamer carbonate arm 3: Single oral dose of TPOXX 600 mg co-administered with single oral dose of 500 mg sucroferric oxyhydroxide chewable tablet arm 4: Single oral dose of TPOXX 600 mg co-administered with a single oral dose of 1334 mg calcium acetate arm 5: Single oral dose of TPOXX 600 mg co-administered with a single oral dose of 500 mg lanthanum carbonate chewable tablet
Interventions: intervention 1: Tecovirimat intervention 2: sevelamer carbonate oral tablet intervention 3: sucroferric oxyhydroxide chewable tablet intervention 4: calcium acetate oral tablet intervention 5: Lanthanum Carbonate Chewable Tablet
Intervention descriptions: intervention 1: oral antiviral intervention 2: phosphate binder intervention 3: phosphate binder intervention 4: phosphate binder intervention 5: phosphate binder

Protocol documents:
Prot_SAP_001.pdf: 
 
A POSTMARKETING OPEN-LABEL, 5-PERIOD CROSSOVER, DRUG-
DRUG INTERACTION STUDY OF ORALLY ADMINISTERED TPOXX® 
WHEN COADMINISTERED WITH 4 DIFFERENT PHOSPHATE 
BINDERS IN HEALTHY ADULT SUBJECTS 
 
 
NCT: 04485039 
 
PROTOCOL: 27JUN2022 
 
SAP: 28JUN2023 
 
 
 
 






SIGA Technologies, Inc. 
TPOXX (Tecovirimat) 
Protocol: SIGA-246-023 (Version 2.0) 
27 January 2022 
 
Page 3 
INVESTIGATOR PROTOCOL AGREEMENT PAGE 
 
I agree to conduct the study as outlined in the protocol titled “A Postmarketing Open-Label, 
5-Period Crossover, Drug-Drug Interaction Study of Orally Administered TPOXX® when 
Coadministered With 4 Different Phosphate Binders in Healthy 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 


SIGA Technologies, Inc. 
TPOXX (Tecovirimat) 
Protocol: SIGA-246-023 (Version 2.0) 
27 January 2022 
 
Page 4 
TABLE OF CONTENTS 
TITLE PAGE .......................................................................................................................... 1 
SIGNATURE PAGE ............................................................................................................... 2 
INVESTIGATOR PROTOCOL AGREEMENT PAGE ..................................................... 3 
TABLE OF CONTENTS ........................................................................................................ 4 
LIST OF TABLES ................................................................................................................... 6 
PROTOCOL SYNOPSIS ....................................................................................................... 7 
1. 
INTRODUCTION ............................................................................................. 16 
1.1 
BACKGROUND ..............................................................................................16 
1.2 
RATIONALE FOR STUDY ............................................................................16 
1.3 
RATIONALE FOR DOSE SELECTION.........................................................16 
1.4 
POTENTIAL RISKS AND BENEFITS ...........................................................17 
1.4.1 
Potential Risks ..............................................................................................17 
1.4.2 
Known Potential Benefits .............................................................................17 
2. 
STUDY OBJECTIVES ...................................................................................... 18 
2.1 
PRIMARY OBJECTIVE ..................................................................................18 
2.2 
SECONDARY OBJECTIVE ............................................................................18 
3. 
STUDY DESIGN AND METHODOLOGY .................................................... 18 
4. 
STUDY POPULATION..................................................................................... 19 
4.1 
INCLUSION CRITERIA .................................................................................20 
4.2 
EXCLUSION CRITERIA ................................................................................21 
4.3 
OTHER SCREENING CONSIDERATIONS ..................................................25 
4.4 
WITHDRAWAL OF SUBJECTS FROM THE STUDY .................................25 
4.4.1 
Reasons for Withdrawal................................................................................25 
4.4.2 
Handling of Withdrawals ..............................................................................26 
4.4.3 
Halting Rules ................................................................................................27 
4.4.4 
Replacements ................................................................................................28 
5. 
STUDY TREATMENTS ................................................................................... 28 
5.1 
TREATMENTS ADMINISTERED .................................................................28 
5.2 
INVESTIGATIONAL PRODUCTS ................................................................29 
5.2.1 
Study Drug Packaging and Storage ..............................................................30 
5.2.2 
Study Drug Accountability ...........................................................................31 
5.3 
METHOD OF ASSIGNING SUBJECTS TO TREATMENT GROUPS .........31 
5.4 
BLINDING .......................................................................................................31 
5.5 
TREATMENT COMPLIANCE .......................................................................31 
5.5.1 
Prior and Concomitant Medications .............................................................32 
5.5.1.1 
Prior Medications ..................................................................................... 32 


SIGA Technologies, Inc. 
TPOXX (Tecovirimat) 
Protocol: SIGA-246-023 (Version 2.0) 
27 January 2022 
 
Page 5 
5.5.1.2 
Concomitant Medications ........................................................................ 32 
6. 
STUDY PROCEDURES ................................................................................... 32 
6.1 
PHARMACOKINETIC ASSESSMENTS AND ENDPOINTS ......................32 
6.1.1 
Pharmacokinetic Sample Collection .............................................................33 
6.1.2 
Pharmacokinetic Sample Analysis................................................................34 
6.2 
SAFETY ASSESSMENTS AND ENDPOINTS ..............................................34 
6.2.1 
Adverse Events .............................................................................................35 
6.2.1.1 
Adverse Event Definitions ....................................................................... 35 
6.2.1.2 
Eliciting and Documenting Adverse Events ............................................ 37 
6.2.1.3 
Reporting Adverse Events ....................................................................... 37 
6.2.1.4 
Reporting of Serious Adverse Events ...................................................... 38 
6.2.1.5 
Assessment of Severity ............................................................................ 39 
6.2.1.6 
Assessment of Causality .......................................................................... 40 
6.2.1.7 
Follow-up of Adverse Events .................................................................. 41 
6.2.1.8 
Reporting of Pregnancy ........................................................................... 41 
6.2.2 
Clinical Laboratory Testing ..........................................................................42 
6.2.3 
Medical History ............................................................................................43 
6.2.4 
Vital Sign Measurements ..............................................................................43 
6.2.5 
Electrocardiograms .......................................................................................43 
6.2.6 
Physical Examinations ..................................................................................44 
6.2.7 
Unscheduled Visits .......................................................................................44 
7. 
STATISTICAL ANALYSIS PLAN ................................................................... 45 
7.1 
SAMPLE SIZE CALCULATIONS..................................................................45 
7.2 
ANALYSIS SETS ............................................................................................45 
7.3 
STATISTICAL ANALYSIS .............................................................................46 
7.3.1 
Pharmacokinetic Analyses ............................................................................46 
7.3.2 
Safety Analyses ............................................................................................47 
7.4 
HANDLING OF BELOW THE LIMIT OF QUANTIFICATION AND 
MISSING DATA ..............................................................................................47 
7.5 
INTERIM ANALYSES ....................................................................................48 
8. 
REFERENCE LIST........................................................................................... 49 
9. 
APPENDICES .................................................................................................... 50 
9.1 
APPENDIX 1: LIST OF ABBREVIATIONS ..................................................50 
9.2 
APPENDIX 2: SCHEDULE OF EVENTS ......................................................51 
9.3 
APPENDIX 3: STUDY GOVERNANCE .......................................................55 
9.3.1 
Data Quality Assurance ................................................................................55 
9.3.2 
Investigator Obligations ...............................................................................56 
9.3.2.1 
Confidentiality ......................................................................................... 56 


SIGA Technologies, Inc. 
TPOXX (Tecovirimat) 
Protocol: SIGA-246-023 (Version 2.0) 
27 January 2022 
 
Page 6 
9.3.2.2 
Institutional Review ................................................................................. 56 
9.3.2.3 
Subject Consent ....................................................................................... 57 
9.3.2.4 
Exclusion of Children .............................................................................. 57 
9.3.2.5 
Study Reporting Requirements ................................................................ 58 
9.3.2.6 
Financial Disclosure and Obligations ...................................................... 58 
9.3.2.7 
Investigator Documentation ..................................................................... 58 
9.3.2.8 
Study Conduct ......................................................................................... 59 
9.3.2.9 
Case Report Forms and Source Documents ............................................ 59 
9.3.2.10 
Adherence to Protocol ............................................................................. 60 
9.3.2.11 
Reporting Adverse Events ....................................................................... 60 
9.3.2.12 
Investigator’s Final Report ...................................................................... 60 
9.3.2.13 
Records Retention .................................................................................... 60 
9.3.2.14 
Publications .............................................................................................. 60 
9.3.3 
Study Management .......................................................................................61 
9.3.3.1 
Monitoring ............................................................................................... 61 
9.3.4 
Safety Monitoring Plan .................................................................................62 
9.3.5 
Medical Monitor ...........................................................................................62 
9.3.6 
Safety Oversight (Independent Safety Monitor) ..........................................62 
9.3.6.2 
Management of Protocol Amendments and Deviations .......................... 63 
9.3.6.3 
Study Termination .................................................................................... 64 
9.3.6.4 
Final Report ............................................................................................. 64 
9.4 
APPENDIX 4: CHANGE HISTORY ..............................................................66 
LIST OF TABLES 
Table 5-1 
Excipients of TPOXX Capsules ...................................................................... 29 
Table 9-1 
Schedule of Events: Period 1 through Period 3 .............................................. 51 
Table 9-2 
Schedule of Events: Period 4 and Period 5 ..................................................... 53 
 


SIGA Technologies, Inc. 
TPOXX (Tecovirimat) 
Protocol: SIGA-246-023 (Version 2.0) 
27 January 2022 
 
Page 7 
PROTOCOL SYNOPSIS 
PROTOCOL NO.: SIGA-246-023 
TITLE: A Postmarketing Open-Label, 5-Period Crossover, Drug-Drug Interaction Study of 
Orally Administered TPOXX® when Coadministered With 4 Different Phosphate Binders in 
Healthy Adult Subjects 
STUDY PHASE: 4 Postmarketing Study 
STUDY SITE: 
 
 
OBJECTIVES: 
Primary: 
The primary objective of this study is to evaluate potential drug-drug interaction as measured 
by the effect of coadministration of 4 separate phosphate binders on the pharmacokinetics 
(PK) of orally administered TPOXX in healthy adult subjects. 
Secondary: 
The secondary objective of this study is to evaluate the safety and tolerability of 600 mg oral 
TPOXX administered with 4 different phosphate binders in healthy adult subjects. 
STUDY DESIGN AND METHODOLOGY: 
This is a postmarketing, open-label, 5-period crossover drug interaction study designed to 
evaluate the potential effects of coadministration of 4 different phosphate binders on the PK 
of orally administered TPOXX in healthy adult subjects. A total of 44 subjects, ages 18 to 50, 
inclusive, will be enrolled and randomly assigned to 1 of 4 treatment sequences. The study 
will consist of a screening period (Day –28 to Day –2), 5 treatment periods (Day –1 to 
Day 31), an end-of-study visit (Day 36 [+2 days]), and a follow-up telephone call (Day 59 
[+4 days]). The treatment sequences and periods will be as follows: 
Treatment 
Sequence 
Period 1 
Treatment 
Period 2 
Treatment 
Period 3 
Treatment 
Period 4 
Treatment 
Period 5 
Treatment 
ABCDE 
A 
B 
C 
D 
E 
ACEBD 
A 
C 
E 
B 
D 
ADBEC 
A 
D 
B 
E 
C 
AEDCB 
A 
E 
D 
C 
B 
• Treatment A: A single oral dose of 600 mg (3 × 200 mg capsules) TPOXX. 
• 
Treatment B: A single oral dose of 600 mg (3 × 200 mg capsules) TPOXX 
coadministered with a single oral dose of 1600 mg (2 × 800 mg tablets) sevelamer 
carbonate (Renvela® or generic equivalent). 
• Treatment C: A single oral dose of 600 mg (3 × 200 mg capsules) TPOXX 
coadministered with a single oral dose of 500 mg sucroferric oxyhydroxide (Velphoro®) 
chewable tablet. 


SIGA Technologies, Inc. 
TPOXX (Tecovirimat) 
Protocol: SIGA-246-023 (Version 2.0) 
27 January 2022 
 
Page 8 
• Treatment D: A single oral dose of 600 mg (3 × 200 mg capsules) TPOXX 
coadministered with a single oral dose of 1334 mg (2 × 667 mg capsules) calcium acetate 
(PhosLo® generic equivalent). 
• Treatment E: A single oral dose of 600 mg (3 × 200 mg capsules) TPOXX 
coadministered with a single oral dose of 500 mg lanthanum carbonate (Fosrenol® or 
generic equivalent) chewable tablet. 
There will be a washout period of 7 days between dosing in each treatment period. All 
subjects will be provided a meal (consisting of approximately 600 calories and 25 g fat). The 
meal should be completed within 30 minutes. 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 study drug administration. Study drug and meals must 
be taken with water only, and no other beverage except water should be ingested within 
3 hours before or 3 hours after study drug administration. Water is allowed at all times 
throughout the study. Subjects must fast for 2 hours after taking study drug as further food 
consumption may affect drug absorption. 
Subjects will report to the study site on Day –1 and remain confined to the study site until 
48 hours after dosing in Period 5 (Day 31). Subjects will be monitored for safety and 
tolerability. Serial blood samples for PK analysis of TPOXX will be collected before dosing 
(0 hour) and up to 48 hours after administration of the study drug(s). 
All subjects will have a follow-up telephone call 30 days after administration of the last dose 
of study drug (Day 59 [+4 days]) to report any serious adverse events (SAEs). At the time of 
discharge from the clinical research unit, subjects will be instructed to notify the investigator 
of any SAEs that occur within 30 days after administration of the last dose of study drug. 
Serious AEs will be followed until the SAE is stable or until resolution as determined by the 
investigator and/or medical monitor. 
The total duration of the study for each subject, including the screening period, treatment 
period, the Day 36 (+2 days) end-of-study visit, and the Day 59 (+4 days) follow-up 
telephone call, will be approximately 87 days. 
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 18 to 50 years of age, inclusive. 
2. Blood phosphorus levels within normal laboratory reference range. 
3. Women of childbearing potential have a negative β human chorionic gonadotropin 
pregnancy test (serum) at the screening visit and a confirmatory negative serum 
pregnancy test on Day –1 before receipt of study drug, and meet one of the following 
criteria: 
a. The subject or their partner has undergone surgical sterilization 
b. The subject is postmenopausal, defined as 12 consecutive months with no menses 
without an alternative medical cause and has a documented plasma 
follicle-stimulating hormone level >40 IU/mL 


SIGA Technologies, Inc. 
TPOXX (Tecovirimat) 
Protocol: SIGA-246-023 (Version 2.0) 
27 January 2022 
 
Page 9 
c. The subject agrees to be abstinent (ie, heterosexually inactive or women in a religious 
order) 
d. The subject agrees to consistently use 1 of the following methods of contraception 
from the beginning of screening (which they had been consistently using for at least 
30 days before the first dose of study drug) through 30 days after the last dose of 
study drug: 
i. 
Condoms, male or female, with a spermicide 
NOTE: For male subjects, condoms must be used for 90 days after last dose of 
study drug 
ii. 
Diaphragm or cervical cap with spermicide 
iii. 
Intrauterine device with spermicide 
iv. 
Oral contraceptives or other hormonal methods 
NOTE: Another nonhormonal method of contraception must be used in 
conjunction with oral contraceptives 
v. 
Male sexual partner who has undergone a vasectomy at least 3 months before 
screening. 
4. Male subjects must agree to not donate sperm from the first dose of study drug through 
90 days after the last dose of study drug. 
5. Subject is considered by the investigator to be in good general health as determined by 
medical history, clinical laboratory test results, vital sign measurements, 12-lead 
electrocardiogram (ECG) results, and physical examination findings at screening. 
6. Subject agrees to comply with the dietary requirements. 
7. Subject agrees to comply with all protocol requirements. 
8. Subject is able to provide written informed consent. 
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 
• Hypertension that is poorly controlled (repeat readings >140 mm Hg systolic 
and/or >90 mm Hg diastolic) 
• 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 


SIGA Technologies, Inc. 
TPOXX (Tecovirimat) 
Protocol: SIGA-246-023 (Version 2.0) 
27 January 2022 
 
Page 10 
• Head trauma resulting in a diagnosis of traumatic brain injury other than 
concussion 
• Frequent episodes of headache. 
3. Subject has received treatment in another clinical study of an investigational drug (or 
medical device) within 30 days or 5 half-lives (whichever is longer) before the first dose 
of study drug. 
4. Subject has a history of relevant drug and/or food allergies (ie, allergy to TPOXX or 
excipients, or any significant food allergy that could preclude a standard diet in the study 
site). 
5. Subject has any condition possibly affecting drug absorption (eg, previous surgery on the 
gastrointestinal tract, including removal of parts of the stomach, bowel, liver, gallbladder, 
or pancreas, with the exception of appendectomy). 
6. Subject has evidence or history of clinically significant allergic (except for untreated, 
asymptomatic, seasonal allergies at time of the first dose of study drug), hematological, 
endocrine, pulmonary, gastrointestinal, cardiovascular, hepatic, psychiatric, or 
neurological disease. Exceptions to these criteria (eg, stable, mild joint disease 
unassociated with collagen vascular disease) may be made following discussions with the 
medical monitor. 
7. Subject has a history of cardiac disease, symptomatic or asymptomatic arrhythmias, 
syncopal episodes, or risk factors for torsades de pointes (eg, heart failure, hypokalemia). 
8. Subject has a family history of sudden cardiac death not clearly due to acute myocardial 
infarction. 
9. 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. 
10. Subject has a history of a peptic ulcer or significant gastrointestinal bleeding. 
11. Subject has a bleeding disorder diagnosed by a doctor (eg, factor deficiency, 
coagulopathy, or platelet disorder requiring special precautions) or significant bruising or 
bleeding difficulties with blood draws. 
12. 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). 
13. Subject has neutropenia or other blood dyscrasia determined to be clinically significant 
by the investigator. 
14. Subject has used any of the following prohibited medications from within 7 days (or 
5 half-lives, whichever is longer) before the first dose of study drug: antidiabetic 
medication; anticoagulants; anticonvulsants; substrates of the breast cancer resistance 
protein transporter including methotrexate, mitoxantrone, imatinib, irinotecan, lapatinib, 
rosuvastatin, sulfasalazine, and topotecan; substrates of CYP2C8 including repaglinide, 
paclitaxel, Montelukast, pioglitazone, rosiglitazone; and substrates of CYP2C19 


SIGA Technologies, Inc. 
TPOXX (Tecovirimat) 
Protocol: SIGA-246-023 (Version 2.0) 
27 January 2022 
 
Page 11 
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. 
15. Subject has a history of drug or alcohol abuse or dependency within the last year before 
screening. 
16. Subject has a current or recent (<30 days before screening) history of clinically 
significant bacterial, fungal, or mycobacterial infection. 
17. Subject has a current clinically significant viral infection. 
18. Subject has a known clinically significant chronic viral infection (eg, human T cell 
lymphotropic virus I or II). 
19. Subject has consumed grapefruit or grapefruit juice, Seville orange or Seville 
orange-containing products (eg, marmalade), or caffeine- or xanthine-containing products 
within 48 hours before the first dose of study drug. 
20. Subject has used any prescription (excluding hormonal birth control) or over-the-counter 
medication (including herbal or nutritional supplements) within 14 days before the first 
dose of study drug. 
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 is a smoker or has used nicotine or nicotine-containing products (eg, cigarettes, 
electronic vapor cigarettes, cigars, chewing tobacco, snuff, nicotine patches, or nicotine 
gum) within 6 months before the first dose of study drug. 
24. Subject has consumed pomegranate or pomegranate juice, pomelo fruits or pomelo juice, 
or alcohol within 72 hours before the first dose of study drug. 
25. Subject reports participation in strenuous activity or contact sports within 24 hours before 
the first dose of study drug. 
26. 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. 
27. Subject has a positive test result for amphetamines (including methamphetamines and 
ecstasy/methylenedioxymethamphetamine), barbiturates, benzodiazepines, cannabinoids 
(including tetrahydrocannabinol), cocaine metabolites, opiates (including heroin, codeine, 
and oxycodone), or alcohol at screening or check-in. 


SIGA Technologies, Inc. 
TPOXX (Tecovirimat) 
Protocol: SIGA-246-023 (Version 2.0) 
27 January 2022 
 
Page 12 
28. 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 count considered to be clinically significant by the investigator 
• Absolute neutrophil count <1000 cells/mm3 
• Platelets not within ±10% of laboratory reference range 
• Alanine aminotransferase >2.0 times above the upper laboratory reference range 
• Aspartate aminotransferase >2.0 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. 
29. Subject has a blood pressure considered to be clinically significant by the investigator. 
Blood pressure may be retested twice in the sitting position at 5-minute intervals. 
30. Subject has a resting heart rate of <40 beats per minute or >110 beats per minute at 
screening. 
31. Subject has an abnormal ECG at screening that is determined by the investigator to be 
clinically significant. 
32. 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. 
33. In the opinion of the investigator, the subject is not suitable for entry into the study. 
EVALUATION PROCEDURES: 
Pharmacokinetic Assessments: 
Blood samples for PK analysis of TPOXX will be collected from all subjects at the following 
time points: within 60 minutes before dosing (0 hour) and at 0.5, 1, 2, 4, 6, 8, 12, 24, and 
48 hours after administration of study drug in each period. For PK blood samples, the 
acceptable window for collection from the scheduled collection time point will be as follows: 
±5 minutes for the time points from 0.5 through 8 hours and ±15 minutes for the time points 
from 12 through 48 hours. 
The following plasma PK parameters will be calculated for TPOXX to the extent that data 
permit: 
• Area under the plasma concentration versus time curve (AUC) from time 0 to 24 hours 
(AUC0-24) 
• AUC from time 0 to 48 hours (AUC0-48) 


SIGA Technologies, Inc. 
TPOXX (Tecovirimat) 
Protocol: SIGA-246-023 (Version 2.0) 
27 January 2022 
 
Page 13 
• AUC from time 0 to infinity (AUC0-inf) 
• AUC from time 0 to the last quantifiable concentration (AUC0-t) 
• Maximum drug concentration in plasma (Cmax) 
• Time to Cmax (Tmax). 
Safety Assessments: 
Safety and tolerability will be assessed by monitoring and recording of adverse events (AEs), 
clinical laboratory test results (hematology, serum chemistry, pregnancy, and urinalysis), vital 
sign measurements (systolic and diastolic blood pressures, heart rate, respiratory rate, and 
body temperature), 12-lead ECG results, and physical examination findings. 
STUDY DRUG, DOSAGE, AND ROUTE OF ADMINISTRATION: 
Single oral dose of 600 mg (3 × 200-mg capsules) TPOXX, administered under fed 
conditions. 
Single oral dose of 1600 mg (2 × 800-mg) sevelamer carbonate (Renvela® or generic 
equivalent) tablet coadministered with TPOXX under fed conditions. 
Single oral dose of 500 mg sucroferric oxyhydroxide (Velphoro®) chewable tablet 
coadministered with TPOXX under fed conditions. Note: Velphoro must be chewed and not 
swallowed whole. 
Single oral dose of 1334 mg (2 × 667-mg) calcium acetate (PhosLo® generic equivalent) 
capsule coadministered with TPOXX under fed conditions. 
Single oral dose of 500 mg lanthanum carbonate (Fosrenol® or generic equivalent) chewable 
tablet coadministered with TPOXX under fed conditions. Note: Fosrenol or generic 
equivalent must be chewed and not swallowed whole. 
STATISTICAL METHODS: 
Complete, detailed statistical methods will be described in the statistical analysis plan. 
Sample Size: 
The sample size (N = 44 [to allow at least 36 enrolled subjects to complete]) for this study is 
based on clinical and practical considerations and not on a formal statistical power 
calculation. The sample size is considered sufficient for the objectives of the study. 
Prior estimates of within-subject variability (CVw) of a single dose of 600 mg TPOXX were 
obtained from Study SIGA-246-018, which evaluated the single-dose PK of TPOXX in a 
similar population. The CVw% for Cmax, AUC0-24, and AUC0-inf ranged from 
11.39% to 12.62%, 9.38% to 18.12%, and 15.70% to 18.02%, respectively. 
For a sensitivity analysis, a range for CVw of 10%, 15%, and 20% across point estimates of 
0.9, 1.0, and 1.1 will be explored. 
For the sensitivity analysis, assuming a range of CVw, a sample size of 36 evaluable subjects, 
it is estimated that the precision (ie, half-width of the 90% confidence interval [CI] on the log 
and ratio scale), and CI with tolerance probability of 80% on the original scale for each point 
estimate will be: 


SIGA Technologies, Inc. 
TPOXX (Tecovirimat) 
Protocol: SIGA-246-023 (Version 2.0) 
27 January 2022 
 
Page 14 
CVw (%) 
Half-Width 
(log scale) 
Half-Width 
(original scale) 
Point Estimate 
90% Confidence Interval 
10 
0.043 
0.044 
0.9 
(0.862, 0.94) 
1.0 
(0.958, 1.044) 
1.1 
(1.054, 1.148) 
15 
0.065 
0.067 
0.9 
(0.843, 0.96) 
1.0 
(0.937, 1.067) 
1.1 
(1.031, 1.174) 
20 
0.086 
0.090 
0.9 
(0.826, 0.981) 
1.0 
(0.918, 1.09) 
1.1 
(1.009, 1.199) 
Abbreviation: CVw, within-subject variability. 
Analysis Populations: 
• The PK population will include subjects who receive at least 1 dose of TPOXX and have 
sufficient concentration data to support accurate estimation of at least 1 PK parameter. 
• The safety population will include all subjects who receive any amount of study drug. 
Pharmacokinetic Analyses: 
Individual plasma concentration and time deviation data will be presented in a data listing. 
Plasma concentration data will be summarized by time point for each treatment using the 
following descriptive statistics: number of subjects, arithmetic mean, standard deviation 
(SD), coefficient of variation (CV), geometric mean, geometric CV, geometric SD, minimum, 
median, and maximum. Individual and mean plasma concentration versus scheduled time 
profiles will be presented in figures on both linear and semilogarithmic scales. 
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 treatment using the following descriptive statistics: number of subjects, 
mean, SD, CV, geometric mean, geometric SD, geometric CV, minimum, median, and 
maximum. Geometric means will be included for AUC0-24 and Cmax.  
A linear mixed model with sequence, treatment, and period as fixed effects and subject 
within sequence as a random effect will be performed on the natural log-transformed values 
of AUC0-24 and Cmax to assess the effect of phosphate binders on the PK of TPOXX. The 
geometric least squares means and corresponding 90% CIs will be computed for AUC0-24 and 
Cmax of TPOXX + phosphate binder versus TPOXX alone by taking the antilog of the least 
squares means from the linear mixed-effect model on the natural logarithms of the 
corresponding PK parameters. A 90% CI for the ratio will be constructed as the antilog of the 
confidence limits of the mean difference. No adjustment will be made for multiplicity. The 
geometric mean ratios and corresponding 90% CIs for AUC0-24 and Cmax for TPOXX will be 
summarized in forest plots for overall assessment of the drug-drug interaction. 
It will be concluded that there is no relevant interaction of phosphate binders on TPOXX if 
the 90% CIs for AUC0-24 and Cmax ratios (TPOXX + phosphate binder/TPOXX alone) are 
completely contained within the [80%, 125%] interval. 
Non-parametric methods will be used to examine median differences in Tmax for TPOXX. 


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Safety Analyses: 
Adverse events will be coded by preferred term and system organ class using the latest 
version of the Medical Dictionary for Regulatory Activities and summarized by treatment 
and overall. All AE data will be presented in a data listing. Treatment-emergent AEs will be 
summarized by treatment and overall, as well as by severity and relationship to study drug. 
Serious AEs and AEs leading to discontinuation of study drug will also be presented in the 
data listings and summarized by treatment and overall. 
Actual values and changes from baseline for clinical laboratory test results, vital sign 
measurements, and 12-lead ECG results will be summarized by treatment 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. 
DATE OF PROTOCOL: 27 January 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 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 the oral formulation of 
TPOXX for the treatment of patients with human smallpox disease caused by variola virus. 
In November 2021, Health Canada approved the oral formulation of TPOXX for the same 
indication. In January 2022, the European Medicines Agency (EMA) approved the oral 
formulation for the treatment of patients with smallpox, monkeypox, cowpox, and 
complications due to replication of vaccinia virus following vaccination against smallpox. 
1.2 
RATIONALE FOR STUDY 
This study is being conducted as an FDA postmarketing commitment (
) to the 
approved New Drug Application for TPOXX. SIGA is required to conduct a drug-drug 
interaction (DDI) study to evaluation the potential effects of coadministration of 4 different 
phosphate binders on the pharmacokinetics (PK) of orally administered TPOXX. This study 
is in accordance with the FDA Guidance for Industry, Clinical Drug Interaction Studies—
Study Design, Data Analysis, and Clinical Implications.2 
1.3 
RATIONALE FOR DOSE SELECTION 
A single dose of 600 mg (3 × 200 mg capsules) TPOXX was chosen as this is the 
recommended dose for TPOXX.  
Sevelamer carbonate, sucroferric oxyhydroxide, calcium acetate, and lanthanum carbonate 
were chosen for this study because they are common phospate binders that patients 
prescribed TPOXX may be concurrently taking. The planned doses for each of these drugs 
were selected based on the FDA Guidance “Clinical Drug Interaction Studies - Study Design, 
Data Analysis, and Clinical Implications”, which states the maximum dose and the shortest 
dosing interval should be used.2 


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Any potential DDI will be determined based on an analysis of TPOXX PK in the presence of 
phosphate-binding drugs. The planned doses of TPOXX and the 4 phosphate binders are 
expected to be sufficiently high to quantify an effect on TPOXX plasma exposure levels. 
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. Pregnancy testing will be performed at the 
screening visit and checked by the investigator for negative pregnancy on Day –1 of each 
period before administration of study drug. Women who are pregnant or lactating or plan to 
become pregnant within 3 months after study drug administration will be excluded from the 
study; if a female subject becomes pregnant during study participation, study drug dosing 
will be discontinued, and the subject will be withdrawn from the study (Section 6.2.1.8). 
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.3 
A single dose of the phosphate binders should not lead to any major AEs, but there may be an 
increased risk of hypercalcemia (specifically with calcium acetate).  Other potential AEs 
include diarrhea, dyspepsia, nausea, vomiting, abdominal pain, flatulence, and hypotension 
(specifically with sucroferric oxyhydroxide).   
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 knowledge gained in 
this study which may aid in the use of TPOXX for the treatment of smallpox in patients 
taking phosphate binders. 


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2. 
STUDY OBJECTIVES 
2.1 
PRIMARY OBJECTIVE 
The primary objective of this study is to evaluate potential DDI as measured by the effect of 
coadministration of 4 separate phosphate binders on the PK of orally administered TPOXX 
in healthy adult subjects. 
2.2 
SECONDARY OBJECTIVE 
The secondary objective of this study is to evaluate the safety and tolerability of 600 mg oral 
TPOXX administered with 4 different phosphate binders in healthy adult subjects. 
3. 
STUDY DESIGN AND METHODOLOGY 
This is a postmarketing, open-label, 5-period crossover drug interaction study designed to 
evaluate the potential effects of coadministration of 4 different phosphate binders on the PK 
of orally administered TPOXX in healthy adult subjects. A total of 44 subjects, ages 18 to 50, 
inclusive, will be enrolled and be randomly assigned to 1 of 4 treatment sequences. The study 
will consist of a screening period (Day –28 to Day –2), 5 treatment periods (Day –1 to 
Day 31), an end-of-study visit (Day 36 [+2 days]), and a follow-up telephone call (Day 59 
[+4 days]). The treatment sequences and periods will be as follows: 
Treatment 
Sequence 
Period 1 
Treatment 
Period 2 
Treatment 
Period 3 
Treatment 
Period 4 
Treatment 
Period 5 
Treatment 
ABCDE 
A 
B 
C 
D 
E 
ACEBD 
A 
C 
E 
B 
D 
ADBEC 
A 
D 
B 
E 
C 
AEDCB 
A 
E 
D 
C 
B 
• Treatment A: A single oral dose of 600 mg (3 × 200 mg capsules) TPOXX. 
• 
Treatment B: A single oral dose of 600 mg (3 × 200 mg capsules) TPOXX 
coadministered with a single oral dose of 1600 mg (2 × 800 mg tablets) sevelamer 
carbonate (Renvela® or generic equivalent). 
• Treatment C: A single oral dose of 600 mg (3 × 200 mg capsules) TPOXX 
coadministered with a single oral dose of 500 mg sucroferric oxyhydroxide (Velphoro®) 
chewable tablet. 


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• Treatment D: A single oral dose of 600 mg (3 × 200 mg capsules) TPOXX 
coadministered with a single oral dose of 1334 mg (2 × 667 mg capsules) calcium acetate 
(PhosLo® generic equivalent). 
• Treatment E: A single oral dose of 600 mg (3 × 200 mg capsules) TPOXX 
coadministered with a single oral dose of 500 mg lanthanum carbonate (Fosrenol® or 
generic equivalent) chewable tablet. 
There will be a washout period of 7 days between dosing in each treatment period. All 
subjects will be provided a meal (consisting of approximately 600 calories and 25 g fat). The 
meal should be completed within 30 minutes. 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 study drug administration. Study drug and meals must 
be taken with water only, and no other beverage except water should be ingested within 
3 hours before or 3 hours after study drug administration. Water is allowed at all times 
throughout the study. Subjects must fast for 2 hours after taking study drug as further food 
consumption may affect drug absorption. 
In each period, subjects will report to the study site on Day –1 and remain confined to the 
study site until 48 hours after dosing in Period 5 (Day 31). Subjects will be monitored for 
safety and tolerability. Serial blood samples for PK analysis of TPOXX will be collected 
before dosing (0 hour) and up to 48 hours after administration of the study drug(s).  
All subjects will have a follow-up telephone call 30 days after administration of the last dose 
of study drug (Day 59 [+4 days]) to report any serious AEs (SAEs). At the time of discharge 
from the clinical research unit, subjects will be instructed to notify the investigator of any 
SAEs that occur within 30 days after administration of the last dose of study drug. Serious 
AEs will be followed until the SAE is stable or until resolution as determined by the 
investigator and/or medical monitor. 
The total duration of the study for each subject, including the screening period, treatment 
period, the Day 36 (+2 days) end-of-study visit, and the Day 59 (+4 days) follow-up 
telephone call, will be approximately 87 days. 
4. 
STUDY POPULATION 
Approximately 44 healthy male and female subjects will be enrolled at a single center in the 
United States to achieve at least 36 evaluable subjects. 


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4.1 
INCLUSION CRITERIA 
Each subject must meet all of the following criteria to be enrolled in this study: 
 The subject is male or female 18 to 50 years of age, inclusive. 
 Blood phosphorus levels within normal laboratory reference range. 
 Women of childbearing potential have a negative β human chorionic gonadotropin 
pregnancy test (serum) at the screening visit and a confirmatory negative serum 
pregnancy test on Day –1 before receipt of study drug, and meet one of the following 
criteria: 
a. The subject or their partner has undergone surgical sterilization 
b. The subject is postmenopausal, defined as 12 consecutive months with no menses 
without an alternative medical cause and has a documented plasma 
follicle-stimulating hormone level >40 IU/mL 
c. The subject agrees to be abstinent (ie, heterosexually inactive or women in a religious 
order) 
d. The subject agrees to consistently use 1 of the following methods of contraception 
from the beginning of screening (which they had been consistently using for at least 
30 days before the first dose of study drug) through 30 days after the last dose of 
study drug: 
i. Condoms, male or female, with a spermicide 
NOTE: For male subjects, condoms must be used for 90 days after last dose of 
study drug 
ii. Diaphragm or cervical cap with spermicide 
iii. Intrauterine device with spermicide 
iv. Oral contraceptives or other hormonal methods 
NOTE: Another nonhormonal method of contraception must be used in 
conjunction with oral contraceptives 


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v. Male sexual partner who had undergone a vasectomy at least 3 months before 
screening. 
 Male subjects must agree to not donate sperm from the first dose of study drug through 
90 days after the last dose of study drug. 
 The subject is considered by the investigator to be in good general health as determined 
by medical history, clinical laboratory test results, vital sign measurements, 12-lead 
electrocardiogram (ECG) results, and physical examination findings at screening. 
 The subject agrees to comply with the dietary requirements. 
 The subject agrees to comply with all protocol requirements. 
 The subject is able 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 
• Hypertension that is poorly controlled (repeat readings >140 mm Hg systolic and/or 
>90 mm Hg diastolic) 
• Thyroidectomy or thyroid disease that required medication within the past 12 months 
• Serious angioedema episodes within the previous 3 years or requiring medication in 
the previous 2 years 
• Head trauma resulting in a diagnosis of traumatic brain injury other than concussion 
• Frequent episodes of headache. 


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 Subject has received treatment in another clinical study of an investigational drug (or 
medical device) within 30 days or 5 half-lives (whichever is longer) before the first dose 
of study drug. 
 Subject has a history of relevant drug and/or food allergies (ie, allergy to TPOXX or 
excipients, or any significant food allergy that could preclude a standard diet in the study 
site). 
 Subject has any condition possibly affecting drug absorption (eg, previous surgery on the 
gastrointestinal tract, including removal of parts of the stomach, bowel, liver, gallbladder, 
or pancreas, with the exception of appendectomy). 
 Subject has evidence or history of clinically significant allergic (except for untreated, 
asymptomatic, seasonal allergies at time of the first dose of study drug), hematological, 
endocrine, pulmonary, gastrointestinal, cardiovascular, hepatic, psychiatric, or 
neurological disease. Exceptions to these criteria (eg, stable, mild joint disease 
unassociated with collagen vascular disease) may be made following discussions with the 
medical monitor. 
 Subject has a history of cardiac disease, symptomatic or asymptomatic arrhythmias, 
syncopal episodes, or risk factors for torsades de pointes (eg, heart failure, hypokalemia). 
 Subject has a family history of sudden cardiac death not clearly due to acute myocardial 
infarction. 
 Subject has a seizure disorder or history of seizures (does not include childhood febrile 
seizures) or a past history that increases seizure risks such as significant head injury that 
caused loss of consciousness or other changes in the subject’s daily function, concussion, 
stroke, central nervous system infection or disease, or alcohol or drug abuse or family 
history of idiopathic seizures. 
 Subject has a history of a peptic ulcer or significant gastrointestinal bleeding. 
 Subject has a bleeding disorder diagnosed by a doctor (eg, factor deficiency, 
coagulopathy, or platelet disorder requiring special precautions) or significant bruising or 
bleeding difficulties with blood draws. 
 Subject has a malignancy that is active, or treated malignancy for which there is not 
reasonable assurance of sustained cure, or malignancy that is likely to recur during the 
period of the study (subject should be in complete remission for at least 5 years). 


SIGA Technologies, Inc. 
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Protocol: SIGA-246-023 (Version 2.0) 
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 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 CYP2C8 including repaglinide, 
paclitaxel, Montelukast, pioglitazone, rosiglitazone; and substrates of CYP2C19 
including S-mephenytoin, clobazam, diazepam, rabeprazole, voriconazole, lansoprazole, 
and omeprazole. Medications not listed here that are known (or thought) to be CYP3A4 
substrates may be allowed at the investigator’s discretion, after consultation with the 
medical monitor, if administration poses little to no risk to the subject. 
 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 (eg, human T cell 
lymphotropic virus I or II). 
 Subject has consumed grapefruit or grapefruit juice, Seville orange or Seville 
orange-containing products (eg, marmalade), or caffeine- or xanthine-containing products 
within 48 hours before the first dose of study drug. 
 Subject has used any prescription (excluding hormonal birth control) or over-the-counter 
medication (including herbal or nutritional supplements) within 14 days before the first 
dose of study drug. 
 Subject demonstrates long-term use (≥14 consecutive days) of glucocorticoids including 
oral or parenteral prednisone or equivalent (>20 mg total dose per day) or high-dose 
inhaled steroids (>800 mcg/day of beclomethasone dipropionate or equivalent) within the 
preceding 1 month (low-dose [≤800 mcg/day of beclomethasone dipropionate or 
equivalent] inhaled and topical steroids are allowed). 


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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 is a smoker or has used nicotine or nicotine-containing products (eg, cigarettes, 
electronic vapor cigarettes, cigars, chewing tobacco, snuff, nicotine patches, or nicotine 
gum) within 6 months before the first dose of study drug. 
 Subject has consumed pomegranate or pomegranate juice, pomelo fruits or pomelo juice, 
or alcohol within 72 hours before the first dose of study drug. 
 Subject reports participation in strenuous activity or contact sports within 24 hours before 
the first dose of study drug. 
 Subject has known hepatitis B or C infection or positive test for hepatitis B surface 
antigen, hepatitis C virus antibody, or human immunodeficiency virus type 1 or 2 
antibodies at screening. 
 Subject has a positive test result for amphetamines (including methamphetamines and 
ecstasy/methylenedioxymethamphetamine), barbiturates, benzodiazepines, cannabinoids 
(including tetrahydrocannabinol), cocaine metabolites, opiates (including heroin, codeine, 
and oxycodone), or alcohol at screening or check-in. 
 Subject has any of the following laboratory test results within 28 days before the first 
dose of study drug: 
• Estimated serum creatinine clearance (Cockcroft-Gault) <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 count considered to be clinically significant by the investigator 
• Absolute neutrophil count <1000 cells/mm3 
• Platelets not within ±10% of laboratory reference range 
• Alanine aminotransferase >2.0 times above the upper laboratory reference range 


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• Aspartate aminotransferase >2.0 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. 
 Subject has a blood pressure considered to be clinically significant by the investigator. 
Blood pressure may be retested twice in the sitting position at 5-minute intervals. 
 Subject has a resting heart rate of <40 beats per minute or >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. 
 In the opinion of the investigator, the subject is not suitable for entry into the study. 
4.3 
OTHER SCREENING CONSIDERATIONS 
• Subjects must be willing to be confined to the study site until Day 31 (5 separate dosing 
periods). 
• Subjects must be willing and agree to return for the end-of-study visit on Day 36 (+2 days) 
and answer a follow-up telephone call on Day 59 (+4 days). 
4.4 
WITHDRAWAL OF SUBJECTS FROM THE STUDY 
4.4.1 
Reasons for Withdrawal 
Subjects can withdraw consent and discontinue from the study at any time, for any reason, 
without prejudice to further treatment. 
The investigator may withdraw a subject from the study for any of the following: 
• The subject is in violation of the protocol. 


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• The subject experiences a serious or intolerable AE. 
• The subject becomes pregnant. 
• The subject is noncompliant. 
• The subject has laboratory abnormalities for assessments listed in Section 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 Version 2.1 July 2017 any other 
Grade 3 or Grade 4 AE; or a Grade 2 or higher rash considered by the investigator to be 
possibly, probably, or definitely related to study drug. 
• The subject develops, during the course of the study, symptoms or conditions listed in the 
exclusion criteria. 
• The subject requires a medication prohibited by the protocol. 
• The subject requests an early discontinuation for any reason. 
• The subject’s primary care provider requests that the subject be withdrawn. 
• The independent safety monitor (ISM), SIGA, or the FDA requests subject withdrawal 
based on study safety findings. 
The investigator can also withdraw a subject upon the request of SIGA or if SIGA terminates 
the study. Upon occurrence of a SAE or intolerable AE, the investigator will confer with 
SIGA. If a subject is discontinued because of an AE, the event will be followed until it is 
resolved or stabilized as determined by the investigator and/or the medical monitor. 
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 shall be recorded by 
the investigator in the electronic case report form (eCRF). Whenever possible, any subject 
who withdraws from the study prematurely will undergo all Day 36/early discontinuation 
visit assessments (+2 days) (Table 9-2). Any subject who fails to return for final assessments 


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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 
The medical monitor, investigator, SIGA, and ISM will review all AEs. All AEs determined 
by the investigator to be severe and possibly, probably, or definitely related to study drug, as 
well as all clinical assessments, laboratory test results, ECG results, or vital sign 
measurements that meet Grade 3 criteria on the DAIDS AE Grading Table5 will be assessed 
by the medical monitor, who will make a recommendation as to whether or not halting of the 
study should occur. At the discretion of the medical monitor, depending on the assessment of 
the severity of the event, the recommendation to halt the study may be made after 
consultation with the investigator, SIGA, and the ISM. 
The study will be temporarily halted (no new enrollments and no further study drug 
administration) by the investigator and the medical monitor, SIGA, and the ISM will be 
promptly notified according to the following criteria: 
• One subject experiences a Grade 4 AE assessed as possibly, probably, or definitely 
related to study drug. 
• There is a subject death assessed as possibly, probably, or definitely related to study 
drug. 
• One subject experiences a seizure assessed as possibly, probably, or definitely related 
to study drug. 
• Two or more subjects experience the same or similar SAEs that are possibly, 
probably, or definitely related to the study drug. 
• Three or more subjects experience the same or similar AEs that are Grade 3 or above 
and are possibly, probably, or definitely related to the study drug. 
Study enrollment and study drug administration would resume if review of the AEs that 
caused the halt resulted in a recommendation to permit further continuation. In such an 
instance, SIGA, with participation by the investigator and the medical monitor, would consult 
with the ISM to conduct the review of all AEs that meet the criteria for halting the study. The 
study would remain suspended until the events were reviewed by the ISM and a 
recommendation was made as to whether the study should be continued or stopped. This 
constitutes a minimum criterion, and the decision to halt the study may be made based on any 
other criteria that, in the judgment of the investigator, with agreement of the medical monitor 


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and ISM, indicate a potentially serious safety concern. The investigator will advise SIGA 
immediately if any of the halting rules are met. 
4.4.4 
Replacements 
At the discretion of the investigator, and after consultation with the medical monitor, any 
subject who withdraws before completing the study may be replaced to retain the target of 
36 evaluable enrolled subjects. 
5. 
STUDY TREATMENTS 
5.1 
TREATMENTS ADMINISTERED 
All subjects will receive the following study treatments as follows:  
• Treatment A: A single oral dose of 600 mg (3 × 200 mg capsules) TPOXX. 
• 
Treatment B: A single oral dose of 600 mg (3 × 200 mg capsules) TPOXX 
coadministered with a single oral dose of 1600 mg (2 × 800 mg tablets) sevelamer 
carbonate (Renvela® or generic equivalent). 
• Treatment C: A single oral dose of 600 mg (3 × 200 mg capsules) TPOXX 
coadministered with a single oral dose of 500 mg sucroferric oxyhydroxide (Velphoro®) 
chewable tablet. 
• Treatment D: A single oral dose of 600 mg (3 × 200 mg capsules) TPOXX 
coadministered with a single oral dose of 1334 mg (2 × 667 mg capsules) calcium acetate 
(PhosLo® or generic equivalent). 
• Treatment E: A single oral dose of 600 mg (3 × 200 mg capsules) TPOXX 
coadministered with a single oral dose of 500 mg lanthanum carbonate (Fosrenol® or 
generic equivalent) chewable tablet. 
There will be a washout period of 7 days between dosing in each treatment period. 
All subjects will be provided a meal (consisting of approximately 600 calories and 25 g fat). 
The meal should be completed within 30 minutes. 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 study drug administration. All study drug will be 
administered to subjects by the study site personnel with approximately 240 mL of water. 


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Study drug and meals must be taken with water only, and no other beverage except water 
should be ingested within 3 hours before or 3 hours after study drug administration. Water is 
allowed at all times throughout the study. Subjects must fast for 2 hours after taking study 
drug as further food consumption may affect drug absorption. Subjects should receive 
standardized meals that are scheduled at the same time in each period of the study. 
5.2 
INVESTIGATIONAL PRODUCTS 
TPOXX will be supplied as 200-mg capsules containing tecovirimat monohydrate as the 
active pharmaceutical ingredient. The TPOXX capsules are immediate release, size 0, orange 
and black, hard gelatin capsules containing white to off white powder. All inactive 
ingredients/excipients are generally recognized as safe and are United States 
Pharmacopeia/National Formulary grade. The TPOXX excipients are shown in Table 5-1. 
Table 5-1 
Excipients of TPOXX Capsules 
Component 
Quality Designation 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abbreviations: EP, European Pharmacopoeia; JP, Japanese Pharmacopoeia; 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: 
 
 
 


SIGA Technologies, Inc. 
TPOXX (Tecovirimat) 
Protocol: SIGA-246-023 (Version 2.0) 
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Further information on TPOXX can be found in the TPOXX investigator brochure4 and 
prescribing information.3 
The phosphate binder study drugs that will be used in this study are as follows: 
Product 
Supplied Formulation 
Sevelamer carbonate (Renvela® or generic equivalent) 
800 mg tablet 
Sucroferric oxyhydroxide (Velphoro®) 
500 mg chewable tablet 
Calcium acetate (PhosLo® generic equivalent) 
667 mg tablet or capsule 
Lanthanum carbonate (Fosrenol® or generic equivalent) 
500 mg chewable tablet 
5.2.1 
Study Drug Packaging and Storage 
TPOXX capsules are packaged, labeled, distributed, and placed on stability testing in 
accordance with Current Good Manufacturing Practice and International Council for 
Harmonisation (ICH) guidelines. 
The 200-mg TPOXX capsules are supplied in 75-mL high-density polyethylene bottles fitted 
with a heat induction seal and child-resistant screw cap closure system. Each bottle of study 
drug will contain 42 capsules and will be labeled with, at a minimum, the study number, 
bottle content, direction for distribution, storage conditions, and cautionary statement. 
SIGA will provide the investigator and study site with adequate quantities of TPOXX.  
All study drug must be stored in a secure area (eg, a locked cabinet), protected from moisture 
and light, and stored at 15°C to 30°C (59°F to 86°F). Study drug should not be refrigerated or 
used beyond the expiration dates provided by the manufacturer. The study site will be 
required to keep a temperature log to establish a record of compliance with these study drug 
storage conditions. All study drug will be kept in a secure cabinet or room with access 
restricted to necessary study site personnel. 
The phosphate binders will be supplied by the study site. The study site pharmacy will 
prepare the study treatments for each subject according to the schedule of events (Table 9-1 
and Table 9-2). 
All study drugs must be stored according to the labeled instructions in a secure cabinet or 
room with access restricted to necessary clinic personnel. The study site will be required to 
keep a temperature log to establish a record of compliance with storage conditions. 


SIGA Technologies, Inc. 
TPOXX (Tecovirimat) 
Protocol: SIGA-246-023 (Version 2.0) 
27 January 2022 
 
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5.2.2 
Study Drug Accountability 
The investigator 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. Study drug accountability will be recorded in the 
subject source documentation, entered into the eCRF, and should be reviewed by the monitor 
during each monitoring visit. On a regular basis and at the completion of the study, to satisfy 
regulatory requirements regarding drug accountability, all study drugs will be reconciled and 
retained or destroyed according to applicable regulations. 
5.3 
METHOD OF ASSIGNING SUBJECTS TO TREATMENT 
GROUPS 
Randomization will occur according to the randomization schedule before study drug 
administration on Day 1 of Period 1 after it has been confirmed that the subject fulfills all 
eligibility criteria. Subjects will be randomly assigned to receive study drug in 1 of 4 
treatment sequences (ABCDE, ACEBD, ADBEC, and AEDCB) in 1:1:1:1 ratio.  
5.4 
BLINDING 
This is an open-label study. 
5.5 
TREATMENT COMPLIANCE 
All doses of the study drugs will be administered in the study site under direct observation of 
study site personnel and recorded in the eCRF. Per standard clinic procedure, study site 
personnel will perform a mouth check and inspect all dose containers to ensure that the entire 
dose was administered. Following completion of dosing procedures and return of dosing 
containers to the pharmacy by team members, pharmacy staff will follow standard clinic 
procedures for study drug reconciliation. SIGA will provide information to PPD for 
destruction of returned used and unused study drug and study drug bottles. 
The date and time of study drug dosing will be captured and recorded on the appropriate page 
of the eCRF. If a subject is not administered study drug, the reason for the missed dose will 
be recorded. 


SIGA Technologies, Inc. 
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Protocol: SIGA-246-023 (Version 2.0) 
27 January 2022 
 
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5.5.1 
Prior and Concomitant Medications 
Restrictions for prior and concomitant medications and therapies are provided in Section 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. 
5.5.1.1 
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. 
5.5.1.2 
Concomitant Medications 
Any concomitant medication deemed necessary for the welfare of the subject during the 
study may be given at the discretion of the investigator. If a prohibited concomitant 
medication listed in Section 4.2 is taken, it will be documented as a protocol deviation and a 
joint decision will be made by the investigator and SIGA to continue or discontinue the 
subject based on the time the medication was administered, its pharmacology and PK, and 
whether the use of the medication will compromise the safety of the subject or the 
interpretation of the data. The investigator is responsible for ensuring that details regarding 
the medication are adequately recorded in both the subject’s source document and the eCRF. 
6. 
STUDY PROCEDURES 
Before performing any study procedures, all potential subjects will sign an ICF as outlined in 
Section 9.3.2.3. Subjects will undergo study procedures at the time points specified in the 
schedule of events (Table 9-1 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. 
6.1 
PHARMACOKINETIC ASSESSMENTS AND ENDPOINTS 
Blood samples for PK analysis of TPOXX will be collected from all subjects at the following 
time points: within 60 minutes before dosing (0 hour) and at 0.5, 1, 2, 4, 6, 8, 12, 24, and 
48 hours after administration of study drug in each period.  
For PK blood samples, the acceptable window for collection from the scheduled collection 
time point will be as follows: ±5 minutes for the time points from 0.5 through 8 hours and 
±15 minutes for the time points from 12 through 48 hours. 


SIGA Technologies, Inc. 
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Protocol: SIGA-246-023 (Version 2.0) 
27 January 2022 
 
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The following plasma PK parameters will be calculated for TPOXX to extent that data permit 
using actual sampling times rather than scheduled sampling times: 
• Area under the plasma concentration versus time curve (AUC) from time 0 to 24 hours 
(AUC0-24) 
• AUC from time 0 to 48 hours (AUC0-48) 
• AUC from time 0 to infinity (AUC0-inf) 
• AUC from time 0 to the last quantifiable concentration (AUC0-t) 
• Maximum drug concentration in plasma (Cmax) 
• Time to Cmax (Tmax). 
6.1.1 
Pharmacokinetic Sample Collection 
Blood samples (approximately 5 mL) for the determination of plasma concentrations of 
TPOXX will be collected in 5-mL lavender-topped K3EDTA Vacutainer® tubes using a 
20 gauge or larger needle, or from an indwelling intravenous catheter using a vacutainer tube. 
Blood samples should be placed on wet ice (approximately 4°C to 8°C) immediately after 
collection and kept at this temperature until processed to separate plasma.  
The exact time and date of sample collection will be recorded for each sample by the 
investigator or designee in the subject’s eCRF, the vacutainer and cryovial labels, and the 
specimen shipping log. In addition, the time of study drug administration before PK sampling 
will be recorded in the subject’s eCRF. Labels will be created by the study site and should 
contain the protocol number, matrix (plasma), subject number, date, and time drawn. For 
information that is not preprinted on the label, a fine tipped indelible marking pen should be 
used to complete the entry. 
Plasma Sample Processing 
The 5-mL blood sample will be centrifuged in a refrigerated centrifuge immediately, if 
possible, or within 60 minutes of collection at 1000 to 1200 × g (2000 to 3000 rpm) for 
10 minutes to separate the plasma. Each plasma sample should be transferred via pipette into 
2 cryovials labeled as described previously and should be capped tightly. The second tube 
will be a duplicate and retained at the study site as a back-up sample. If red blood cells are 
inadvertently drawn into the plasma, the sample should be re-centrifuged as soon as possible. 


SIGA Technologies, Inc. 
TPOXX (Tecovirimat) 
Protocol: SIGA-246-023 (Version 2.0) 
27 January 2022 
 
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Adequate space between the solution and the tube cap should be allowed for expansion 
during freezing.  
Cryovial tubes containing plasma samples must be frozen at –70°C or below until shipment 
in a freezer equipped with a temperature monitor and temperature-activated alarm. 
Uncentrifuged specimens should not be frozen. 
Plasma samples for bioanalytical analysis will be split upon collection at the site. The study 
site will batch ship sets of frozen plasma samples. A log sheet listing the samples being 
shipped will be included in each shipment. The samples will be sent on dry ice via courier to 
Alturas Analytics (Moscow, ID USA). The back-up sets will remain at the study site until 
further notice from SIGA. The study site will contact Alturas Analytics and coordinate the 
shipment prior to sending the samples. Shipments before weekends or holidays must be 
avoided. 
The samples will be shipped for analysis to:  
Alturas Analytics 
1917 South Main Street 
Moscow, ID 83843, USA 
Alturas Analytics will store all plasma samples at –70°C until analysis for TPOXX is 
complete at which time SIGA will advise Alturas Analytics 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 assay for TPOXX in human plasma method in accordance with the US FDA 
Guidance for Industry on Bioanalytical Method Validation.6 
6.2 
SAFETY ASSESSMENTS AND ENDPOINTS 
Safety and tolerability will be assessed by monitoring and recording of AEs, clinical 
laboratory test results (hematology, serum chemistry, pregnancy, and urinalysis), vital sign 
measurements (systolic and diastolic blood pressures, heart rate, respiratory rate, and body 
temperature), 12-lead ECG results, and physical examination findings. Adverse events will 


SIGA Technologies, Inc. 
TPOXX (Tecovirimat) 
Protocol: SIGA-246-023 (Version 2.0) 
27 January 2022 
 
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be assessed from the time of the first dose of study drug in Period 1 until the follow-up 
telephone call on Day 59 (+4 days). 
For all safety assessments, the investigator will determine whether results are clinically 
significant or not clinically significant. Clinical significance is defined as any variation in a 
result that has medical relevance and may result in an alteration in medical care (eg, active 
observation, diagnostic measures, or therapeutic measures). If a clinical significance change 
from baseline is noted, the result and reason for significance will be documented and an AE 
reported on the AE page in the subject’s eCRF. The investigator will continue to 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. 
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. 
6.2.1 
Adverse Events 
The investigator is responsible for reporting all AEs that are observed or reported during the 
study, regardless of their relationship to study drug or clinical significance. If there is any 
doubt as to whether a clinical observation is an AE, the event should be reported. 
6.2.1.1 
Adverse Event Definitions 
An AE is defined as any untoward medical occurrence, including those AEs that result from 
dosing errors, which may present during administration of a study drug or during a 
reasonable follow-up period and which does not necessarily have a causal relationship with 
the study drug(s). An AE is any unfavorable and unintended sign (eg, a clinically significant 
abnormal laboratory finding), symptom, or disease temporally associated with the use of a 
medicinal product, whether or not considered to be related to the medicinal product. All AEs 
will be followed until the AE is resolved or stabilized as determined by the investigator 
and/or the medical monitor. Subjects will be instructed to contact the investigator at any time 
after randomization 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 to the study 
drug. 


SIGA Technologies, Inc. 
TPOXX (Tecovirimat) 
Protocol: SIGA-246-023 (Version 2.0) 
27 January 2022 
 
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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. 
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 
the study drug and the AE. A suspected adverse reaction implies a lesser degree of certainty 
about causality than an adverse reaction, which means any AE caused by a study drug. 
An AE or suspected adverse reaction is considered “unexpected” if it is not listed in the 
TPOXX full prescribing information3 or if it occurs with specificity or severity that has not 
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 TPOXX 
full prescribing information referred only to elevated hepatic enzymes or hepatitis. Similarly, 
cerebral thromboembolism and cerebral vasculitis would be unexpected (by virtue of greater 
specificity) if the TPOXX full prescribing information listed only cerebral vascular accidents. 
“Unexpected,” as used in this definition, also refers to AEs or suspected adverse reactions 
that are mentioned in the TPOXX full prescribing information as occurring with a class of 
drugs or as anticipated from the pharmacological properties of the drug but are not 
specifically mentioned as occurring with the particular drug under investigation. 
An AE or suspected adverse reaction is considered an SAE if, in the view of either the 
investigator or SIGA, it results in any of the following outcomes: 
• Results in death. 
• Is life-threatening (subject is at immediate risk of death at the time of the event). 
• Requires inpatient hospitalization or prolongation of existing hospitalization, other than 
elective hospitalization, during the period of protocol defined surveillance. 
• Results in congenital anomaly or birth defect. 
• Results in a persistent or significant disability/incapacity. 
• Any other important medical event that may not result in death, be life-threatening, or 
requires hospitalization may be considered an SAE when, based on appropriate medical 
judgment, the event may jeopardize the subject and may require medical or surgical 


SIGA Technologies, Inc. 
TPOXX (Tecovirimat) 
Protocol: SIGA-246-023 (Version 2.0) 
27 January 2022 
 
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intervention to prevent one of the outcomes listed in this definition or is otherwise 
considered to be medically significant. 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical 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 or SIGA, its occurrence places the subject at immediate risk of death. It does 
not include an AE or suspected adverse reaction that, had it occurred in a more severe form, 
might have caused death. 
Serious AEs will be followed until the SAE is stable or until resolution as determined by the 
investigator and/or the medical monitor. 
6.2.1.2 
Eliciting and Documenting Adverse Events 
The investigator is responsible for ensuring that all AEs and SAEs are recorded in the eCRF 
and reported to SIGA by PPD. Adverse events and SAEs will be assessed from the first dose 
of study drug in Period 1 through the telephone call on Day 59 (+4 days). 
At every study visit or assessment, subjects will be asked a standard question to elicit any 
medically related changes in their well-being. They will also be asked if they have been 
hospitalized, had any accidents, used any new medications, or changed concomitant 
medication regimens (both prescription and over-the-counter medications). 
In addition to subject observations, AEs will be documented from any data collected on the 
AE page in the eCRF (eg, 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 or observed from the first dose of study drug in Period 1 through the 
follow-up telephone call on Day 59 (+4 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, 


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Protocol: SIGA-246-023 (Version 2.0) 
27 January 2022 
 
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dosage, 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.  
All AEs will be followed until they are resolved or stabilized as determined by the 
investigator and/or medical monitor. These data will be reviewed on an ongoing basis by the 
study coordinator, the investigator, the medical monitor, and the ISM. This requirement 
indicates that for some events, follow-up may be required after the subject has completed 
study participation. These events will be reported by SIGA, as required, to the FDA. 
Any medical condition that is present at the time that the subject is screened but does not 
deteriorate should not be reported as an AE. However, if it deteriorates at any time during the 
study, it should be recorded as an AE. Prior to this, medical conditions reported by subjects 
are considered medical history. 
6.2.1.4 
Reporting of Serious Adverse Events 
Any AE considered serious by the investigator or which meets SAE criteria (Section 6.2.1.1), 
or any other event or condition regardless of grade, which in their judgment represents a 
reportable event, must be reported to the medical monitor and SIGA as soon as the 
investigator becomes aware of the event. In addition, the event must be reported to PPD via 
the SAE hotline. The PPD SAE Report Form must be submitted within 24 hours of 
knowledge of the event. SIGA 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 ISM will also receive these reports. 
For this study, the following contact information will be used for SAE reporting: 


SIGA Technologies, Inc. 
TPOXX (Tecovirimat) 
Protocol: SIGA-246-023 (Version 2.0) 
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Medical Monitor: 
 
 
 
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 early termination from the study site, the 
subject will be 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 59 [+4 days]) to report any SAEs. 
6.2.1.5 
Assessment of Severity 
All AEs will be graded for intensity according to the current DAIDS Table for Grading the 
Severity of Adult and Pediatric Adverse Events Version 2.1 July 2017.5 
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): Events require minimal or no treatment and do not interfere with the 
subject’s daily activities. 
• Grade 2 (Moderate): Events result in a low level of inconvenience or concern with the 
therapeutic measures and may cause some interference with normal functioning. 
• Grade 3 (Severe): Events interrupt a subject’s usual daily activity, may require systemic 
drug therapy or other treatment, and are usually incapacitating. 
• Grade 4 (Life-threatening): Event that, in the opinion of the investigator, places the 
subject at immediate risk of death from the reaction as it occurred (ie, it does not include 
a reaction that, had it occurred in a more severe form, might have caused death). 
• Grade 5 (Death). 
Changes in the severity of an AE should be documented to allow an assessment of the 
duration of the event at each level of intensity to be performed. An AE characterized as 
intermittent requires documentation of the onset and duration of each episode. 


SIGA Technologies, Inc. 
TPOXX (Tecovirimat) 
Protocol: SIGA-246-023 (Version 2.0) 
27 January 2022 
 
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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 received the study drug. 
The investigator who examines and evaluates the subject will determine AE causality based 
on the temporal relationship to administration of the study drug, the pharmacology of the 
study drug, and their clinical judgment. Terms used to describe the degree of causality 
between each study drug and an AE are definitely related, probably related, possibly related, 
unlikely related, or not related. 
The best estimate at the time of reporting of an event and the degree of certainty about the 
causal relationship between the study drug administration and the AE will be graded as 
follows: 
Associated 
• Definitely Related: The AE and administration of study drug are related in time, and a 
direct association can be demonstrated (eg, the event disappears or decreases with 
reduction in dose or cessation of study drug and recurs with re-exposure). 
• Probably Related: The AE and administration of study drug are reasonably related in time 
and/or follow a known pattern of response, and the AE is more likely explained by study 
drug than other causes. 
• Possibly Related: The AE and administration of study drug are reasonably related in time 
and/or follow a known pattern of response, but the AE can be explained equally well by 
causes other than study drug (eg, could readily have been produced by the subject’s 
clinical state or could have been due to environmental or other interventions). 
Not Associated 
• Unlikely Related: A potential relationship between study drug and the AE could exist 
(ie, the possibility cannot be excluded), but the AE is most likely explained by causes 
other than the study drug (eg, could readily have been produced by the subject’s clinical 
state or could have been due to environmental or other interventions). 


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Protocol: SIGA-246-023 (Version 2.0) 
27 January 2022 
 
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• Not Related: The AE is clearly due to extraneous causes (eg, underlying disease, 
environment) or exposure to the study drug has not occurred. Such events MUST have an 
alternative, definitive etiology documented in the subject’s medical record. 
6.2.1.7 
Follow-up of Adverse Events 
All AEs must be reported in detail on the appropriate page in the eCRF and followed until 
they are resolved or stabilized as determined by the investigator and/or 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 female subject becomes pregnant during study participation, 
study drug dosing will be discontinued, and the subject will be withdrawn from the study. 
The pregnancy itself is not considered an SAE. However, the investigator must complete the 
pregnancy report form and fax it to PPD Pharmacovigilance within 24 hours of knowledge of 
the pregnancy. After delivery or termination of pregnancy, the follow-up pregnancy report 
form should be completed and submitted via fax to PPD Pharmacovigilance. Spontaneous 
abortions should always be reported as SAEs. Pregnancy data will be captured and followed 
by PPD. All pregnancies and outcomes will be tracked. The case will not be closed until after 
the child is followed for 3 months. 
If there are complications during the pregnancy, the complications will be recorded as AEs in 
the usual manner. The subject will be asked to report the outcome of the pregnancy. If there is 
a congenital anomaly in the infant, this will be recorded as an SAE in the data forms for the 
mother (ie, the study subject). 
If a subject becomes pregnant during the study after receiving the study drug, all safety 
evaluations will be collected as per protocol. In addition, at the time that the pregnancy is 
reported, consent will be requested to contact the subject and her physician in the postpartum 
period to assess delivery and health status of the neonate. 
If the partner of a male subject becomes pregnant, the partner will be asked for consent to 
allow her treating physician to provide SIGA or its designee with follow-up information 
regarding the pregnancy and its outcome. 


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6.2.2 
Clinical Laboratory Testing 
Clinical laboratory testing will be performed by the PPD Central Laboratory. Blood and urine 
samples will be collected at the time points indicated in the schedule of events (Table 9-1 and 
Table 9-2) and will be prepared using standard procedures.  
Repeat clinical laboratory tests may be performed at the discretion of the investigator, if 
necessary, to evaluate inclusion and exclusion criteria or clinical laboratory abnormalities. 
PPD central laboratory will provide the reference ranges for all clinical laboratory safety 
parameters. 
The following clinical laboratory assessments will be performed: 
Hematology 
Hematocrit, hemoglobin, mean corpuscular hemoglobin, mean 
corpuscular hemoglobin concentration, total and differential 
leukocyte count (basophils, eosinophils, lymphocytes, monocytes, 
neutrophils), mean corpuscular volume, platelet count, red blood 
cell count, and red cell distribution width 
Serum Chemistry 
Alanine aminotransferase, albumin, alkaline phosphatase, anion 
gap, aspartate aminotransferase, bilirubin (total), blood urea 
nitrogen, calcium, carbon dioxide, chloride, creatinine clearance 
(calculateda), gamma-glutamyltransferase, globulin, glucose, lactate 
dehydrogenase, phosphorus, potassium, sodium, total protein, and 
uric acid 
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, turbidity, 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 A1c and a fasting lipid panel including cholesterol (total, 
high-density lipoprotein, calculated low-density lipoprotein, and triglycerides) will be 
performed at screening. 
Serum pregnancy test (β human chorionic gonadotropin) for women of childbearing potential 
will be performed at screening. A urine pregnancy test will be performed at check-in on 
Day –1). A positive urine pregnancy test will be verified with a follow-up serum pregnancy 
test. 


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TPOXX (Tecovirimat) 
Protocol: SIGA-246-023 (Version 2.0) 
27 January 2022 
 
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A serum follicle-stimulating hormone test for postmenopausal women will be performed at 
screening.  
Human immunodeficiency virus (type 1 and 2) antibodies, hepatitis B surface antigen, and 
hepatitis C virus antibody will be assessed at screening only.  
A urine drug screen for alcohol, 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. At check-in on Day –1., 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 study site. 
Abnormal clinical laboratory values will be flagged as either high or low (or normal or 
abnormal) based on the reference ranges for each laboratory parameter. The investigator will 
determine whether any of the abnormally high or low results are clinically significant or not 
clinically significant.  
6.2.3 
Medical History 
A complete medical history will be obtained, including a review of systems; recreational, 
prescription, and over-the-counter drug use; nicotine and alcohol use; and past 
hospitalizations.  
6.2.4 
Vital Sign Measurements 
Vital signs will be measured after the subject has been in a seated position for at least 
5 minutes at the time points indicated in the schedule 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 12-lead ECG will be obtained after the subject has been in a supine position for at least 
10 minutes at the time points indicated in the schedule of events (Table 9-1 and Table 9-2). 


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On Day 1 of each period, an ECG will be recorded 4 hours after study drug administration. 
The acceptable window for collection from the scheduled collection time point is 
±15 minutes. 
Electrocardiogram assessments will include comments on whether the tracings are normal or 
abnormal, rhythm, presence of arrhythmia or conduction defects, morphology, any evidence 
of myocardial infarction, or ST-segment, T-wave, and U-wave abnormalities. In addition, 
measurements of the following intervals will be measured and reported: heart rate; PR, RR, 
and QT interval; QTcF, QT interval corrected using Fridericia’s formula; and QRS duration. 
All ECGs must be performed by an experienced ECG technician. 
The investigator will determine whether any of the 12-lead ECG results are clinically 
significant or not clinically significant. 
6.2.6 
Physical Examinations 
A full physical examination will be performed at the time points indicated in the schedule of 
events (Table 9-1 and 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); 
pulmonary (chest) auscultation of lungs; abdomen; skin; musculoskeletal system; lymphatic 
system; and neurologic system (cranial nerves, sensation, motor function, coordination, 
reflexes, and mental status). 
A symptom-directed physical examination will be performed at the time points indicated in 
the schedule of events (Table 9-1 and Table 9-2) (for those subjects who require it), and at 
unscheduled visits as necessary. This examination will include an assessment of the heart, 
lungs, abdomen, a neurologic review, and a review of symptoms for assessments and/or 
follow-up of reported or potential AEs. 
Height and weight and will be measured at screening only. 
6.2.7 
Unscheduled Visits 
Subjects will be provided with the contact information for the study site personnel. Subjects 
are free to contact study site personnel at any time, and the site may require an unscheduled 
visit for the purpose of physical examinations, laboratory tests, etc. Unscheduled visits will 
be documented by the site personnel in the source documents. Unscheduled procedures and 
laboratory tests and results will also be recorded in the eCRF. 


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7. 
STATISTICAL ANALYSIS PLAN 
7.1 
SAMPLE SIZE CALCULATIONS 
The sample size (N = 44 [to allow at least 36 enrolled subjects to complete]) for this study is 
based on clinical and practical considerations and not on a formal statistical power 
calculation. The sample size is considered sufficient for the objectives of the study. 
Prior estimates of within-subject variability (CVw) of a single dose of 600 mg TPOXX were 
obtained from Study SIGA-246-018, which evaluated the single-dose PK of TPOXX in a 
similar population. The CVw% for Cmax, AUC0-24 and AUC0-inf ranged from 
11.39% to 12.62%, 9.38% to 18.12%, and 15.70% to 18.02%, respectively. 
For a sensitivity analysis, a range for CVw of 10%, 15%, and 20% across point estimates of 
0.9, 1.0, and 1.1 will be explored. 
For the sensitivity analysis, assuming a range of CVw, a sample size of 36 evaluable subjects, 
it is estimated that the precision (ie, half-width of the 90% confidence interval [CI] on the log 
and ratio scale), and CI with tolerance probability of 80% on the original scale for each point 
estimate will be: 
CVw (%) 
Half-Width 
(log scale) 
Half-Width 
(original scale) 
Point Estimate 
90% Confidence Interval 
10 
0.043 
0.044 
0.9 
(0.862, 0.94) 
1.0 
(0.958, 1.044) 
1.1 
(1.054, 1.148) 
15 
0.065 
0.067 
0.9 
(0.843, 0.96) 
1.0 
(0.937, 1.067) 
1.1 
(1.031, 1.174) 
20 
0.086 
0.090 
0.9 
(0.826, 0.981) 
1.0 
(0.918, 1.09) 
1.1 
(1.009, 1.199) 
Abbreviation: CVw, within-subject variability. 
7.2 
ANALYSIS SETS 
The analysis populations are as follows: 
• The PK population will include subjects who receive at least 1 dose of TPOXX and have 
sufficient concentration data to support accurate estimation of at least 1 PK parameter. 
• The safety population will include all subjects who receive any amount of study drug. 


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7.3 
STATISTICAL ANALYSIS 
Details of all statistical analyses will be described in a statistical analysis plan. All data 
collected will be presented in data listings. Data from subjects excluded from an analysis 
population will be presented in the data listings, but not included in the calculation of 
summary statistics. 
For categorical variables, frequencies and percentages will be presented. Continuous 
variables will be summarized using descriptive statistics (number of subjects, mean, median, 
standard deviation [SD], minimum, and maximum). 
Baseline demographic and background variables will be summarized overall for all subjects. 
The number of subjects who enroll in the study and the number and percentage of subjects 
who complete the study will be presented. Frequency and percentage of subjects who 
withdraw or discontinue from the study, and the reason for withdrawal or discontinuation, 
will also be summarized. 
7.3.1 
Pharmacokinetic Analyses 
Individual plasma concentration and time deviation data will be presented in a data listing. 
Plasma concentration data will be summarized by time point for each treatment using the 
following descriptive statistics: number of subjects, arithmetic mean, SD, coefficient of 
variation (CV), geometric mean, geometric CV, geometric SD, minimum, median, and 
maximum. Individual and mean plasma concentration versus scheduled time profiles will be 
presented in figures on both linear and semilogarithmic scales. 
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 treatment using the following descriptive statistics: number of subjects, 
mean, SD, CV, geometric mean, geometric SD, geometric CV, minimum, median, and 
maximum. Geometric means will be included for AUC0-24 and Cmax. 
A linear mixed model with sequence, treatment, and period as fixed effects and subject 
within sequence as a random effect will be performed on the natural log-transformed values 
of AUC0-24 and Cmax to assess the effect of phosphate binders on the PK of TPOXX. The 
geometric least squares means and corresponding 90% CIs will be computed for AUC0-24 and 
Cmax of TPOXX + phosphate binder versus TPOXX alone by taking the antilog of the least 
squares means from the linear mixed-effect model on the natural logarithms of the 
corresponding PK parameters. A 90% CI for the ratio will be constructed as the antilog of the 


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Protocol: SIGA-246-023 (Version 2.0) 
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confidence limits of the mean difference. No adjustment will be made for multiplicity. The 
geometric mean ratios and corresponding 90% CIs for AUC0-24 and Cmax for TPOXX will be 
summarized in forest plots for overall assessment of the DDI. 
It will be concluded that there is no relevant interaction of phosphate binders on TPOXX if 
the 90% CIs for AUC0-24 and Cmax ratios (TPOXX + phosphate binder/TPOXX alone) are 
completely contained within the [80%, 125%] interval. 
Non-parametric methods will be used to examine median differences in Tmax for TPOXX. 
7.3.2 
Safety Analyses 
Adverse events will be coded by preferred term and system organ class using the latest 
version of the Medical Dictionary for Regulatory Activities and summarized by treatment 
and overall. All AE data will be presented in a data listing. Treatment-emergent AEs will be 
summarized by treatment and overall, as well as by severity and relationship to study drug. 
Serious AEs and AEs leading to discontinuation of study drug will also be presented in the 
data listings and summarized by treatment and overall. 
Actual values and changes from baseline for clinical laboratory test results, vital sign 
measurements, and 12-lead ECG results will be summarized by treatment 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. 
7.4 
HANDLING OF BELOW THE LIMIT OF 
QUANTIFICATION AND MISSING DATA 
Plasma concentrations that are below the limit of quantification (BLQ) will be treated as zero 
for descriptive statistics. 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 will be performed in this study. 


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8. 
REFERENCE LIST 
1. Breman JG, Henderson DA. Diagnosis and management of smallpox. N Engl J Med. 
2002;346(17):1300-8. 
2. Department of Health and Human Services (DHHS), Food and Drug Administration, 
Center for Drug Evaluation and Research, Center for Drug Evaluation and Research. 
Guidance for Industry: Clinical Drug Interaction Studies—Cytochrome P450 Enzyme- 
and Transporter-Mediated Dug Interactions. January 2020 [cited 24 Jan 2022]. Available 
from: https://www.fda.gov/media/134581/download. 
3. TPOXX (tecovirimat) [full prescribing information]. SIGA Technologies, Inc. Corvallis 
(OR); 2018. 14 p. [cited 2021 Jan 19]. Available from 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/208627s000lbl.pdf. 
4. SIGA Technologies, Inc. TPOXX. Investigator’s brochure, 17th ed. Corvallis (OR); 2021. 
122 p. 
5. 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 24 Jan 2022]. Available from: 
https://rsc.niaid.nih.gov/sites/default/files/daidsgradingcorrectedv21.pdf. 
6. Department of Health and Human Services (DHHS), Food and Drug Administration, 
Center for Drug Evaluation and Research, Center for Biologics Evaluation and Research 
(US). Guidance for Industry. Bioanalytical Method Validation. May 2018 [cited 
24 Jan 2022]. Available from: https://www.fda.gov/files/drugs/published/Bioanalytical-
Method-Validation-Guidance-for-Industry.pdf. 


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9. 
APPENDICES 
9.1 
APPENDIX 1: LIST OF ABBREVIATIONS 
Abbreviation 
Term 
AE 
adverse event 
AUC 
area under the plasma concentration versus time curve 
AUC0-24 
area under the plasma concentration versus time curve from time 0 
to 24 hours  
BLQ 
below the limit of quantification 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
Cmax 
maximum drug concentration in plasma 
CRA 
clinical research associate 
CV 
coefficient of variation 
CVw 
within-subject variability 
DAIDS 
Division of Acquired Immune Deficiency Syndrome 
DDI 
drug-drug interaction 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
FDA 
Food and Drug Administration 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IRB 
institutional review board 
ISM 
independent safety monitor 
PK 
pharmacokinetic(s) 
QTcF 
QT interval corrected using Fridericia’s formula 
SAE 
serious adverse event 
SD 
standard deviation 
SOP 
standard operating procedures 
Tmax 
time to maximum drug concentration in plasma 


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Protocol: SIGA-246-023 (Version 2.0) 
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9.2 
APPENDIX 2: SCHEDULE OF EVENTS 
Table 9-1 
Schedule of Events: Period 1 through Period 3 
Phase Screening Check-in 
Treatment Period 1 
Treatment Period 2 
Treatment Period 3 
Procedure(a) 
Day –28 to –2 
–1 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 11 12 13 14 
15 16 17 18 19 20 
 
Day 
 
 
 
 
 
 
 
 
–1 
1 
2 
3 
4 
5 
6 
–1 
1 
2 
3 
4 
5 
6 
Admission to clinic 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Domiciled at clinic 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history(b) 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination(c) 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height and weight  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital sign measurements(d) 
X 
X 
X 
X 
X 
 
 
 
X 
X 
X 
X 
 
 
 
X 
X 
X 
X 
 
 
 
Glycosylated hemoglobin (HbA1c) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Fasting lipid panel(e) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical laboratory testing(f) 
X(g) 
X 
 
X 
 
 
 
 
X 
 
X 
 
 
 
 
X 
 
X 
 
 
 
 
Serum follicle-stimulating hormone(h) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum pregnancy test(i) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine pregnancy test(i) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine drug/alcohol screen(j) 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serology (HBsAg, HCV, and HIV) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization(k) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
12-lead electrocardiogram(l) 
X 
X 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
Administration of study drug(s)(m) 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
Pharmacokinetic sample collection(n) 
 
 
X 
X 
X 
 
 
 
 
X 
X 
X 
 
 
 
 
X 
X 
X 
 
 
 
Adverse events 
 
 
X 
Prior/concomitant medications 
X 
Abbreviations: ECG, electrocardiogram; HBsAg, hepatitis B surface antigen; HCV, hepatitis C virus; HIV, human immunodeficiency virus; 
PK, pharmacokinetic. 
Notes: 
(a) When procedures overlap or occur at the same time point, all blood draws should follow vital signs or ECGs, and PK sampling should be timed to occur last 
and as close to the scheduled time window as possible. 
(b) Medical history will include a review of systems; recreational, prescription, and over-the-counter drug use; nicotine and alcohol use; and past hospitalizations. 


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(c) 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). Symptom-directed physical examination will include an assessment of the heart, 
lungs, abdomen, a neurologic review, and a review of symptoms for assessment and/or follow-up of reported or potential adverse events. 
(d) Vital sign measurements will include systolic and diastolic blood pressures, heart rate, respiratory rate, and body temperature. Vital signs will be measured at 
screening, and in each period, at check-in; within 60 minutes prior to dosing; and at 4, 8, 12, 24, and 48 hours following dosing in each period after the subject 
has been in a seated position for at least 5 minutes. 
(e) Fasting lipid panel will include cholesterol (total, high-density lipoprotein, calculated low-density lipoprotein, and triglycerides). 
(f) Clinical laboratory testing will include hematology and serum chemistry.  
(g) Clinical laboratory testing at screening will include hematology, serum chemistry, and urinalysis. 
(h) For postmenopausal women, a serum follicle-stimulating hormone test will be performed at screening. 
(i) Women of childbearing potential only. 
(j) 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. 
(k) Randomization will occur according to the randomization schedule before study drug administration on Day 1 of Period 1 after it has been confirmed that the 
subject fulfills all eligibility criteria. Subjects will be randomly assigned to receive study drug in 1 of 4 treatment sequences (ABCDE, ACEBD, ADBEC, and 
AEDCB) in 1:1:1:1 ratio. 
(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 of each period, an ECG will be 
recorded 4 hours after study drug administration. The acceptable window for collection from the scheduled collection time point is ±15 minutes. 
(m) All subjects will be provided a meal (consisting of approximately 600 calories and 25 g fat).  The meal should be completed within 30 minutes. Subjects 
should be administered study drug(s) as soon as possible following completion of the meal but no more than 30 minutes should elapse between meal 
completion and study drug administration. Study drug and meals must be taken with water only, and no other beverage except water should be ingested within 
3 hours before or 3 hours after study drug administration. Subjects must fast for 2 hours after taking study drug. The time of study drug dosing will be called 
“0” hour in each period. 
Treatment A: A single oral dose of 600 mg (3 × 200 mg capsules) TPOXX 
Treatment B: A single oral dose of 600 mg (3 × 200 mg capsules) TPOXX coadministered with a single oral dose of 1600 mg (2 × 800 mg tablets) sevelamer 
carbonate (Renvela® or generic equivalent) 
Treatment C: A single oral dose of 600 mg (3 × 200 mg capsules) TPOXX coadministered with a single oral dose of 500 mg sucroferric oxyhydroxide 
(Velphoro®) chewable tablet. 
Treatment D: A single oral dose of 600 mg (3 × 200 mg capsules) TPOXX coadministered with a single oral dose of 1334 mg (2 × 667 mg capsules) calcium 
acetate (PhosLo® generic equivalent). 
Treatment E: A single oral dose of 600 mg (3 × 200 mg capsules) TPOXX coadministered with a single oral dose of 500 mg lanthanum carbonate (Fosrenol® 
or generic equivalent) chewable tablet. 
(n) Blood samples for PK analysis of TPOXX will be collected from all subjects at the following time points: within 60 minutes before dosing (0 hour) and at 0.5, 
1, 2, 4, 6, 8, 12, 24, and 48 hours after administration of study drug in each period. For PK blood samples, the acceptable window for collection from the 
scheduled collection time point will be as follows: ±5 minutes for the time points from 0.5 through 8 hours and ±15 minutes for the time points from 
12 through 48 hours. 


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Table 9-2 
Schedule of Events: Period 4 and Period 5 
Phase 
Treatment Period 4 
Treatment Period 5 
End of Study Visit or 
Early Termination(b) 
Follow-up 
Telephone Call(c) 
Procedure(a) 
Day 
21 
22 
23 
24 
25 
26 
27 
28 
29 
30 
31 
36 (+2) 
59 (+4) 
 
Day 
–1 
1 
2 
3 
4 
5 
6 
–1 
1 
2 
3 
 
 
Domiciled at clinic 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Discharge from clinic 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Outpatient visit 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Physical examination(d) 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Vital sign measurements(e) 
X 
X 
X 
X 
 
 
 
X 
X 
X 
X 
X 
 
Clinical laboratory testing(f) 
X 
 
X 
 
 
 
 
X 
 
X 
 
X(g) 
 
12-lead electrocardiogram(h) 
 
X 
 
 
 
 
 
 
X 
 
 
X 
 
Administration of study drug(s)(i)  
 
X 
 
 
 
 
 
 
X 
 
 
 
 
Pharmacokinetic sample collection(j) 
 
X 
X 
X 
 
 
 
 
X 
X 
X 
 
 
Adverse events 
X 
 
Serious adverse events 
X 
Prior/concomitant medications 
X 
Abbreviations: ECG, electrocardiogram; PK, pharmacokinetic. 
Notes: 
(a) When procedures overlap or occur at the same time point, all blood draws should follow vital signs or ECGs, and PK sampling should be timed to occur last 
and as close to the scheduled time window as possible. 
(b) The end-of-study visit will occur 7 days after the last dose of study drug.  
(c) The follow-up telephone call will be made 30 days after the last dose of study drug (Day 59 [+4 days]). Discharge will follow all safety assessments and PK 
sample collections. 
(d) Symptom-directed physical examination will include an assessment of the heart, lungs, abdomen, a neurologic review, and a review of symptoms for 
assessment and/or follow-up of reported or potential adverse events. 
(e) Vital sign measurements will include systolic and diastolic blood pressures, heart rate, respiratory rate, and body temperature. Vital signs will be measured 
after the subject has been seated for at least 5 minutes. Vital signs will be measured at screening, and in each period, vital sign measurements will be measured 
at check-in; within 60 minutes prior to dosing; and at 4, 8, 12, 24, and 48 hours after the study drug administration. 
(f) Clinical laboratory testing will include hematology and serum chemistry.  
(g) Clinical laboratory testing at end of study or early discontinuation will include hematology, serum chemistry, and urinalysis. 
(h) A single 12-lead ECG will be collected after the subject has been in the supine position for at least 10 minutes. In each period, an ECG will be recorded 4 
hours after the study drug administration. The acceptable window for collection from the scheduled collection time point is ±15 minutes. 
(i) All subjects will be provided a meal (consisting of approximately 600 calories and 25 g fat).  The meal should be completed within 30 minutes. Subjects 
should be administered study drug(s) as soon as possible following completion of the meal but no more than 30 minutes should elapse between meal 
completion and study drug administration. Study drug and meals must be taken with water only, and no other beverage except water should be ingested within 


SIGA Technologies, Inc. 
TPOXX (Tecovirimat) 
Protocol: SIGA-246-023 (Version 2.0) 
27 January 2022 
 
Page 54 
3 hours before or 3 hours after study drug administration.   Subjects must fast for 2 hours after taking study drug. The time of study drug dosing will be called 
“0” hour in each period. 
Treatment A: A single oral dose of 600 mg (3 × 200 mg capsules) TPOXX 
Treatment B: A single oral dose of 600 mg (3 × 200 mg capsules) TPOXX coadministered with a single oral dose of 1600 mg (2 × 800 mg tablets) sevelamer 
carbonate (Renvela® or generic equivalent) 
Treatment C: A single oral dose of 600 mg (3 × 200 mg capsules) TPOXX coadministered with a single oral dose of 500 mg sucroferric oxyhydroxide 
(Velphoro®) chewable tablet. 
Treatment D: A single oral dose of 600 mg (3 × 200 mg capsules) TPOXX coadministered with a single oral dose of 1334 mg (2 × 667 mg capsules) calcium 
acetate (PhosLo® generic equivalent). 
Treatment E: A single oral dose of 600 mg (3 × 200 mg capsules) TPOXX coadministered with a single oral dose of 500 mg lanthanum carbonate (Fosrenol® 
or generic equivalent) chewable tablet. 
(j) Blood samples for PK analysis of TPOXX will be collected from all subjects at the following time points: within 60 minutes before dosing (0 hour) and at 0.5, 
1, 2, 4, 6, 8, 12, 24, and 48 hours after administration of study drug in each period. For PK blood samples, the acceptable window for collection from the 
scheduled collection time point will be as follows: ±5 minutes for the time points from 0.5 through 8 hours and ±15 minutes for the time points from 
12 through 48 hours.


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


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


SIGA Technologies, Inc. 
TPOXX (Tecovirimat) 
Protocol: SIGA-246-023 (Version 2.0) 
27 January 2022 
 
Page 57 
compliance with the ICH harmonised tripartite guideline E6(R2): Good Clinical Practice will 
be maintained by the site and will be available for review by SIGA or its designee. 
All IRB approvals should be signed by the IRB chairman or designee and must identify the 
IRB name and address, the clinical protocol by title or protocol number or both, and the date 
approval or a favorable opinion was granted. 
9.3.2.3 
Subject Consent 
Written documentation of informed consent in compliance with US Title 21 CFR Part 50 
shall be obtained from each subject before any study-related procedures are performed and 
study drug is administered. If any institution-specific modifications to study-related 
procedures are proposed or made by the site, the consent should be reviewed by SIGA or its 
designee or both before IRB submission. Once reviewed, the investigator will submit the ICF 
to the IRB for review and approval before the start of the study. If the ICF is revised during 
the course of the study, all active participating subjects must sign the revised ICF. 
Before recruitment and enrollment, each prospective subject or his/her legal guardian will be 
given a full explanation of the study and will be 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 his 
or her consent to participate in the study by signing the ICF. A copy of the ICF will be 
provided to the subject/legal guardian. 
9.3.2.4 
Exclusion of Children 
Effort will be made to include women and minorities in proportions similar to that of the 
community from which they are recruited. Because this study is designed to establish safety 
of the study drug in adults, enrollment will be limited to persons at least 18 years of age, and 
no older than 50 years. Children are excluded from participation in this clinical study because 
it does not meet the Department of Health and Human Services’ guidelines (45 CFR 46, 
Subpart D, 401-409) for inclusion of children in research. These guidelines provide guidance 
for the protection of children in research. Generally, healthy children can be studied when the 
research is considered as “not greater than minimal risk.” Children can be involved in 
research with greater than minimal risk only when it presents the prospect of direct benefit to 
the individual child or is likely to yield generalizable knowledge about the child’s disorder or 
condition. 


SIGA Technologies, Inc. 
TPOXX (Tecovirimat) 
Protocol: SIGA-246-023 (Version 2.0) 
27 January 2022 
 
Page 58 
9.3.2.5 
Study Reporting Requirements 
By participating in this study, the investigator agrees to submit reports of SAEs according to 
the time line and method outlined in this protocol. In addition, the investigator agrees to 
submit annual reports to his or her IRB as appropriate. 
9.3.2.6 
Financial Disclosure and Obligations 
The investigator is required to provide financial disclosure information to allow SIGA to 
submit the complete and accurate certification or disclosure statements required under US 
Title 21 CFR Part 54. In addition, the investigator must provide to SIGA a commitment to 
promptly update this information if any relevant changes occur during the course of the 
investigation and for 1 year following the completion of the study. 
Neither SIGA nor PPD is financially responsible for further testing or treatment of any 
medical condition that may be detected during the screening process. In addition, in the 
absence of specific arrangements, neither SIGA nor PPD is financially responsible for further 
treatment of the disease under study. 
9.3.2.7 
Investigator Documentation 
Prior to beginning the study, the investigator will be asked to comply with ICH 
E6(R2) Section 8.2 and US Title 21 of the CFR by providing essential documents, including 
but not limited to, the following: 
• IRB approval. 
• An original investigator-signed investigator agreement page of the protocol. 
• Form FDA 1572, fully executed, and all updates on a new fully executed 
Form FDA 1572. 
• Curriculum vitae for the principal investigator and each subinvestigator listed on Form 
FDA 1572. Current licensure must be noted on the curriculum vitae. Curriculum vitae 
will be signed and dated by the principal investigators and subinvestigators at study 
start-up, indicating that they are accurate and current. 
• Financial disclosure information to allow SIGA to submit complete and accurate 
certification or disclosure statements required under US Title 21 CFR Part 54. In 
addition, the investigators must provide to SIGA a commitment to promptly update this 


SIGA Technologies, Inc. 
TPOXX (Tecovirimat) 
Protocol: SIGA-246-023 (Version 2.0) 
27 January 2022 
 
Page 59 
information if any relevant changes occur during the course of the investigation and for 
1 year after the completion of the study. 
• An IRB-approved ICF, samples of site advertisements for recruitment for this study, and 
any other written information about this study that is to be provided to the subject or legal 
guardians. 
• Laboratory certifications and reference ranges for any local laboratories used by the site, 
in accordance with US Title 42 CFR Part 493. 
9.3.2.8 
Study Conduct 
The investigator agrees to perform all aspects of this study in accordance with the ethical 
principles that have their origin in the Declaration of Helsinki, ICH E6(R2): Good Clinical 
Practice; the protocol; and all national, state, and local laws or regulations. 
9.3.2.9 
Case Report Forms and Source Documents 
Site personnel will maintain source documentation, enter subject data into the eCRF as 
accurately as possible, and will rapidly respond to any reported discrepancies. 
Electronic CRFs and electronic data capture will be utilized. The electronic data capture 
system is validated and compliant with US Title 21 CFR Part 11. Each person involved with 
the study will have an individual identification code and password that allows for record 
traceability. Thus, the system, and any subsequent investigative reviews, can identify 
coordinators, investigators, and individuals who have entered or modified records, as well as 
the time and date of any modifications. There may be an internal quality review audit of the 
data and additional reviews PPD’s CRA. 
Each eCRF is presented as an electronic copy, allowing data entry by site personnel, who can 
add and edit data, add new subjects, identify and resolve discrepancies, and view records. 
This system provides immediate direct data transfer to the database, as well as immediate 
detection of discrepancies, enabling site coordinators to resolve and manage discrepancies in 
a timely manner. 
Paper copies of the eCRFs and other database reports may be printed and signed by the 
investigator. This system provides site personnel, PPD’s CRA’s, and reviewers with access to 
hardcopy audits, discrepancy reviews, and investigator comment information. 


SIGA Technologies, Inc. 
TPOXX (Tecovirimat) 
Protocol: SIGA-246-023 (Version 2.0) 
27 January 2022 
 
Page 60 
9.3.2.10 
Adherence to Protocol 
The investigator agrees to conduct the study as outlined in this protocol, in accordance with 
ICH E6(R2) and all applicable guidelines and regulations. 
9.3.2.11 
Reporting Adverse Events 
By participating in this study, the investigator agrees to submit reports of SAEs according to 
the timeline and method outlined in this protocol. In addition, the investigator agrees to 
submit annual reports to his or her IRB as appropriate. The investigator also agrees to 
provide the sponsor 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 the sponsor and regulatory authorities with any reports required. 
9.3.2.13 
Records Retention 
Essential documents should be retained until at least 2 years after the last approval of a 
marketing application in an ICH region and until there are no pending or contemplated 
marketing applications in an ICH region or until at least 2 years have elapsed since the 
formal discontinuation of clinical development of the study drug. These documents should be 
retained for a longer period, however, if required by applicable regulatory requirements or by 
an agreement with SIGA. SIGA is responsible for informing the investigator/institution when 
these documents no longer need to be retained. 
9.3.2.14 
Publications 
All information concerning TPOXX, SIGA operations, patent application, formulas, 
manufacturing processes, basic scientific data, and formula information, supplied by SIGA to 
the investigator and not previously published, is considered confidential and remains the sole 
property of SIGA. The investigator agrees to use this information only to accomplish this 
study and will not use it for other purposes without SIGA’s written consent. The investigator 
understands that the information developed in the clinical study will be used by SIGA, in 
connection with the continued development of TPOXX, and thus may be disclosed as 
required to other clinical investigators or government regulatory agencies. To permit the 


SIGA Technologies, Inc. 
TPOXX (Tecovirimat) 
Protocol: SIGA-246-023 (Version 2.0) 
27 January 2022 
 
Page 61 
information derived from the clinical studies to be used, the investigator is obligated to 
provide SIGA with all data obtained in the study. Any publication or other public 
presentation of results from this study, including manuscripts and materials for presentation 
at scientific meetings, should be provided to SIGA at least 30 working days before abstract or 
other relevant submission deadlines. Authorship of publications resulting from this study will 
be determined at the discretion of SIGA. 
9.3.3 
Study Management 
9.3.3.1 
Monitoring 
9.3.3.1.1 
Monitoring of the Study 
Site monitoring for safety is conducted to ensure that human subject protection, study 
procedures, and laboratory, study drug dosing, and data collection processes are of high 
quality and meet SIGA, GCP/ICH, and regulatory guidelines. PPD CRA(s) will conduct site 
monitoring visits as detailed in the monitoring plan. 
Site investigators will allow the CRA(s), the designated IRB, SIGA or its designee and the 
FDA to review, audit, and inspect study documents (eg, ICFs, drug accountability and 
distribution forms, eCRF), pertinent hospital and site records, and source documentation for 
verification of the study data.  
Clinical research associates will conduct site visits in accordance with PPD SOPs to monitor 
the following: study operations, the quality of data collected in the research records, the 
accuracy and timeliness of data entered in the database, and to determine that all process and 
regulatory requirements are met. Study monitoring visits will occur at initiation of the study 
site, at intervals determined by SIGA during conduct of the study, and at completion of the 
study.  
The CRA will maintain current personal knowledge of the study through observation, review 
of study records and source documentation, and discussion of the conduct of the study with 
the investigator and staff. During the routine monitoring visits, the CRA will perform a 100% 
source document verification of all subject data entered into the eCRF. Discrepancies, if any, 
will be clarified with the study site coordinator and investigator, and corrected at the site by 
the study coordinator. Any questions or required data clarifications will be sent to the study 
site electronically.  


SIGA Technologies, Inc. 
TPOXX (Tecovirimat) 
Protocol: SIGA-246-023 (Version 2.0) 
27 January 2022 
 
Page 62 
9.3.4 
Safety Monitoring Plan 
Close cooperation between the designated members of the study team will occur to evaluate 
and respond to individual AEs in a timely manner. Designated team members (investigator, 
subinvestigators, study coordinator, and other designated study clinicians) will review the 
subject safety information and data (laboratory test results, ECGs, AEs, and concomitant 
medications) and update the PPD project team and the ISM on the status of all enrolled 
subjects at their site on a weekly basis (or more frequently if required because of an 
unexpected safety issue) through completion of each subject’s final study visit. 
9.3.5 
Medical Monitor 
The medical monitor, or their qualified designee, will receive reports within 24 hours of 
study site awareness of all SAEs and within 7 days of study site awareness of all other AEs. 
The safety monitors will review all safety data and alert the medical monitor of SAEs and 
AEs of interest. The medical monitor may make a request for data to the investigator as 
necessary for safety evaluations.  
The medical monitor will review each significant AE in a timely fashion and ensure that 
appropriate management is initiated and completed. Drug safety representatives and the 
medical monitor will have direct contact with the investigators and follow all significant 
events as needed. 
9.3.6 
Safety Oversight (Independent Safety Monitor) 
In addition to the investigator’s ongoing review of the safety data, the ISM will review the 
protocol for any major concerns and will be involved in data review in coordination with the 
investigator. The primary role of the ISM will be to evaluate the study safety and tolerability 
data. The ISM will provide independent safety monitoring in a timely fashion, which will 
include reviewing individual SAE reports and a review of periodic cumulative AE reports. 
Clinical safety and laboratory data, clinical records, and other safety study-related records 
will be made available for the ISM to review. Based on review of this data, the ISM may 
make recommendations regarding the safe continuation of the study. Specific details will be 
outlined in the Safety and Medical Management Plan. 
9.3.6.1.1 
Inspection of Records 
The investigator and institution involved in the study will permit study-related monitoring, 
audits, IRB review, and regulatory inspections by providing direct access to all study records. 


SIGA Technologies, Inc. 
TPOXX (Tecovirimat) 
Protocol: SIGA-246-023 (Version 2.0) 
27 January 2022 
 
Page 63 
In the event of an audit, the investigator agrees to allow the sponsor, their representatives, the 
FDA, or other regulatory agencies access to all study records. 
The investigator should promptly notify SIGA and study site of any audits scheduled by any 
regulatory authorities and promptly forward copies of any audit reports received to SIGA. 
9.3.6.2 
Management of Protocol Amendments and Deviations 
9.3.6.2.1 
Modification of the Protocol 
Any changes in this research activity, except those necessary to remove an apparent 
immediate hazard to the subject, must be reviewed and approved by the sponsor or designee. 
Amendments to the protocol must be submitted in writing to the investigator’s IRB for 
approval before subjects are enrolled into an amended protocol. 
9.3.6.2.2 
Protocol Deviations 
The investigator or designee must document and explain in the subject’s source 
documentation any deviation from the approved protocol. The investigator may implement a 
deviation from, or a change to, the protocol to eliminate an immediate hazard to study 
subjects without prior IRB approval. As soon as possible after such an occurrence, the 
implemented deviation or change, the reasons for it, and any proposed protocol amendments 
should be submitted to the IRB for review and approval, to SIGA for agreement, and to the 
regulatory authorities, if required. 
A protocol deviation is any change, divergence, or departure from the study design or 
procedures defined in the protocol. An important protocol deviation (sometimes referred to 
as a protocol violation or a major protocol deviation) is a subset of protocol deviations that 
might significantly affect the reliability of the study data or that might significantly affect a 
subject’s safety. An important deviation can include nonadherence to inclusion or exclusion 
criteria or nonadherence to FDA regulations or ICH E6(R2) guidelines. 
Protocol deviations will be documented by the clinical monitor throughout the course of 
monitoring visits. The investigator will be notified in writing by the monitor of deviations. 
The IRB should be notified of all protocol deviations, if appropriate, in a timely manner. 


SIGA Technologies, Inc. 
TPOXX (Tecovirimat) 
Protocol: SIGA-246-023 (Version 2.0) 
27 January 2022 
 
Page 64 
9.3.6.3 
Study Termination 
Although SIGA has every intention of completing the study, they reserve the right to 
discontinue it at any time for clinical or administrative reasons. 
An initiative for closure of the clinical investigative site or termination of the study can be 
taken at any time either by SIGA, PPD, or the investigator provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. Reasons for such action 
include, but are not limited to: 
• Study site closure 
o Inadequate site recruitment/enrollment of subjects 
o Failure of an investigator to comply with the protocol, PPD SOPs, GCP guidelines, or 
applicable federal regulations 
• Termination of enrollment 
o Enrollment of the required estimated number of subjects for the study 
• Study termination 
o Completion of the study 
o Safety concerns 
In addition, the ISM and FDA have the prerogative to delay or terminate the study. 
The end of the study is defined as the date on which the last subject completes the last visit 
(includes the end-of-study visit and the follow-up telephone call). Any additional long-term 
follow-up that is required for monitoring of the resolution of an AE or finding may be 
reported through an amendment to the clinical study report. 
9.3.6.4 
Final Report 
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. 


SIGA Technologies, Inc. 
TPOXX (Tecovirimat) 
Protocol: SIGA-246-023 (Version 2.0) 
27 January 2022 
 
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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 investigator will be provided with the final 
approved clinical study report, as appropriate. 
 
 


SIGA Technologies, Inc. 
TPOXX (Tecovirimat) 
Protocol: SIGA-246-023 (Version 2.0) 
27 January 2022 
 
Page 66 
9.4 
APPENDIX 4: CHANGE HISTORY 
Protocol Amendment 1 dated January 27, 2022 was issued to update the medical monitor and 
update the study design per request from the clinic to keep subjects domiciled at the study 
site for the duration of the study (Day –1 to Day 31) versus subjects checking out 48 hours 
after each dose in each period. 
Protocol Section 
Change 
Title page and Section 6.2.1.4 
Reporting for Serious Adverse 
Events 
PPD Medical Monitor information was updated. 
Synopsis and Section 2.1 Primary 
Objective 
Primary objective was updated to “The primary 
objective of this study is to evaluate potential 
drug-drug interaction as measured by the effect of 
coadministration of 4 separate phosphate binders on 
the PK of orally administered TPOXX in healthy 
adult subjects.” 
Synopsis and Section 3 Study 
Design and Methodology 
Removed “check-in and” and updated treatment 
period to (Day –1 to Day 31). 
The study will consist of a screening period 
(Day -28 to Day –2), 5 check in and treatment 
periods (Day –1 to Day 31), an end-of-study visit 
(Day 36 [+2 days]), and a follow-up telephone call 
(Day 59 [+4 days]). 
Synopsis and Section 3 Study 
Design and Methodology 
Added “in Period 5 (Day 31)” 
In each period, subjects will report to the study site 
on Day –1 and remain confined to the study site 
until 48 hours after dosing in Period 5 (Day 31). 
Synopsis and Section 4.2 Exclusion 
Criteria 
“Day 1 of each period” was changed to “the first 
dose of study drug” in exclusion criteria 19 and 24 
Section 4.3 Other Screening 
Considerations 
Clarified that subjects will be confined to the study 
site until Day 31 (5 separate periods). 
Section 5.2 Investigational Product  
Reference to the prescribing information was added.  
Section 6.1.1 Pharmacokinetic 
Sample Collection 
Updated Alturas Analytics address and instructions 
for back-up samples. 
Section 6.2.2 Clinical Laboratory 
Testing 
• “on Day –1 of each period” was updated to “at 
check-in (Day –1)”. 
• Removed serum pregnancy test and added a urine 
pregnancy test at Check-in on Day -1. 
• Added clarification that urine drug screen at 
Check-in on Day -1 will be performed and read 
locally and that blood alcohol will be tested using 
a breathalyzer device at the study site. 


SIGA Technologies, Inc. 
TPOXX (Tecovirimat) 
Protocol: SIGA-246-023 (Version 2.0) 
27 January 2022 
 
Page 67 
Section 8 Reference List 
• Additional information for the TPOXX full 
prescribing reference was added. 
• Added reference for DAIDS grading and citation 
was added to Section 4.2.3 and Section 6.2.1.5. 
• Updated version, year, and page number of the 
tecovirimat IB. 
Appendix 2 Schedule of Events 
Table 9-1 
• “X” was removed from Day –1 for admission to 
clinic in treatment period 2 and 3. 
• Line for domiciled at clinic was added. 
• Discharge from clinic line and corresponding 
footnote (b) were removed. 
• “X” was removed from Day –1 for serum 
pregnancy test and urine drug/alcohol screen in 
treatment period 2 and 3. 
• Line for urine pregnancy was added. 
• “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” 
was added to the end of footnote (j). 
Appendix 2 Schedule of Events 
Table 9-2 
• Line for domiciled at clinic was added. 
• “X” was removed from Day 3 for discharge from 
the clinic in treatment period 4. 
• Line for serum pregnancy test and corresponding 
footnote (h) and urine drug/alcohol screen and 
corresponding footnote (i) were removed in 
treatment period 4 and 5. 
• Line for adverse events was added. Adverse 
events will be collected through Day 36 (end of 
study visit or early termination). 
Throughout the protocol 
Minor administrative changes were made. 
 


 
Confidential 
SIGA Technologies, Inc. 
 
 
Protocol: SIGA-246-023 
 
 
 A POSTMARKETING OPEN-LABEL, 5-PERIOD CROSSOVER, DRUG-
DRUG INTERACTION STUDY OF ORALLY ADMINISTERED TPOXX® 
WHEN COADMINISTERED WITH 4 DIFFERENT PHOSPHATE 
BINDERS IN HEALTHY ADULT SUBJECTS 
 
28JUN2023 
 
Draft Statistical Analysis Plan 
 
Version 2.0 
 
Prepared by: 
 
PPD 
3900 Paramount Parkway 
Morrisville, NC 27560 USA 
 
 
Date: ________________ 
 
 
 
Date: ________________ 


SIGA Technologies, Inc. 
Draft Statistical Analysis Plan, Version 2.0 
Protocol: SIGA-246-023 
Date Issued: 8OCT2022 
  
Page 2 of 30 
 
 
TABLE OF CONTENTS 
 
 
LIST OF ABBREVIATIONS ...................................................................................................... 4 
1. 
INTRODUCTION ............................................................................................................ 5 
2. 
STUDY OBJECTIVES..................................................................................................... 5 
2.1 
PRIMARY OBJECTIVE ......................................................................................................... 5 
2.2 
SECONDARY OBJECTIVE .................................................................................................... 5 
3. 
STUDY DESIGN ............................................................................................................... 5 
4. 
GENERAL STATISTICAL CONSIDERATIONS ....................................................... 6 
4.1. 
SAMPLE SIZE ..................................................................................................................... 7 
4.2. 
RANDOMIZATION, STRATIFICATION, AND BLINDING ......................................................... 8 
4.3. 
ANALYSIS POPULATION .................................................................................................... 8 
5. 
SUBJECT DISPOSITION ............................................................................................... 9 
5.1 
DISPOSITION ...................................................................................................................... 9 
5.2 
PROTOCOL DEVIATIONS .................................................................................................... 9 
5.3 
INCLUSION AND EXCLUSION CRITERIA .............................................................................. 9 
5.4 
TREATMENT COMPLIANCE ................................................................................................ 9 
6. 
DEMOGRAPHICS AND BASELINE CHARACTERISTICS .................................. 10 
6.1 
DEMOGRAPHICS .............................................................................................................. 10 
6.2 
MEDICAL HISTORY .......................................................................................................... 10 
7. 
TREATMENTS AND MEDICATIONS ....................................................................... 10 
7.1 
PRIOR AND CONCOMITANT MEDICATIONS ...................................................................... 10 
7.2 
MEDICAL OR SURGICAL TREATMENT PROCEDURES ........................................................ 10 
7.3 
STUDY TREATMENT ........................................................................................................ 11 
8. 
PHARMACOKINETICS ............................................................................................... 11 
8.1 
DATA HANDLING ............................................................................................................ 11 
8.2 
PHARMACOKINETIC CONCENTRATIONS ........................................................................... 11 
8.3 
PLASMA PHARMACOKINETIC PARAMETERS .................................................................... 12 
8.4 
PHARMACOKINETIC STATISTICAL ANALYSIS .................................................................. 13 
9. 
SAFETY ANALYSIS ..................................................................................................... 13 
9.1 
ADVERSE EVENTS ........................................................................................................... 13 
9.2 
CLINICAL LABORATORY EVALUATIONS .......................................................................... 15 
9.3 
VITAL SIGN MEASUREMENTS .......................................................................................... 16 
9.4 
PHYSICAL EXAMINATION ................................................................................................ 16 
9.5 
ELECTROCARDIOGRAMS .................................................................................................. 16 
10. 
INTERIM ANALYSIS ................................................................................................... 17 
11. 
CHANGES IN THE PLANNED ANALYSIS .............................................................. 17 
12. 
REFERENCES ................................................................................................................ 18 


SIGA Technologies, Inc. 
Draft Statistical Analysis Plan, Version 2.0 
Protocol: SIGA-246-023 
Date Issued: 8OCT2022 
  
Page 3 of 30 
 
13. 
SCHEDULE OF EVENTS ............................................................................................. 19 
14. 
INDEX OF TABLES AND FIGURES .......................................................................... 24 
15. 
INDEX OF LISTINGS ................................................................................................... 25 
 
 
 


SIGA Technologies, Inc. 
Draft Statistical Analysis Plan, Version 2.0 
Protocol: SIGA-246-023 
Date Issued: 8OCT2022 
  
Page 4 of 30 
 
List of Abbreviations 
AE 
Adverse event 
AUC 
area under the curve 
AUC0-inf 
area under the curve from time 0 extrapolated to infinity 
AUCt 
area under the curve from time 0 to the last measurable observed concentration 
BLQ 
below the limit of quantification 
BMI 
body mass index 
CI 
confidence interval 
CL/F 
apparent total body clearance 
Cmax 
maximum observed concentration 
CSR 
clinical study report 
CTMS 
Clinical Trial Management System 
CV 
coefficient of variation 
DDI 
drug-drug Interaction 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EOS 
end of study 
FDA 
Food and Drug Administration 
g 
grams 
ICF 
Informed Consent Form 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
milligrams 
PD 
pharmacodynamic 
PK 
pharmacokinetic 
PT 
preferred term 
QTcF 
QT interval corrected for heart rate using Fridericia’s formula 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
standard deviation 
SOC 
system organ class 
t1/2 
apparent terminal elimination half-life 
TLFs 
tables, listings and figures 
Tmax 
time of maximum observed concentration 
Vz/F 
apparent volume of distribution during the terminal phase 
 
 


SIGA Technologies, Inc. 
Draft Statistical Analysis Plan, Version 2.0 
Protocol: SIGA-246-023 
Date Issued: 8OCT2022 
  
Page 5 of 30 
 
1. Introduction 
A single dose of 600 mg (3 × 200 mg capsules) TPOXX was chosen as this is the recommended 
dose for TPOXX. Sevelamer carbonate, sucroferric oxyhydroxide, calcium acetate, and 
lanthanum carbonate were chosen for this study because they are common phosphate binders that 
patients prescribed TPOXX may be concurrently taking. The planned doses for each of these 
drugs were selected based on the FDA Guidance “Clinical Drug Interaction Studies - Study 
Design, Data Analysis, and Clinical Implications”, which states the maximum dose and the 
shortest dosing interval should be used. 2 Any potential drug-drug interaction (DDI) will be 
determined based on an analysis of TPOXX PK in the presence of phosphate-binding drugs, 
compared to TPOXX PK in the absence of these phosphate binders. The planned doses of 
TPOXX and the 4 phosphate binders are expected to be sufficiently high to quantify an effect on 
TPOXX plasma exposure levels. 
 
The purpose of this statistical analysis plan (SAP) is to define the planned statistical analysis of 
the study data consistent with the study objectives. This SAP is written based on Protocol: SIGA-
246-023, version 2.0, dated 27 January 2022. 
2. Study Objectives 
2.1 
Primary Objective 
The primary objective of this study is to evaluate potential DDI as measured by the effect of 
coadministration of 4 separate phosphate binders on the PK of orally administered TPOXX in 
healthy adult subjects. 
2.2 
Secondary Objective 
The secondary objective of this study is to evaluate the safety and tolerability of 600 mg oral TPOXX 
administered with 4 different phosphate binders in healthy adult subjects. 
 
3. Study Design 
 
This is a postmarketing, open-label, 5-period crossover drug interaction study designed to 
evaluate the potential effects of coadministration of 4 different phosphate binders on the PK of 
orally administered TPOXX in healthy adult subjects. A total of 44 subjects, ages 18 to 50, 
inclusive, will be enrolled and randomly assigned to 1 of 4 treatment sequences. The study will 
consist of a screening period (Day –28 to Day –2), 5 treatment periods (Day –1 to Day 31), an 
end-of-study visit (Day 36 [+2 days]), and a follow-up telephone call (Day 59 [+4 days]). The 
treatment sequences and periods will be as follows: 
 
Treatment 
Sequence 
Period 1 
Treatment 
Period 2 
Treatment 
Period 3 
Treatment 
Period 4 
Treatment 
Period 5 
Treatment 
ABCDE  
A  
B  
C  
D  
E  
ACEBD  
A  
C  
E  
B  
D  
ADBEC  
A  
D  
B  
E  
C  
AEDCB  
A  
E  
D  
C  
B  
 
 


SIGA Technologies, Inc. 
Draft Statistical Analysis Plan, Version 2.0 
Protocol: SIGA-246-023 
Date Issued: 8OCT2022 
  
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• Treatment A: A single oral dose of 600 mg (3 × 200 mg capsules) TPOXX.  
• Treatment B: A single oral dose of 600 mg (3 × 200 mg capsules) TPOXX 
coadministered with a single oral dose of 1600 mg (2 × 800 mg tablets) sevelamer 
carbonate (Renvela® or generic equivalent).  
• Treatment C: A single oral dose of 600 mg (3 × 200 mg capsules) TPOXX 
coadministered with a single oral dose of 500 mg sucroferric oxyhydroxide (Velphoro®) 
chewable tablet.  
• TPOXX + Calcium Acetate: A single oral dose of 600 mg (3 × 200 mg capsules) TPOXX 
coadministered with a single oral dose of 1334 mg (2 × 667 mg capsules) calcium acetate 
(PhosLo® generic equivalent).  
• Treatment E: A single oral dose of 600 mg (3 × 200 mg capsules) TPOXX 
coadministered with a single oral dose of 500 mg lanthanum carbonate (Fosrenol® or 
generic equivalent) chewable tablet.  
 
There will be a washout period of 7 days between dosing in each treatment period. All subjects 
will be provided a meal (consisting of approximately 600 calories and 25 g fat). The meal should 
be completed within 30 minutes. 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 study drug administration. Study drug and meals must be taken with water only, 
and no other beverage except water should be ingested within 3 hours before or 3 hours after 
study drug administration. Water is allowed at all times throughout the study. Subjects must  
refrain from taking food for 2 hours after taking study drug as further food consumption may 
affect drug absorption. 
 
In each period, subjects will report to the study site on Day –1 and remain confined to the study 
site until 48 hours after dosing in Period 5 (Day 31). Subjects will be monitored for safety and 
tolerability. Serial blood samples for PK analysis of TPOXX will be collected before dosing (0 
hour) and up to 48 hours after administration of the study drug(s). 
 
All subjects will have a follow-up telephone call 30 days after administration of the last dose of 
study drug (Day 59 [+4 days]) to report any serious adverse events (SAEs). At the time of 
discharge from the clinical research unit, subjects will be instructed to notify the investigator of 
any SAEs that occur within 30 days after administration of the last dose of study drug. Serious 
AEs will be followed until the SAE is stable or until resolution as determined by the investigator 
and/or medical monitor. 
 
The total duration of the study for each subject, including the screening period, treatment period, 
the Day 36 (+2 days) end-of-study visit, and the Day 59 (+4 days) follow-up telephone call, will 
be approximately 87 days. 
 
Schedules of assessments can be found in Section 13. 
4. General Statistical Considerations 
All statistical analyses will be conducted using statistical analysis system SAS® Version 9.4 
(SAS Institute, Cary, NC).  


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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.  
General study descriptors, as in subject disposition, demographics, protocol deviations, and 
enrollment characteristics, will be summarized for all randomized subjects, regardless of 
treatment sequence. Otherwise, safety outcomes, as in adverse events, lab values, vital signs, and 
electrocardiogram measures, will be summarized by treatment. The treatments below will be 
used for such presentation: 
• TPOXX 
• TPOXX + Sevelamer Carbonate  
• TPOXX + Sucroferric Oxyhydroxide 
• TPOXX + Calcium Acetate 
• TPOXX + Lanthanum Carbonate 
 
All data listings will be sorted by treatment and subject number. 
No algorithm for imputation of missing data will be employed. Missing data will be treated as 
missing. If partial data exists for concomitant medications, the start dates will be imputed to the 
first of the month (for missing day) or first of the year (for missing day and month) for purposes 
of assigning a prior mediation flag. 
There are no plans to derive visit windows; visits will be used in the analyses as reported on the 
eCRF. 
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 day the subject checks in (Day -1) 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. 
Sample Size 
The sample size (N = 44 [to allow at least 36 enrolled subjects to complete]) for this study is 
based on clinical and practical considerations and not on a formal statistical power calculation. 
The sample size is considered sufficient for the objectives of the study.  
 


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Prior estimates of within-subject variability (CVw) of a single dose of 600 mg TPOXX were 
obtained from Study SIGA-246-018, which evaluated the single-dose PK of TPOXX in a similar 
population. The CVw% for Cmax, AUC0-24 and AUC0-inf ranged from 11.39% to 12.62%, 9.38% 
to 18.12%, and 15.70% to 18.02%, respectively.  
 
For a sensitivity analysis, a range for CVw of 10%, 15%, and 20% across point estimates of 0.9, 
1.0, and 1.1 will be explored. For the sensitivity analysis, assuming a range of CVw, a sample 
size of 36 evaluable subjects, it is estimated that the precision (ie, half-width of the 90% 
confidence interval [CI] on the log and ratio scale), and CI with tolerance probability of 80% on 
the original scale for each point estimate will be: 
CVw (%)  
Half-Width 
(log scale)  
Half-Width 
(original scale)  
Point Estimate  
90% 
Confidence 
Interval  
10 
0.043 
0.044 
0.9 
(0.862, 0.94) 
1.0 
(0.958, 1.044) 
1.1 
(1.054, 1.148) 
15 
0.065 
0.067 
0.9 
(0.843, 0.96) 
1.0 
(0.937, 1.067) 
1.1 
(1.031, 1.174) 
20 
0.086 
0.090 
0.9 
(0.826, 0.981) 
1.0 
(0.918, 1.09) 
1.1 
(1.009, 1.199) 
 
4.2. 
Randomization, Stratification, and Blinding 
PPD statistician will generate the randomization schedule. Eligible subjects who meet all 
inclusion and none of the exclusion criteria will be randomly assigned. Randomization numbers 
will be assigned before the first dose of investigational drug is administered at the Baseline Visit. 
 
Eligible subjects will be randomly assigned to one of the 4 aforementioned sequences in 1:1:1:1 
ratio based on the randomization schedule prepared before the study by PPD randomization 
statistician. 
This is an open label study and no stratification will be used. 
4.3. 
Analysis Population 
The analysis populations are as follows:  
 
• 
The PK Population will include subjects who receive at least 1 dose of TPOXX and have 
sufficient concentration data to support accurate estimation of at least 1 PK parameter.  
 
• 
The Safety Population will include all subjects who receive any amount of study drug. 


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5. Subject Disposition 
5.1 
Disposition 
The following will be summarized for the safety population, by treatment sequence and overall 
for all subjects: 
 
• The number of subjects who received each treatment sequence 
• 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 data will be presented in a data listing. 
5.2 
Protocol Deviations 
Protocol deviations will be collected during monitoring visits. All protocol deviations are to be 
recorded in CTMS (Clinical Trial Management System) with the indication of whether these are 
important.  These data will be listed including the assignment of not important or important.  A 
protocol deviation is any change, divergence, or departure from the study design or procedures 
defined in the protocol. An important protocol deviation (sometimes referred to as a protocol 
violation or a major protocol deviation) is a subset of protocol deviations that might significantly 
affect the reliability of the study data or that might significantly affect a subject’s safety. 
 
Important protocol deviations will be summarized overall. All protocol deviations will be 
presented in a data listing, including the categorization of the deviation as important or not 
important. 
5.3 
Inclusion and Exclusion Criteria 
Inclusion and exclusion criteria deviations will be presented in a data listing. 
5.4 
Treatment Compliance 
 
All doses of the study drugs will be administered in the study site under direct observation of 
study site personnel and recorded in the eCRF. Per standard clinic procedure, study site 
personnel will perform a mouth check and inspect all dose containers to ensure that the entire 
dose was administered. Following completion of dosing procedures and return of dosing 
containers to the pharmacy by team members, pharmacy staff will follow standard clinic 
procedures for study drug reconciliation. SIGA will provide information to PPD for destruction 
of returned used and unused TPOXX study drug and study drug bottles.  
 
The date and time of study drug dosing will be captured and recorded on the appropriate page of 
the eCRF. If a subject is not administered study drug, the reason for the missed dose will be 
recorded. 
 


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Treatment compliance, defined as the percentage of capsules consumed, will be summarized by 
treatment using statistics for continuous variables as well as presented in a listing.  
6. Demographics and Baseline Characteristics 
6.1 
Demographics 
Demographic information collected at screening will be presented in a data listing. 
Descriptive statistics will be calculated for the following continuous demographic characteristics:  
• Age (years) 
• Weight (kg) 
• Height (cm) 
• Body mass index (BMI) (kg/m2) 
Frequency counts and percentages will be tabulated for the categorical variables: 
• Sex 
• Race 
• Ethnicity 
The summaries will be presented overall for the safety population. 
6.2 
Medical History 
The medical history data will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA, version to be delineated in the clinical study report [CSR]) and presented in a data 
listing. 
7. Treatments and Medications 
7.1 
Prior and Concomitant Medications 
Medications taken within 30 days prior to the signing of the informed consent form (ICF) up 
until the first dose of study drug will be classified as prior medications. Medications that start on 
or after the first dose of study drug will be classified as concomitant.  
 
If a prohibited concomitant medication listed in Section 4.2 of the protocol is taken, it will be 
documented as a protocol deviation and a joint decision will be made by the investigator and 
SIGA to continue or discontinue the subject based on the time the medication was administered, 
its pharmacology and PK, and whether the use of the medication will compromise the safety of 
the subject or the interpretation of the data. 
 
The investigator is responsible for ensuring that details regarding the medication are adequately 
recorded in both the subject’s source document and the eCRF. 
 
All prior and concomitant medications will be coded according to the World Health Organization 
Drug Dictionary (version to be delineated in the CSR) and will be summarized by treatment.  
 
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. 


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7.3 
Study Treatment 
The study drug administration and drug accountability data as collected on eCRF will be 
presented in the data listings, including but not limited to the treatment sequence, time point and 
date, study dose, and reason for adjustment if any.  
8. Pharmacokinetics 
Individual TPOXX plasma concentration and time data will be presented in a data listing and 
individual plots based on the safety population, and all summaries and analyses of the PK data of 
TPOXX will be based on the PK population as defined in Section 4.3.   
8.1 
Data Handling 
The following procedures will be used for plasma concentrations data of TPOXX below the lower 
limit of quantification (LLOQ) and missing values: 
 
• Concentration values that are below limit of quantification (BLQ) will be reported as 
provided by the bioanalytical data in the PK data listings. 
• For the calculation of concentration summary statistics, BLQ values will be replaced with 
zero at individual timepoints.  
• If the mean concentration value is less than the lower limit of quantitation (LLOQ) value, 
then the mean concentration value will be set to BLQ in tables with other summary 
statistics reported as not applicable (NA) except for median, minimum and maximum,  
where BLQ were reported. The mean concentration plotted as zero in linear scale graphics 
and missing in semi-logarithmic scale graphics.   
• For calculation of PK parameters, BLQ concentration values prior to the first measurable 
concentration will be set to zero. Post-dose BLQ values after the first quantifiable time 
point that are followed by measurable concentrations will be set to half the value of LLOQ. 
Post-dose BLQ value after first quantifiable time point that are not followed by measurable 
concentrations will be replaced by zero. 
• Missing concentration values will not be imputed and will be excluded from the 
calculations. 
• Default significant figures used for reporting in text, tables, and summary statistics of the 
study report is three significant figures, except for N (number of subjects in the group) and 
n (number of subjects in the group with reported data), where integer will be presented. 
 
8.2 
Pharmacokinetic Concentrations 
Blood samples for PK analysis of TPOXX will be collected from all subjects at the following 
time points: within 60 minutes before dosing (0 hour) and at 0.5, 1, 2, 4, 6, 8, 12, 24, and 48 
hours after administration of study drug in each period. 
For PK blood samples, the acceptable window for collection from the scheduled collection time 
point will be as follows: ±5 minutes for the time points from 0.5 through 8 hours and ±15 
minutes for the time points from 12 through 48 hours.  
Individual plasma concentration and time deviation data will be presented in a data listing. 
Plasma concentration data will be summarized by time point for each treatment using the 


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following descriptive statistics: number of subjects, arithmetic mean, SD, coefficient of variation 
(CV), geometric mean, geometric CV, geometric SD, minimum, median, and maximum.  
Individual and mean plasma concentration versus scheduled time profiles will be presented in 
figures on both linear and semilogarithmic scales. 
8.3 
Plasma Pharmacokinetic Parameters  
Plasma concentration-time data will be analyzed by non-compartmental analysis using Phoenix® 
WinNonlin® Version 8.3 (Certara USA, Inc., Princeton, NJ). The following plasma PK 
parameters will be calculated for TPOXX to the extent that data permit using actual sampling 
times rather than scheduled sampling times: 
Cmax 
Maximum drug concentration in plasma 
Tmax 
Time of maximum drug concentration in plasma 
AUC0-24 
Area under the plasma concentration-time curve (AUC) from time 0 to 
24 hours, calculated using the linear up log down rule 
AUC0-48 
AUC from time 0 to 48 hours, calculated using the linear up log down 
rule 
AUC0-t 
AUC from time 0 to the last quantifiable concentration, calculated using 
the linear up log down rule  
AUC0-inf 
AUC from time 0 extrapolated to infinity, calculated using the linear up 
log down rule  
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: 
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 
t1/2 
Apparent terminal elimination half-life, calculated as: ln (2) / λz 
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  
λz lower 
Lower bound used for the estimation of λz  
λz upper 
Upper bound used for the estimation of λz  
Span 
Number of elapsed half-lives over which λz is estimated, calculated as 
(λz upper – λz lower) / t½ 
Rsq 
r2, the coefficient of determination (goodness of fit statistic); λz and all 
associated parameters will only be reported where r2 ≥ 0.80.  
 


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The individual PK parameters will be presented in data listings and summarized by treatment 
using the following descriptive statistics: number of subjects, mean, SD, CV, geometric mean, 
geometric SD, geometric CV, minimum, median, and maximum. Tmax will be summarized using 
number of observations, median, minimum, and maximum only. 
8.4 
Pharmacokinetic Statistical Analysis 
A linear mixed model with sequence, treatment, and period as fixed effects and subject within 
sequence as a random effect will be performed on the natural log-transformed values of AUCs 
(AUC0-24, AUC0-48, AUC0-t, and AUC0-inf) and Cmax to assess the effect of phosphate binders on 
the PK of TPOXX. The geometric least square means and corresponding 90% CIs will be 
computed for AUCs and Cmax of TPOXX + phosphate binder versus TPOXX alone by taking the 
anti-log of the least squares means from the linear mixed-effect model on the natural logarithms 
of the corresponding PK parameters. A 90% CI for the ratio will be constructed as the anti-log of 
the confidence limits of the mean difference. No adjustment will be made for multiplicity.  
It will be concluded that there is no relevant interaction of phosphate binders on TPOXX if the 
90% CIs for AUCs and Cmax ratios (TPOXX + phosphate binder/TPOXX alone) are completely 
contained within the (80%, 125%) interval. 
Non-parametric methods will be used to examine median differences in Tmax for TPOXX. 
The geometric mean ratios and corresponding 90% CIs for AUCs and Cmax for TPOXX will be 
presented in forest plots for overall assessment of the DDI. 
9. Safety Analysis 
 
All safety summaries and analyses will be based upon the safety population. 
 
9.1 
Adverse Events 
 
An AE is defined as any untoward medical occurrence, including those AEs that result from dosing 
errors, which may present during administration of a study drug or during a reasonable follow-up 
period and which does not necessarily have a causal relationship with the study drug(s). All AEs 
reported or observed from the first dose of study drug in Period 1 through the Day 36 End of Study 
Visit will be recorded on the AE page in the eCRF. 
 
All AEs will be followed until the AE is resolved or stabilized as determined by the investigator 
and/or the medical monitor. Subjects will be instructed to contact the investigator at any time after 
randomization if any symptoms develop. 
 
A serious AE (SAE) is defined as any AE that results in any of the following outcomes: death, a 
life-threatening AE, inpatient hospitalization or prolongation of existing hospitalization, a 
congenital anomaly or birth defect, a persistent or significant incapacity or substantial disruption 
of the ability to conduct normal activities of daily living. 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 


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medical or surgical intervention to prevent one of the outcomes listed in this definition. All SAEs 
reported or observed from the first dose of study drug in Period 1 through follow-up telephone call 
on Day 59 (+4 days) will be recorded on the AE page in the eCRF. 
 
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. 
 
The AE’s relationship to study treatment will be evaluated by the investigator. The following 
relationships will be collected on eCRF: definitely related, probably related, possibly related, 
unlikely related, or not related. 
 
The AEs that are evaluated as definitely, probably, or possibly related will be considered 
treatment-related AEs for summary purpose. 
 
The severity of AEs will be classified by the investigator as mild, moderate, severe, life 
threatening, or death. 
 
An overall AE summary will be generated presenting the frequency and percentage of subjects 
and the number of AEs for the following: 
• Any AE 
• Any treatment-related AE  
• Any moderate AE 
• Any treatment-related moderate AE 
• Any treatment-related severe AE 
• Any SAE 
• Any treatment-related SAE 
• Any AE leading to early discontinuation 
• Any death  
 
All AEs will be coded using MedDRA (version to be delineated in the CSR). The AEs will also 
be summarized by system organ class (SOC), preferred term (PT), by severity and relationship to 
study treatment.  
 
The AE summary tables will be sorted by SOC and PT. System organ class will be displayed in 
descending order of overall frequency then alphabetically. Preferred term will be displayed in 
descending order of overall frequency and then alphabetically within SOC. A subject with 2 or 
more events within the same level of summarization will be counted only once in that level using 
the most severe incident or most related incident. Percentages will be based on the number of 
subjects in the safety population. 
 
In summaries of AEs by treatment, AEs will be summarized according to the most recent 
treatment received prior to the AE onset. For example, an AE that occurred on or after 


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administration of the study drug on Day 1 of Period 1 but before the administration of study drug 
on Day 1 of Period 2 will be summarized for study drug administered in Period 1.  
All AEs will be presented in a data listing. Separate data listings will be generated for 
treatment-related AEs, SAEs, and AEs leading to study discontinuation.  
 
9.2 
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 clearance (calculateda), 
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, turbidity, 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 timepoints 
indicated in the schedule of assessments (schedules of assessments can be found in Section 13). 
Glycosylated hemoglobin A1c and a fasting lipid panel including cholesterol (total, high-density 
lipoprotein, calculated low-density lipoprotein, and triglycerides) will be performed at screening.  
 
Note: All lab parameters will be graded according to the Division of Acquired Immune 
Deficiency Syndrome (DAIDS)3 toxicity grading scale and will be adjusted according to local 
laboratory reference ranges. 
 
Serum pregnancy test (β human chorionic gonadotropin) for women of childbearing potential 
will be performed at screening. A urine pregnancy test will be performed at check-in on Day –1. 
A positive urine pregnancy test will be verified with a follow-up serum pregnancy test. 
 
A serum follicle-stimulating hormone test for postmenopausal women will be performed at 
screening.  
 
Human immunodeficiency virus (type 1 and 2) antibodies, hepatitis B surface antigen, and 
hepatitis C virus antibody will be assessed at screening only. 
 
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. 


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Actual results and change from baseline for hematology, serum chemistry and urinalysis at each 
time point will be summarized for the safety population. 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. Abnormal laboratory values for 
hematology, serum chemistry and urinalysis, defined as any laboratory value with a toxicity 
grade of 1 or above, will be presented in a listing. 
 
9.3 
Vital Sign Measurements 
Vital signs will include systolic and diastolic blood pressure, pulse rate, respiratory rate, and 
body temperature, and will be measured at the timepoints indicated in the schedule of 
assessments (schedules of assessments can be found in Section 13). 
 
All vital sign, body weight, and height measurements will be presented in a data listing. The 
actual values and change from baseline values at each time point will be summarized for the 
safety population. 
9.4 
Physical Examination 
A full physical examination will include, at minimum, assessment of skin, head, ears, eyes, nose, 
throat, neck, thyroid, lungs, heart, cardiovascular, abdomen, lymph nodes, and musculoskeletal 
system/extremities. A brief physical examination will include, at minimum, assessment of skin, 
lungs, cardiovascular system, and abdomen (liver and spleen). 
 
Full physical examinations will be performed at Screening (Visit 1), and abbreviated physical 
examinations will be performed at the timepoints indicated in the schedule of assessments 
(schedules of assessments can be found in Section 13). 
 
A symptom-directed physical examination will be performed at the time points indicated in the 
schedule of events (for those subjects who require it), and at unscheduled visits as necessary. 
This examination will include an assessment of the heart, lungs, abdomen, a neurologic review, 
and a review of symptoms for assessments and/or follow-up of reported or potential AEs. 
 
All physical examination results will be presented in a data listing. 
 
9.5 
Electrocardiograms 
Single 12-lead ECGs will be obtained after the subject has been in the supine position for at least 
10 minutes. A single repeat measurement is permitted at screening for eligibility determination. 
Electrocardiogram assessments will include comments on whether the tracings are normal or 
abnormal, rhythm, presence of arrhythmia or conduction defects, morphology, any evidence of 
myocardial infarction, or ST-segment, T-wave, and U-wave abnormalities. 
 
In addition, measurements of the following intervals will be measured and reported: heart rate; 
PR, RR, and QT interval; QTcF, QT interval corrected using Fridericia’s formula; and QRS 
duration. All ECGs must be performed by an experienced ECG technician.  
 


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Single 12-lead ECG will be performed at the timepoints indicated in the schedule of assessments 
(schedules of assessments can be found in Section 13). 
 
Actual values at baseline for numeric ECG data will be summarized by visit and treatment for 
subjects in the safety population. 
 
All ECG data will be presented in a data listing. 
 
10. Interim Analysis 
 
No formal interim analyses will be performed in this study.  
 
11. Changes in the Planned Analysis 
 
Any changes from this statistical analysis plan will be documented in the CSR for this study. 


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12. 
References 
 
1. Breman JG, Henderson DA. Diagnosis and management of smallpox. N Engl J Med. 
2002;346(17):1300-8. 
2. Department of Health and Human Services (DHHS), Food and Drug Administration, Center 
for Drug Evaluation and Research, Center for Drug Evaluation and Research. Guidance for 
Industry: Clinical Drug Interaction Studies—Cytochrome P450 Enzyme-and Transporter-
Mediated Dug Interactions. January 2020 [cited 24 Jan 2022]. Available from: 
https://www.fda.gov/media/134581/download. 
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. 


 
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13. 
Schedule of Events 
Schedule of Events: Period 1 through Period 3 
Phase 
Screenin
g 
Check-
in 
Treatment Period 1 
Treatment Period 2 
Treatment Period 3 
Procedure(a) 
Day –28 to –2 
–1 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 11 12 13 14 15 16 17 18 19 20 
 
Day 
 
 
 
 
 
 
 
 
–1 
1 
2 
3 
4 
5 
6 
–1 
1 
2 
3 
4 
5 
6 
Admission to clinic 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Domiciled at clinic 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X X 
X 
X 
X 
X 
X 
X 
X 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history(b) 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination(c) 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height and weight  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital sign measurements(d) 
X 
X 
X 
X 
X 
 
 
 
X 
X 
X 
X 
 
 
 
X 
X 
X 
X 
 
 
 
Glycosylated hemoglobin (HbA1c) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Fasting lipid panel(e) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical laboratory testing(f) 
X(g) 
X 
 
X 
 
 
 
 
X 
 
X 
 
 
 
 
X 
 
X 
 
 
 
 
Serum follicle-stimulating 
hormone(h) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum pregnancy test(i) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine pregnancy test(i) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine drug/alcohol screen(j) 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serology (HBsAg, HCV, and HIV) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization(j) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
12-lead electrocardiogram(l) 
X 
X 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
Administration of study drug(s)(m) 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
Pharmacokinetic sample collection(n) 
 
 
X 
X 
X 
 
 
 
 
X 
X 
X 
 
 
 
 
X 
X 
X 
 
 
 
Adverse events 
 
 
X 
Prior/concomitant medications 
             X 
Abbreviations: ECG, electrocardiogram; HBsAg, hepatitis B surface antigen; HCV, hepatitis C virus; HIV, human immunodeficiency virus; 
PK, pharmacokinetic. 


 
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Protocol: SIGA-246-023 
Date Issued: 03/10/2022 
 
 
Page 20 of 30 
 
Notes: 
(a) When procedures overlapped or occurred at the same time point, all blood draws followed vital signs or ECGs, and PK sampling was timed to 
occur last and as close to the scheduled time window as possible. 
(b) Medical history included a review of systems; recreational, prescription, and over-the-counter drug use; nicotine and alcohol use; and past 
hospitalizations. 
(c) A full physical examination included, 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). Symptom-directed physical examination included an 
assessment of the heart, lungs, abdomen, a neurologic review, and a review of symptoms for assessment and/or follow-up of reported or potential 
adverse events. 
(d) Vital sign measurements included systolic and diastolic blood pressures, heart rate, respiratory rate, and body temperature. Vital signs were 
measured at screening, and in each period, on Day –1; within 60 minutes prior to dosing; and at 4, 8, 12, 24, and 48 hours following dosing in each 
period after the subject has been in a seated position for at least 5 minutes. 
(e) Fasting lipid panel included cholesterol (total, high-density lipoprotein, calculated low-density lipoprotein, and triglycerides). 
(f) Clinical laboratory testing included hematology and serum chemistry.  
(g) Clinical laboratory testing at screening included hematology, serum chemistry, and urinalysis. 
(h) For postmenopausal women, a serum follicle-stimulating hormone test was performed at screening. 
(i) Women of childbearing potential only. 
(j) Included 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 was collected and sent to the central laboratory at the screening visit. A urine drug screen and 
alcohol breath test using a breathalyzer was performed and read locally on Day –1. 
(k) Randomization occurred according to the randomization schedule before study drug administration on Day 1 of Period 1 after it has been 
confirmed that the subject fulfilled all eligibility criteria. Subjects were randomly assigned to receive study drug in 1 of 4 treatment sequences 
(ABCDE, ACEBD, ADBEC, and AEDCB) in 1:1:1:1 ratio. 
(l) A single 12-lead ECG was obtained after the subject had been in the supine position for at least 10 minutes. On Day 1 of each period, an ECG was 
recorded 4 hours after study drug administration. The acceptable window for collection from the scheduled collection time point was ±15 minutes. 
(m) All subjects were provided a meal (consisting of approximately 600 calories and 25 g fat). The meal was completed within 30 minutes. Subjects 
were administered study drug(s) as soon as possible following completion of the meal but no more than 30 minutes elapsed between meal 
completion and study drug administration. Study drug and meals were taken with water only, and no other beverage except water was ingested 
within 3 hours before or 3 hours after study drug administration. Subjects fasted for 2 hours after taking study drug. The time of study drug dosing 
was called “0” hour in each period. 
Treatment A: A single oral dose of 600 mg (3 × 200 mg capsules) TPOXX. 
Treatment B: A single oral dose of 600 mg (3 × 200 mg capsules) TPOXX coadministered with a single oral dose of 1600 mg (2 × 800 mg tablets) 
sevelamer carbonate (Renvela® or generic equivalent). 
Treatment C: A single oral dose of 600 mg (3 × 200 mg capsules) TPOXX coadministered with a single oral dose of 500 mg sucroferric 
oxyhydroxide (Velphoro®) chewable tablet. 


 
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Protocol: SIGA-246-023 
Date Issued: 03/10/2022 
 
 
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TPOXX + Calcium Acetate: A single oral dose of 600 mg (3 × 200 mg capsules) TPOXX coadministered with a single oral dose of 1334 mg (2 × 
667 mg capsules) calcium acetate (PhosLo® generic equivalent). 
Treatment E: A single oral dose of 600 mg (3 × 200 mg capsules) TPOXX coadministered with a single oral dose of 500 mg lanthanum carbonate 
(Fosrenol® or generic equivalent) chewable tablet. 
(n) Blood samples for PK analysis of TPOXX were collected from all subjects at the following time points: within 60 minutes before dosing (0 hour) 
and at 0.5, 1, 2, 4, 6, 8, 12, 24, and 48 hours after administration of study drug in each period. For PK blood samples, the acceptable window for 
collection from the scheduled collection time point was as follows: ±5 minutes for the time points from 0.5 through 8 hours and ±15 minutes for 
the time points from 12 through 48 hours. 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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Protocol: SIGA-246-023 
Date Issued: 03/10/2022 
 
 
Page 22 of 30 
 
Schedule of Events: Period 4 and Period 5 
Phase 
Treatment Period 4 
Treatment Period 5 
End of Study Visit 
or Early 
Termination(b) 
Follow-up 
Telephone 
Call(c) 
Procedure0 
Day 21 
22 
23 
24 
25 
26 
27 
28 
29 
30 
31 
36 (+2) 
59 (+4) 
 
Day –1 
1 
2 
3 
4 
5 
6 
–1 
1 
2 
3 
 
 
Domiciled at clinic 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Discharge from clinic 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Outpatient visit 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Physical examination(d) 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Vital sign measurements(e) 
X 
X 
X 
X 
 
 
 
X 
X 
X 
X 
X 
 
Clinical laboratory testing(f) 
X 
 
X 
 
 
 
 
X 
 
X 
 
X(g) 
 
12-lead electrocardiogram(h) 
 
X 
 
 
 
 
 
 
X 
 
 
X 
 
Administration of study drug(s)(i) 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
Pharmacokinetic sample 
collectionError! Reference source not found. 
 
X 
X 
X 
 
 
 
 
X 
X 
X 
 
 
Adverse events 
X 
 
Serious adverse events 
X 
Prior/concomitant medications 
X 
Abbreviations: ECG, electrocardiogram; PK, pharmacokinetic. 
Notes: 
(a) When procedures overlapped or occurred at the same time point, all blood draws followed vital signs or ECGs, and PK sampling was timed to 
occur last and as close to the scheduled time window as possible. 
(b) The end-of-study visit occurred 7 days after the last dose of study drug.  
(c) The follow-up telephone call was made 30 days after the last dose of study drug (Day 59 [+4 days]). Discharge followed all safety assessments and 
PK sample collections. 
(d) Symptom-directed physical examination included an assessment of the heart, lungs, abdomen, a neurologic review, and a review of symptoms for 
assessment and/or follow-up of reported or potential adverse events. 
(e) Vital sign measurements included systolic and diastolic blood pressures, heart rate, respiratory rate, and body temperature. Vital signs were 
measured after the subject has been seated for at least 5 minutes. Vital signs were measured at screening, and in each period, vital sign 
measurements were measured at check-in; within 60 minutes prior to dosing; and at 4, 8, 12, 24, and 48 hours after the study drug administration. 
(f) Clinical laboratory testing included hematology and serum chemistry.  
(g) Clinical laboratory testing at end of study or early discontinuation included hematology, serum chemistry, and urinalysis. 
(h) A single 12-lead ECG was collected after the subject had been in the supine position for at least 10 minutes. In each period, an ECG was recorded 4 
hours after the study drug administration. The acceptable window for collection from the scheduled collection time point was ±15 minutes. 


 
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Date Issued: 03/10/2022 
 
 
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(i) All subjects were provided a meal (consisting of approximately 600 calories and 25 g fat).  The meal was completed within 30 minutes. Subjects 
were administered study drug(s) as soon as possible following completion of the meal but no more than 30 minutes elapsed between meal 
completion and study drug administration. Study drug and meals were taken with water only, and no other beverage except water was ingested 
within 3 hours before or 3 hours after study drug administration.   Subjects fasted for 2 hours after taking study drug. The time of study drug dosing 
was called “0” hour in each period. 
Treatment A: A single oral dose of 600 mg (3 × 200 mg capsules) TPOXX. 
Treatment B: A single oral dose of 600 mg (3 × 200 mg capsules) TPOXX coadministered with a single oral dose of 1600 mg (2 × 800 mg tablets) 
sevelamer carbonate (Renvela® or generic equivalent). 
Treatment C: A single oral dose of 600 mg (3 × 200 mg capsules) TPOXX coadministered with a single oral dose of 500 mg sucroferric 
oxyhydroxide (Velphoro®) chewable tablet. 
TPOXX + Calcium Acetate: A single oral dose of 600 mg (3 × 200 mg capsules) TPOXX coadministered with a single oral dose of 1334 mg (2 × 
667 mg capsules) calcium acetate (PhosLo® generic equivalent). 
Treatment E: A single oral dose of 600 mg (3 × 200 mg capsules) TPOXX coadministered with a single oral dose of 500 mg lanthanum carbonate 
(Fosrenol® or generic equivalent) chewable tablet. 
(j) Blood samples for PK analysis of TPOXX was collected from all subjects at the following time points: within 60 minutes before dosing (0 hour) 
and at 0.5, 1, 2, 4, 6, 8, 12, 24, and 48 hours after administration of study drug in each period. For PK blood samples, the acceptable window for 
collection from the scheduled collection time point was as follows: ±5 minutes for the time points from 0.5 through 8 hours and ±15 minutes for 
the time points from 12 through 48 hours. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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Protocol: SIGA-246-023 
Date Issued: 03/10/2022 
 
 
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14. 
Index of Tables and Figures 
Table/Figure 
Number 
Name 
Population 
Table 14.1.1   Subject Disposition                         
All Randomized 
Subjects 
Table 14.1.2   Demographic and Baseline Characteristics    
Safety Population 
Table 14.1.3   Important Protocol Deviations               
Safety Population 
Table 14.1.4   Overall Summary of Concomitant Medications 
Safety Population 
Table 14.2.1   Summary of Plasma Concentrations of TPOXX by Treatment  PK Population 
Table 14.2.2   Summary of Plasma Pharmacokinetic Parameters of TPOXX   PK Population 
Table 14.2.3.1 Relative Bioavailability Assessment of TPOXX            PK Population 
Table 14.2.3.2 Non-Parametric Statistical Analysis of TPOXX            PK Population 
Table 14.3.1.1 Overall Summary of Adverse Events                       Safety Population 
Table 14.3.1.2 Adverse Events by System Organ Class and Preferred 
Term  
Safety Population 
Table 14.3.1.3 Serious Adverse Events by System Organ Class and 
Preferred Term  
Safety Population 
Table 14.3.1.4 Adverse Events by Relationship to Study Drug            Safety Population 
Table 14.3.1.5 Adverse Events by Severity                     
Safety Population 
Table 
14.3.4.1.1 
Summary and Change from Baseline in Hematology          Safety Population 
Table 
14.3.4.1.2 
Shift from Baseline in Hematology 
Safety Population 
Table 
14.3.4.2.1 
Summary and Change from Baseline in Chemistry           Safety Population 
Table 
14.3.4.2.2 
Shift from Baseline in Chemistry                     
Safety Population 
Table 
14.3.4.3.1 
Summary and Change from Baseline in Urinalysis          Safety Population 
Table 
14.3.4.3.2 
Shift from Baseline in Urinalysis                    
Safety Population 
Table 14.3.5   Summary and Change from Baseline in Vital Signs 
Measurements       
Safety Population 


 
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Protocol: SIGA-246-023 
Date Issued: 03/10/2022 
 
 
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Table 14.3.6   Summary and Change from Baseline in Electrocardiogram 
Measurements       
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  
Safety Population 
Figure 14.2.3 
Forest Plot to Assess the Relative Bioavailability of 
TPOXX     
PK Population 
 
 
 
15. 
Index of Listings 
Listing Number 
Name 
Listing 16.1.7     
Randomization 
Listing 16.2.1     
Subject Disposition 
Listing 16.2.2  
Protocol Deviations 
Listing 16.2.3     
Subjects Excluded From Analysis Populations 
Listing 16.2.4.1   
Demographic and Baseline Characteristics 
Listing 16.2.4.2   
Medical History 
Listing 16.2.4.3   
Prior and Concomitant Medication 
Listing 16.2.4.4   
Medical or Surgical Treatment Procedures 
Listing 16.2.5     
Study Drug Administration 
Listing 16.2.6.1   
Individual Plasma Concentrations OF TPOXX BY TREATMENT 
Listing 16.2.6.2   
Individual Plasma Pharmacokinetic Parameters of TPOXX by Treatment 
Listing 16.2.7.1   
Adverse Events 
Listing 16.2.7.2   
Serious Adverse Events 
Listing 16.2.7.3   
Adverse Events Leading to Early Study Discontinuation 
Listing 16.2.7.4   
Treatment-Related Adverse Events 
Listing 16.2.8.1   
Hematology Laboratory Test Results 
Listing 16.2.8.2   
Abnormal Laboratory Results (Toxicity Grade of at least 1) in Hematology 
Listing 16.2.8.3   
Serum Chemistry Laboratory Test Results 
Listing 16.2.8.4   
Abnormal Laboratory Results (Toxicity Grade of at least 1) in Chemistry 


 
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Protocol: SIGA-246-023 
Date Issued: 03/10/2022 
 
 
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Listing 16.2.8.5   
Urinalysis Laboratory Test Results 
Listing 16.2.8.6   
Abnormal Laboratory Results (Toxicity Grade of at least 1) in Urinalysis 
Listing 16.2.9.1   
Vital Sign Measurements 
Listing 16.2.9.2   
Electrocardiograms 
Listing 16.2.9.3 
Physical Examinations 
Listing 16.2.9.4  
Follow-Up Call 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 




 
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Protocol: SIGA-246-023 
Date Issued: 03/10/2022 
 
 
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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 
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 
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 
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 
Creatine Kinase, High 
3 to < 6 x ULN 
6 to < 10x ULN 
10 to < 20 x ULN 
≥ 20 x ULN 
Creatinine, High 
    *Report only one 
1.1 to 1.3 x ULN 
> 1.3 to 1.8 x ULN  
OR Increase to 1.3 to  
< 1.5 x participant’s  
baseline 
> 1.8 to < 3.5  
x ULN OR Increase  
to 1.5 to < 2.0 x  
participant’s baseline 
≥ 3.5 x ULN OR 
Increase of ≥ 2.0 x  
participant’s baseline 
Creatinine Clearance 2 
or eGFR, Low 
*Report only one 
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 
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 


 
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Date Issued: 03/10/2022 
 
 
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Hemoglobin3, Low 
       (g/dL; mmol/L) 17 
       ≥ 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 
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  
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  
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 
Urate (umol/L), High 
      (umol/L; µmol/L) 
>1 x ULN 
>1 x ULN 
NA 
NA 
NA 
Eosinophils  
      (10^9/L; /mm3) 
>1 x ULN 
>1 x baseval 
NA 
NA 
NA 
Hemoglobin3, Low 
       (g/dL; mmol/L) 4 
       ≥ 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 


 
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Date Issued: 03/10/2022 
 
 
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Absolute Lymphocyte  
Count, Low  
      (cell/mm3; cells/L)  
      > 5 years of age  
     (not HIV infected) 
600 to < 650 
0.600 x 109 to 
< 0.650 x 109 
500 to < 600 
0.500 x 109 to 
< 0.600 x 109 
350 to < 500 
0.350 x 109 to 
< 0.500 x 109 
< 350 
< 0.350 x 109 
Absolute Neutrophil  
Count (ANC), Low 
     (cells/mm3; cells/L)  
     > 7 days of age  
800 to 1,000 
0.800 x 109 to 1.000 x 109 
600 to 799 
0.600 x 109 to 0.799 x 
109 
400 to 599 
0.400 x 109 to 0.599 x 109 
< 400 
< 0.400 x 109 
Neutrophils/Leukocytes (%) 
 
 
 
 
Platelets, Decreased 
        (cells/mm3; cells/L) 
100,000 to < 125,000  
100.000 x 109 to < 125.000 
x 109 
50,000 to < 100,000 
50.000 x 109 to < 100.000 
x 109 
25,000 to < 50,000  
25.000 x 109 to < 50.000 x 
109 
< 25,000  
< 25.000 x 109 
Leukocytes, white blood cell 
decreased 
      (10^9/L; /mm3) 
<LLN - 3.0 x 10^9 /L 
<LLN - 3000/mm3 
<3.0 - 2.0 x 10^9 /L 
<3000 - 2000/mm3 
<2.0 - 1.0 x 10^9 /L 
<2000 - 1000/mm3 
<1.0 x 10^9 /L 
<1000/mm3 
Leukocytes, Leukocytosis 
      (10^9/L; /mm3) 
NA 
NA 
>100 x 10^9/L 
>100000/mm3 
NA 
Urobilinogen (umol/dL) 
 
 
 
 
1 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. 
2 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. 
3 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). 
4 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.