A Randomized, Placebo-controlled, Double-blinded Trial of the Safety and Efficacy of Tecovirimat for the Treatment of Adult and Pediatric Patients With Monkeypox Virus Disease
Phase: PHASE2
Conditions: Monkeypox
Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

A randomized, placebo-controlled, 
double-blinded trial of the safety and 
efficacy of tecovirimat for the treatment 
of adult and pediatric patients with 
monkeypox virus disease
Protocol
Version 4.0
Dated 15 December 2023
Approved 24 January 2024
NCT05559099

Abbreviated Title: PALM 007 
Version: 4.0 
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Version Date: December 15, 2023 
Abbreviated Title: PALM 007 
Version Date: December 15, 2023 
Title: A randomized, placebo-controlled, double-blinded trial of the safety and efficacy of 
tecovirimat for the treatment of adult and pediatric patients with monkeypox virus disease 
Investigational Agents: 
Drug Name: 
tecovirimat (TPOXX®) 
Manufacturer: 
Catalent Pharma Solutions and SIGA Technologies, Inc. 
Drug Sponsor: 
SIGA Technologies, Inc. 
Study Sponsors: National Institute of Allergy and Infectious Diseases (NIAID), National 
Institutes of Health (NIH), United States of America, and Institut National de la Recherche 
Biomédicale (INRB), Democratic Republic of the Congo (DRC) 

Abbreviated Title: PALM 007 
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KEY ROLES 
Democratic Republic of 
Congo (DRC) Principal Investigator: 
Jean-Jacques Muyembe-Tamfum, MD, PhD 
Director-General, DRC INRB 
Professor of Microbiology, Kinshasa University 
Medical School 
Kinshasa Gombe 
DRC 
Phone: +243 892625954 
Email: jjmuyembet@gmail.com 
DRC Co-principal Investigator: 
Placide Mbala, MD, PhD 
Operations Manager PALM project  
Head of Epidemiology Department and Pathogen 
Genomic Laboratory 
INRB 
5345, avenue de la démocratie, Gombe, Kinshasa 
DRC 
Phone: +243 822851584 
Email: mbalaplacide@gmail.com 
U.S. Protocol Co-chair: 
Olivier Tshiani Mbaya, MD, MTM&GH  
Medical Affairs Scientist 
Clinical Monitoring Research Program Directorate 
(CMRPD) 
Frederick National Laboratory  
Leidos Biomedical Research, Inc.  
5601 Fishers Lane, Room 4C30  
Rockville, MD 20852 
Phone: +1-240-529-4773 
Email: olivier.tshianimbaya@nih.gov 
U.S. Protocol Co-Chair: 
Veronique Nussenblatt, MD, ScM, M.H.S 
Laboratory of Clinical Immunology and 
Microbiology 
NIAID, NIH 
9000 Rockville Pike  
Building 10, Room 11C438  
Bethesda, MD 20892 
Phone: +1-240-812-2075 
Email: veronique.nussenblatt@nih.gov 
Statistical Lead: 
Tyler Bonnett, MS  
Biostatistician III  
CMRPD 
Frederick National Laboratory 

Abbreviated Title: PALM 007 
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Leidos Biomedical Research, Inc. 
Support to: NIAID/Division of Clinical Research 
(DCR)/Biostatistics Research Branch (BRB) 
5601 Fishers Lane, Room 4B58  
Rockville, Maryland 20852 
Phone: 240-344-9540 
Email: tyler.bonnett@nih.gov 
Statistical Co-Lead: 
Lori Dodd, PhD  
BRB, DCR, NIAID 
5601 Fishers Lane, Room 4B53  
Rockville, MD 20852 
Phone: 240-669-5247 
Email: doddl@niaid.nih.gov 
Clinical Laboratory Specialist Co-Lead: Daniel Mukadi, MD, MSc 
Director, Rodolphe Mérieux Laboratory  
INRB, Goma 
29, Avenue des Orchidées, quartier les volcans, 
commune de Goma, ville de Goma, Nord Kivu 
DRC 
Phone: +243 812 965 243 / +243 998 273 290 
Email: drmukadi@gmail.com 
Clinical Laboratory Specialist Co-Lead: Irina Berry, PhD 
Integrated Research Facility  
NIAID/NIH 
8200 Research Plaza 
Frederick, MD 21702 
Phone: +1 240-236-9503 
Email: irina.maljkovicberry@nih.gov 
Data Coordinating Center: 
Clinical Trials Research Section 
BRB, DCR, NIAID 
5601 Fishers Lane, Room 4C31  
Rockville, MD 20852 
Scientific advisors: 
H. Clifford Lane, MD, NIAID
Richard Davey, MD, NIAID
Study sites: 
There will be several enrollment sites in the DRC that fall under the purview of the Kinshasa 
ethics committee (EC). 

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Institutional Review Board (IRB)/EC: 
Kinshasa School of Public Health Ethics Committee Board of DRC  
University of Kinshasa 
Lemba-Kinshasa, DRC  
B.P.127, Kinshasa XI  
FWA #00025422 
 
 
 
 

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TABLE OF CONTENTS 
KEY ROLES ................................................................................................................................. 2 
1 
PROTOCOL SUMMARY .................................................................................................... 9 
1.1 
Synopsis.......................................................................................................................... 9 
1.2 
Schema ......................................................................................................................... 13 
1.3 
Schedule of Activities .................................................................................................. 14 
2 
INTRODUCTION .............................................................................................................. 18 
2.1 
Background .................................................................................................................. 18 
2.1.1 Monkeypox Virus ................................................................................................... 18 
2.1.2 Epidemiology .......................................................................................................... 18 
2.1.3 Transmission ........................................................................................................... 18 
2.1.4 Clinical Manifestations ........................................................................................... 18 
2.1.5 Recent Outbreak ...................................................................................................... 19 
2.1.6 Vaccination Against MPXV ................................................................................... 19 
2.1.7 Treatment ................................................................................................................ 20 
2.2 
Risk/Benefit Assessment .............................................................................................. 20 
2.2.1 Known Potential Risks ............................................................................................ 20 
2.2.2 Known Potential Benefits ........................................................................................ 21 
2.2.3 Assessment of Potential Risks and Benefits ............................................................ 21 
2.3 
Study Rationale ............................................................................................................ 22 
3 
OBJECTIVES AND ENDPOINTS ..................................................................................... 22 
4 
STUDY DESIGN ................................................................................................................ 25 
4.1 
Overall Design .............................................................................................................. 25 
4.2 
Scientific Rationale for Study Design .......................................................................... 25 
4.3 
Justification for Dose .................................................................................................... 26 
5 
STUDY POPULATION ..................................................................................................... 26 
5.1 
Inclusion Criteria .......................................................................................................... 26 
5.2 
Exclusion Criteria ......................................................................................................... 27 
5.3 
Pregnant or Breastfeeding Women ............................................................................... 27 
5.4 
Inclusion of Vulnerable Participants ............................................................................. 27 
5.5 
Lifestyle Considerations ............................................................................................... 28 
5.6 
Screen Failures ............................................................................................................. 28 
5.7 
Community Engagement .............................................................................................. 28 
5.8 
Strategies for Recruitment and Retention ..................................................................... 29 
5.9 
Costs ............................................................................................................................. 29 
5.10 Compensation ............................................................................................................... 29 
6 
STUDY INTERVENTION ................................................................................................. 30 
6.1 
Study Intervention Description ..................................................................................... 30 
6.2 
Dosing and Administration .......................................................................................... 30 
6.2.1 Dose Modifications ................................................................................................. 30 
6.3 
Preparation/Handling/Storage/Accountability ............................................................. 31 
6.3.1 Acquisition and Accountability .............................................................................. 31 
6.3.2 Formulation, Appearance, Packaging, and Labelling ............................................. 31 
6.3.3 Product Storage and Stability .................................................................................. 31 
6.3.4 Preparation .............................................................................................................. 31 
6.4 
Measures to Minimize Bias: Randomization and Blinding .......................................... 31 

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6.4.1 Randomization ........................................................................................................ 31 
6.4.2 Blinding/Unblinding ............................................................................................... 32 
6.5 
Study Intervention Compliance .................................................................................... 34 
6.6 
Concomitant Therapy ................................................................................................... 34 
6.7 
Prohibited Medications ................................................................................................. 34 
7 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ............................................................................ 35 
7.1 
Discontinuation of Study Intervention .......................................................................... 35 
7.2 
Participant Discontinuation/Withdrawal from the Study .............................................. 35 
7.3 
Lost to Follow-up ......................................................................................................... 35 
8 
STUDY ASSESSMENTS AND PROCEDURES .............................................................. 35 
8.1 
Personnel for Study Procedures .................................................................................... 35 
8.2 
Site-Specific Considerations ......................................................................................... 35 
8.3 
Study Schedule ............................................................................................................. 35 
8.4 
Study Evaluations and Procedures ............................................................................... 36 
8.4.1 Operational and Clinical Assessments .................................................................... 36 
8.4.2 Research Laboratory Evaluations ............................................................................ 39 
8.4.3 Clinical Laboratory Evaluations .............................................................................. 39 
9 
SAFETY AND OTHER ASSESSMENTS ......................................................................... 39 
9.1 
Safety Definitions, Management, and Reporting .......................................................... 39 
9.1.1 Definitions............................................................................................................... 39 
9.1.2 Documenting, Assessing, Recording, and Reporting Events .................................. 42 
9.1.2.1 
Investigator Assessment of Adverse Events .................................................... 43 
9.1.2.1.1 Severity Grading .......................................................................................... 43 
9.1.2.1.2 Laboratory Value Assessment and Clinical Significance Criteria .............. 44 
9.1.2.1.3 Causality ...................................................................................................... 45 
9.1.2.2 
Recording of Events ......................................................................................... 46 
9.1.2.3 
Investigator Reporting Responsibilities ........................................................... 46 
9.1.2.3.1 Serious Adverse Events (Expedited Reporting) .......................................... 46 
9.1.2.3.2 Unanticipated Problems ............................................................................... 47 
9.1.2.3.3 Non-compliance and Protocol Deviations .................................................. 47 
9.1.2.3.4 Pregnancy .................................................................................................... 47 
9.1.2.4 
Sponsor’s Reporting Responsibilities .............................................................. 47 
9.2 
Withdrawal Criteria for an Individual Participant ........................................................ 48 
9.2.1 Re-enrollment and Unplanned Procedure Repetition .............................................. 48 
9.2.2 Replacement of Withdrawn Participants or Participants Who Discontinue  
Study Agent ........................................................................................................................ 48 
9.3 
Additional Safety Oversight ......................................................................................... 48 
9.3.1 Pharmacovigilance Committee ............................................................................... 48 
9.3.2 Medical Monitor ...................................................................................................... 48 
9.3.3 Oversight Committees ............................................................................................. 49 
9.3.3.1 
Data and Safety Monitoring Board .................................................................. 49 
9.4 
Pausing Rules ............................................................................................................... 49 
9.4.1 Reporting a Pause .................................................................................................... 50 
9.4.2 Resumption Following a Pause ............................................................................... 50 
9.4.3 Discontinuation of Study Agent .............................................................................. 50 

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9.5 
Halting Rules for the Protocol ...................................................................................... 50 
9.5.1 Reporting a Study Halt ............................................................................................ 51 
9.5.2 Resumption of a Halted Study ................................................................................. 51 
9.5.3 Discontinuation of Study Agent .............................................................................. 51 
9.6 
IRB/EC and Institutional Reporting Procedures ........................................................... 51 
10 STATISTICAL CONSIDERATIONS ................................................................................ 51 
10.1 Design Overview .......................................................................................................... 51 
10.2 Populations for Analyses .............................................................................................. 52 
10.3 Study Endpoints and Statistical Analyses ..................................................................... 52 
10.3.1 
General Approach ............................................................................................... 52 
10.3.2 
Endpoints ............................................................................................................. 52 
10.3.2.1 Primary Endpoint ............................................................................................ 52 
10.3.2.2 Secondary and Exploratory Endpoints ............................................................. 54 
10.3.2.3 Primary Endpoint Analysis ............................................................................. 54 
10.3.2.4 Secondary Endpoint Analyses ......................................................................... 55 
10.3.2.5 Exploratory Endpoint Analyses ....................................................................... 55 
10.3.2.6 Subgroup Analyses .......................................................................................... 56 
10.3.2.7 Additional Planned Analyses .......................................................................... 56 
10.3.3 
Baseline Descriptive Statistics ............................................................................. 57 
10.4 Power and Sample Size ................................................................................................ 57 
10.4.1 
Sample Size Re-estimation .................................................................................. 58 
10.5 Planned Interim Monitoring ......................................................................................... 58 
10.5.1 
Interim Monitoring for Efficacy and Futility ....................................................... 59 
11 REGULATORY AND OPERATIONAL CONSIDERATIONS ........................................ 59 
11.1 Informed Consent Process ............................................................................................ 59 
11.1.1 
Consent/Assent Procedures and Documentation ................................................. 59 
11.1.2 
Consent for Minors When They Reach the Age of Majority .............................. 60 
11.2 Study Discontinuation and Closure .............................................................................. 61 
11.3 Confidentiality and Privacy .......................................................................................... 62 
11.4 Future Use of Stored Specimens and Data ................................................................... 62 
11.5 Safety Oversight ........................................................................................................... 62 
11.6 Data Management and Monitoring ............................................................................... 62 
11.6.1 
Data Management Responsibilities ..................................................................... 62 
11.6.2 
Data Capture Methods ......................................................................................... 62 
11.6.3 
Types of Data....................................................................................................... 63 
11.6.3.1 Source Documents and Access to Source Data/Documents ............................ 63 
11.6.4 
Record Retention ................................................................................................. 63 
11.6.5 
Site Monitoring Plan ............................................................................................ 63 
11.7 Data Sharing Plan ......................................................................................................... 64 
11.7.1 
Human Data Sharing Plan ................................................................................... 64 
11.8 Collaborative Agreements ............................................................................................ 64 
11.8.1 
Agreement Type .................................................................................................. 64 
11.9 Conflict of Interest Policy ............................................................................................. 64 
12 ABBREVIATIONS ............................................................................................................ 64 
13 REFERENCES .................................................................................................................... 66 
APPENDIX A: Chemistry, Hematology, and Coagulation Parameter Grading Scale ............... 69 

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APPENDIX B: Hemoglobin Laboratory Value Grading Scale .................................................. 73 
APPENDIX C: Sample Size Update ........................................................................................... 74 
APPENDIX D: Pharmacokinetics (PK) Sampling Specifications Plan ..................................... 77 
 
LIST OF TABLES 
Table 1. Standard event recording, assessment, and reporting timeframes. .................................. 43 
Table 2. WHO smallpox baseline lesion severity categories ........................................................ 56 
Table 3. Number of events needed for 80% and 85% power. The shaded region represents the 
rate ratio, number of events, and projected sample size for the trial before accounting for 
potential drop out. ......................................................................................................................... 58 
Table 4. Revised Power Calculations ........................................................................................... 75 
Table 5. Interim Analysis Boundaries for the Original and Updated Designs ............................. 75 
Table 6. Interim monitoring strategies for protocol versions 3 and 4 ........................................... 76 
 
LIST OF FIGURES 
Figure 1. Study Schema. ............................................................................................................... 13 
Figure 2. Time to lesion resolution among a cohort of N=228 patients with laboratory-confirmed 
mpox in the 2007-2011 INRB/USAMRIID observational study. ................................................ 53 
Figure 3. Primary analysis. ........................................................................................................... 54 
 
 
 

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1 
PROTOCOL SUMMARY 
1.1 
Synopsis 
Title:  
A randomized, placebo-controlled, double-blinded trial of the 
safety and efficacy of tecovirimat for the treatment of adult and 
pediatric patients with monkeypox virus disease 
Study Description: 
This is a randomized, placebo-controlled, double-blind study to 
test the safety and efficacy of the antiviral drug tecovirimat in 
adults and children with laboratory-confirmed monkeypox virus 
(MPXV) disease at study sites in the DRC. Participants will be 
randomly assigned to receive oral tecovirimat or placebo (1:1 
via block randomization, stratified by study site and days from 
onset of prodromal symptoms ≤7 days or >7 days), each 
administered in the hospital with standard-of-care (SOC) 
treatment for 14 days. Participants will be followed for 28 days 
with an optional visit at Day 59 for long-term assessment. 
Objectives: 
Primary Objective: 
1. To evaluate the clinical efficacy, as assessed by time to 
lesion resolution, of tecovirimat plus SOC versus 
placebo plus SOC for patients with mpox. 
 
Secondary Objectives: 
1. To evaluate the clinical efficacy, as assessed by time to 
lesion resolution, of tecovirimat plus SOC versus 
placebo plus SOC for patients with mpox, according to 
duration of symptoms (≤7 days or >7 days). 
2. To evaluate the virologic efficacy, as assessed by PCR 
separately of blood, skin lesion, and oropharynx 
samples, of tecovirimat plus SOC relative to placebo 
plus SOC  
3. To evaluate the clinical efficacy of tecovirimat plus 
SOC versus placebo plus SOC in patients with mpox as 
assessed by mortality, clinical severity, and duration of 
symptoms. 
4. To evaluate the safety of tecovirimat plus SOC relative 
to placebo plus SOC in patients with mpox. 
 
Exploratory Objectives: 
1. To evaluate the frequency and characteristics of 
persistent residual lesions. 
2. To describe lesion progression longitudinally over 
the study period. 
3. To evaluate exposure history of confirmed mpox cases 

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and to identify risk factors for MPXV infection. 
4. To develop a baseline disease severity metric 
for mpox. 
5. To evaluate the potential impact of the presence of anti- 
orthopoxvirus (OPXV) antibodies on the course of disease 
and the clinical efficacy of tecovirimat. 
6. To evaluate persistence of MPXV PCR positivity in 
blood, skin lesions, and the oropharynx. 
7. To evaluate the trajectory of MPXV immunoglobulin 
(Ig) M and IgG over time during infection. 
8. To assess genomic variability in MPXV isolated from 
participants based on geographic and clinical 
differences. 
9. To assess whether viral resistance develops due 
to selective pressure by treatment. 
10. To assess the effect of HIV infection on mpox 
clinical outcomes and treatment effect. 
11. To measure tecovirimat drug levels in a real-world 
scenario. 
12. To describe clinically and virologically any cases of 
recrudescent disease as defined by the protocol (see 
section 9.1.2). 
Endpoints: 
Primary Endpoint: Time to lesion resolution, defined as the first 
day on which all lesions on the total body are scabbed or 
desquamated or a new layer of epidermis has formed (see 
section 8.4.1), up to 28 days after randomization. 
 
Secondary Endpoints: 
1. Time to lesion resolution, as defined in the primary 
endpoint, according to stratification by time from onset 
of illness as ≤ 7 days or > 7 days. 
2. Proportions with negative PCR results separately by 
blood, oropharyngeal swab, and lesion swab samples 
14 days after randomization. 
3. Mortality within the first 28 days after randomization. 
4. Time to death up to 28 days after randomization. 
5. Frequency and duration of clinical symptoms 
(including nausea, vomiting, abdominal pain, diarrhea, 
anorexia, cough, lymphadenopathy, dysphagia, sore 
throat, muscle aches, fatigue/lack of energy, fever, 
chills, night sweats, headache, ocular lesions, eye pain, 
change in vision, buccal ulcers, nasal congestion, 

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cough, joint pain, pain with urination, painful skin 
lesions, pruritic skin lesions). 
6. Incidence of serious adverse events (SAEs), adverse 
events (AEs) requiring drug discontinuation, and 
incidence of other AEs. 
7. Incidence of bacterial infections. Bacterial infections 
will be defined clinically with laboratory and 
radiographical confirmation when possible. 
8. Automated image analysis of lesion counts and 
characteristics over time. 
 
Exploratory Endpoints: 
1. Presence, location, and duration of persistent residual 
lesions, defined as any lesion (in any area of the body) 
unresolved after all assessment-region lesions are 
scabbed or desquamated. 
2. Longitudinal description of lesion progression over 
the study period. 
3. Number and percentage of confirmed mpox cases 
reporting exposure to animals, symptomatic humans, 
or with no known exposures. 
4. Associations between measures of baseline disease 
severity (including lesion counts, duration of 
symptoms, and comorbidities) and efficacy endpoints.  
5. Differences in outcomes based on the presence of 
anti-OPXV antibodies. 
6. Viral load and proportion with negative PCR results in 
blood, oropharyngeal swab, and open lesion swab 
samples over time and time to the first negative PCR 
result in each of these specimens up to 28 days after 
randomization. 
7. Change in antibody titer over time. 
8. Sequencing differences between virus isolated from 
participants from different geographic areas and with 
differing clinical trajectories and responses to 
tecovirimat. 
9. Sequencing differences between virus isolated prior to 
and after treatment. 
10. Differences in severity and duration of MPXV 
infection and treatment effect by HIV status and HIV 
viral load. 
11. Pre-dose concentration in all participants and 4h post-dose 
concentration only in participants ≥18 years of age of 

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tecovirimat in blood measured on day 7. 
12. Incidence of recrudescent disease and description of 
clinical and virologic characteristics of recrudescent 
disease cases. 
Study Population: 
Patients of any age with laboratory-confirmed MPXV infection. 
Sample Size: N=600 
Accrual Ceiling: 1000 screened participants, in order to enroll 
up to 600  participants. 
Phase: 
3 
Description of Study 
Intervention: 
Tecovirimat capsules or placebo capsules will be administered 
orally to participants for 14 days as follows: 
• ≥120 kg: three capsules three times a day (total 
daily tecovirimat dose: 1,800 mg). 
• 40 to <120 kg: three capsules twice a day (total 
daily tecovirimat dose: 1,200 mg). 
• 25 to <40 kg: two capsules twice a day (total daily 
tecovirimat dose: 800 mg). 
• 13 to <25 kg: one capsule twice a day (total daily 
tecovirimat dose: 400 mg). 
• 6 to <13 kg: ½ the contents of a capsule twice daily (total 
daily tecovirimat dose: 200 mg). 
• 3 to <6 kg: ¼ the contents of a capsule twice daily (total 
daily tecovirimat dose: 100 mg). 
Study Duration: 
Up to 5 years, but could be shortened depending on the pace of 
enrollment 
Participant Duration: 
Up to 59 days 
 
 
 
 

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1.2 
Schema 
Days -1 to 1 
 
 
 
 
 
Day 1 
 
 
 
 
 
 
 
 
 
 
 
 
 
Day 1 to 
14 
 
 
 
Day 29 
 
 
 
 
Day 59  
(optional) 
 
 
 
 
 
 
Figure 1. Study Schema. 
 
Enrollment and  
Randomization: 
 
- Perform baseline assessments (refer to 
Section 1.3, Schedule of Activities). 
- Randomize to study arm. 
Tecovirimat 
(n=300) 
Placebo 
(n=300) 
Final Study Visit 
-
Perform final study assessments (see 
Section 1.3, Schedule of Activities). 
- Perform study assessments (refer to Section 1.3, Schedule of Activities). 
- Administer study agent (Days 1 to 14). 
- Perform study assessments (refer to Section 1.3, Schedule of Activities). 
Recruitment & Screening: 
- Obtain informed consent. 
- Screen potential participants/assess eligibility. 

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1.3 
Schedule of Activities 
Evaluation/Procedure 
Screen 
Baseline 
Follow-Up 
Sick visitn 
Pregnancy 
outcome 
follow-up 
(optional) 
Day +/- Window 
−1 or 1 
1 
2 
3 
4 
5 
6 
7p 
8 
9+ while hospitalizedd 
29±7a 
59±7b 
OPERATIONAL AND CLINICAL ASSESSMENTS 
Informed consentl 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Eligibility (inclusion/exclusion) 
assessment 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
 
Xk 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
 
Xk 
 
 
 
 
 
 
 
 
 
 
 
Medication review 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Daily until discharge 
X 
 
X 
 
Weight 
X 
Xc 
Xc 
Xc 
Xc 
Xc 
Xc 
Xc 
Xc 
Daily through last day of 
study drug administrationc 
 
 
X 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
Arm circumference (age 3 months 
to ≤ 5 years) 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
Pregnancy test (serum or urine; 
females of childbearing potential) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs 
 
X 
X 
X 
X 
X 
X 
X 
X 
Daily until discharge 
X 
X 
X 
 
Lesion Assessmente 
 
X 
X 
X 
X 
X 
X 
X 
X 
Daily until resolution of 
lesions 
Xe 
 
Xo 
 
Current symptoms 
 
X 
X 
X 
X 
X 
X 
X 
X 
Daily until discharge 
X 
X 
X 
 
Assessment of AEs/SAEs 
 
X 
X 
X 
X 
X 
X 
X 
X 
Daily until discharge 
X 
X 
X 
 
Completion of pregnancy outcome 
case report form 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
STUDY DRUG ADMINISTRATION 
Study drug administration 
Tecovirimat or placebo daily orally for 14 days 

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Evaluation/Procedure 
Screen 
Baseline 
Follow-Up 
Sick visitn 
Pregnancy 
outcome 
follow-up 
(optional) 
Day +/- Window 
−1 or 1 
1 
2 
3 
4 
5 
6 
7p 
8 
9+ while hospitalizedd 
29±7a 
59±7b 
RESEARCH LABORATORY EVALUATIONSm 
MPXV PCR (blood) with CT 
Xf 
Xg 
 
X 
 
X 
 
X 
 
Every other day until 
negative x2 
 
 
X 
 
Blood for storage 
 
X 
 
 
 
 
 
X 
 
Day 13 
X 
X 
X 
 
Oropharyngeal swab 
Xf 
Xg 
 
X 
 
X 
 
X 
 
Every other day until 
negative x2 
 
 
X 
 
Skin lesions swab 
Xf 
Xg 
 
X 
 
X 
 
X 
 
Every other day until 
negative x2 
 
 
X 
 
CLINICAL LABORATORY EVALUATIONSm 
HIV antibody testi 
 
X 
 
 
 
 
 
 
 
 
 
 
 
HIV viral loadi 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Varicella zoster virus PCRj 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
Malaria rapid testj 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
Glucose (mg/dl) 
 
Xh 
 
X 
 
X 
 
X 
 
Every other day until 
discharge 
X 
 
X 
 
Hemoglobin (g/dL) 
X 
Xh 
 
X 
 
X 
 
X 
 
Every other day until 
discharge 
X 
 
X 
 
Hematocrit (L/L) 
 
Xh 
 
X 
 
X 
 
X 
 
Every other day until 
discharge 
X 
 
X 
 
Creatinine (mg/dL) 
 
Xh 
 
X 
 
X 
 
X 
 
Every other day until 
discharge 
X 
 
X 
 
Potassium (mmol/L) 
 
Xh 
 
X 
 
X 
 
X 
 
Every other day until 
discharge 
X 
 
X 
 
Sodium (mmol/L) 
 
Xh 
 
X 
 
X 
 
X 
 
Every other day until 
discharge 
X 
 
X 
 
eGFR (mL/min/1.73m2) 
 
Xh 
 
X 
 
X 
 
X 
 
Every other day until 
discharge 
X 
 
X 
 
AST (U/L) 
 
Xh 
 
X 
 
X 
 
X 
 
Every other day until 
discharge 
X 
 
X 
 
ALT (U/L) 
 
Xh 
 
X 
 
X 
 
X 
 
Every other day until 
discharge 
X 
 
X 
 

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Evaluation/Procedure 
Screen 
Baseline 
Follow-Up 
Sick visitn 
Pregnancy 
outcome 
follow-up 
(optional) 
Day +/- Window 
−1 or 1 
1 
2 
3 
4 
5 
6 
7p 
8 
9+ while hospitalizedd 
29±7a 
59±7b 
BUN (mg/dL) 
 
Xh 
 
X 
 
X 
 
X 
 
Every other day until 
discharge 
X 
 
X 
 
CBC with differential (c/mm3) 
 
Xh 
 
X 
 
X 
 
X 
 
Every other day until 
discharge 
X 
 
X 
 
Calcium (mg/dL) 
 
Xh 
 
X 
 
X 
 
X 
 
Every other day until 
discharge 
X 
 
X 
 
Total protein (g/dL) 
 
Xh 
 
X 
 
X 
 
X 
 
Every other day until 
discharge 
X 
 
X 
 
C-reactive protein (ug/mL) 
 
Xh 
 
 
 
 
 
X 
 
Day 13 
X 
 
X 
 
Creatinine kinase (U/L) 
 
Xh 
 
X 
 
X 
 
X 
 
Every other day until 
discharge 
X 
 
X 
 
Total CO2 (mEq/L) 
 
Xh 
 
X 
 
X 
 
X 
 
Every other day until 
discharge 
X 
 
X 
 
Chloride (mEq/L) 
 
Xh 
 
X 
 
X 
 
X 
 
Every other day until 
discharge 
X 
 
X 
 
Alkaline phosphatase (IU/L) 
 
Xh 
 
X 
 
X 
 
X 
 
Every other day until 
discharge 
X 
 
X 
 
t-Bilirubin (mg/dL) 
 
Xh 
 
X 
 
X 
 
X 
 
Every other day until 
discharge 
X 
 
X 
 
Amylase (U/L) 
 
Xh 
 
 
 
 
 
X 
 
Day 13 
X 
 
X 
 
Albumin (g/dL) 
 
Xh 
 
X 
 
X 
 
X 
 
Every other day until 
discharge 
X 
 
X 
 
PT (sec)/INR 
 
Xh 
 
 
 
 
 
X 
 
Day 13 
 
 
 
 
Urinalysis, dipstick 
 
Xh 
 
X 
 
X 
 
X 
 
Every other day until 
discharge 
X 
 
X 
 
Abbreviations: AE, adverse event; ALT, alanine transaminase; activated partial thromboplastin time; AST, aspartate transaminase; BUN, blood urea nitrogen; 
CBC, complete blood count; cluster of differentiation 4 count; CO2, carbon dioxide; CT, cycle threshold; eGFR, estimated glomerular filtration rate; HIV, 
human immunodeficiency virus; INR, international normalized ratio; MPXV, monkeypox virus; PCR, polymerase chain reaction; PT, prothrombin time; SAE, 
serious adverse event. 
a This study visit will include a +/- 7-day visit window for participants discharged prior to Day 29. For participants who remain inpatient through Day 29, the 
visit should take place exactly on Day 29, but clinical and research labs will not be collected if already collected on Day 28. For participants who are 
discharged prior to Day 29 but within the visit window (i.e., Day 22 to Day 28), the Day 29 visit will be the day of discharge. 

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b The Day 59 visit is optional and may be completed in person or by phone. Failure to complete a Day 59 visit will not result in a protocol deviation. Some 
procedures may not be able to be performed if the visit takes place over the phone. 
c Only for participants who weigh <40 kg. For these participants, weight will be taken each morning before breakfast and used to calculate the study drug dose 
for that day. 
d After completion of the 14-day treatment period, participants are eligible for discharge at the discretion of the treating physician only after all mpox lesions 
on the total body are scabbed or desquamated and they have received two consecutive negative results on the blood PCR test. The date of discharge will be 
documented.  
e During daily lesion assessments, photographs may be taken of the body, which may include different part of the body and the face, including the eyes. While 
the participant still has unresolved lesions in the target region, assessment of whether there are unresolved lesions on other areas of the body will be optional 
but preferred. Once all lesions in the target region are resolved, a simplified full body lesion assessment will be done daily until all lesions are resolved (or Day 
29, whichever comes first). 
f Any positive MPXV PCR from blood, oropharynx, or skin lesion collected up to 48 hours prior to informed consent may be used to establish eligibility. 
g The baseline specimen will ideally be collected within 24 hours prior to randomization. If the specimen cannot be collected within 24 hours and there is a 
specimen available that was collected within 48 hours prior to randomization, the 48-hour specimen may be used as the baseline sample. 
h Any laboratory tests obtained within 1 day prior to randomization do not need to be repeated on day 1. 
i Participants may opt out of HIV testing. HIV viral load may be performed for HIV-infected individuals only. Tests will be performed retrospectively. 
j Although collection is highly desirable, these labs may be waived if not feasible, per investigator discretion. Varicella zoster virus PCR may be done 
retrospectively. 
k Clinical and demographic information collected within 48 hours of randomization may be collected for study purposes. 
l A signed screening consent will be obtained prior to performing screening procedures; once eligibility is confirmed, consent for study participation will be 
obtained using a main study consent prior to performing Day 1 procedures. 
m Research and clinical labs at all time points, though highly desirable, may be waived if not feasible (e.g., due to blood draw volume concerns related to 
participant weight or hemoglobin or due to site logistics), per investigator discretion. 
n If a participant reaches full body lesion resolution but subsequently develops at least one new lesion consistent with mpox after discharge but while still enrolled 
in the study, they will be eligible to make an optional “Sick Visit” and they will be offered standard of care for mpox.  
o Full body lesion count will be performed. 
p An additional voluntary/optional blood sample will be obtained from all participants ≥18 years of age at 4 hours after receiving their first dose of study drug on 
day 7 to be used for PK analysis. 
 
 

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2 
INTRODUCTION 
2.1 
Background 
2.1.1 
Monkeypox Virus 
Monkeypox virus belongs to the family of Poxviridae and the genus of Orthopoxvirus, which 
comprises 10 species, of which Monkeypox, Variola, Vaccinia, and Cowpox viruses represent 
pathogens of medical interest for humans.1 Monkeypox virus is antigenically related to Variola, 
the causative agent of smallpox, and Vaccinia viruses. The Monkeypox virus is a brick-shaped, 
enveloped virus of 200-250 nm, with characteristic surface tubules and a dumbbell-shaped core 
component.2 Its genome consists of linear double-stranded DNA, and the virion is composed of 4 
major elements (core, lateral bodies, outer membrane, and the outer lipoprotein envelope) that 
intervene at different steps of the virus’ life cycle.3 Monkeypox virus was first identified as the 
cause of pox-like illness in captive monkeys in a laboratory at the Institute of Copenhagen in 
1958.4 Since its first human identification in 1970 in the DRC, the majority of subsequent cases 
were mainly reported from rain forest areas of Central Africa and sporadic other cases from West 
Africa.5 Genetic evolution of the virus revealed the existence of two Monkeypox virus clades, the 
Congo Basin (CB) and the West African (WA) clade, presenting nucleotide changes in their 
sequences6 with different clinical expressions and geographic locations. The WA clade was 
reported to be less severe than the CB clade with a case-fatality rate of 0-6%; while the CB clade 
presented a mortality estimated to be 11%, with a higher percentage observed in children 
(~17%).6,7 
 
2.1.2 
Epidemiology 
Although mpox disease has clinical similarities with smallpox disease, the human epidemiology 
of the disease differs significantly. Mpox surveillance is not well established, and limited 
information is available on the prevalence and incidence of the disease in the countries most 
affected. Early epidemiological data came from investigations of outbreaks in Central and 
Western Africa and depicted different epidemiology profiles of the disease depending on the 
surveillance period.8 Furthermore, data collected during the first outbreak of mpox in United 
States (US, 2003), due to imported wild animals from West Africa, have added to what is known 
about the disease epidemiology, even though no inter-human transmission was reported.9-11 
 
2.1.3 
Transmission 
Several animal reservoirs have been implicated in the primary transmission of MPXV 
infection.4,12 However, epidemiological investigations have defined a close link with forest-
dwelling rodents (Gambia pouched rat, rope squirrel).13 The initial transmission mode described 
was a primary transmission from animal to human.8 Direct contact with infected animals or 
possible ingestion of inadequately cooked meat are the main modes of primary contamination. 
Secondary contamination does occur, and during the 1996-1997 outbreak in the DRC, 8-15% of 
contacts reported respiratory droplets, direct contact with muco-cutaneous lesions, or fomites as 
modes of secondary transmission.8 
 
2.1.4 
Clinical Manifestations 
The clinical features of the disease are typical of an acute febrile rash illness and are preceded by 
a viral incubation period from 4 to up to 21 days and is characterized by two phases: the 

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prodromal and rash phases. The prodromal phase includes general signs like fever, headache, 
chills, sweats, sore throat, myalgias, prostration, and lymphadenopathy (cervical, sub- 
mandibular, axillary, inguinal). Lymphadenopathy represents the pathognomonic sign of the 
disease and contributes to clinically differentiate mpox from variola (smallpox) and other viral 
rash illnesses (chickenpox).2 The rash phase can last between 2 and 4 weeks. Skin lesions are 
characteristic of the disease with uniform progression from macules to papules, vesicles, 
pustules, umbilication, crusting, and finally desquamation. Lesions have a centrifugal 
distribution starting from the head and the face of the patient with extension to the trunk and the 
extremities of the body.2 Other extra-cutaneous findings include gastro-intestinal symptoms. 
Two types of complications are frequently described and may be related to bacterial 
superinfection (bronchopneumonia, encephalitis, sepsis, ocular infection) and dehydration.14 
Subclinical infection and asymptomatic cases have also been reported with an estimated rate of 
approximately 30%.15 
 
2.1.5 
Recent Outbreak 
Among the cases reported worldwide, the DRC has the highest number of cases with more than 
1000 cases reported each year since 2005. Data reported from week 1 to 21 in 2021 by the 
DRC’s Ministry of Health epidemiological surveillance showed that 20% (104/516) of health 
zones in the country, including Boende and Kole, have reported cases clinically compatible with 
mpox disease. On December 9, 2021, the World Health Organization (WHO) reported an 
outbreak that was declared by the Congolese authorities in the Tunda health district in Kibombo 
territory in Maniema province. The index case was reported in Tunda health district the week of 
October 03, 2021. The epidemic continues to spread geographically in the province of Maniema 
with evidence of sustained human-to-human transmission in 7 health zones including Tunda, 
Kindu, Obokote, Samba, Kibombo, Kunda, and Lubutu. The Ministry of Health epidemiological 
report of week 1 to 18 in 2022 listed 513 clinically confirmed cases and 39 deaths. Additional 
Health Zones have identified suspected cases in Kibombo and Kindu with epidemiological 
links.16,17 As the frequency of mpox cases has been increasing over the last decades, and because 
of the significant morbidity it causes to individuals in areas with limited-resources, research 
efforts to find a cure against this disease is more relevant than ever. 
 
2.1.6 
Vaccination Against MPXV 
Smallpox vaccines induce cross-reactive antibodies that protect against infection from other 
Orthopoxvirus species. Live vaccinia virus vaccine (first generation), which was used during the 
smallpox eradication program, was estimated to be 85% effective against MPXV infection.18 The 
vaccination program was discontinued after smallpox eradication was declared in 1980, causing 
the proportion of the unvaccinated population to rise. Furthermore, this first generation of 
vaccinia vaccine can cause SAEs and is contradicted in pregnant women, immunocompromised 
people, and people with a history of eczema.18 Improved manufacturing procedures allowed the 
development of the second (ACAM2000), third (JYNNEOS), and fourth generation vaccinia 
vaccines with reduced side effects and simplified administration. New generation vaccine 
effectiveness (JYNNEOS), immunogenicity, and safety are also being evaluated in healthcare 
personnel at risk of MPXV infection in the Boende area in DRC18 where an Ebola vaccine 
clinical trial with a modified vaccinia virus Ankara (MVA) vector was also performed. 
 

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2.1.7 
Treatment 
To date, most of the patients in remote regions affected by mpox receive only supportive and 
symptomatic care as standard treatment. However, several investigational antivirals, initially 
developed against smallpox, demonstrate activity against MPXV and other Orthopoxviruses in 
vitro and in animal models,19 but none has been evaluated in a clinical trial. The most promising 
is tecovirimat, which is a drug developed by SIGA Technologies, Inc. (SIGA)20 and approved by 
the US Food and Drug Administration (FDA) for the treatment of smallpox.21 The FDA initially 
granted SIGA approval of tecovirimat for the treatment of human smallpox disease in adults and 
pediatric patients weighing at least 13 kg under the Animal Rule (SIGA New Drug Application 
208627 and SIGA Investigational New Drug [IND] application 69019), and has since expanded 
the approval to individuals weighing at least 3 kg. Tecovirimat is also authorized by the 
European Medicines Agency for the treatment of smallpox, mpox, and cowpox.22 Tecovirimat 
inhibits the exit of viral particles from an OPXV-infected cell, thereby inhibiting systemic spread 
of infection. The p37 protein target of tecovirimat is highly conserved in all species of 
Orthopoxviruses and is similarly targeted by tecovirimat with equivalent efficiency. There are no 
mammalian homologs to p37, and no orthologous genes exist outside the Poxviridae family. 
Therefore, no off-target activity has been observed. The pharmacology of tecovirimat has been 
evaluated in nonclinical in vitro and in vivo studies designed to assess the activity and 
mechanism of action of tecovirimat. In vivo efficacy studies were conducted in non- human 
primates and rabbits; numerous additional exploratory studies were also conducted in different 
animal models.23 The clinical pharmacological and safety results from these studies are 
encouraging. Also, safe administration of tecovirimat has been recently reported in some of the 
confirmed cases identified in the US and Europe.24 
 
2.2 
Risk/Benefit Assessment  
2.2.1 
Known Potential Risks 
Tecovirimat: The safety of oral tecovirimat was evaluated in 359 healthy adult participants ages 
18-79 years in a Phase 3 clinical trial. The most frequently reported adverse reactions (occurring 
in at least 5% of participants) were headache and nausea. Abdominal pain and vomiting each 
occurred in 2% of participants. A total of 6 participants discontinued drug due to mild adverse 
reactions and one abnormal electroencephalogram change. Additional details on less common 
adverse reactions and the adverse reactions that led to drug discontinuation are found in the 
TPOXX prescribing information.21 
 
Tecovirimat is a weak inducer of cytochrome P450 (CYP) 3A and a weak inhibitor of CYP2C8 
and CYP2C19. However, the effects are not expected to be clinically relevant for most substrates 
of those enzymes based on the magnitude of interactions and a 14-day duration of tecovirimat 
administration, with the exception of repaglinide and midazolam as follows. 
 
Co-administration of repaglinide and tecovirimat may cause mild to moderate hypoglycemia. In a 
drug interaction study, 10 of 30 healthy participants experienced mild (6 participants) or 
moderate (4 participants) hypoglycemia following co-administration of repaglinide (2 mg) and 
tecovirimat. Symptoms resolved in all participants after intake of food and/or oral glucose. Due 
to the risk of hypoglycemia, individuals with concomitant use of a meglitinide (repaglinide, 

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nateglinide) are excluded from enrollment in this study; similarly, use of these drugs is 
prohibited during study participation. 
 
Tecovirimat decreased the concentration of midazolam when the drugs were co-administered in a 
drug interaction study. Therefore, individuals with concomitant use of midazolam are excluded 
from enrollment in this study; similarly, use of this drug is prohibited during study participation. 
Refer to the TPOXX prescribing information for additional information on drug interactions.21 
 
Phlebotomy: The primary risks of phlebotomy include local discomfort, occasional bleeding or 
bruising of the skin at the site of needle puncture, hematoma, and, rarely, infection or fainting. 
Because ongoing clinical care of participants may require frequent blood draws independent of 
actual study-related assessments, it will be important that study teams ensure that research blood 
draws do not exceed the guidelines set forth by each institution’s safety regulations. 
 
Swabs: Collection of the swab samples may be uncomfortable but should not be painful. 
 
Photography: Taking pictures of the face (including eyes) and body may be embarrassing to 
some people. These photographs may be used for teaching or education purposes, as well as for 
future research projects by the study team or other researchers. They may also be published in 
medical journals, without identifying the participant. We will attempt to preserve the anonymity 
of the participant as much as possible, while providing the information needed to support the 
research being published. Photographs will be stored securely, but there is a slight risk of loss of 
confidentiality. 
 
Confidentiality: We will maintain participants’ samples and data securely and confidentially to 
the extent possible, but there is a slight risk that someone will gain unauthorized access to 
samples and/or data, resulting in a loss of confidentiality. 
 
2.2.2 
Known Potential Benefits 
All participants may benefit from the supportive care and clinical oversight provided by 
participation in the study and free of charge. 
 
There is also significant benefit for the local community. Training will be provided to local 
hospitals and health care workers, and the study sites will benefit from logistic and material 
support. In addition, the knowledge gained from this study will provide important information 
about treatment options for MPXV infection, which currently has no approved treatment options, 
and thus this will be of great benefit for both the local and international community. 
 
Alternatives to participation: Individuals who do not participate in this study may continue to 
receive SOC treatment or discuss other treatment options with their personal health care 
provider. 
 
2.2.3 
Assessment of Potential Risks and Benefits 
Mpox disease is associated with significant morbidity but has no approved treatments in the 
DRC. Tecovirimat, developed for the treatment of smallpox, has a well-defined safety profile and 
has been recommended by the US Centers for Disease Control and Prevention (CDC) for control 

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of mox outbreaks;25,26 however, this is currently stockpiled by the Strategic National Stockpile 
and may only be administered with an IND. It is approved by the European Medicines Agency 
(EMA) for the treatment of mpox disease, and although it has not been studied for the indication 
of mpox disease in humans, animal and human safety data have not raised significant safety 
concerns. Therefore, the risks of tecovirimat treatment are reasonable given its potential benefit 
as an effective treatment. Risks associated with tecovirimat treatment in this study will be 
minimized by following the approved dosing for smallpox for individuals who weigh at least 13 
kg and following dosing based on PK modeling for those weighing <13 kg. We will be excluding 
individuals who may be at increased risk of AEs from treatment. All participants will be 
hospitalized for at least 14 days to allow for close supervision. In addition, study procedures will 
be limited to minimize risks and collect only the information needed to assess the study 
objectives. Participants will be provided a limited insurance to cover injury as the resultant of his 
participation to study activities. 
 
2.3 
Study Rationale 
Human mpox cases have been increasing in sub-Saharan Africa since 2000,27 and sporadic 
outbreaks outside of Africa have occurred.9,28 Cessation of routine smallpox vaccination in the 
late 1970s has resulted in the eruption of susceptible populations to other Orthopoxviruses. The 
similarity between MPXV and the variola virus, coupled with the high comorbidity on affected 
individuals from areas with limited resources, have placed mpox treatments at the forefront of 
public health and scientific research agendas in many countries. 
 
In the US, while one vaccine, JYNNEOS (also known as Imvamune or Imvanex), has been 
licensed to prevent mpox, there are no approved treatment options for mpox. Symptomatic and 
supportive treatments are currently the only options for clinical management. However, pre-
clinical evidence for the efficacy of several compounds against MPXV infection is encouraging. 
ST-246 (USAN tecovirimat, used under compassionate use and sold under the brand name 
TPOXX), developed by SIGA for treatment of smallpox, may present an attractive option for the 
treatment of mpox. Phase 1 clinical trials have demonstrated a reasonable safety profile of 
tecovirimat in healthy volunteers.29,30 Additionally, current US CDC guidance recommends that 
tecovirimat, currently administered under an IND, can be used for control of mpox outbreaks. In 
January 2022, the EMA approved SIGA’s Marketing Application for oral tecovirimat to be 
administered for 14 days. However, no randomized controlled clinical trial has yet evaluated the 
efficacy of tecovirimat for treatment of human mpox. A lack of understanding about mpox and 
the need for effective, proven outbreak control measures necessitate further research activities. 
This effort should include clinical trials to evaluate potential medical countermeasures against 
mpox. 
 
3 
OBJECTIVES AND ENDPOINTS 
Primary Objective: 
1. To evaluate the clinical efficacy, as assessed by time to lesion resolution, of tecovirimat 
plus SOC versus placebo plus SOC for patients with mpox. 
 
 

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Secondary Objectives: 
1. To evaluate the clinical efficacy, as assessed by time to lesion resolution, of tecovirimat 
plus SOC versus placebo plus SOC for patients with mpox, according to duration of 
symptoms (≤7 days or >7 days). 
2. To evaluate the virologic efficacy, as assessed by PCR separately of blood, skin lesion, 
and oropharynx samples, of tecovirimat plus SOC relative to placebo plus SOC for 
patients with mpox. 
3. To evaluate the clinical efficacy of tecovirimat plus SOC versus placebo plus SOC in 
patients with mpox as assessed by mortality, clinical severity, and duration of 
symptoms. 
4. To evaluate the safety of tecovirimat plus SOC relative to placebo plus SOC in patients 
with mpox. 
 
Exploratory Objectives: 
1. To evaluate the frequency and characteristics of persistent residual lesions. 
2. To describe lesion progression longitudinally over the study period. 
3. To evaluate exposure history of confirmed mpox cases and to identify risk factors for 
MPXV infection. 
4. To develop a baseline disease severity metric for mpox. 
5. To evaluate the potential impact of the presence of anti-OPXV antibodies on the course 
of disease and the clinical efficacy of tecovirimat. 
6. To evaluate persistence of MPXV PCR positivity in blood, skin lesions, and the 
oropharynx. 
7. To evaluate the trajectory of MPXV IgM and IgG over time during infection. 
8. To assess genomic variability in MPXV isolated from participants based on geographic 
and clinical differences. 
9. To assess whether viral resistance develops due to selective pressure by treatment. 
10. To assess the effect of HIV infection on mpox clinical outcomes and treatment effect. 
11. To determine tecovirimat drug levels in a real-world scenario. 
12. To describe clinically and virologically any cases of recrudescent disease as defined by 
the protocol (see section 9.1.2). 
 
Primary Endpoint: Time to lesion resolution, defined as the first day on which all lesions on the 
total body are scabbed or desquamated or a new layer of epidermis has formed (see section 
8.4.1), up to 28 days after randomization. 
 
Secondary Endpoints: 
1. Time to lesion resolution, as defined in the primary endpoint, according to stratification 
by time from onset of illness as ≤ 7 days or > 7 days. 

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2. Proportions with negative PCR results separately by blood, oropharyngeal swab, and 
lesion swab samples 14 days after randomization. 
3. Mortality within the first 28 days after randomization. 
4. Time to death up to 28 days after randomization. 
5. Frequency and duration of clinical symptoms (including nausea, vomiting, abdominal 
pain, diarrhea, anorexia, cough, lymphadenopathy, dysphagia, sore throat, muscle aches, 
fatigue/lack of energy, fever, chills, night sweats, headache, ocular lesions, eye pain, 
change in vision, buccal ulcers, nasal congestion, cough, joint pain, pain with urination, 
painful skin lesions, pruritic skin lesions). 
6. Incidence of SAEs, AEs requiring drug discontinuation, and incidence of other AEs. 
7. Incidence of bacterial infections. Bacterial infections will be defined clinically with 
laboratory and radiographical confirmation when possible. 
8. Automated image analysis of lesion counts and characteristics over time. 
 
Exploratory Endpoints: 
1. Presence, location, and duration of persistent residual lesions, defined as any lesion (in 
any area of the body) unresolved after all assessment-region lesions are scabbed or 
desquamated. 
2. Longitudinal description of lesion progression over the study period. 
3. Number and percentage of confirmed mpox cases reporting exposure to animals, 
symptomatic humans, or with no known exposures. 
4. Associations between measures of baseline disease severity (including lesion counts, 
duration of symptoms, and comorbidities) and efficacy endpoints. 
5. Differences in outcomes based on the presence of anti-OPXV antibodies. 
6. Viral load and proportion with negative PCR results in blood, oropharyngeal swab, 
and open lesion swab samples over time and time to the first negative PCR result in 
each of these specimens up to 28 days after randomization. 
7. Change in antibody titer over time. 
8. Sequencing differences between virus isolated from participants from different 
geographic areas and with differing clinical trajectories and responses to tecovirimat. 
9. Sequencing differences between virus isolated prior to and after treatment. 
10. Differences in severity and duration of MPXV infection and treatment effect by HIV 
status, including HIV viral load. 
11. Pre-dose concentration in all participants and 4h post-dose concentration only in participants 
≥18 years of age of tecovirimat in blood measured on day 7. 
12. Incidence of recrudescent disease and description of clinical and virologic 
characteristics of recrudescent disease cases. 

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4 
STUDY DESIGN 
4.1 
Overall Design 
This is a randomized, placebo-controlled, double-blind study to test the antiviral drug tecovirimat 
for the treatment of adults and children with laboratory-confirmed MPXV disease at participating 
sites in DRC. Study sites will be in geographic locations where cases of mpox were reported and 
previous surveillance activities related to this disease have been carried out, namely, in the health 
zones of Boende in Tshuapa, Kole in Sankuru, and Tunda in Maniema. We anticipate that those 
3 health zones will ensure the completion of the study accrual in the 5 years of the study 
duration. Sites will be opened one after another to ensure correct workflow of activities within a 
site and synchronization of activities between sites later on. 
 
Eligible and consented participants (N=600) will be randomized 1:1 to receive either tecovirimat 
or placebo; all participants will also receive SOC treatment standardized at each site according to 
local/site practice and outlined in a manual of operations. Randomization will be stratified 
according to time since prodromal symptom onset (≤7 days or >7 days) and study site. A 
participant will be considered enrolled beginning from when the informed consent form is signed 
and randomization to an assigned treatment has occurred. Once enrolled, study drug 
administration will begin according to study group assignment. Tecovirimat will be administered 
as described below (section 6.2). Study drug and placebo administration will be for 14 days. 
 
Participants will be hospitalized throughout the period of study treatment for free and will 
undergo frequent clinical and laboratory assessments for safety and efficacy evaluations (see 
section 1.3 for a detailed schedule of assessments). Participants and up to 2 accompanying family 
members will receive a daily stipend (section 5.9). Participants will be eligible for discharge at 
the discretion of the treating physician when all mpox lesions on the total body are scabbed with 
no residual inflammation or desquamated or new layer of epidermis and the participant has 
received two consecutive negative blood PCR results, but not before day 14 when study drug 
administration is complete. If a participant reaches full body lesion resolution but subsequently 
develops at least one new lesion consistent with mpox after discharge but while still enrolled in 
the study, they will be eligible to make a “Sick Visit” as defined in the Schedule of Activities 
and will be offered standard of care for mpox. Day 29 is the final required study visit, but 
participants may return for an optional visit at Day 59 for long-term clinical and laboratory 
evaluations. Interim monitoring of study safety and integrity will be performed by a data and 
safety monitoring board (DSMB). The DSMB may recommend stopping the study early for 
efficacy if there is clear and substantial evidence of a treatment benefit, or for evidence of harm 
or futility. 
 
4.2 
Scientific Rationale for Study Design 
Data from an observational study on mpox, carried out in the Sankuru province of the DRC 
between 2007 and 2011 as part of a joint effort involving the DRC National Institute of 
Biomedical Research (Institut National de Recherche Biomédicale; INRB) and the US Army 
Medical Research Institute of Infectious Diseases (USAMRIID), have considerably contributed 
to the development of the study design. Data were available on 228 patients with PCR-confirmed 
MPXV disease and included a limited set of baseline characteristics and demographics, 
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stage (macule, papule, vesicle, pustule, umbilication, scabbing, or desquamating). The primary 
endpoint is designed to quantify the resolution of mpox illness. Specifically, the primary 
endpoint is “time to lesion resolution,” defined as the time for all lesions to reach a scabbed or 
desquamating stage. Faster resolution of painful lesions is meaningful to the patient and lesion 
scabbing and desquamation coincides with resolution of viremia and clinical symptoms. 
 
Additionally, a patient is no longer considered infectious when all lesions are desquamated. Time 
to one or two negative PCR results were deemed to be of less clinical importance to the patient 
and are considered as secondary endpoints. 
 
Randomization will be used to eliminate the selection bias, to balance the groups with respect to 
many known and unknown confounding or prognostic variables. A placebo control group will be 
incorporated in order to fully understand whether the drug under investigation is effective. 
Furthermore, to avoid any disclosure related to the administration of the drug from the study’s 
investigator or participants and to preclude any influence by the study investigators, the study 
was designed to be double blinded. 
 
4.3 
Justification for Dose 
Tecovirimat will be administered at the FDA-approved dose (for individuals weighing ≥13 kg) 
for the treatment of smallpox, which is caused by another Orthopoxvirus (variola virus) that is 
closely related to MPXV. The approved treatment duration for smallpox is 14 days, which did 
not result in severe or serious AEs; accordingly, under this protocol, study drug will be 
administered for 14 days. For participants weighing <13 kg, oral rather than intravenous dosing 
(as indicated under the FDA approval) will be used; SIGA provided oral tecovirimat dosing for 
these participants based on population pharmacokinetic (PK) modeling. 
 
5 
STUDY POPULATION 
5.1 
Inclusion Criteria 
Individuals must meet all the following criteria to be included in the study: 
1. Laboratory-confirmed MPXV infection as determined by PCR obtained from blood, 
oropharynx, or skin lesion within 48 hours of screening. 
2. Mpox illness of any duration provided that the patient has at least one active, not yet 
scabbed, lesion. 
3. Weight ≥3 kg. 
4. Men and non-pregnant women of reproductive potential must agree to use effective 
means of contraception when engaging in sexual activities that can result in pregnancy, 
from the time of enrollment through the end of study participation. Acceptable methods 
of contraception include the following: 
• Hormonal contraception. 
• Male or female condom. 
• Diaphragm or cervical cap with a spermicide. 
• Intrauterine device. 

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5. Stated willingness to comply with all study procedures (including required inpatient 
stay) and availability for the duration of the study. 
6. Ability to provide informed consent personally or by a legally or culturally acceptable 
representative if the patient is unable to do so. 
 
5.2 
Exclusion Criteria 
Individuals meeting any of the following criteria are not eligible for enrollment in the study: 
1. Current or planned use of a meglitinide (repaglinide, nateglinide). 
2. Planned use of midazolam while on study drug. 
3. Severe anemia, defined as hemoglobin <7 g/dL. 
4. Current or planned use of another investigational drug at any point during study 
participation. 
5. Patients who, in the judgement of the investigator, will be at significantly increased risk 
as a result of participation in the study. 
6. Participants who are unable to safely swallow oral medications, such as those who are at 
risk of aspiration. 
 
5.3 
Pregnant or Breastfeeding Women 
No adequate and well-controlled studies in pregnant women have been conducted; therefore, 
there are no human data to establish the presence or absence of tecovirimat-associated risk in 
pregnancy. Given that pregnant women may be at risk for more severe disease and possible 
congenital mpox disease, pregnant women will be enrolled in this study if the principal 
investigator agrees that the benefits of receiving TPOXX outweigh its risks. If possible, long- 
term outcomes will be assessed in pregnant participants. 
 
In animal reproduction studies, no embryofetal developmental toxicity was observed in mice 
during the period of organogenesis at tecovirimat exposures (area under the curve [AUC]) up to 
23 times higher than human exposure at the recommended human dose (RHD). In rabbits, no 
embryofetal developmental toxicity was observed during organogenesis at tecovirimat exposures 
(AUC) less than human exposures at the RHD. In a mouse pre-/post-natal development study, no 
toxicities were observed at maternal tecovirimat exposures up to 24 times higher than human 
exposure at the RHD. 
 
Similarly, there are no data to assess the effect on milk production, the presence of the drug in 
human milk, and/or the effects on the breastfed child. When administered to lactating mice, 
tecovirimat was present in the milk.21 The developmental and health benefits of breastfeeding 
should be weighed against the mother’s clinical need for TPOXX and any potential adverse 
effects on the breastfed child from TPOXX or from the underlying maternal condition. 
 
5.4 
Inclusion of Vulnerable Participants 
Children: Tecovirimat is approved in the US for the treatment of smallpox disease in children 
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smallpox in children weighing at least 13 kg. This study will enroll all children who meet 
eligibility if they weigh at least 3 kg. Using population PK modeling, SIGA has provided 
dosages that will allow for oral dosing in participants weighing <13 kg. The incidence of 
mortality from mpox in children is higher than in adults,31 so inclusion of this population is 
particularly important for this study. Since tecovirimat has potential benefit as a treatment for 
mpox disease, which can cause significant morbidity and has no currently approved treatments in 
the DRC, children who meet the weight requirements will be allowed to enroll in this study. 
 
Adults who lack capacity to consent to research participation: Adults who are unable to 
consent are eligible for enrollment in this protocol because mpox may cause severe disease, and 
data obtained from these individuals are necessary to answer important scientific questions about 
this disease and possible treatments. Similarly, enrolled participants who lose the ability to 
provide ongoing consent during study participation may continue in the study. The risks and 
benefits of participation for adults unable to consent should be the same as those described for 
less vulnerable participants. The process for obtaining consent for these individuals is described 
below (section 11.1.1). 
 
5.5 
Lifestyle Considerations 
During this study, participants are asked to refrain from use of any of the following throughout 
study participation: 
• Meglitinides (repaglinide, nateglinide) 
• Midazolam. 
• Another investigational drug. 
 
Men and women participants of childbearing age will be required to use an accepted form of 
contraception outlined in section 5.1. 
 
5.6 
Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical trial but are 
not subsequently assigned to the study intervention or entered in the study. A minimal set of 
screen failure information is required to ensure transparent reporting of screen failure 
participants, to meet the Consolidated Standards of Reporting Trials (CONSORT) publishing 
requirements and to respond to queries from regulatory authorities. Minimal information 
includes demography, screen failure details, eligibility criteria, and any SAE. 
 
Individuals who do not meet the criteria for participation in this trial (screen failure) because of a 
modifiable factor may be rescreened. Rescreened participants should be assigned the same 
participant number as for the initial screening. 
 
5.7 
Community Engagement 
Community-level meetings before the start of the study will be conducted in order to improve the 
understanding of the research by potential study participants. Community-level consultations 
will be implemented by the social mobilization group of the study team in the form of 
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research information available in the community from which potential research participants can 
be recruited. These pre-study activities will be organized in collaboration with the Ministry of 
Health staff and international nongovernmental organizations working in the health system of the 
study region. The survey team will oversee outreach activities and assess the messages to be 
communicated to the community to avoid any misunderstanding or miscommunication. 
Community residents will be invited to a central meeting place where the study is explained, and 
questions can be asked. At the end of this process, the authorization to carry out the research in 
the community can be given by the leader of the community or a representative in the event of 
their absence. Although such authorization can in no way replace the consent of individuals, it 
represents the engagement of the community. The study team will attempt to identify hotspots of 
resistance in the community to the study and will present adequate solutions during the study to 
mitigate or eliminate mistrust. 
 
5.8 
Strategies for Recruitment and Retention 
Patients with MPXV infection at participating health centers will be approached by a member of 
the study team and offered potential participation in this study. All participants enrolled in the 
study will be hospitalized during the study treatment period to avoid missed or delayed study 
activities during this critical period. Special dispositions will be put in place to offer 
accommodation at the hospital for family members who will accompany study participants. 
Phone calls will be established with the participant after their discharge to remind them of the 
follow-up visit. 
 
5.9 
Costs 
There will be no costs to participants for participating in this study. Hospitalization and treatment 
will be free of charge. Meals will be provided daily to the participant and up to two individuals 
accompanying the participant during the participant’s hospitalization with an approximate value 
of $8, equivalent in local currency to 16,000 CDF, per person per day. 
 
5.10 
Compensation 
Study participants and up to two individuals accompanying the participant will receive US$15, 
equivalent of 30,000 Congolese francs in local currency, to compensate for their time and 
inconvenience at study screening. If they qualify and are enrolled in the study, the participant 
and up to two individuals accompanying them will also receive US$15 for Day 29 and for Day 
59. An additional stipend of $4, equivalent in local currency to 8,000 CDF, will be provided 
daily to the participant and up to two individuals accompanying the participant while the 
participant is hospitalized. Round trip travel to the study site for screening and for each study 
visit (Days 29 and 59) will be provided for the participant and up to two individuals 
accompanying the participant. If a participant develops new lesions consistent with mpox after 
discharge but while still enrolled in the study, travel will be provided for at least one sick visit 
for the participant and up to two individuals accompanying the participant.  
 
If a participant does not sign a screening consent but is eligible to join the study and signs the 
main study consent, the participant and up to two others will receive $15, equivalent in local 
currency to 30,000 Congolese francs (CDF), for the first study visit. Travel will also be provided 
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6 
STUDY INTERVENTION 
6.1 
Study Intervention Description 
Tecovirimat is an antiviral drug against variola (smallpox) virus that is manufactured by Catalent 
Pharma Solutions and distributed by SIGA Technologies, Inc. under the brand name TPOXX. It 
is approved by the US FDA for the treatment of human smallpox disease in adults and pediatric 
patients weighing at least 3 kg. It works by inhibiting the OPXV VP37 envelope-wrapping 
protein, which is encoded by and highly conserved in all members of the Orthopoxvirus genus. 
Its effects on the VP37 protein ultimately prevent the formation of egress-competent enveloped 
virions necessary for virus transmission. See the TPOXX prescribing information for additional 
details.21 
 
6.2 
Dosing and Administration 
Tecovirimat capsules or placebo capsules will be administered orally to participants for 14 days 
as follows. 
• ≥120 kg: three capsules three times a day (total daily tecovirimat dose: 1,800 mg). 
• 40 to <120 kg: three capsules twice a day (total daily tecovirimat dose: 1,200 mg). 
• 25 to <40 kg: two capsules twice a day (total daily tecovirimat dose: 800 mg). 
• 13 to <25 kg: one capsule twice a day (total daily tecovirimat dose: 400 mg). 
• 6 to <13 kg: ½ the contents of a capsule twice daily (total daily tecovirimat dose: 200 mg). 
• 3 to <6 kg: ¼ the contents of a capsule twice daily (total daily tecovirimat dose: 100 mg). 
 
For participants who weigh <40 kg, weight will be taken each day before breakfast and used to 
determine the tecovirimat dose or equivalent number of placebo capsules for that day. The study 
agent should be taken within 30 minutes after a full meal of moderate or high fat, defined as 600 
calories and 25g of fat. Infants and small children who are unable to will not be required to 
consume the calorie and fat requirement. 
 
No dose adjustments will be made for pregnant women. 
 
Preparation instructions for pediatric participants and participants who are unable to swallow 
capsules are provided in section 6.3.4. 
 
6.2.1 
Dose Modifications 
No dosage adjustment is required for patients with mild, moderate, or severe renal or hepatic 
impairments at baseline. See section 9.4 for pausing rules. 
 
Missed doses 
If a participant misses: 
1. less than 24 hours of therapy: restart regular dosing schedule. 

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2. between 24-48 hours of therapy, may restart the regular dosing schedule at the 
physician’s discretion. 
3. more than 48 hours of therapy, discontinue the study drug. 
 
6.3 
Preparation/Handling/Storage/Accountability  
6.3.1 
Acquisition and Accountability 
Acquisition: Tecovirimat and placebo will be shipped from the US to the study site where 
administration will take place, in compliance with all applicable transport guidelines. 
 
Accountability: The study pharmacist will be responsible for maintaining an accurate record of 
the study arm codes, inventory, and an accountability record of study agent supplies. 
 
6.3.2 
Formulation, Appearance, Packaging, and Labelling 
Tecovirimat is available as immediate-release capsules containing tecovirimat monohydrate 
equivalent to 200 mg of tecovirimat for oral administration. The capsules are imprinted in white 
ink with “SIGA” followed by the SIGA logo followed by “®” on an orange body, and a black 
cap imprinted in white ink with “ST-246®.” The capsules include the following inactive 
ingredients: colloidal silicon dioxide, croscarmellose sodium, hydroxypropyl methyl cellulose, 
lactose monohydrate, magnesium stearate, microcrystalline cellulose, and sodium lauryl sulfate. 
The capsule shell is composed of gelatin, FD&C blue #1, FD&C red #3, FD&C yellow #6, and 
titanium dioxide. 
 
The placebo product is identical to the tecovirimat in all aspects except it contains no active drug. 
 
The capsules will be stored at 20°C to 25°C (68°F to 77°F); excursions permitted 15°C to 30°C 
(59°F to 86°F). 
 
6.3.3 
Product Storage and Stability 
Tecovirimat capsules may be stored up to 84 months in the original container at 20°C to 25°C 
(68°F to 77°F), with excursions permitted from 15°C to 30°C (59°F to 86°F). 
 
6.3.4 
Preparation 
For participants who cannot swallow capsules, study drug can be prepared by carefully mixing 
the required contents in 30 mL of liquid (e.g., milk, chocolate milk) or soft food (e.g., apple 
sauce, yogurt). The entire mixture should be administered within 30 minutes of its preparation. 
 
6.4 
Measures to Minimize Bias: Randomization and Blinding  
6.4.1 
Randomization 
Once eligibility has been confirmed, participants will be eligible for randomization. 
Randomization will be performed onsite by the site pharmacist. Regardless of whether the 
randomization process occurs online or offline, participants will be randomized via permuted 
block randomization in a 1:1 ratio to tecovirimat or placebo within randomization strata of days 
from onset of prodromal symptoms (≤7 days or >7 days) and study site. 

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Because of the rural location of study sites, a consistent and strong internet connection is not 
guaranteed. While randomization using a secure online portal is preferred, a backup procedure for 
randomization via sequentially numbered secure envelope will be in place at study sites. 
Backup randomization envelopes for each stratum will be shipped to the site in advance of study 
start in secure boxes and stored in an access-controlled location. 
 
A randomization procedure document will be developed prior to study start to provide details on 
the randomization process and procedures for maintaining the integrity of the randomization. 
The treatment allocation table and the program used to generate the treatment allocation table 
will be maintained by the data coordinating center on secure servers. The block size or sizes used 
to create the treatment allocation table will not be revealed to anyone outside the unblinded team 
responsible for creating the table. 
 
6.4.2 
Blinding/Unblinding 
Study team members, including the pharmacovigilance team, and participants will be blinded to 
treatment arm assignment throughout the duration of the study. To preserve blinding, after 
preparation, the drug or placebo will be placed outside the pharmacy for pick-up. The pharmacist 
will alert the responsible study team member that the treatment is ready to be picked up. The 
unblinded pharmacy staff is responsible for maintaining security of the study treatment 
assignments. 
 
Scheduled unblinding: 
After all participants have completed the final study visit (or in the event that the study is 
stopped early), the study will be unblinded and participants will be informed about their study 
treatment assignment by the study team. 
 
Unscheduled unblinding: 
Intentional: 
By the Medical Monitor (MM) or other pharmacovigilance/safety/oversight/regulatory 
entity to clarify a potential safety signal or comply with a regulatory requirement. 
 
NOTE: This specifically does NOT cover an urgent need to know at the site level for 
subject treatment imperative, which is covered in the next section, after that immediately 
below: 
• The DSMB may unblind itself at any time, and for any data and number of cases if 
indicated in keeping with its charter and its oversight and safety role. Action will proceed 
at the discretion of the DSMB chair and will be documented confidentially and internally 
by the DSMB Executive Secretary. The DSMB may work directly with the unblinded 
data and statistical team that supports it to accomplish this. The impacted data and 
outcome of such non routine review should be confidentially and internally documented 
through the DSMB Executive Secretary. Disclosure of this review should be at the 
discretion of the DSMB in a manner that does not unduly compromise the study blind or 
integrity. Should the review indicate an action is needed for subject safety or study 
integrity, etc., that action will be taken at the direction of the DSMB and chair in a 

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discrete manner that accomplishes the study imperative while minimally impacting the 
study blind or integrity. 
• The MM, pharmacovigilance committee, or protocol level Principal Investigator/Chair, 
may request unblinded review of an event or series of events or other study data by the 
DSMB (general process outlined above) to clarify a potential safety signal or to comply 
with a regulatory requirement such as Safety Oversight or Event Reporting. Such a 
request is made in writing, specifying the impacted data/study records, the concern or 
requirement being met, and any other information that will help define, facilitate, but also 
limit the review to help preserve study integrity and blind. The request is made through 
the DSMB Executive Secretary. As outlined above, the DSMB will conduct the review as 
narrowly as possible, utilizing unblinded study team members such as the unblinded data 
and statistical staff, and will issue a summary statement as it sees fit, to balance the 
request against the need to maintain the study blind and study integrity. 
• At all times, and in all manners, the human subject protection priority will be met in 
a way that maximally protects study and data integrity, while avoiding or else 
strictly limiting to ‘need to know,’ the breadth and the degree of any unblinding. 
• A summary record of the names, roles, and unblinded records disclosed to parties who 
become unblinded is maintained by the study staff who reveal blinded data. This is 
documented, and forwarded WITHOUT FURTHER UNBLNDING INFORMATION, to 
the unblinded study statistician and the clinical trials monitors. 
 
By a study site investigator to meet an urgent need to know at the site level for subject 
treatment imperative: 
• An emergency request for unblinding of treatment assignment at the site level is 
permitted ONLY when knowledge of the treatment will clearly and urgently impact 
subject protection, e.g. by significantly altering treatment choices or clinical options. 
• Such requests may be made directly by or through (in the case of a request from outside 
the study, e.g. by a clinician) a site investigator to the site pharmacist, who provides the 
required information directly and in the most limited manner possible to the site 
investigator. 
• At all times, and in all manners, the human subject protection priority will be met in 
a way that maximally protects study and data integrity, while avoiding or else 
strictly limiting to ‘need to know,’ the breadth and the degree of any unblinding. 
• If there is disagreement at the site level the decision is urgently (phone or other timely 
and reliable method) elevated to the MM and/or study clinical leadership for a decision. 
 
Unintentional: If unintentional unblinding of study agent assignment occurs, the site principal 
investigator will create a plan for ongoing management of the participant(s) involved and for 
preventing the recurrence of a similar incident, as appropriate. If the protocol team determines 
that the unintentional unblinding may have a significant impact on the study plan (e.g., if the 
treatment codes for multiple participants were accidentally revealed), the need for a protocol 
amendment will be addressed as soon as possible. 
 

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Intentional and unintentional unscheduled unblinding will be documented in the appropriate 
source and/or research record and will include the reason for the unscheduled unblinding, the 
date it occurred, who approved the unblinding, who was unblinded, who was notified of the 
unblinding, and the plan for the participant. The site principal investigator will report all cases of 
intentional and unintentional unscheduled unblinding to the DSMB in writing within 1 business 
day after site awareness via email to the DSMB outlining the reason for the unblinding and the 
date it occurred. The report will also be submitted to the MM. If the unblinding meets the 
definition of a reportable event, it will be reported to the IRB/EC according to their respective 
procedures. 
 
If an SAE has resulted in unblinding, this information will be included in the SAE report. 
 
6.5 
Study Intervention Compliance 
The pharmacist will monitor the inventory of investigative products through the distribution log, 
which will record entries and exits, quarantines, transfers between sites, and the conditions of 
storage, as well as any comments useful to inform about the quality of the product. During the 
dispensing of the product, the dispensing log will be completed with participant number, quantity 
(mg) of product received, day, date, batch of medication, and initials of the pharmacist and the 
preparer. 
 
The pharmacist will perform the randomization and keep a randomization log to document the 
link between the participant number and the product assigned. 
 
Study drug will be administered to participants under direct observation by a member of the study 
team. 
 
A quality log will be kept documenting any temperature excursions affecting the study agents 
(less than 15°C and more than 30°C). Temperature excursions outside of this range will be 
reported, and the log will be made available to the principal investigator, pharmaceutical 
company, and study pharmacist to establish whether the affected product can be used. All critical 
issues/conditions relating to the quality of the product will be documented. 
 
A destruction log will be available at the site to document the destruction of all expired or 
damaged product batches. 
 
6.6 
Concomitant Therapy 
All concomitant prescription and nonprescription (including over-the-counter, herbal, or 
traditional) medications taken during study participation will be recorded. For this protocol, a 
prescription medication is defined as a medication that can be prescribed only by a properly 
authorized/licensed clinician. 
 
6.7 
Prohibited Medications 
Participants who are currently or plan to use a meglitinide (repaglinide, nateglinide) or 
midazolam will be excluded from this study. If the need to use one of these drugs arises after 

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enrollment into the study, the participant will not be allowed to continue study drug 
administration. 
 
7 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL 
7.1 
Discontinuation of Study Intervention 
Study intervention may be discontinued for an individual participant or groups of participants 
(i.e., pausing), or it may be discontinued for all participants and enrollment suspended (i.e., 
halting). Pausing and halting rules and procedures are described in sections 9.4 and 9.5. 
 
7.2 
Participant Discontinuation/Withdrawal from the Study 
Participants are free to withdraw from participation in the study at any time upon request. 
Criteria and procedures for withdrawal and replacement of a participant by the investigator are 
provided in section 9.2. 
 
7.3 
Lost to Follow-up 
If a patient cannot be located or contacted (i.e., the patient lost to follow-up) between the time of 
discharge and Study Day 59, their completion date will be considered the last known date of 
contact with them by study personnel. 
 
8 
STUDY ASSESSMENTS AND PROCEDURES 
8.1 
Personnel for Study Procedures 
Assessments and study procedures may be performed by members of the investigative team and 
clinical team as assigned. 
 
The study will be conducted in accordance with the protocol, Good Clinical Practice (GCP), and 
all applicable US and host country ethical and regulatory requirements. 
 
8.2 
Site-Specific Considerations 
Due to the remote area in which the study will be implemented, participating sites in this study 
may face significant resource challenges. Therefore, the SOC regimen will not be set by the 
protocol. Rather, SOC will be standardized at each site according to local/site practices and 
availability of resources. Furthermore, sites should make every effort to comply with the study 
evaluations outlined below; however, the inability of a site to collect the full frequency of 
research assessments due to unavoidable resource limitations, and despite best efforts, will not 
constitute a protocol deviation. 
 
8.3 
Study Schedule 
See section 1.3 for a detailed schedule of procedures. The day when the participant is 
randomized to their assigned treatment arm is denoted as Study Day 1. Screening procedures will 
occur in the day prior to or the same day as (but prior to) randomization (Study Day -1 to 1). 
Note that there is no Study Day 0. Study Day -1 is the 24-hour day prior to the day of 
randomization. The first day after randomization is Study Day 2. Subsequent days will be 

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numbered chronologically through Day 59 of study. Therefore, the Day 29 visit occurs 28 days 
after randomization and the Day 59 visit occurs 58 days after randomization. 
 
8.4 
Study Evaluations and Procedures  
8.4.1 
Operational and Clinical Assessments 
Informed Consent 
The investigator or a qualified and previously designated member of the study team will review 
the informed consent documents with the participant. If a participant is incapable of reading the 
informed consent, the study procedures will be explained in the local language preferred by the 
participant. Each consent will be attended by a witness in addition to the investigator or 
previously designated study team member, and the witness will also sign the informed consent. 
The date that informed consent was obtained will be documented on the informed consent form. 
A signed screening consent will be obtained prior to performing screening procedures; once 
eligibility is confirmed, consent for study participation will be obtained using a main study 
consent prior to performing Day 1 procedures. 
 
Demographics 
The following information should be recorded from the participant or surrogate: 
• Age 
• Sex 
• Geographic region (health zone) of residence 
 
Medical History 
The following information should be recorded: 
• Focused medical history regarding mpox and confirmation of at least one active, not yet 
scabbed, mpox lesion (to be recorded as part of eligibility determination). 
• Current symptoms (nausea, vomiting, abdominal pain, anorexia, cough, 
lymphadenopathy, dysphagia, fever, headache, ocular lesions, and buccal ulcers). 
• Current comorbidities (HIV, tuberculosis, malaria, hypertension, diabetes mellitus, 
asthma, hepatitis, hyperlipidemia, cancer, heart failure, renal disease, liver disease, 
chronic obstructive pulmonary disease (COPD), COVID-19, neoplasm, obstructive sleep 
apnea, obesity, immunosuppressive disorder other than HIV, sickle cell anemia, 
concurrent bacterial infections such as urinary tract, ear nose and/or throat, pulmonary, 
central nervous system, skin or gastrointestinal infection, bacteremia/sepsis or other. 
Bacterial infections will be defined clinically with laboratory and radiographical 
confirmation when possible. 
• Smallpox vaccination status or presence of vaccination scar. 
• Risk factors for MPXV infection such as questions related to: recent contact with known 
mpox case including type of contact, residing or visiting an area with an active mpox 
outbreak, animal handling. 
 

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Medication Review 
All concomitant prescription and nonprescription (including over-the-counter, herbal, or 
traditional) medications taken during study participation will be recorded. All medications taken 
by the participant up to one week prior to enrollment will be recorded. 
 
Vital signs 
Temperature, heart rate, respiratory rate, and blood pressure will be measured, with oxygen 
saturation measured if possible. 
 
Weight 
Weight will be measured at screening for all participants and used to determine study drug dose 
throughout the treatment period for participants ≥40 kg. For participants <40 kg, weight will be 
taken every day before breakfast during the treatment period and used to determine daily study 
drug dose. 
 
Height 
Height will be obtained for all participants at screening. 
 
Arm circumference 
Arm circumference will be obtained at screening for participants aged 3 months to ≤ 5 years. 
 
Pregnancy Testing 
Serum or urine pregnancy testing will be performed for females of childbearing potential only. 
 
HIV Testing 
HIV testing will be performed retrospectively on blood collected at Day 1 for participants who 
agree to be tested. If possible, all HIV-infected participants, whether with previously known or 
newly diagnosed infection, will be contacted by a study staff member for referral to a local HIV 
treatment center or contacted by a health zone official in charge of coordinating activities related 
to the HIV program. Viral load may be performed for HIV-infected participants. 
 
Malaria testing 
Rapid malaria testing may be done at Day 1 for all participants. Although collection is highly 
desirable, malaria testing may be waived if not feasible, per investigator discretion. 
 
Varicella zoster virus (VZV) testing 
VZV PCR testing may be done retrospectively on blood collected at Day 1 for all participants. 
Although collection is highly desirable, VZV PCR may be waived if not feasible, per 
investigator discretion. 
 
Determination of Eligibility 
Once the screening procedures are complete, eligibility will be determined based on the inclusion 
and exclusion criteria. Participants that are found to be ineligible will be informed during the 
screening evaluation, and the reason for their ineligibility will be discussed and documented. 
 

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Lesion Assessments 
• Target region assessment: Total number of lesions in the assessment region will be 
counted and recorded until all lesions in the assessment region are scabbed or 
desquamated (“resolved”). A lesion is considered ‘scabbed’ when the pustule has 
resolved, the lesion no longer appears inflamed, and scab (keratotic crust or eschar) is the 
only remaining component of the lesion. Desquamation refers to loss of the scab and the 
presence of intact epidermis at the site of previous involvement. 
In order to be considered “resolved,” a lesion must fit into one of last stages of lesion 
evolution: 
1. Scab formation of entire lesion/lesion is otherwise flat with no residual 
inflammation 
2. Desquamation (loss of scab) 
3. New layer of epidermis (scar) 
• Consensus guidelines on lesion characteristics will be developed to standardize the 
manual count. Photographs of the assessment region and other parts of the body will be 
collected and later analyzed using a computer-vision algorithm to determine lesion 
counts. These counts will be compared to the manual count to evaluate the accuracy of 
the manual count. A protocol standardizing the collection of assessment region 
photographs will be developed. 
• The target assessment region is composed of the right leg (including the front and back of 
the foot) and right arm (including the front and back of the hand). In the event that a 
participant is missing a part of a right limb, the left leg (including the front and back of 
the foot) and left arm (including the front and back of the hand) may be used as the target 
assessment region. The target assessment region will be undefined for any participants 
who do not have either a) both a right leg and right arm or b) both a left leg and left arm. 
In the event that such participants are enrolled in the study, target region assessment will 
not be performed (e.g., no counts will be performed since the assessment region would be 
ill-defined). Full body assessments described below would still be performed so that 
determination of the primary endpoint can still occur. 
• Full body assessment: After resolution of lesions in the target region, assessment of lesion 
counts will progress to a simplified full-body evaluation, not requiring lesion counting, 
will record whether all lesions are resolved (“yes/no”). This assessment will continue 
until all lesions are resolved (or Day 29, whichever comes first), at which point the 
primary endpoint is met. Photography of residual lesions not in the assessment region will 
be taken as well as of the entire body once all of the lesions have resolved. 
• If a participant reaches full body lesion resolution but subsequently develops at least one 
new lesion consistent with mpox after discharge but while still enrolled in the study, they 
will be eligible to make a “Sick Visit” as defined in the Schedule of Activities and will be 
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Randomization 
Randomization defines Study Day 1. Randomization will only occur when a given individual has 
met all eligibility criteria as outlined above (sections 5.1 and 5.2). 
 
Study Drug Administration 
Study drug administration will begin on Day 1 and continue for 14 days, as described in section 
6. 
 
SOC Received 
SOC will be outlined in a manual of operations and treatments will be recorded. 
 
Assessment of AEs/SAEs 
See section 9. 
 
8.4.2 
Research Laboratory Evaluations 
Blood will be collected via venipuncture for MPXV PCR with CT, and blood will be stored for 
antibody titer measurements, viral sequencing, and other future research testing. Swabs will be 
collected from the oropharynx and open skin lesions for viral load and sequencing assessments. 
All collected specimens will be stored for later assessment. An additional voluntary/optional 
blood sample will be obtained from all participants ≥18 years of age at 4 hours after receiving 
their first dose of study drug on day 7 to be used for PK analysis (Appendix D). The blood 
volume to draw will be specified in the Laboratory Manual. 
 
8.4.3 
Clinical Laboratory Evaluations 
Laboratory testing, including urinalysis, will be performed as described in section 1.3, and 
results will be shared with participants if they want them. While every effort should be made to 
obtain these laboratories as indicated, note that the frequency and volume of blood draws is 
always subject to the clinical judgment of the site investigator as to safety and logistical 
considerations. Hence, though highly desirable, these evaluations may be waived if not feasible 
(e.g., due to blood draw volume concerns related to participant weight or due to site logistics), 
per investigator discretion. The blood volume to draw will be specified in the Laboratory 
Manual. 
 
9 
SAFETY AND OTHER ASSESSMENTS 
Assessment of AEs/SAEs: Information about AEs/SAEs will be assessed via appropriate 
questioning and examination at each study contact. Additional procedures may be performed 
(e.g., clinical laboratory evaluations) as needed to further characterize events. 
 
9.1 
Safety Definitions, Management, and Reporting 
9.1.1 
Definitions 
Adverse Event: An AE is any untoward or unfavorable medical occurrence in a human subject, 
including any abnormal sign (e.g., abnormal physical exam or laboratory finding), symptom, or 
disease, temporally associated with the subject’s participation in the research, whether or not 
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Adverse Reaction (AR): An AR means any AE caused (see “Causality” below) by a study 
agent. ARs are a subset of all suspected adverse reactions (SARs; defined below) where there is 
reason to conclude that the study agent caused the event. 
 
Suspected Adverse Reaction (SAR): SAR means any AE for which there is a reasonable 
possibility that the study agent caused the AE. “Reasonable possibility” means there is evidence 
to suggest a causal (see “Causality” below) relationship between the study agent and the AE. A 
SAR implies a lesser degree of certainty about causality than an AR, which means any AE 
caused by a study agent. 
 
Serious Adverse Event (SAE): An SAE 
• is an AE that results in death. 
• is an AE that is life-threatening event (places the subject at immediate risk of death from 
the event as it occurred). 
• is an AE that requires inpatient hospitalization or prolongs an existing hospitalization. 
NOTE: 
o Hospitalization is considered required if outpatient treatment would generally be 
considered inappropriate. 
o Same-day surgical procedures that are required to address an AE are considered 
hospitalizations, even if they do not involve an overnight admission. 
o Hospitalization due to a condition that has not worsened and that pre-dates study 
participation (e.g., elective correction of an unchanged baseline skin lesion), or 
due to social circumstance (e.g., prolonged stay to arrange aftercare), or that is 
planned/required “per protocol” AND that proceeds without prolongation or 
complication, is NOT considered an SAE by this criterion. 
• is, or results in, a persistent or significant incapacity or substantial disruption of the 
ability to conduct normal life functions. 
• is a congenital anomaly/birth defect/miscarriage/stillbirth. 
• is a medically important event. 
 
NOTE: Medical and scientific judgment should be exercised. Events that significantly jeopardize 
the subject and/or require intervention to prevent one of the SAE outcomes listed above are 
generally considered medically important and are thus SAEs. 
 
Unexpected Adverse Event (UAE): A UAE is unexpected if it is not listed in the investigator’s 
brochure or package insert (for marketed products) at the frequency, AND specificity, AND 
severity that has been observed. 
o Such events should also be evaluated for possible reporting as unanticipated problems 
(UPs) (see section 9.1.2.3.2). 
o Unexpected, as used in this definition, also refers to AEs or SARs that are mentioned in 
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from the pharmacological properties of the study agent but are not specifically 
mentioned as occurring with the particular study agent under investigation. 
 
Serious and Unexpected Suspected Adverse Reaction (SUSAR): A SUSAR is a SAR (defined 
above) that is both serious and unexpected. 
 
Unanticipated Problem (UP): A UP is any event, incident, experience, or outcome that is: 
1. unexpected in terms of nature, severity, or frequency in relation to: 
a. the research (including but not limited to risks) as described in the IRB/EC- 
approved research protocol and informed consent document, investigator’s 
brochure, or other study documents; and 
b. the characteristics of the subject population being studied; and is 
2. possibly, probably, or definitely related (see “Causality” below) to participation in the 
research; and 
3. suggests the research places subjects or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or 
recognized, per the documents currently approved by the IRB/EC. 
NOTE: 
o An SAE always meets this “greater risk” criterion. 
o An incident, experience, or outcome that meets the definition of a UP generally 
will warrant consideration of changes to the protocol or informed consent form, 
or to study procedures (e.g., the MOP for the study), in order to protect the 
safety, welfare, or rights of participants or others. Some UPs may warrant a 
corrective and preventive action plan (CAPA) at the discretion of the oversight 
entities. 
 
Unanticipated Problem that is not an Adverse Event (UPnonAE): A UPnonAE belongs to a 
subset of UPs that: 
• meets the definition of a UP, AND 
• does NOT fit the definition of an AE or an SAE. 
NOTE: Examples of UPnonAEs include, but are not limited to: 
o a breach of confidentiality 
o prolonged shedding of a vaccine virus beyond the anticipated timeline 
o unexpectedly large number of pregnancies on a study 
o subject departure from an isolation unit prior to meeting all discharge criteria 
o accidental destruction of study records 
o unaccounted-for study agent 
o overdosage, underdosage, or other significant error in administration or use of 
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o development of an actual or possible concern for study agent purity, sterility, 
potency, dosage, etc. 
NOTE: A decision to temporarily quarantine, or to permanently not use all or 
part of study agent supply due to an unexpected finding or event (e.g., 
particulate, cloudiness, temperature excursion), even if there is no known or 
proven issue (i.e., out of an “abundance of caution”), is considered a 
UPnonAE. 
 
Non-compliance: Failure of investigator(s) to follow the applicable laws, regulations, or 
institutional policies governing the protection of human subjects in research, or the requirements 
or determinations of the IRB/EC, whether intentional or not. 
1. Serious non-compliance: Non-compliance, whether intentional or not, that results in 
harm or otherwise materially compromises the rights, welfare and/or safety of the 
subject. Non-compliance that materially affects the scientific integrity or validity of the 
research may be considered serious non-compliance, even if it does not result in direct 
harm to research subjects. 
2. Continuing non-compliance: A pattern of recurring non-compliance that either has 
resulted, or, if continued, may result in harm to subjects or otherwise materially 
compromise the rights, welfare and/or safety of subjects, affect the scientific integrity of 
the study or validity of the results. The pattern may comprise repetition of the same non- 
compliant action(s), or different noncompliant events. Such non-compliance may be 
unintentional (e.g., due to lack of understanding, knowledge, or commitment), or 
intentional (e.g., due to deliberate choice to ignore or compromise the requirements of 
any applicable regulation, organizational policy, or determination of the IRB/EC). 
 
Protocol Deviation (PD): Any change, divergence, or departure from the IRB-approved 
research protocol. 
  
• 
Major Deviations: Deviations from the IRB/EC-approved protocol that have, or may 
have the potential to negatively impact, the rights, welfare, or safety of the participant, 
or to substantially negatively impact the scientific integrity or validity of the study. 
  
• 
Minor Deviations: Deviations that do not have the potential to negatively impact the 
rights, safety, or welfare of participants or others, or the scientific integrity or validity 
of the study. 
 
9.1.2 
Documenting, Assessing, Recording, and Reporting Events 
ALL AEs, including those that may appear to have a non-study cause (see “Causality” below) 
and including any baseline condition (with the exception of mpox lesions) that worsens by at 
least 1 grade (see Section 9.1.2.1.1 Severity Grading below), will be documented (e.g., on the 
clinical chart/progress notes/clinical laboratory record) and recorded (e.g., in the study-specified 
case report form [CRF]/research database), and all Grade 3 and above AEs will be reported (e.g., 
cumulatively from the research database, or according to protocol-specified expedited reporting 
mechanism) to the pharmacovigilance committee from the time informed consent is obtained 
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regarding AEs will be elicited by open-ended questioning and examinations. AEs indicating the 
presence of infections including urinary tract; ear, nose, and/or throat; ocular; pulmonary; central 
nervous system; skin or gastrointestinal infection; bacteremia/sepsis; or other will be defined 
clinically with laboratory and radiographical confirmation when possible. In participants with 
recrudescent disease, defined as the appearance of at least one new lesion consistent with mpox 
in a participant still enrolled in the study who has previously reached full body lesion resolution, 
the mpox lesion(s) and mpox diagnosis themselves will not be an AE but other symptoms or 
diagnoses will be considered AEs. 
 
AEs and SAEs will generally be recorded, assessed, and reported according to the timeframes 
outlined in Table 1. 
 
Table 1. Standard event recording, assessment, and reporting timeframes. 
Event type 
Record, assess, and report through 
Timeline for reporting 
Related SAEs 
End of subject participation in study, 
or if study personnel become aware 
thereafter 
• Deaths and life-threatening 
SAEs: no later than the first 
business day following the day 
of study personnel awareness 
• All other SAEs: no later than the 
third business day following the 
day of study personnel 
awareness 
Unrelated SAEs End of subject participation in study 
Related and 
unrelated non- 
serious AEs 
End of subject participation in study 
Record in research database no less 
than every week 
 
9.1.2.1 
Investigator Assessment of Adverse Events 
The principal investigator and/or designee will review all data on each participant on a regular 
basis (at least weekly) to ensure safety and data accuracy. The principal investigator will 
personally conduct or supervise the investigation and provide appropriate delegation of 
responsibilities to other members of the research staff. The investigator will assess all AEs with 
respect to seriousness (according to SAE definition above), severity (intensity or grade, see 
below), and causality (relationship to study agent and relationship to participation in the 
research, see below). 
 
9.1.2.1.1 Severity Grading 
The investigator will grade the severity of each AE, including laboratory and testing 
abnormalities and results, as follows. Chemistry, hematology (with the exception of hemoglobin), 
and coagulation parameters will be graded according to the table in APPENDIX A. Hemoglobin 

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values will be graded according to the table in APPENDIX B. Any values/events not included in 
Appendices A or B will be graded according to the “Common Terminology Criteria for Adverse 
Events (CTCAE)” (v 5.0) which can be found at: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. Laboratory values 
that are not graded in Appendices A or B or the CTCAE v5.0 will be evaluated by the clinician, 
and if clinically significant, the resulting clinical diagnosis will be considered an AE, recorded in 
the database, and reported as an AE as described below (section 9.1.2.1.2). 
 
Events that are NOT gradable using the above specified tables will be graded as follows: 
• Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated. 
• Grade 2: Moderate; minimal, local or noninvasive intervention indicated; limiting age-
appropriate instrumental activities of daily living (ADL)*. 
• Grade 3: Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self care 
ADL**. 
• Grade 4: Life threatening consequences; urgent intervention indicated.  
• Grade 5: Death related to AE. 
*Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the 
telephone, managing money, etc.  
**Self care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, 
taking medications, and not bedridden. 
 
NOTE: A participant death should always be reported as grade 5. 
 
9.1.2.1.2 Laboratory Value Assessment and Clinical Significance Criteria 
ALL abnormal lab values of grade 3 or above are REPORTABLE unless present at baseline. 
Abnormal lab values not included in CTCAE v5.0 (with the exception of hemoglobin, see 
Appendices A and B) are considered CLINICALLY SIGNIFICANT, and are to be recorded in 
the research database, and reported, if they meet ONE or more of the criteria below.  
• result in a study agent dosage adjustment, interruption, or discontinuation 
• are accompanied by clinically abnormal signs or symptoms that are likely related to the 
laboratory abnormality (e.g., clinical jaundice) 
• indicate a possible organ toxicity (e.g., elevated serum creatinine) 
• result in additional/repeat testing or medical intervention (procedures/treatments) (e.g., 
EKG to evaluate arrhythmia potential with a high serum potassium; one or more EKGs to 
assess an elevated troponin level; potassium supplementation for hypokalemia) 
• indicates possible over-dosage 
• are considered clinically significant by the investigator or pharmacovigilance committee. 
 

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9.1.2.1.3 Causality 
Causality (likelihood that the event is caused by the study agent) will be assessed by the principal 
investigator considering the factors listed under the following categories: 
 
Definitely Related 
• reasonable temporal relationship 
• follows a known response pattern 
• clear evidence to suggest a causal relationship 
• there is no alternative etiology 
 
Probably Related 
• reasonable temporal relationship 
• follows a suspected response pattern (based on similar agents) 
• no evidence of a more likely alternative etiology 
 
Possibly Related 
• reasonable temporal relationship 
• little evidence for a more likely alternative etiology 
 
Unlikely Related 
• does not have a reasonable temporal relationship and/or 
• there is good evidence for a more likely alternative etiology 
 
Not Related 
• does not have a temporal relationship and/or 
• is definitely due to an alternative etiology 
 
Note: Other factors (e.g., dechallenge, rechallenge, if applicable) should also be considered for 
each causality category when appropriate. Causality assessment is based on available 
information at the time of the assessment of the AE. The investigator may revise the causality 
assessment as additional information becomes available. 
 
Causality assessment will be reviewed by the sponsor. The sponsor may make the final 
determination on the “reasonable possibility” that the event was “related” (comprising definitely, 
probably, and possibly related) or “unrelated” (comprising unlikely and not related) to the study 
agent. 
 

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9.1.2.2 
Recording of Events 
AEs will be promptly recorded in the research database no less than every week, regardless of 
possible relationship to study interventions. If a diagnosis is clinically evident (or subsequently 
determined), the diagnosis rather than the individual signs and symptoms or laboratory 
abnormalities will be recorded as the AE. The investigator will review events regularly to ensure 
they have been captured correctly and to perform assessment of events individually and 
cumulatively to assess possible safety trends. 
 
9.1.2.3 
Investigator Reporting Responsibilities 
The site principal investigator and/or equally qualified designee will check daily for events that 
may require expedited reporting. 
 
The site principal investigator and/or equally qualified designee will also monitor all 
accumulating data no less than weekly, or according to study site procedures, whichever is more 
frequent. 
 
Data will be reviewed by the site principal investigator/designee on a regular basis for accuracy 
and completeness. 
 
Data will be submitted to the pharmacovigilance committee in keeping with all applicable 
agreements and when requested, such as for periodic safety assessments, and preparation of final 
study reports. 
 
The principal investigator, protocol chair, and/or other study designee will ensure prompt 
reporting to safety oversight bodies (e.g., pharmacovigilance committee, DSMB), regulatory 
entities, and stakeholders as specified below, and according to any additional requirements or 
agreements. 
 
9.1.2.3.1 Serious Adverse Events (Expedited Reporting) 
Unless otherwise specified above, all SAEs (regardless of relationship and whether or not they 
are also UPs) must be reported to the DRC pharmacovigilance committee as specified by the 
pharmacovigilance committee (e.g., research electronic data capture [REDCap] system; use 
email if REDCap is not available). If the preferred/indicated mechanism for reporting is not 
available, the pharmacovigilance committee/MM should be contacted by telephone, fax, or other 
reasonable mechanism to avoid delays in reporting. 
 
Unless otherwise specified above, deaths and immediately life-threatening SAEs must be 
reported to the pharmacovigilance committee promptly, and no later than the first business day 
following the day of study personnel awareness. 
 
All other SAEs must be reported to the pharmacovigilance committee no later than the third 
business day following the day of study personnel awareness. 
 
If an individual participant experiences multiple SAEs in a closely timed/overlapping “cause- 
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primary/precipitating event(s) individually. SAEs that are determined to be definitely secondary 
to other SAEs will be detailed in the narrative portion of the report of the relevant 
primary/precipitating SAE. A clinical rationale and findings to support such reporting should be 
part of the narrative. 
 
For each SAE report, the research database entry MUST match the corresponding entries on the 
SAE report (e.g., start and stop dates, event type, relationship, and grade), and must be updated 
if necessary (e.g., if the SAE report was generated after the corresponding AE was entered in the 
research database). 
 
Unless otherwise specified above, SAEs that have not resolved by the end of the per-protocol 
follow-up period for the participant are to be followed until final outcome is known (to the 
degree permitted by the IRB/EC-approved informed consent form). If it is not possible to obtain 
a final outcome for an SAE (e.g., the participant is lost to follow-up), and to update the 
pharmacovigilance committee, the last known status and the reason a final outcome could not be 
obtained will be recorded by the investigator on an SAE report update and the CRF. 
 
9.1.2.3.2 Unanticipated Problems 
UPs (as defined in this protocol, or as defined by the IRB/EC of record, whichever definition is 
more conservative) must be reported to the Data Coordinating Center and local IRB/EC as per 
local institutional requirements. UPs may include problems with protocol implementation, 
participant safety, and/or concerns regarding informed consent. Initial reports must be 
communicated no later than 7 calendar days of site awareness of the event. 
 
All UPs that are also SAEs will be reported via the SAE CRF to the pharmacovigilance 
committee no later than when they are due to be reported to the Data Coordinating Center and 
local IRB/EC. 
 
9.1.2.3.3 
Non-compliance and Protocol Deviations 
It is the responsibility of the investigator to use continuous vigilance to identify and report 
deviations and/or noncompliance to the IRB/EC as described in the MOP. All deviations must 
be addressed in study source documents and reported to the INRB and the Data Coordination 
Center. 
 
9.1.2.3.4 Pregnancy 
Participants found to be pregnant during the study will not be excluded from the study. When 
possible, they will be followed to determine the outcome of the pregnancy. Pregnancy itself is 
not an AE, but events that meet AE or SAE criteria in relation to pregnancy, delivery, or the 
conceptus/neonate (see section 9.1.1) are reportable. 
 
9.1.2.4 
Sponsor’s Reporting Responsibilities 
SUSARs, as defined in the International Council for Harmonisation of Technical Requirements 
for Pharmaceuticals for Human Use (ICH) E6 5.17 guideline, will be reported to all participating 
country regulatory authorities, and all participating Investigators as Safety Reports. 
 

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The Sponsor (INRB) will also submit an Annual Report of the progress of the investigation to all 
participating country regulatory authorities. 
 
AEs that are also UPs will be summarized by the Sponsor (INRB) and distributed to investigators 
if they are relevant to other sites. 
 
9.2 
Withdrawal Criteria for an Individual Participant 
An individual participant will be withdrawn from the study for any of the following: 
• An individual participant’s decision. (The investigator should attempt to determine the 
reason for the participant’s decision.) 
• Non-compliance with study procedures to the extent that it is potentially harmful to the 
participant or to the integrity of the study data. 
• The investigator determines that continued participation in the study would not be in the 
best interest of the participant. 
 
9.2.1 
Re-enrollment and Unplanned Procedure Repetition 
Unless otherwise specified within this protocol, each person who is a participant in this study 
may be enrolled and may pass through each step and process outlined in the protocol only 
ONCE (i.e., participants may not “go back” and repeat a protocol step already completed). On a 
case-by-case basis a request for re-enrollment or for repetition of a protocol step or procedure 
already completed may be submitted to, reviewed by, and approved by the MM in writing. The 
MM may also recommend or require consultation of the IRB/EC and/or DSMB. 
 
9.2.2 
Replacement of Withdrawn Participants or Participants Who Discontinue 
Study Agent 
Participants who are withdrawn from the study or discontinue study drug will not be replaced. 
 
All participants exposed to study agent MUST be included in the safety dataset. 
 
9.3 
Additional Safety Oversight  
9.3.1 
Pharmacovigilance Committee 
A pharmacovigilance committee will conduct safety oversight for this study. The DRC National 
Pharmacovigilance Centre is located at the University of Kinshasa. It receives all reports of 
AE/SAEs, analyses them, and sends monthly reports to the Directorate of Pharmacy and 
Medicine (Direction de la Pharmacie et du Médicament; DPM) and Congolese Pharmaceutical 
Regulatory Authority (Autorité Congolaise de Réglementation Pharmaceutique; ACOREP). 
 
9.3.2 
Medical Monitor 
A MM in the DRC has been appointed for oversight of safety in this clinical study. The MM will 
be responsible for performing oversight and review of safety assessments. 
 

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9.3.3 
Oversight Committees 
9.3.3.1 
Data and Safety Monitoring Board 
The NIAID intramural DSMB includes independent experts that do not have direct involvement 
in the conduct of the study and have no significant conflicts of interest as defined by NIAID 
policy. The DSMB will be supplemented with local subject matter experts at the chair’s 
discretion. The DSMB will review the study protocol, consent document(s), and investigator 
brochure prior to initiation and twice a year thereafter, or as may be determined by the DSMB. 
The DSMB may convene additional reviews as necessary. The DSMB will review the study data 
as needed to evaluate the safety, efficacy, study progress, and conduct of the study. 
 
All deaths, SAEs, UPs, pregnancies, and safety reports will be reported to the DSMB at the same 
time they are submitted to the IRB and pharmacovigilance committee unless otherwise specified 
herein. Any other study documents requested by the DSMB will be submitted for periodic 
scheduled DSMB reviews. 
 
All cases of intentional or unintentional unblinding will be reported to the DSMB not later than 
one business day from the time of study personnel awareness. 
 
The principal investigator will notify the DSMB at the time pausing or halting criteria are met 
and obtain a recommendation concerning continuation, modification, or termination of the study. 
The principal investigator will submit the written DSMB summary reports with 
recommendations to the IRB/EC. 
 
The DSMB is the primary entity charged with NON-EMERGENCY, FIREWALLED ad hoc 
review of unblinded data, as may be indicated, to facilitate safety/pharmacovigilance team 
assessment of potential signals or to fulfill regulatory/oversight body requirements or requests. 
See section 6.4.2. 
 
9.4 
Pausing Rules 
“Pausing” is discontinuation of study intervention/treatment/dosing (agent/placebo/procedure, 
etc.) in a single participant or, at the discretion of the MM in consultation with the 
pharmacovigilance committee, a protocol-defined group or “arm,” until a decision is made to 
either resume or permanently discontinue such activity. Participants continue to be followed for 
safety during a pause. 
 
The pausing criteria for individual participants in this study include any one or more of the 
following: 
• A participant experiences an SAE that is unexpected (per the product label) and possibly, 
probably, or definitely related to a study agent; 
• The development of an unexpected lab toxicity of grade 3 or greater that is deemed by the 
investigator to be possibly, probably, or definitely related to a study agent will trigger a 
review by the MM that may result in pausing the study drug. 

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• A participant has a hemoglobin level <7 g/dL. This would only lead to the cessation of 
blood draws until the hemoglobin level stabilizes and the clinician at bedside judges it to 
be safe to resume blood draws. 
• A participant with signs or symptoms thought to be resulting from anemia at any 
hemoglobin level. This would only lead to the cessation of blood draws until the 
hemoglobin level stabilizes and the clinician at bedside judges it to be safe to resume 
blood draws. 
 
The principal investigator/study chair(s) or the MM in consultation with the pharmacovigilance 
committee may also pause dosing/study interventions for one or more participants for any safety 
issue. The DSMB may recommend a pause to the MM and pharmacovigilance committee. The 
IRB/EC may also recommend a pause. 
 
9.4.1 
Reporting a Pause 
If a pausing criterion is met, a description of the AE(s) or safety issue must be reported by the 
principal investigator/study chair(s) within 1 business day to the MM and pharmacovigilance 
committee and the IRB/EC according to their requirements. The principal investigator/study 
chair(s) will also notify the DSMB. In addition, the MM or designee, in consultation with the 
pharmacovigilance committee, will notify all other site investigators by email or through the 
specified pathway. 
 
9.4.2 
Resumption Following a Pause 
The MM in consultation with the pharmacovigilance committee, and in collaboration with the 
principal investigator/study chair(s) and DSMB, will determine if study activities including study 
agent administration and/or other study interventions may be resumed, and any additional 
modifications or requirements that may apply, for the impacted participant(s), or whether the 
events that triggered the pause require expansion to a study halt (see below). 
 
The MM or designee, in consultation with the pharmacovigilance committee will notify the 
principal investigator/study chair(s) of the decision. The principal investigator/study chair(s) will 
notify the IRB/EC of the decision according to the IRB’s/EC’s processes. 
 
9.4.3 
Discontinuation of Study Agent 
A participant who does not resume study agent/intervention/treatment will continue to be 
followed for protocol-specified safety assessments or as clinically indicated, whichever is more 
conservative. 
 
9.5 
Halting Rules for the Protocol 
“Halting” is discontinuation of study intervention/treatment/dosing (agent/placebo/procedure, 
etc.) for all participants in a study and suspension of enrollment until a decision is made to either 
resume or permanently discontinue such activity. Participants continue to be followed for safety 
during a halt. 
 

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The halting rules are: 
• The MM, in consultation with the pharmacovigilance committee may recommend to halt 
the study if a pattern of AEs emerges which elevates the concern for study related 
toxicity. 
• Any safety issue that the principal investigator/study chair(s) or the MM, in consultation 
with the pharmacovigilance committee determines should halt the study. The DSMB may 
recommend a halt to the MM and pharmacovigilance committee. 
 
In addition, any regulatory body having oversight authority may halt the study at any time. The 
IRB/EC may halt the study at their sites. Country-specific regulatory authorities may halt the 
study for sites under their jurisdiction. The DSMB may recommend a study halt. 
 
9.5.1 
Reporting a Study Halt 
If a halting criterion is met, a description of the AE(s) or safety issue must be reported by the 
principal investigator/study chair(s), within 1 business day to the MM and pharmacovigilance 
committee and the IRB/EC according to their requirements. The principal investigator/study 
chair(s) will also notify the DSMB. In addition, the MM and/or pharmacovigilance committee or 
designee will notify all other site investigators by email or through the specified pathway. 
 
9.5.2 
Resumption of a Halted Study 
The MM and pharmacovigilance committee, in collaboration with the principal 
investigator/study chair(s) and DSMB, will determine if study activities, including enrollment, 
study agent administration, and/or other study interventions, may be resumed and any additional 
modifications or requirements that may apply. 
 
The MM and/or pharmacovigilance committee or designee will notify the principal 
investigator/study chair(s) of the decision. The principal investigator/study chair(s) will notify the 
IRB/EC of the decision according to the IRB’s/EC’s processes. 
 
9.5.3 
Discontinuation of Study Agent 
Participants who do not resume study agent/study intervention will continue to be followed for 
protocol-specified safety assessments or as clinically indicated, whichever is more conservative. 
 
9.6 
IRB/EC and Institutional Reporting Procedures 
As a general statement, safety and other reportable events will be reported per the institutional 
requirements of each participating entity. 
 
10 
STATISTICAL CONSIDERATIONS 
10.1 
Design Overview 
This is a randomized, placebo-controlled, double-blind trial to test superiority of the antiviral 
drug tecovirimat, as described above. Figure 1 provides a study schema of the trial design. 
 

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To date there have been no studies of mpox therapeutics in humans to inform the design of the 
present trial. As such, there are no standards for study endpoints. The primary endpoint was 
largely informed by subject matter experts with experience treating mpox and secondary analysis 
of data generated from an observational study of mpox patients in DRC carried out by the DRC’s 
INRB in collaboration with the USAMRIID between 2007 and 2011. 
 
The present trial design reflects the major clinical characteristics of mpox disease and includes 
multiple secondary endpoints ordered by importance as well as a sample size re- estimation 
procedure described in section 10.4.1. 
 
10.2 
Populations for Analyses 
The primary analysis and secondary efficacy analyses will be based on an intention-to-treat 
(ITT) population consisting of all randomized participants and described in detail in the 
statistical analysis plan (SAP). Safety analyses including 28-day mortality, incidence of SAEs, 
incidence of AEs requiring drug discontinuation, and incidence of other AEs will be based on an 
as-treated population consisting of all participants who received at least one dose of tecovirimat 
or placebo. 
 
10.3 
Study Endpoints and Statistical Analyses  
10.3.1 
General Approach 
This is a randomized, placebo-controlled, double-blind trial testing a superiority hypothesis with 
a two-sided type I error rate of 5%. Secondary endpoints have been ordered according to relative 
importance. 
 
A statistical analysis plan will be developed prior to unblinding of the study and database lock. 
 
10.3.2 
Endpoints 
10.3.2.1 
Primary Endpoint 
The primary endpoint is time (days) to lesion resolution, defined as the first day on which all 
lesions on the total body are scabbed or desquamated or a new layer of epidermis has formed 
(see section 8.4.1), up to 28 days after randomization. 
 
Justification 
 
The primary endpoint emphasizes the clinical relevance of lesion resolution for patients with 
mpox. Mpox lesions are painful and reduce patients’ ability to carry out ordinary tasks such as 
swallowing. Lesions progress through discrete stages at roughly the same rate starting with 
macules (flat lesions) and moving on to papules (raised), vesicles (raised and filled with clear 
fluid), pustules (filled with opaque fluid), and finally scab and fall off (desquamate). Lesion 
scabbing and desquamation generally coincides with resolution of other symptoms and is an 
important criterion for discharge in clinical practice (in addition to blood PCR negativity, which 
is included as a secondary endpoint). Therefore, demonstration of an improvement in time to 
lesion resolution would provide a direct clinical benefit to patients. 
 

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Figure 2 displays time to lesion resolution (as defined for this primary endpoint) for N=228 
patients with laboratory-confirmed mpox from the aforementioned 2007-2011 
INRB/USAMRIID observational study. The median time to lesion resolution was 9 days. In 
addition to the clinical significance noted above, part of the motivation for this primary endpoint 
is that this leaves sufficient room to observe a potential treatment effect of tecovirimat. Note also 
that the study duration for the observational trial was 22 days and 176/228 (77.2%) were 
observed to meet the endpoint. Thus, we expect that the 28-day duration planned for the present 
trial will provide ample time to observe events. Section 10.4 describes the power and sample size 
calculations for the trial in detail. The trial is designed to achieve 85% power to detect a lesion 
resolution event rate ratio of 1.40, which requires 318 overall resolution events. Extrapolating the 
77% event rate from the observational study provides a conservative estimate of the required 
sample size and still results in a reasonable sample size. NOTE: Updated power and sample size 
calculations based on the sample size re-estimation plan described below are provided in 
APPENDIX C. 
 
 
Figure 2. Time to lesion resolution among a cohort of N=228 patients with laboratory-
confirmed mpox in the 2007-2011 INRB/USAMRIID observational study. 
 
 
Finally, note that similar primary endpoints have been used for studies of other diseases with 
characteristic skin lesions. For example, time to 100% crusting has been employed as a primary 
endpoints in trials of oral acyclovir for treatment of varicella (chickenpox).32 
 

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Hypothesis 
 
The primary null hypothesis is that time to lesion resolution does not differ between study arms. 
 
10.3.2.2 
Secondary and Exploratory Endpoints 
Secondary and exploratory endpoints are listed in Section 3. Brief analysis plans for these 
endpoints are contained in Section 10.3.2.4 and 10.3.2.5. Full details will be contained in the 
SAP. 
 
10.3.2.3 
Primary Endpoint Analysis 
The primary analysis of time to lesion resolution will be assessed using a Fine-Gray competing 
risks model33 and will be stratified by days from onset of symptoms to randomization (≤7 days vs 
>7 days; Figure 3). The statistical significance of the primary endpoint will be assessed using 
Gray’s test with a two-sided type I error rate of α=0.05. Gray’s test is analogous to the log-rank 
test comparing Kaplan-Meier curves (and results in the same sample size calculations) but is 
specific to the competing-risk setting.  
 
Figure 3. Primary analysis. 
 
 
There is no validated measure of baseline disease severity for mpox. Stratification by duration of 
symptoms aligns with the prevailing knowledge that antivirals are most efficacious when 
administered early in the course of infection and on data from the INRB/USAMRIID 
observational study showing that the correlation between days from symptom onset and time to 
lesion resolution was higher than both the correlation between baseline lesion count and time to 
resolution and between baseline viral load and time to resolution. Of note, development and 
validation of a baseline disease severity metric is an exploratory aim of this study. 
 
The statistical analysis plan will include procedures for handling missing data as well as provide 
technical details for how analyses will be performed. 
 
Stratified time to lesion 
resolution 
Time to lesion 
resolution 
Time to lesion 
resolution 
Duration of 
symptoms  
≤7 days 
Duration of 
symptoms  
>7 days 
Statistically 
significant 
Two-sided α=0.05 
Two-sided α=0.05 
Two-sided α=0.05 
Primary Endpoint: Family-wise type I error rate = 0.05 

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10.3.2.4 
Secondary Endpoint Analyses 
• The primary analysis will be repeated within the two randomization strata (≤ 7days or > 7 
days from symptom onset to randomization), reporting 95% confidence intervals rather 
than p-values. 
• The proportion with negative blood, oropharyngeal swab, and lesion swab PCR results 14 
days after randomization will be summarized with point estimates and 95% confidence 
intervals (CIs). The difference in proportions and 95% CIs for the difference will be 
presented for each compartment.  
• Time to death will be assessed using a Cox proportional hazards models, with estimates 
and 95% CIs for the hazard ratio for death within 28 days reported for an overall 
stratified model and within each stratum. 
• Mortality within the first 28 days by study arm will be summarized by proportions with 
95% CIs and the difference in proportions with a 95% CI. 
• Frequency of clinical symptoms by symptom and study arm will be summarized as 
proportions at baseline and selected timepoints described in the SAP. Duration of clinical 
symptoms will be summarized according to median days and interquartile range. 
• Incidence of SAEs, AEs requiring drug discontinuation, and other AEs will be 
summarized by proportions and differences in proportions with 95% CIs where 
appropriate. AEs will be coded using the current version of the Medical Dictionary for 
Regulatory Activities (MedDRA). Each AE will be graded by severity and relationship to 
underlying disease or study intervention. AEs will be presented by System Organ Class, 
severity, and causality. AEs leading to premature discontinuation from the study 
intervention will be presented in tables as described above and listed. Listings will be 
prepared of all AEs and all SAEs. 
• Incidence of bacterial infections by study arm will be summarized by proportions and 
differences in proportions with 95% CIs as appropriate. 
 
10.3.2.5 
Exploratory Endpoint Analyses 
• Frequency and location of persistent residual lesions by location and study arm will be 
provided. 
• Lesion progression over the study period will be compared using descriptive analyses of 
lesion count trajectories. An automated image analysis algorithm will be trained using 
longitudinal photographs of lesions. Lesion counts and characteristics from photographs 
will be assessed and compared to evaluate the performance of the algorithm relative to a 
human rater. 
• Number and percentage of confirmed mpox cases reporting exposure to animals, 
symptomatic humans, or with no known exposures will be provided. 
• Viral persistence in blood, oropharyngeal swabs, and skin lesion swabs will be 
summarized by the proportion with negative results for each sample type (out of those 
positive at baseline) at timepoints specified in the SAP. . Viral load from all sample types 
will be shown longitudinally by study arm as medians and interquartile ranges. 

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• Time to the first negative blood, oropharyngeal swab, and open lesion swab PCR result 
will be summarized using the Fine-Gray procedure as described above. Treatment effect 
rate ratios and accompanying 95% CIs as well as plots of the cumulative incidence 
function for each event will be provided. 
• Antibody titers will be summarized with geometric means and geometric standard 
deviations by study arm. Change from baseline at selected timepoints will be provided. 
• Pre-dose concentration of tecovirimat in blood measured on day 7 will be reported for the 
tecovirimat arm using the minimum value, 25th percentile, median, 75th percentile, 
maximum, mean, and standard deviation. 
• Incidence of recrudescent disease and description of clinical and virologic characteristics 
of recrudescent disease cases will be provided. 
 
 
10.3.2.6 
Subgroup Analyses 
Planned subgroup analyses will evaluate the treatment effect across the following subgroups: 
duration of symptoms prior to randomization (≤7 days or >7 days), study site (if more than one 
site enrolls participants), age, sex, baseline lesion burden according to a scale developed for 
smallpox by WHO (see Table 2 below), baseline viral load (≤ median or > median), HIV status, 
virus clade (if available), and presence/absence of anti-OPXV antibodies. A forest plot will 
display point estimates and 95% CIs for the lesion resolution rate ratio by subgroup. Interaction 
tests will be conducted to determine whether the effect of treatment varies by subgroup. 
Additional subgroups may be identified and evaluated. Full details of planned subgroup analyses 
will be provided in the statistical analysis plan. 
 
Table 2. WHO smallpox baseline lesion severity categories 
WHO smallpox baseline lesion 
severity category 
Number of lesions 
Subclinical 
0 – 4 
Mild 
5 – 25 
Moderate 
26 – 100 
Severe 
101 – 250 
Grave 
>250 
 
10.3.2.7 
Additional Planned Analyses 
Efforts will be made to develop a baseline disease severity metric for use in future studies of 
human mpox. Risk classification models will be implemented to summarize the strength of the 
relationships between baseline characteristics (including age, sex, baseline lesion count, type and 
duration of symptoms, viral load, and selected comorbidities) and the primary and secondary 
endpoints. 
 

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10.3.3 
Baseline Descriptive Statistics 
Baseline characteristics will be summarized by treatment arm. For continuous measures the 
mean, standard deviation, minimum, 25th percentile, median, 75th percentile, and maximum value 
will be provided. Categorical variables will be described by the number and proportion in each 
category. The proportion of missingness for each variable will be provided. 
 
10.4 
Power and Sample Size 
This section describes the original power and sample size calculations. Updated power and 
sample size calculations based on the sample size re-estimation plan described below are 
provided in APPENDIX C. 
 
For the test of the primary endpoint, the two key determinants of power are the total number of 
lesion resolution events, E, and the treatment-to-control ratio of the rate of lesion resolution, θ. 
The number of events required to achieve power 1 −𝛽𝛽 to detect a rate ratio of θ using a two- 
tailed test with type I error rate α=0.05 is approximately 
𝐸𝐸= 4൫1.96 + 𝑧𝑧𝛽𝛽൯
2
{ln(𝜃𝜃)}2
, 
where 𝑧𝑧𝛽𝛽 is the 100(1 −𝛽𝛽)th percentile of the standard normal distribution. 
 
Table 3 displays the power of this test for various scenarios. In total, 318 patients with lesion 
resolution up to 28 days after randomization are needed to detect a 40% improvement in the rate 
of lesion resolution as measured by the rate ratio (akin to a “hazard ratio” but for a positive 
outcome; values greater than one indicate improved outcomes) with 85% power and a two-sided 
type one error rate of α=0.05. Extrapolating the observed event rate of 77% from the 2007-2011 
INRB/USAMRIID observational study yields a total targeted sample size of 413 participants. 
Although every effort will be made to eliminate patient dropout, a total sample size of 450 is 
planned to account for potential dropout. 
 
Note that the 77% event rate used to determine the sample size is derived from an observational 
cohort and thus is most likely to correspond to the event rate on the control arm in this trial. 
Assuming the hypothesized rate ratio of 1.40 is accurate, the event rate on the tecovirimat arm 
(and therefore the overall event rate) will be higher than 77%. A higher rate of events will 
increase the power of the trial. Therefore, if the overall event rate is higher than expected, the 
power of the trial will be higher than 85%. One could argue that the planned sample size could 
be decreased and the trial could still expect to enroll sufficient participants to hit the 318 events 
necessary to achieve 85% power. However, one benefit of the somewhat conservative approach 
to sample size taken here is that by enrolling more participants, the power for subgroup and 
secondary analyses will be improved. 
 

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Table 3. Number of events needed for 80% and 85% power. The shaded region represents 
the rate ratio, number of events, and projected sample size for the trial before accounting 
for potential drop out. 
Rate 
Ratio 
(θ) 
Scenario for 80% Power (β=0.20) 
Scenario for 85% Power (β=0.15) 
Number of Events 
Needed 
Number of Patients 
Needed* 
Number of Events 
Needed 
Number of Patients 
Needed* 
1.15 
1608 
2089 
1839 
2389 
1.20 
945 
1228 
1081 
1404 
1.25 
631 
820 
722 
938 
1.30 
457 
594 
522 
678 
1.35 
349 
454 
399 
519 
1.40 
278 
362 
318 
413 
1.45 
228 
297 
261 
339 
1.50 
191 
249 
219 
285 
1.55 
164 
213 
187 
243 
1.60 
143 
186 
163 
212 
1.65 
126 
164 
144 
188 
* Assumes that 77% of patients will experience the event and does not account for potential dropout. 
Seventy-seven percent was the observed percentage of patients who reached lesion resolution (as defined 
above) within 22 days in the 2007-2011 INRB/USAMRIID observational study. 
 
Updated power and sample size calculations based on the sample size re-estimation plan 
described below are provided in APPENDIX C. 
 
10.4.1 
Sample Size Re-estimation 
A blinded sample size re-estimation will be conducted at the midpoint of the trial when 159 
lesion resolution events have occurred (i.e., at 50% information). The blinded overall rate of 
events will be computed and provided to a sample size re-estimation committee. The committee 
will be tasked with assessing whether the sample size should be increased either in response to a 
lower than expected event rate (which may lead to more than 450 participants required to 
achieve 318 resolutions) or in order to increase the overall power of the study (i.e., to target 
greater than 318 events, which may be desirable if enrollment allows). Results of the re-
estimation are provided in APPENDIX C. 
 
10.5 
Planned Interim Monitoring 
A DSMB will monitor ongoing results to ensure the well-being and safety of participants as well 
as study integrity. The DSMB will be asked to recommend stopping the study early for efficacy 
only when there is substantial evidence of a treatment benefit. Similarly, the DSMB will be 
asked to recommended stopping early for futility only when there is substantial evidence to make 
such a recommendation. 

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10.5.1 
Interim Monitoring for Efficacy and Futility 
The Lan-DeMets spending function analog of the O’Brien-Fleming boundaries will be used to 
monitor the primary endpoint as a guide for the DSMB for an overall two-sided type-I error rate 
of 0.05. The original study design called for interim efficacy analyses to be conducted at 
approximately 33%, 67%, and 100% of total information. Updated interim monitoring 
considerations based on the sample size re-estimation plan described above are provided in 
APPENDIX C. 
 
The statistical analysis plan will provide a more detailed description of the stopping boundaries 
used for interim analyses. 
 
Conditional power will be presented as an additional guide to the DSMB at interim efficacy 
analyses. If conditional power is less than 20% under the original trial assumptions, 
consideration should be given to stopping the trial. 
 
The unblinded statistical team will prepare these closed reports for DSMB review and 
recommendations. Analyses will be presented with blinded codes for treatment arms to protect 
against the possibility that the DSMB report may fall into the wrong hands. A DSMB charter 
will further describe procedures and membership. 
 
11 
REGULATORY AND OPERATIONAL CONSIDERATIONS 
11.1 
Informed Consent Process 
11.1.1 
Consent/Assent Procedures and Documentation 
Informed consent is a process where information is presented to enable persons to voluntarily 
decide whether or not to participate as a research participant. It is an ongoing conversation 
between the human research participant and the researchers which begins before consent is given 
and continues until the end of the participant’s involvement in the research. Discussions about 
the research will provide essential information about the study and include purpose, duration, 
experimental procedures, alternatives, risks, and benefits. Coercion and undue influence will be 
minimized by informing participants that their decision to join the study will not affect any 
medical care they are currently receiving, or their eligibility to participate in other research 
studies. Participants will be given as much time as they need to read the consent forms and ask 
questions of the investigators. Participants will also be given time to discuss their participation 
with family members, friends, and other healthcare providers. 
 
The informed consent procedure will be conducted in the native or preferred language of the 
patients by a qualified person formally identified by the principal investigator. Written 
information and consent forms will be provided to the patients for their review in language 
spoken in the study area and understood by the participant. 
 
Informed consent will be obtained in person by a study team member authorized to obtain 
consent. The privacy of the participant will be maintained. The consenting investigator and 
participant will be located in a private area (e.g., clinic consult room). Participants over 18 years 
of age will sign the informed consent documents (in a language understood by the participant) 

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prior to any procedures being done specifically for the study. The signature of a culturally 
acceptable representative of the potential participant will be obtained for adults who are impaired 
and unable to provide informed consent. In the case of adults whose ability to consent is 
uncertain, capacity to consent will be evaluated by the principal or associate investigator(s). 
 
Parental/guardian permission and minor assent for children through 17 years of age will be 
obtained according to local standards and country-specific requirements. In DRC an assent must 
be obtained for children aged 12 to 17 years. Children that are too young to sign an assent form 
can be enrolled provided informed consent is signed/marked by a parent or guardian. If a minor 
participant expresses reluctance to participate in the study during the assent process, he or she 
will not be enrolled, notwithstanding consent from his or her parents/guardians. 
 
A copy of the informed consent documents will be given to the participants for their records. The 
consenting investigator will document the signing of the consent forms in the participant’s study 
record. The investigator will confirm that written legally effective consent has been obtained 
prior to initiating any study interventions. 
 
The rights and welfare of the participants will be protected by emphasizing to them that the 
quality of their medical care will not be adversely affected if they decline to participate in this 
study. The participants may withdraw consent at any time throughout the course of the trial. 
 
11.1.2 
Consent for Minors When They Reach the Age of Majority 
When a pediatric participant reaches age 18, continued participation (including ongoing 
interactions with the participant or continued analysis of identifiable data) will require that 
consent be obtained from the now adult with the standard protocol consent document to ensure 
legally effective informed consent has been obtained. 
 
If reconsent is not feasible, we request waiver of informed consent to continue to use data and/or 
specimens for those individuals who become lost to follow up or who have been taken off study 
prior to reaching the age of majority. 
 
Requirements for waiver of consent consistent with 45 CFR 46.116(f)(3): 
(1) The research involves no more than minimal risk to the subjects. 
a. Analysis of samples and data from this study involves no additional risks to 
subjects. 
(2) The research could not practicably be carried out without the waiver or alteration. 
a. Considering the potential length of time between the minor’s last contact 
with the research team and their age of majority, it may be very difficult to 
locate them again. A significant reduction in the number of samples analyzed 
is likely to impact the quality of the research. 

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(3) As the research involves using identifiable private information or identifiable 
biospecimens, the research could not practicably be carried out without using such 
information or biospecimens in an identifiable format. 
a. Though the purpose of future studies cannot yet be known, they often involve 
the correlation of clinical outcomes and clinical interventions with laboratory 
studies. Such information would be unavailable if access to medical record 
numbers was unavailable. 
(4) The waiver or alteration will not adversely affect the rights and welfare of the 
subjects. 
a. Retention of these samples or data does not affect the welfare of subjects. 
(5) Whenever appropriate, the subjects will be provided with additional pertinent 
information after participation. 
a. We only request a waiver of consent for those subjects who have been lost to 
follow-up or who have completed study participation prior to reaching the 
age of majority. 
 
11.2 
Study Discontinuation and Closure 
This study may be temporarily suspended or prematurely terminated if there is sufficient 
reasonable cause. Written notification documenting the reason for study suspension or 
termination will be provided by the suspending or terminating party to the principal 
investigators, pharmacovigilance committee, and regulatory authorities. If the study is 
prematurely terminated or suspended, the principal investigator will promptly inform the study 
participants, IRB/EC, pharmacovigilance committee, and relevant regulatory authorities, as 
applicable, and will provide the reason(s) for the termination or suspension. Study participants 
will be informed of changes to study visit schedule, if applicable. 
 
Circumstances that may warrant termination or suspension include, but are not limited to: 
• Determination of unexpected, significant, or unacceptable risk to participants. 
• Demonstration of efficacy that would warrant stopping. 
• Insufficient compliance to protocol requirements. 
• Data that are not sufficiently complete and/or evaluable. 
• Determination that the primary endpoint has been met. 
• Determination of futility. 
 
In the case of a temporary suspension, the study may resume once concerns about safety, protocol 
compliance, and/or data quality are addressed and satisfy the IRB/EC, pharmacovigilance 
committee, and regulatory authorities, as applicable. 
 

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11.3 
Confidentiality and Privacy 
All records will be kept confidential to the extent provided by federal, state, and local laws in the 
jurisdictions in which the study is conducted. Study monitors and other authorized individuals 
may inspect all documents and records required to be maintained by the investigator, including 
but not limited to, medical records. Records will be kept locked and data will be coded. Any 
personally identifiable information maintained for this study will be kept on restricted-access 
computers and networks. Personally identifiable information will only be shared with individuals 
authorized to receive it under this protocol. Individuals not authorized to receive personally 
identifiable information will be provided with coded information only, as needed. Clinical 
information will not be released without written permission of the participant, except as 
necessary for monitoring by the IRB/EC, NIAID, local regulatory agencies, the pharmaceutical 
supporter, or other authorized individuals. 
 
11.4 
Future Use of Stored Specimens and Data 
Coded data and specimens will be stored indefinitely for future research related to mpox and 
other infectious diseases after the study is complete. Plans for future use of data and specimens 
will be described in the informed consent document. Case report forms will be retained in secure 
facilities at the study sites. Coded data will be retained in the data management system on secure, 
password-protected servers maintained by the Data Coordinating Center at NIAID. Coded 
specimens will be stored in secure facilities. The key to the participant codes will be maintained 
securely at the study sites. 
 
Other investigators (at NIH, at INRB, and elsewhere) may wish to study these data and/or 
specimens. In that case, the principal investigators and the steering committee will review the 
request. If the planned research falls within the category of “human subjects research” on the part 
of the investigators, IRB/EC review(s) and approval(s) will be obtained as appropriate. This 
includes the investigators sending out coded and linked specimens or data and getting results that 
they can link back to their participants. 
 
11.5 
Safety Oversight 
Safety oversight for this study is described in section 9.3. 
 
11.6 
Data Management and Monitoring  
11.6.1 
Data Management Responsibilities 
The site investigator is responsible for assuring that the data collected is complete, accurate, and 
recorded in a timely manner. Source documentation (the point of initial recording of information) 
should support the data transferred to the electronic data system and, when possible, should be 
signed and dated by the person recording and/or reviewing the data. All data should be reviewed 
by the Investigator and co-signed as required. 
 
11.6.2 
Data Capture Methods 
Study data collected at the bedside at study sites will later be recorded on paper CRFs. CRFs will 
be scanned and submitted to an electronic system provided by NIAID and managed by the CTRS 
Data Management Team. The INRB Data Management team will have access to these scanned 

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images, and they will enter the data in the REDCap clinical data management system (CDMS) 
provided by NIAID. The data system includes password protection and internal quality checks, 
to identify inconsistent, incomplete, or inaccurate data. Any corrections to the electronic data 
systems will be tracked electronically (password protected and through an audit trail) with time, 
date, individual making the correction, and what was changed. AEs and concomitant medications 
will be coded according to the most current versions of MedDRA and WHODrug, respectively. 
The CTRS Data Management team, in collaboration with the INRB’s Coordinating Center Data 
Management team, will be responsible for data management, data entry review, quality review, 
analysis, and reporting of the study data. 
 
11.6.3 
Types of Data 
Source documents may include, but are not limited to, the participant’s medical records, 
laboratory reports, ECG tracings, x-rays, radiologist’s reports, participant’s diaries, biopsy 
reports, ultrasound photographs, progress notes, pharmacy records, and any other similar reports 
or records of procedures performed during the subject’s participation in the study. 
 
11.6.3.1 
Source Documents and Access to Source Data/Documents 
Source documents include all recordings of observations or notations of clinical activities, and all 
reports and records necessary for the evaluation and reconstruction of the clinical trial. 
 
11.6.4 
Record Retention 
The protocol team is responsible for retaining all essential documents listed in the ICH Good 
Clinical Practice Guideline. All essential documentation for all study participants is to be 
maintained by the investigators in a secure storage facility for a minimum of 3 years per NIAID 
policies or per in-country local or federal regulatory requirements (whichever is longer). These 
records are also to be maintained in compliance with IRB/EC and local medical records retention 
requirements, whichever is longest. All stored records are to be kept confidential to the extent 
required by applicable laws in the jurisdiction in which they are stored. 
 
11.6.5 
Site Monitoring Plan 
As per ICH-GCP 5.18, clinical protocols are required to be adequately monitored by the study 
sponsor. This study monitoring will be conducted according to the “NIAID Intramural Clinical 
Monitoring Guidelines.” If feasible, monitors under contract to the NIAID/Office of Clinical 
Research Policy and Regulatory Operations (OCRPRO) or their designee may visit the clinical 
research site to monitor aspects of the study in accordance with the appropriate regulations and 
the approved protocol. The objectives of a monitoring visit would be: 1) to verify the existence 
of signed informed consent documents and documentation of the Informed Consent Form 
process for each monitored participant; 2) to verify the prompt and accurate recording of all 
monitored data points, and prompt reporting of all SAEs; 3) to compare data abstracts with 
individual participants’ records and source documents (participants’ charts, laboratory analyses 
and test results, medical progress notes, nurses’ notes, and any other relevant original participant 
information); and 4) to help ensure investigators are in compliance with the protocol. The 
monitors also may inspect the clinical site regulatory files to ensure that regulatory requirements 
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being followed. During the monitoring visits, the investigator (and/or designee) and other study 
personnel should be available to discuss the study progress and monitoring visit. 
 
11.7 
Data Sharing Plan 
11.7.1 
Human Data Sharing Plan 
At the completion of the trial, a comprehensive study report will be prepared in concert with the 
DRC and will be made available to the DSMB and study partners. . The relevant primary and 
secondary outcome data from this trial will also be entered into ClinicalTrials.gov for access by 
other researchers. In addition, it is the intention of the extended protocol team that de-identified 
data from this trial will be made available upon request to outside investigators upon scientific 
review of the merits of their proposed research plan. This availability will be in accordance with 
the WHO Joint statement on public disclosure of results from clinical trials. To facilitate this, a 
Presentations and Publications subcommittee (which will include full representation of the DRC 
and any additional institution who may join the study as well as representation from the extended 
protocol team) will be created to receive, review for scientific merit, and, if appropriate, approve 
these requests for use of de-identified data arising from the trial. 
 
11.8 
Collaborative Agreements  
11.8.1 
Agreement Type 
Agreements for each participating site will be executed as needed. 
 
11.9 
Conflict of Interest Policy 
The independence of this study from any actual or perceived influence, such as by the 
pharmaceutical industry, is critical. Therefore, any actual conflict of interest of persons who have 
a role in the design, conduct, analysis, publication, or any aspect of this trial will be disclosed 
and managed. Furthermore, persons who have a perceived conflict of interest will be required to 
have such conflicts managed in a way that is appropriate to their participation in the design and 
conduct of this trial. The study leadership in conjunction with NIAID has established policies 
and procedures for all study group members to disclose all conflicts of interest and will establish 
a mechanism for the management of all reported dualities of interest. 
 
12 
ABBREVIATIONS 
ADL 
activities of daily living 
AE 
adverse event 
ALT 
alanine transaminase 
aPTT 
activated partial thromboplastin time 
AR 
adverse reaction 
AST 
aspartate transaminase 
AUC 
area under the curve 
BRB 
Biostatistics Research Branch 
BUN 
blood urea nitrogen 
CAPA 
corrective and preventive action plan 
CB 
Congo Basin 

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CBC 
complete blood count 
CDC 
Centers for Disease Control and Prevention 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
CMRPD 
Clinical Monitoring Research Program Directorate 
CT 
cycle threshold 
CONSORT 
Consolidated Standards of Reporting Trials 
CRF 
case report form 
CYP 
cytochrome P450 
DCR 
Division of Clinical Research 
DNA 
deoxyribonucleic acid 
DRC 
Democratic Republic of Congo 
DSMB 
Data and Safety Monitoring Board 
EC 
ethics committee 
EMA 
European Medicines Agency 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HIV 
human immunodeficiency virus 
ICH 
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
Ig 
immunoglobulin 
IND 
investigational new drug (application) 
INR 
international normalized ratio 
INRB 
Institut National de Recherche Biomédicale 
IRB 
institutional review board 
mITT 
modified intention-to-treat 
MM 
medical monitor 
MOP 
manual of procedures 
MPXV 
monkeypox virus 
MVA 
modified vaccinia virus Ankara 
NIAID 
National Institute of Allergy and Infectious Diseases 
NIH 
National Institutes of Health 
OCRPRO 
Office of Clinical Research Policy and Regulatory Operations 
OHRP 
Office for Human Research Protections 
OPXV 
orthopoxvirus 
PCR 
polymerase chain reaction 
PK 
pharmacokinetic 
PT 
prothrombin time 
REDCap 
research electronic data capture 
RHD 
recommended human dose 
RPR 
Rapid Plasma Reagin 
SAE 
serious adverse event 
SAR 
suspected adverse reaction 
SOC 
standard of care 
SUSAR 
serious and unexpected suspected adverse reaction 

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UP 
unanticipated problem 
UPnonAE 
unanticipated problem that is not an adverse event 
USAMRIID 
US Army Medical Research Institute of Infectious Diseases 
USAN 
United States adopted name 
US 
United States 
VZV 
Varicella zoster virus 
WA 
West African 
WHO 
World Health Organization 
 
13 
REFERENCES 
1. 
Shchelkunov SN, Marennikova SS, Moyer RW. Classification of Poxviruses and Brief 
Characterization of the Genus.  Orthopoxviruses Pathogenic for Humans. New York: 
Springer; 2005:11-18. 
2. 
Parker S, Nuara A, Buller RM, Schultz DA. Human monkeypox: an emerging zoonotic 
disease. Future Microbiol 2007;2(1):17-34. DOI: 10.2217/17460913.2.1.17. 
3. 
Laliberte JP, Moss B. Lipid membranes in poxvirus replication. Viruses 2010;2(4):972-
986. 
4. 
Parker S, Buller RM. A review of experimental and natural infections of animals with 
monkeypox virus between 1958 and 2012. Future virology 2013;8(2):129-157. 
5. 
Ladnyj I, Ziegler P, Kima E. A human infection caused by monkeypox virus in 
Basankusu Territory, Democratic Republic of the Congo. Bulletin of the World Health 
Organization 1972;46(5):593-597. 
6. 
Chen N, Li G, Liszewski MK, et al. Virulence differences between monkeypox virus 
isolates from West Africa and the Congo basin. Virology 2005;340(1):46-63. 
7. 
Sale TA, Melski JW, Stratman EJ. Monkeypox: an epidemiologic and clinical 
comparison of African and US disease. Journal of the American Academy of 
Dermatology 2006;55(3):478-481. 
8. 
Sklenovska N, Van Ranst M. Emergence of monkeypox as the most important 
orthopoxvirus infection in humans. Frontiers in public health 2018;6:241. 
9. 
United States Centers for Disease Control and Prevention. Monkeypox in the United 
States. (https://www.cdc.gov/poxvirus/monkeypox/outbreak.html ). 
10. 
Reed KD, Melski JW, Graham MB, et al. The detection of monkeypox in humans in the 
Western Hemisphere. New England Journal of Medicine 2004;350(4):342-350. 
11. 
United States Centers for Disease Control and Prevention. Multistate Outbreak of 
Monkeypox --- Illinois, Indiana, and Wisconsin, 2003. 
(https://www.cdc.gov/mmwr/preview/mmwrhtml/mm5223a1.htm). 
12. 
Thomassen HA, Fuller T, Asefi-Najafabady S, et al. Pathogen-host associations and 
predicted range shifts of human monkeypox in response to climate change in central 
Africa. PLoS One 2013;8(7):e66071. 
13. 
Alakunle E, Moens U, Nchinda G, Okeke MI. Monkeypox virus in Nigeria: infection 
biology, epidemiology, and evolution. Viruses 2020;12(11):1257. 
14. 
Reynolds MG, McCollum AM, Nguete B, Shongo Lushima R, Petersen BW. Improving 
the Care and Treatment of Monkeypox Patients in Low-Resource Settings: Applying 
Evidence from Contemporary Biomedical and Smallpox Biodefense Research. Viruses 
2017;9(12). DOI: 10.3390/v9120380. 
15. 
Jezek Z, Fenner F. Human monkeypox: Karger Publishers, 1988. 

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16. 
World Health Organization. Weekly Bulletin on outbreaks and other emergencies: Week 
51 13-19 December 2021. 19 December 
(https://apps.who.int/iris/bitstream/handle/10665/350880/OEW51-1319122021.pdf). 
17. 
Online News Today. Maniema province monkeypox outbreak: WHO details. December 
22, 2021 (http://outbreaknewstoday.com/maniema-province-monkeypox-outbreak-who-
details-20779/). 
18. 
Sklenovska N. Monkeypox Virus. In: Malik YS, Singh RK, Dhama K, eds. Animal-
Origin Viral Zoonoses. Livestock Diseases and Management. Singapore: Springer; 
2020:39-68. 
19. 
Parker S, Handley L, Buller RM. Therapeutic and prophylactic drugs to treat 
orthopoxvirus infections. Future Virol 2008;3(6):595-612. DOI: 
10.2217/17460794.3.6.595. 
20. 
Mucker EM, Goff AJ, Shamblin JD, et al. Efficacy of tecovirimat (ST-246) in nonhuman 
primates infected with variola virus (Smallpox). Antimicrob Agents Chemother 
2013;57(12):6246-53. DOI: 10.1128/AAC.00977-13. 
21. 
SIGA Technologies Inc. TPOXX (tecovirimat) [full US prescribing information]. 
05/2022. 
(https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/214518s000lbl.pdf). 
22. 
European Medicines Agency. Human medicine European public assessment report 
(EPAR): Tecovirmat SIGA. 01/2022. 
(https://www.ema.europa.eu/en/medicines/human/EPAR/tecovirimat-siga). 
23. 
Grosenbach DW, Honeychurch K, Rose EA, et al. Oral Tecovirimat for the Treatment of 
Smallpox. N Engl J Med 2018;379(1):44-53. DOI: 10.1056/NEJMoa1705688. 
24. 
Adler H, Gould S, Hine P, et al. Clinical features and management of human monkeypox: 
a retrospective observational study in the UK. Lancet Infect Dis 2022. DOI: 
10.1016/S1473-3099(22)00228-6. 
25. 
Centers for Disease Control and Prevention. Monkeypox: Treatment. June 17, 2022 
(https://www.cdc.gov/poxvirus/monkeypox/treatment.html). 
26. 
Centers for Disease Control and Prevention. Monkeypox: Treatment Information for 
Healthcare Professionals. June 17, 2022 
(https://www.cdc.gov/poxvirus/monkeypox/clinicians/treatment.html). 
27. 
Rimoin AW, Mulembakani PM, Johnston SC, et al. Major increase in human monkeypox 
incidence 30 years after smallpox vaccination campaigns cease in the Democratic 
Republic of Congo. Proceedings of the National Academy of Sciences 
2010;107(37):16262-16267. 
28. 
World Health Organization. Monkeypox - United Kingdom of Great Britain and Northern 
Ireland. (https://www.who.int/emergencies/disease-outbreak-news/item/monkeypox---
united-kingdom-of-great-britain-and-northern-ireland-ex-nigeria). 
29. 
Jordan R, Leeds JM, Tyavanagimatt S, Hruby DE. Development of ST-246® for 
Treatment of Poxvirus Infections. Viruses 2010;2(11):2409-2435. 
(https://www.mdpi.com/1999-4915/2/11/2409). 
30. 
Jordan R, Tien D, Bolken TC, et al. Single-dose safety and pharmacokinetics of ST-246, 
a novel orthopoxvirus egress inhibitor. Antimicrobial agents and chemotherapy 
2008;52(5):1721-1727. 
31. 
World Health Organization. Monkeypox. 19 May 2022 (https://www.who.int/news-
room/fact-sheets/detail/monkeypox). 

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32. 
Wallace MR, Bowler WA, Murray NB, Brodine SK, Oldfield EC, 3rd. Treatment of adult 
varicella with oral acyclovir. A randomized, placebo-controlled trial. Ann Intern Med 
1992;117(5):358-63. DOI: 10.7326/0003-4819-117-5-358. 
33. 
Fine JP, Gray RJ. A Proportional Hazards Model for the Subdistribution of a Competing 
Risk. Journal of the American Statistical Association 1999;94(446):496-509. 
 

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APPENDIX A: Chemistry, Hematology, and Coagulation Parameter Grading Scale 
CHEMISTRY 
PARAMETER 
Qualifier 
NORMAL 
LIMITS 
GRADE 1  
MILD 
GRADE 2  
MODERATE 
GRADE 3  
SEVERE 
GRADE 4  
POTENTIALLY LIFE 
THREATENING 
Albumin (g/dL): 
Low 
  
3.3-5.5 
g/dL 
<LLN - 3 g/dL; <LLN - 
30 g/L 
<3 - 2 g/dL; <30 - 20 
g/L 
<2 g/dL; <20 g/L  
Life-threatening 
consequences; urgent 
intervention indicated  
Alkaline 
phosphatase (IU/L): 
High 
male 
53-128 U/L 
>ULN - 2.5 x ULN if 
baseline was normal; 
2.0 - 2.5 x baseline if 
baseline was abnormal  
>2.5 - 5.0 x ULN if 
baseline was normal; 
>2.5 - 5.0 x baseline 
if baseline was 
abnormal  
>5.0 - 20.0 x ULN if 
baseline was normal; 
>5.0 - 20.0 x baseline 
if baseline was 
abnormal  
>20.0 x ULN if baseline 
was normal; >20.0 x 
baseline if baseline was 
abnormal  
female 
42-141 U/L 
>ULN - 2.5 x ULN if 
baseline was normal; 
2.0 - 2.5 x baseline if 
baseline was abnormal  
>2.5 - 5.0 x ULN if 
baseline was normal; 
>2.5 - 5.0 x baseline 
if baseline was 
abnormal  
>5.0 - 20.0 x ULN if 
baseline was normal; 
>5.0 - 20.0 x baseline 
if baseline was 
abnormal  
>20.0 x ULN if baseline 
was normal; >20.0 x 
baseline if baseline was 
abnormal  
Amylase (U/L): 
High 
  
14-97 U/L 
>ULN - 1.5 x ULN  
>1.5 - 2.0 x ULN; 
>2.0 - 5.0 x ULN 
and asymptomatic  
>2.0 - 5.0 x ULN with 
signs or symptoms; 
>5.0 x ULN and 
asymptomatic  
>5.0 x ULN and with 
signs or symptoms  
AST (U/L): High 
  
<=38 U/L 
>ULN - 3.0 x ULN if 
baseline was normal; 
1.5 - 3.0 x baseline if 
baseline was abnormal  
>3.0 - 5.0 x ULN if 
baseline was normal; 
>3.0 - 5.0 x baseline 
if baseline was 
abnormal  
>5.0 - 20.0 x ULN if 
baseline was normal; 
>5.0 - 20.0 x baseline 
if baseline was 
abnormal  
>20.0 x ULN if baseline 
was normal; >20.0 x 
baseline if baseline was 
abnormal  
ALT (U/L): High 
  
<=47 U/L 
>ULN - 3.0 x ULN if 
baseline was normal; 
1.5 - 3.0 x baseline if 
baseline was abnormal  
>3.0 - 5.0 x ULN if 
baseline was normal; 
>3.0 - 5.0 x baseline 
if baseline was 
abnormal  
>5.0 - 20.0 x ULN if 
baseline was normal; 
>5.0 - 20.0 x baseline 
if baseline was 
abnormal 
>20.0 x ULN if baseline 
was normal; >20.0 x 
baseline if baseline was 
abnormal  
Bilirubin, Blood, 
High 
  
0.2-1.6 
mg/dL 
>ULN - 1.5 x ULN if 
baseline  
was normal; >1.0 - 1.5 x 
baseline if baseline was 
abnormal 
>1.5 - 3.0 x ULN if 
baseline 
was normal; >1.5 - 
3.0 x 
baseline if baseline 
>3.0 - 10.0 x ULN if 
baseline 
was normal; >3.0 - 
10.0 x 
baseline if baseline 
>10.0 x ULN if baseline 
was 
normal; >10.0 x 
baseline if 
baseline was abnormal 

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was 
abnormal 
was 
abnormal 
BUN (mg/dL) 
  
7-22 mg/dL 
No AE grading reference range available. If abnormal, clinician to determine if abnormal lab is 
clinically significant. 
Calcium (mg/dL): 
High 
  
8.0-10.3 
mg/dL 
Corrected serum 
calcium of >ULN - 11.5 
mg/dL; >ULN - 2.9 
mmol/L; Ionized 
calcium >ULN - 1.5 
mmol/L  
Corrected serum 
calcium of >11.5 - 
12.5 mg/dL; >2.9 - 
3.1 mmol/L; Ionized 
calcium >1.5 - 1.6 
mmol/L; 
symptomatic  
Corrected serum 
calcium of >12.5 - 
13.5 mg/dL; >3.1 - 3.4 
mmol/L; Ionized 
calcium >1.6 - 1.8 
mmol/L; 
hospitalization 
indicated  
Corrected serum 
calcium of >13.5 
mg/dL; >3.4 mmol/L; 
Ionized calcium >1.8 
mmol/L; life-threatening 
consequences 
Calcium (mg/dL): 
High 
  
8.0-10.3 
mg/dL 
Corrected serum 
calcium of <LLN - 8.0 
mg/dL; <LLN - 2.0 
mmol/L; Ionized 
calcium <LLN - 1.0 
mmol/L  
Corrected serum 
calcium of <8.0 - 7.0 
mg/dL; <2.0 - 1.75 
mmol/L; Ionized 
calcium <1.0 - 0.9 
mmol/L; 
symptomatic  
Corrected serum 
calcium of <7.0 - 6.0 
mg/dL; <1.75 - 1.5 
mmol/L; Ionized 
calcium <0.9 - 0.8 
mmol/L; 
hospitalization 
indicated  
Corrected serum 
calcium of <6.0 mg/dL; 
<1.5 mmol/L; Ionized 
calcium <0.8 mmol/L; 
life-threatening 
consequences  
Chloride (mEq/L) 
  
98-108 
mmol/L 
No AE grading reference range available. If abnormal, clinician to determine if abnormal lab is 
clinically significant. 
C-reactive protein 
(ug/mL) 
  
< 7.5 mg/L 
No AE grading reference range available. If abnormal, clinician to determine if abnormal lab is 
clinically significant.  
Creatinine (mg/dL): 
High 
  
≤1.2 
>ULN - 1.5 x ULN 
>1.5 - 3.0 x baseline 
- 1.5 - 3.0 x ULN 
>3.0 x baseline; 3.0 -- 
6.0 x ULN 
>6.0 x ULN 
eGFR 
(mL/min/1.73m2) 
  
>=90 
No AE grading reference range available. If abnormal, clinician to determine if abnormal lab is 
clinically significant. 
Creatinine kinase 
(U/L): High 
male 
39-380 U/L 
>ULN - 2.5 x ULN  
>2.5 x ULN - 5 x 
ULN  
>5 x ULN - 10 x ULN 
>10 x ULN  
female  
30-190 U/L 
>ULN - 2.5 x ULN  
>2.5 x ULN - 5 x 
ULN  
>5 x ULN - 10 x ULN 
>10 x ULN  
Glucose (mg/dL): 
High 
  
  
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Glucose (mg/dL): 
Low 
  
  
<LLN - 55 mg/dL; 
<LLN - 3.0 
mmol/L 
<55 - 40 mg/dL; 
<3.0 - 2.2 
mmol/L 
<40 - 30 mg/dL; <2.2 
- 1.7 
mmol/L 
<30 mg/dL; <1.7 
mmol/L; life-threatening 
consequences; 
seizures 
Potassium 
(mmol/L): High 
  
3.6-5.1 
> ULN - 5.5 mmol/L 
>5.5 - 6.0 mmol/L; 
intervention 
initiated  
>6.0 - 7.0 mmol/L; 
hospitalization 
indicated 
>7.0 mmol/L; life-
threatening 
consequences 
Potassium 
(mmol/L): Low 
  
3.6-5.1 
<LLN-3.0mmol/L 
Symptomatic with 
<LLN-3.0 mmol/L; 
intervention 
indicated 
<3.0-2.5 mmol/L; 
hospitalization 
indicated 
<2.5 mmol/L; life-
threatening 
consequences 
Sodium (mmol/L): 
High 
  
130-145 
146-150 
>150-155; 
intervention 
indicated 
155-160; 
hospitalization 
indicated 
≥ 160; life-threatening 
consequences 
Sodium (mmol/L): 
Low 
  
130-145 
<130 
125-129 mmol/L 
and asymptomatic 
125-129 mmol/L 
symptomatic; 120-124 
mmol/L regardless of 
symptoms 
≤ 120; life-threatening 
consequences 
Total CO2 (mEq/L) 
  
18-33 
mmol/L 
No AE grading reference range available. If abnormal, clinician to determine if abnormal lab is 
clinically significant. 
Total protein (g/dL) 
  
6.4-8.1 
g/dLb 
No AE grading reference range available. If abnormal, clinician to determine if abnormal lab is 
clinically significant. 
  
HEMATOLOGY 
PARAMETER 
Qualifier 
NORMAL 
LIMITS 
GRADE 1 MILD 
GRADE 2 
MODERATE 
GRADE 3 SEVERE 
GRADE 4  
POTENTIALLY LIFE 
THREATENING 
Hematocrit (L/L): 
low  
  
32.5 – 46.2 
No AE grading reference range available. If abnormal, clinician to determine if abnormal lab is 
clinically significant. 
Lymphocytes % 
  
13.9 – 44.4 
No AE grading reference range available. If abnormal, clinician to determine if abnormal lab is 
clinically significant. 
Lymphocytes #: 
Low 
  
1.0 – 3.4 x 
10³/µl 
<LLN - 800/mm3; 
<LLN - 0.8 x 10e9/L  
<800 - 500/mm3; 
<0.8 - 0.5 x 10e9 /L  
<500 - 200/mm3; <0.5 
- 0.2 x 10e9 /L  
<200/mm3; <0.2 x 10e9 
/L  
MCV 
  
  
No AE grading reference range available. If abnormal, clinician to determine if abnormal lab is 
clinically significant. 
Neutrophils % 
  
49.1 – 76.9 
No AE grading reference range available. If abnormal, clinician to determine if abnormal lab is 
clinically significant. 

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Neutrophils #: Low 
  
2.4 – 7.5 x 
10³/µl 
<LLN - 1500/mm3; 
<LLN - 1.5 x 10e9 /L  
<1500 - 1000/mm3; 
<1.5 - 1.0 x 10e9 /L  
<1000 - 500/mm3; 
<1.0 - 0.5 x 10e9 /L  
<500/mm3; <0.5 x 10e9 
/L  
Platelets: Low 
  
136 – 388 
<LLN - 75,000/mm3; 
<LLN - 75.0 x 10e9 /L  
<75,000 - 
50,000/mm3; <75.0 
- 50.0 x 10e9 /L 
<50,000 - 
25,000/mm3; <50.0 - 
25.0 x 10e9 /L  
<25,000/mm3; <25.0 x 
10e9 /L  
WBC: High 
  
4-
11.5x10³/µl 
  
  
>100x 10³/µl 
  
WBC: Low 
  
4-
11.5x10³/µl 
<LLN - 3000/mm3; 
<LLN - 3.0 x 
10e9 /L 
<3000 - 2000/mm3; 
<3.0 - 2.0 
x 10e9 /L 
<2000 - 1000/mm3; 
<2.0 - 1.0 
x 10e9 /L 
<1000/mm3; <1.0 x 
10e9 /L 
COAGULATION 
PARAMETER 
Qualifier 
NORMAL 
LIMITS 
GRADE 1  
MILD 
GRADE 2 
MODERATE 
GRADE 3  
SEVERE 
GRADE 4  
POTENTIALLY LIFE 
THREATENING 
INR: high 
  
<1.2 
>1.2 - 1.5; >1 - 1.5 x 
baseline if on 
anticoagulation; 
monitoring only 
indicated  
>1.5 - 2.5; >1.5 - 2.5 
x baseline if on 
anticoagulation; 
dose adjustment 
indicated  
>2.5; >2.5 x baseline 
if on anticoagulation; 
bleeding  
  
PT (sec); not on 
anticoagulation: 
High 
  
11-13 sec 
1.1 to < 1.25 
x ULN 
1.25 to < 1.50 
x ULN 
1.50 to < 3.00 
x ULN 
≥ 3.00 x ULN 
Adapted from Common Terminology Criteria for Adverse Events (CTCAE)” (v 5.0). Available from: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.  
 
 
 

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APPENDIX B: Hemoglobin Laboratory Value Grading Scale 
PARAMETER 
QUALIFIER 
GRADE 1  
MILD 
GRADE 2 
MODERATE 
GRADE 3  
SEVERE 
GRADE 4  
POTENTIALLY 
LIFE 
THREATENING 
Hemoglobin (g/dL): Low,  
≥ 13 years of age  
Male 
10.0 to 10.9  
9.0 to < 10.0 
7.0 to < 9.0 
< 7.0 
Female 
9.5 to 10.4 
8.5 to < 9.5 
6.5 to < 8.5 
< 6.5 
Hemoglobin (g/dL): Low,  
57 days of age to < 13 years of age 
Male and Female 
9.5 to 10.4  
8.5 to < 9.5  
6.5 to < 8.5  
< 6.5  
Hemoglobin (g/dL): Low,  
36 to 56 days of age 
Male and Female 
8.5 to 9.6  
7.0 to < 8.5  
6.0 to < 7.0  
< 6.0  
Hemoglobin (g/dL):  Low,  
22 to 35 days of age 
Male and Female 
9.5 to 11.0  
8.0 to < 9.5  
6.7 to < 8.0  
< 6.7  
Hemoglobin (g/dL): Low,  
8 to ≤ 21 days of age 
Male and Female 
11.0 to 13.0  
9.0 to < 11.0  
8.0 to < 9.0  
< 8.0  
Hemoglobin (g/dL): Low,  
≤ 7 days of age 
Male and Female 
13.0 to 14.0  
10.0 to < 13.0  
9.0 to < 10.0  < 9.0  
From the Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events, Corrected Version 2.1, 
July 2017. Available from: https://rsc.niaid.nih.gov/sites/default/files/daidsgradingcorrectedv21.pdf 

Abbreviated Title: PALM 007 
Version: 4.0 
 
74 
Version Date: December 15, 2023 
 
 
APPENDIX C: Sample Size Updates 
1. Original Power and Sample Size Calculations 
The original study design anticipated requiring 450 participants to achieve 318 lesion resolution 
events, an implied event rate of approximately 70%. 318 events are sufficient to provide 85% 
power to detect a 40% improvement in the rate of lesion resolution as measured by the 
subdistribution hazard ratio. Details for the original sample size calculations are provided in 
section 10.4 and in the statistical analysis plan. 
 
The study protocol also pre-specified a blinded sample size re-estimation procedure to occur at 
50% information under the original design (i.e., after 159 lesion resolution events; see section 
10.4.1). 
 
1.1. 
Size Re-Estimation Procedure Details 
The sample size re-estimation committee meeting occurred on 29 August 2023 and included data 
on 165 total events. The blinded report reviewed by the committee and the meeting minutes were 
archived to serve as documentation of the considerations made by the committee and their 
decisions regarding the sample size and interim monitoring plan, detailed below. These changes 
to the study protocol will be accompanied by a corresponding update to the statistical analysis 
plan. 
 
1.2. 
Updated Power and Sample Size Calculations – Protocol Version 3.0 
This section describes the updated power and sample size calculations which formed the basis 
for protocol version 3.0. Protocol version 3.0 increased the target number of lesion resolution 
events to 440. A subsequent sample size increase later increased the target number of events to 
550. 
 
The sample size re-estimation committee determined that the study design should be updated to 
target 440 lesion resolution events rather than the 318 specified by the original design. This 
decision reflects a higher-than-anticipated event rate and steady enrollment, the combination of 
which presents an opportunity to increase statistical power without changing the target 
enrollment of 450 participants. In addition to providing greater statistical power for the primary 
endpoint, statistical power for secondary and exploratory endpoints (including subgroup 
analyses) will also be increased. Given the operational difficulty imposed by the study setting, 
the committee felt it appropriate to maximize the resources currently deployed and attempt to 
provide the most definitive evidence possible. Table 4 describes the revised power calculations 
for the trial. The hypothesized subdistribution hazard ratio of 1.40 used to estimate power 
(indicating a 40% improvement in the rate of lesion resolution, accounting for the competing risk 
of death) remains unchanged. The assumed split for stratification by days from symptom onset to 
randomization (75% ≤7 days; 25% >7 days) is based on current trial data as of 29 August 2023. 
 

Abbreviated Title: PALM 007 
Version: 4.0 
 
75 
Version Date: December 15, 2023 
 
Table 4. Revised Power Calculations 
Overall 
Days from symptom onset to 
randomization ≤7 days, 75% 
of overall 
Days from symptom onset to 
randomization >7 days, 25% of 
overall 
N 
N Events 
Power 
N 
N Events 
Power 
N 
N Events 
Power 
450 
440 
94.2% 
338 
331 
86.5% 
112 
109 
41.9% 
Calculations assume a 98% event rate and a true subdistribution hazard ratio of 1.40 overall and within 
each stratum. 
 
1.3. 
Updated Interim Monitoring Plan – Protocol Version 3.0 
This section describes the updated interim monitoring plan for protocol version 3.0, which 
targeted 440 total lesion resolution events. Protocol version 4.0 increases the target number of 
events to 550, which necessitates further updates to the interim monitoring plan. Refer to 
Appendix C section 1.4 for the current interim monitoring plan. 
 
Adjusting the target number of events midtrial requires an update to the interim monitoring plan. 
Interim analysis boundaries for statistical monitoring will still be based on the information time 
of the analysis (i.e., the proportion of events observed thus far), but the calculations will assume 
that 440 events will be represented in the final data rather than 318.  
 
The higher-than-anticipated overall event rate reviewed by the sample size re-estimation 
committee suggested that the first interim analysis (scheduled for 19 October 2023) would 
contain approximately 200-220 events, substantially more events than intended under the 
original design. To address this and due to the rapid enrollment that resulted in the first interim 
analysis occurring at 50% information,  the committee determined that the interim monitoring 
plan should reduce the number of planned interim analyses from 3 (at 1/3, 2/3, and full 
information) to 2 (at approximately 1/2 and full information). This was initially approved by the 
DSMB. However, later the DSMB requested updating the interim monitoring plan  to add an  
interim analysis  at approximately 75% information (330 events), midway between the first 
interim and the final analysis. Table 5 outlines the Z score boundaries and p-value thresholds for 
significance under the original and updated strategies for interim efficacy analyses using the 
Lan-DeMets spending function analog of the O’Brien-Fleming boundaries, as described in the 
original protocol and statistical analysis plan.  
 
Table 5. Interim Analysis Boundaries for the Original and Updated Designs 
Strategy 
Information Time 
Z Score Boundary 
Nominal Alpha  
(p-value threshold for 
significance) 
Original design 
Target 318 events 
Perform 3 analyses 
0.33 (106 events) 
±3.71 
0.0002 
0.67 (212 events) 
±2.51 
0.0120 
1 (318 events) 
±1.99 
0.0463 
Updated design 
Target 440 events 
Perform 3 analyses 
0.50 (220 events) 
±2.96 
0.0031 
0.75 (330 events) 
±2.36 
0.0183 
1 (440 events) 
±2.01 
0.0440 
 

Abbreviated Title: PALM 007 
Version: 4.0 
 
76 
Version Date: December 15, 2023 
 
1.4. 
Updated Interim Monitoring Plan – Protocol Version 4.0 
Protocol version 4.0 further increases the target number of lesion resolution events from 440 to 
550. This decision was made by the blinded study team based on multiple motivating factors. 
Given the logistical complexities of operating the trial and the unpredictable nature of outbreak 
settings, the study team anticipates limited opportunity for other randomized trials to enroll large 
numbers of cases of clade I monkeypoxvirus. Therefore, the study must aim to provide definitive 
evidence not only relating to the primary endpoint but extending to secondary and exploratory 
endpoints as well as subgroup analyses. Absent definitive evidence of efficacy or futility (which 
may trigger a DSMB recommendation to stop the trial early), there is a scientific benefit in 
continuing to enroll participants while the outbreak is ongoing and there remains enough study 
product to randomize and treat participants. An internal pharmacy inventory estimated that there 
is currently enough study product available in country to randomize and treat up to 600 total 
participants. We will therefore target enrolling up to 600 participants, with the expectation that 
this will provide data on approximately 550 lesion resolution events.   
Note – at the time protocol version 4.0 was drafted, talks had already begun for scheduling the 
second interim analysis review, expected to contain data on 330 lesion resolution events. This 
was initially expected to represent 75% information time. However, given the revised target of 
550 events, the analysis will take place at approximately 60% information time. This has a small 
impact on the thresholds for declaring statistical significance, described in Table 6. 
Table 6. Interim monitoring strategies for protocol versions 3 and 4 
 
Information Time 
Z Score 
Boundary 
Nominal Alpha 
(p-value threshold 
for significance) 
Version 3.0 (target 440 total 
events) 
0.50 (220 events) 
±2.96 
0.0031 
0.75 (330 events) 
±2.36 
0.0183 
1 (440 events) 
±2.01 
0.0440 
Version 4.0 (target 550 total 
events) 
0.40 (220 events)* 
±3.36 
0.0008 
0.60 (330 events) 
±2.68 
0.0074 
1 (550 events) 
±1.98 
0.0476 
*Because the first interim analysis has already occurred at the time of this update, the nominal 
alpha spent on the interim was approximately 0.0031 (the amount spent at that analysis 
according to the active protocol at that time, 3.0). The remaining alpha is distributed over the 
next two planned analyses as a function of the true information time and will be calculated by the 
unblinded statistics team when performing the analyses). 
 
 
 

Abbreviated Title: PALM 007 
Version: 4.0 
77 
Version Date: December 15, 2023 
APPENDIX D: Pharmacokinetics (PK) Sampling Specifications Plan 
Summary: An additional voluntary/optional blood sample will be obtained from all participants 
≥18 years of age at 4 hours after receiving their first dose of study drug on day 7 to be used for 
PK analysis. 
Purpose: There are no published data to establish therapeutic levels of tecovirimat in humans 
infected with monkeypox virus. Absorption of the drug may be affected by certain parameters 
like sex, age, metabolism, and the bioavailability the drug is optimal when the drug is 
administered in a fed state. Given the unknowns regarding tecovirimat concentrations in the 
setting of mpox, an exploratory objective was included in the PALM007 protocol to measure 
tecovirimat levels at day 7, when steady-state drug concentrations are expected to be achieved. 
The addition of the post-4-hour blood draw is necessary to calculate the Cmax or peak 
concentration of drug. This additional blood draw from participants receiving placebo will be 
stored for future research and may be used as quality controls in the PK analysis.  
Risk to participants: The risks of phlebotomy are like those with other blood draws in the 
study. There is a risk of anemia with the additional blood draw. The blood draw will be deferred 
if the participant has a hemoglobin level ≤ 7 g/dL or signs thought to be resulting from anemia at 
any hemoglobin level below the normal range.  
Procedure: Adult participants will be informed of the reason for the intended blood draw and 
will have the option to decline the draw via checkboxes to opt in or opt out in the informed 
consent document. For those who agree, up to 4 mL of additional blood for PK assessment will 
be drawn 4 hours after the first dose of tecovirimat is administered on day 7. 

Summary of protocol changes 
PALM007: A randomized, placebo-controlled, double-blind trial of the safety and efficacy 
of tecovirimat for the treatment of adult and pediatric patients with monkeypox virus 
disease 
Version 1.0, dated 19 August 2022, approved on 7 Sept 2022 
Version 2.0, dated 28 November 2022, approved on 9 December 2022 
1. Clinical labs and mpox PCR will be obtained every other day throughout the
hospitalization.
2. All PCR sample collections will be stopped after there are negative results x2 for each
individual sample.
3. The discharge criteria no longer include the 24-hour limit. We just
consider a negative result x 2 according to the laboratory schedule
which is every other day.
4.
The paragraph stating that all laboratory samples should be collected prior to randomization
has been removed (we agree as long as they were obtained on day 1)
5.
Paragraphs have been added to indicate that the baseline specimen will ideally be collected
within 24hours prior to randomization. If the specimen cannot be collected within 24 hours
and there is a specimen available that was collected within 48 hours prior to randomization,
the 48-hour specimen may be used as the baseline sample.
6.
The subscript "m" has been modified to add the bolded text: "Although strongly desirable,
research laboratory and clinical tests at all stages may be disregarded at the discretion of the
investigator if not feasible (e.g., due to problems with blood collection volume related to the
participant's weight or hemoglobin or due to site logistics)
7.
The following wording has been added to section 9.4 regarding hemoglobin. "A participant
with a hemoglobin level <7 g/dl. This would lead to the cessation of blood draws until the
hemoglobin level stabilizes and the bedside clinician judges it is safe to resume blood
draws.” “A participant with signs or symptoms thought to be the result of anemia at any
hemoglobin level. This would lead to the cessation of blood draws until the hemoglobin level
stabilizes and the bedside clinician feels it is safe to resume blood draws.”
8.
Section 5.9 (Costs) has been amended to read: "There will be no cost to participants to
participate in this study. Hospitalization and treatment will be free of charge. Meals will be
provided daily to the participant and to a maximum of two persons accompanying the
participant during the participant's hospitalization of an approximate value of $8, equivalent
in local currency to 16,000 Congolese francs, per person per day.
9.
Section 5.10 (Compensation): "Study participants and up to two accompanying persons will
receive US$15, equivalent to 30,000 Congolese francs in local currency, to compensate for
their time and inconvenience during the study. The participant will be required to pay a fee at
the time of registration for the study and at each subsequent study visit (days 29 and 59). If a
selected participant does not meet the study criteria, $15, equivalent to 30,000 Congolese
francs in local currency, will be provided to the participant and two accompanying persons to
compensate for their time and inconvenience. An additional allowance of $4, equivalent to
8,000 Congolese francs in local currency, will be paid daily to the participant and up to two
accompanying persons during the hospitalization. A round trip to the study site for
registration and for each study visit will be provided. A trip to the study site for registration
and each study visit (days 29 and 59) will be provided to the participant and up to two
accompanying persons. If a participant does not sign a screening consent but is eligible to
join the study and signs the consent for the main study, the participant and up to two other

accompanying persons will receive $15 American, equivalent in local currency to 30,000 
Congolese francs, for the first study visit. Travel will also be provided as indicated above. 
The screening form and informed consent form have been edited accordingly.” 
10. Section 9.3.3.1 NON EMERGENCY has been replaced with "NON URGENT"; it was a 
recommendation for change from the DSMB.  
11. The first secondary endpoint was changed to: Time to first negative blood PCR result until 28 
days after randomization. The STATS section has been modified to reflect this change.  
12. The third secondary evaluation criterion has been removed. The STATS section has been 
modified to reflect this change.  
 
Version 3.0, dated 1 September 2023, approved on 6 Oct 2023 
1. Monkeypox disease was changed to “mpox” throughout the protocol. When referring 
to viral 
infection or the virus itself, the term monkeypox virus is used. 
2. A row was added to the schedule of activities for “pregnancy outcome.” 
3. An additional visit was added to the Schedule of Activities for sick visits post 
discharge to be able to capture data from participants who may present with 
recrudescent mpox lesions after 
whole body lesion resolution (we have had two such participants). If this occurs, PCR of 
blood, OP and skin lesions will be obtained as well as clinical labs and total lesion count. 
An exploratory objective and endpoint were added to reflect this. 
4. The lab AE grading table adapted from the CTCAE v5.0 was added as an appendix. 
Another appendix was added for hemoglobin grading based off the DAIDS v2.1 grading 
document. 
5. Edits made to say that clinical labs or events that cannot be graded according to 
CTCAE will be evaluated by the clinician and if considered clinically significant (definition 
provided in protocol), the resulting clinical diagnosis will be considered an AE and 
reported. 
6. Several Stats edits from Tyler including: 1) Proportion PCR negative in each 
compartment at Day 15 added as secondary with no formal testing 2) Designation of key 
objectives removed. 
7. We have decided against collecting conjunctival swabs, csf and amniotic fluid as part 
of this study. These had been added to previous revisions but have since been removed. 
8. Due to testing/work load constraints, CRP and amylase will only be tested on days 1, 
7, 13, 29. CK will be done retrospectively. 
9. CD4 count was taken out of the protocol since these cannot be measured 
retrospectively. 
10. Edits to Exploratory objective #6: Viral persistence was changed to persistent PCR 
positivity. 
Version 4.0, dated 15 December 2023, approved on 24 Jan 2024 
1. Pharmacokinetic (PK) sampling specifications: Appendix D:  
a. Addition of Appendix D describing an additional voluntary/optional blood 
sample to be collected from all participants aged fi 18 years 4 hours after 
receiving their first dose of study drug on day 7 to be used to calculate Cmax or 
maximum drug concentration. 
b. Exploratory objective 10 was modified to add measurement of concentration 4 
hours after administration and this was also added to the schedule of activities. 

2. Increase sample size and update power and sample size calculations based on
sample size re-estimation plan. Appendix C: Sample Size Updates added.
3. Update of the provisional monitoring plan for the protocol: Appendix C
4. Added wording compensation to indicate that the trip will be covered for at least one
sickness visit for the participant and up to two accompanying.