A Randomized, Placebo-Controlled, Double-Blinded Trial of the Safety and Efficacy of Tecovirimat for the Treatment of Human Mpox Virus Disease
Phase: PHASE3
Conditions: MPOX
Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

A5418 
 
 
A Randomized, Placebo-Controlled, Double-Blinded Trial of the Safety and Efficacy of 
Tecovirimat for the Treatment of Human Monkeypox Virus Disease 
 
Study of Tecovirimat for Human Monkeypox Virus (STOMP) 
 
A Multicenter Trial of the AIDS Clinical Trials Group (ACTG) 
 
 
Sponsored by:  
National Institute of Allergy 
and Infectious Diseases 
 
 
 
Industry Support Provided by: 
SIGA Pharmaceutical 
 
 
IND # 163182 
 
 
 
Protocol Chair:  
 
 
 
 
 
 
Timothy Wilkin, MD, MPH 
 
 
Protocol Vice Chairs:  
 
 
 
 
 
William A. Fischer II, MD 
Jason Zucker, MD 
 
DAIDS Clinical Representative: 
Arzhang Cyrus Javan, MD, 
MPH, DTM&H 
 
Clinical Trials Specialists:   
 
 
 
 
Lara A. Hosey, MA, CCRP 
Jhoanna C. Roa, MD 
 
 
 
FINAL Version 3.0 
November 8, 2022 
 
 
 
 
 

 
 
A5418 
FINAL Version 3.0 
08Nov2022 
 
 
 
A Randomized, Placebo-Controlled, Double-Blinded Trial of the Safety and Efficacy of 
Tecovirimat for the Treatment of Human Monkeypox Virus Disease 
 
SIGNATURE PAGE 
 
 
I will conduct the study in accordance with the provisions of this protocol and all applicable 
protocol-related documents. I agree to conduct this study in compliance with United States 
(U.S.) Health and Human Service regulations (45 CFR 46); applicable U.S. Food and Drug 
Administration regulations; standards of the International Conference on Harmonization 
Guideline for Good Clinical Practice (E6); Institutional Review Board/Ethics Committee 
determinations; all applicable in-country, state, and local laws and regulations; and other 
applicable requirements (e.g., U.S. National Institutes of Health, Division of AIDS) and 
institutional policies. 
 
 
 
Principal Investigator: _______________________________________________ 
Print/Type 
 
 
 
Signed: ___________________________________ Date: _____________ 
 Name/Title 
 
 

 
 
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Page 
 
TABLE OF CONTENTS 
SIGNATURE PAGE .................................................................................................................... 2 
SITES PARTICIPATING IN THE STUDY .................................................................................... 6 
PROTOCOL TEAM ROSTER ..................................................................................................... 7 
STUDY MANAGEMENT ........................................................................................................... 11 
GLOSSARY OF PROTOCOL-SPECIFIC TERMS ..................................................................... 14 
SCHEMA .................................................................................................................................. 15 
1.0 
HYPOTHESIS AND STUDY OBJECTIVES ................................................................... 17 
1.1 
Hypothesis ......................................................................................................... 17 
1.2 
Primary Objective ............................................................................................... 17 
1.3 
Secondary Objectives ........................................................................................ 17 
1.4 
Exploratory Objectives ....................................................................................... 17 
2.0 
INTRODUCTION ........................................................................................................... 18 
2.1 
Background ........................................................................................................ 18 
2.2 
Rationale ........................................................................................................... 24 
3.0 
STUDY DESIGN ........................................................................................................... 28 
4.0 
SELECTION AND ENROLLMENT OF PARTICIPANTS ................................................ 31 
4.1 
Inclusion Criteria (All participants; Arms A, B, and C) ......................................... 31 
4.2 
Additional Inclusion Criteria for Arms A and B .................................................... 32 
4.3 
Additional Inclusion Criteria for Arm C ................................................................ 32 
4.4 
Exclusion Criteria (All participants; Arms A, B, and C) ....................................... 33 
4.5 
Study Enrollment Procedures............................................................................. 34 
4.6 
Co-enrollment Guidelines ................................................................................... 35 
5.0 
STUDY TREATMENT ................................................................................................... 35 
5.1 
Regimens and Duration ..................................................................................... 36 
5.2 
Study Product Formulation and Storage ............................................................ 38 
5.3 
Study Product Supply, Distribution, and Accountability ...................................... 39 
5.4 
Concomitant Medications ................................................................................... 39 
6.0 
CLINICAL AND LABORATORY EVALUATIONS ........................................................... 41 
6.1 
Schedule of Evaluations..................................................................................... 41 
6.2 
Timing of Evaluations ......................................................................................... 56 
6.3 
Instructions for Evaluations (Arms A, B, and C) ................................................. 57 
6.4 
Instructions for Evaluations (Additional Sampling Cohort) .................................. 70 
6.5 
Modifications for Participants under 18 Years of Age ....................................... 71 
6.6  
Virologic Assessments for Participants Enrolled/Followed Remotely......... 71 
7.0 
ADVERSE EVENTS AND STUDY MONITORING ......................................................... 71 
7.1 
Definition of Adverse Events .............................................................................. 71 
7.2 
Adverse Event Collection Requirements for This Protocol ................................. 72 
7.3 
Expedited Adverse Event (EAE) Reporting to DAIDS ........................................ 72 
7.4 
Follow-up of Participants Reporting Adverse Events .......................................... 73 
7.5 
Study Monitoring ................................................................................................ 73 

 
 
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CONTENTS (Cont'd) 
Page 
 
8.0 
CLINICAL MANAGEMENT ISSUES .............................................................................. 74 
8.1 
Toxicity .............................................................................................................. 74 
8.2 
Pregnancy.......................................................................................................... 75 
8.3 
Breastfeeding ..................................................................................................... 75 
9.0 
CRITERIA FOR DISCONTINUATION ........................................................................... 75 
9.1 
Permanent and Premature Treatment Discontinuation ....................................... 75 
9.2 
Premature Study Discontinuation ....................................................................... 76 
10.0 
STATISTICAL CONSIDERATIONS ............................................................................... 76 
10.1 
General Design Issues ....................................................................................... 76 
10.2 
Outcome Measures ............................................................................................ 78 
10.3 
Randomization and Stratification ........................................................................ 79 
10.4 
Sample Size and Accrual ................................................................................... 80 
10.5 
Data and Safety Monitoring ................................................................................ 82 
10.6 
Analyses ............................................................................................................ 84 
10.7 
Unblinding .......................................................................................................... 87 
11.0 
PHARMACOLOGY PLAN .............................................................................................. 87 
11.1 
Pharmacology Objectives .................................................................................. 90 
11.2 
Pharmacology Study Design .............................................................................. 90 
12.0 
DATA COLLECTION AND MONITORING ..................................................................... 91 
12.1 
Records to Be Kept ............................................................................................ 91 
12.2 
Role of Data Management ................................................................................. 92 
12.3 
Clinical Site Monitoring and Record Availability .................................................. 92 
13.0 
PARTICIPANTS ............................................................................................................ 92 
13.1 
Institutional Review Board (IRB) Review and Informed Consent ........................ 92 
13.2 
Participant Confidentiality ................................................................................... 92 
13.3 
Study Discontinuation ........................................................................................ 93 
14.0 
PUBLICATION OF RESEARCH FINDINGS .................................................................. 93 
15.0 
BIOHAZARD CONTAINMENT ...................................................................................... 93 
16.0 
REFERENCES .............................................................................................................. 94 
APPENDIX I: INFORMED CONSENT AND AUTHORIZATION TO USE AND DISCLOSE 
PROTECTED HEALTH INFORMATION FOR ADULTS AND PARTICIPANTS 
REACHING AGE OF MAJORITY (AOM) WHO ARE ENROLLED/FOLLOWED IN 
PERSON ....................................................................................................................... 99 
APPENDIX II: INFORMED CONSENT AND AUTHORIZATION TO USE AND DISCLOSE 
PROTECTED HEALTH INFORMATION FOR ADULTS AND PARTICIPANTS 
REACHING AGE OF MAJORITY (AOM) WHO ARE ENROLLED/FOLLOWED 
REMOTELY ................................................................................................................ 118 
ATTACHMENT A: CONSENT FOR USE OF SAMPLES IN OTHER STUDIES FOR ADULTS 
AND PARTICIPANTS REACHING AGE OF MAJORITY (AOM) ................................ 136 
APPENDIX III: INFORMED CONSENT TO PARTICIPATE IN ADDITIONAL SAMPLING FOR 
ADULT PARTICIPANTS WHO ARE ENROLLED/FOLLOWED IN PERSON ............. 139 

 
 
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CONTENTS (Cont'd) 
Page 
 
APPENDIX IV: INFORMED CONSENT AND AUTHORIZATION TO USE AND DISCLOSE 
PROTECTED HEALTH INFORMATION FOR PARENTS/LEGAL GUARDIANS OF 
CHILDREN WHO ARE ENROLLED/FOLLOWED IN PERSON .................................. 143 
APPENDIX V INFORMED CONSENT AND AUTHORIZATION TO USE AND DISCLOSE 
PROTECTED HEALTH INFORMATION FOR PARENTS/LEGAL GUARDIANS OF 
CHILDREN WHO ARE ENROLLED/FOLLOWED REMOTELY .................................. 161 
ATTACHMENT B: CONSENT FOR USE OF SAMPLES IN OTHER STUDIES FOR 
PARENTS/LEGAL GUARDIANS OF CHILDREN ........................................................ 179 
APPENDIX VI: PARTICIPANT ASSENT FORM FOR STUDY PARTICIPATION FOR 
PARTICIPANTS AGED 7 TO AGE OF MAJORITY (AOM) WHO ARE 
ENROLLED/FOLLOWED IN PERSON ....................................................................... 182 
APPENDIX VII: PARTICIPANT ASSENT FORM FOR STUDY PARTICIPATION FOR 
PARTICIPANTS AGED 7 TO AGE OF MAJORITY (AOM) WHO ARE 
ENROLLED/FOLLOWED REMOTELY ....................................................................... 188 
 

 
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SITES PARTICIPATING IN THE STUDY 
 
 
A5418 is a multicenter study open to select U.S.- and non-U.S.-based clinical research sites. 
 
 
 
 
 

 
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PROTOCOL TEAM ROSTER 
 
Chair 
Timothy Wilkin, MD, MPH 
Weill Cornell Chelsea CRS 
53 West 23rd Street, 6th Floor 
New York, NY 10010 
Phone: 212-746-7202 
E-mail: tiw2001@med.cornell.edu 
 
Vice Chairs 
William Fischer, MD 
The University of North Carolina School of 
Medicine 
Division of Pulmonary and Critical Care 
Medicine 
Institute for Global Health and Infectious 
Diseases 
Chapel Hill, NC 27599-7215 
E-mail: WFischer@med.unc.edu 
 
Jason Zucker, MD 
Columbia Physicians & Surgeons (P&S) CRS 
Columbia University Irving Medical Center 
Department of Medicine 
Division of Infectious Diseases 
622 West 168th Street 
PH 8th Floor, Room 876 
New York, NY 10032 
Phone: 212-305-5265 
E-mail: jz2700@cumc.columbia.edu 
 
DAIDS Clinical Representative  
Arzhang Cyrus Javan, MD, MPH, DTM&H 
Translational Research Program 
5601 Fishers Lane 
Room 9E41, MSC 98303 
Rockville, MD 20892-9830 
Phone: 240-475-6683 
E-mail: arzhang.javan@nih.gov
Clinical Trials Specialists 
Lara Hosey, MA, CCRP 
ACTG Network Coordinating Center 
Social & Scientific Systems, Inc., 
A DLH Holdings Company 
8757 Georgia Avenue, 12th Floor 
Silver Spring, MD 20910 
Phone: 301-628-3395 
E-mail: Lara.Hosey@dlhcorp.com 
 
Jhoanna Roa, MD 
ACTG Network Coordinating Center 
Social & Scientific Systems, Inc., 
A DLH Holdings Company 
8757 Georgia Avenue, 12th Floor 
Silver Spring, MD 20910 
Phone: 301-628-3196 
E-mail: Jhoanna.Roa@dlhcorp.com 
 
Statisticians (Blinded) 
Caitlyn McCarthy, MA 
Statistical and Data Analysis Center 
Harvard School of Public Health, FXB 535 
Boston, MA 02115 
Phone: 617-432-7524 
E-mail: cmccarth@sdac.harvard.edu 
 
Pooja Saha, PhD 
Statistical and Data Analysis Center 
Harvard School of Public Health 
FXB Building, Room 547A 
651 Huntington Avenue 
Boston, MA 02115-6017 
Phone: 617-432-2814 
E-mail: psaha@sdac.harvard.edu 
 
Lu (Summer) Zheng, PhD 
Statistical and Data Analysis Center 
Harvard School of Public Health 
FXB Building, Room 613 
651 Huntington Avenue 
Boston, MA 02115-6017 
Phone: 617-432-3021 
E-mail: szheng@sdac.harvard.edu

 
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Statisticians (Unblinded) 
Carlee Moser, PhD 
Center for Biostatistics in AIDS Research 
Harvard T.H. Chan School of Public Health 
FXB Building, Room 513 
Boston, MA 02115 
Phone: 617-432-2526 
E-mail: cmoser@sdac.harvard.edu 
 
Justin Ritz, MS 
Statistical and Data Analysis Center 
Harvard School of Public Health 
FXB Building, Room 510 
Boston, MA 02115 
Phone: 617-432-3034 
E-mail: jritz@sdac.harvard.edu 
 
Data Managers 
Stephanie Caruso, MBA 
Frontier Science & Technology Research 
Foundation, Inc. 
4033 Maple Road 
Amherst, NY 14226 
Phone: 716-834-0900 Ext. 7322 
E-mail: scaruso@frontierscience.org 
 
Elizabeth Siciliano, MPH 
Frontier Science & Technology Research 
Foundation, Inc. 
4033 Maple Road 
Amherst, NY  14226-1056 
Phone: 716-824-0900 Ext 7276 
Fax: 716-834-8432 
E-mail: siciliano@frontierscience.org  
 
Alexander Watson, MPH 
Frontier Science & Technology Research 
Foundation, Inc. 
4033 Maple Road 
Amherst, NY 14226-1056 
Phone: 716-834-0900 
E-mail: watson@frontierscience.org
DAIDS Pharmacists 
Shawn Chiambah, PhD 
Division of AIDS 
5601 Fishers Lane, Room 9A26 
Rockville, MD 20892 
Phone: 301-761-7336 
E-mail: shawn.chiambah@nih.gov 
 
Azizza Davis, PharmD 
National Institutes of Health (NIH)  
5601 Fishers Lane, Room 9E14 
Room 9A21 
Bethesda, MD 20892 
Phone: 240-669-5248 
E-mail: azizza.davis@nih.gov 
 
Immunologist  
Cheryl Day, PhD 
Emory Vaccine Center 
954 Gatewood Road NE, Room 1024 
Atlanta, GA 30329 
Phone: 404-727-4374 
E-mail: cheryl.day@emory.edu 
 
Virologists 
Alex Greninger, MD, PhD, MPhil, MS 
University of Washington 
Retrovirus Laboratory 
300 9th Avenue, RM725 
Seattle, WA 98104 
Phone: 415-439-3448 
E-mail: agrening@uw.edu 
 
Christine Johnston, MD, MPH 
University of Washington Positive Research 
CRS 
Harborview Medical Center ACTU 
Box 359928, 325 Ninth Avenue 
Seattle, WA 98104 
Phone: 206-520-4340 
E-mail: cjohnsto@uw.edu

 
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Virologists (Cont’d) 
Davey Smith, MD, MAS 
Antiviral Research Center 
University of California, San Diego 
220 Dickinson Street 
San Diego, CA 92103 
Phone: 619-543-7449 
Fax: 619-298-0177 
E-mail: d13smith@health.ucsd.edu 
 
Pharmacologists 
Jennifer Kiser, PharmD, PhD 
University of Colorado  
Skaggs School of Pharmacy and 
Pharmaceutical Sciences 
12850 E Montview Boulevard, C238 
Aurora, CO 80045 
Phone: 303-724-6131 
E-mail: jennifer.kiser@cuanschutz.edu 
 
Edmund Capparelli, PharmD, PhD 
University of California San Diego 
9500 Gilman Drive, MC 0760 
La Jolla, CA 92093-0760 
Phone: 858-246-0009 
E-mail: ecapparelli@ucsd.edu 
 
Investigators 
Judith Currier, MD, MSc 
Clinical AIDS Research and Education 
(CARE) Center CRS 
911 Broxton Ave, Suite 200 
Los Angeles, CA 90024 
Phone: 310-825-6689 
E-mail: jscurrier@mednet.ucla.edu 
 
Joseph Eron, MD 
University of North Carolina  
Global HIV Prevention and Treatment CTU 
Bioinformatics Building 
130 Mason Farm Road, Suite 210  
Chapel Hill, NC 27599-7215 
Phone: 919-843-2722 
E-mail: jeron@med.unc.edu
Investigators (Cont’d) 
Rajesh Gandhi, MD 
Harvard Medical School 
GRB 504, Infectious Disease 
55 Fruit Street 
Boston, MA 02114 
Phone: 617-726-3811 
E-mail: rgandhi@mgh.harvard.edu 
 
Matthew Hamill, MBChB, PhD 
Johns Hopkins University CRS 
AIDS Clinical Trials Unit 
1830 E. Monument Street, Suite 8074 
Baltimore, MD 21205 
Phone: 410-550-9080 
Email: mhamill6@jhu.edu 
 
Kieron Leslie, MBBS, DTMH 
University of California, San Francisco 
HIV/AIDS CRS 
Dermatology Department 
UCSF 1701 Divisadero St 
San Francisco, CA 94115 
Phone: 415-710-4181 
E-mail: Kieron.Leslie@ucsf.edu 
 
Sharon Nachman, MD 
SUNY Health Science Center at Stony 
Brook  
Division of Pediatric Infectious Diseases 
Health Sciences Center, Suite T11-060 
Stony Brook, NY 11794-8111 
Phone: 631-444-7692 
E-mail: 
sharon.nachman@stonybrookmedicine.edu 
 
Field Representative  
Jonathan Berardi, MS, APRN, FNP-C 
Weill Cornell Uptown CRS (7803) 
525 East 68th Street 
Baker 24 
New York, NY 10065 
Phone: 212-746-7864 
E-mail: jlb4002@med.cornell.edu

 
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08Nov2022 
 
Community Scientific Subcommittee (CSS) 
Representatives 
Danielle Campbell, MPH 
University of California, Los Angeles 
CARE Center CRS (601) 
1399 S. Roxbury Drive 
Los Angeles, CA 90035 
Phone: 310-910-8341 
E-mail: dacampbe@health.ucsd.edu 
 
Stanford Chimutimunzeve 
Milton Park CRS (30313) 
76 Mvumba Street 
Mufakose 
Harare 
ZIMBABWE 
Phone: +263 774-767395 
E-mail: stanchimutimunzeve@gmail.com 
 
Industry Representative 
Emily Blum, BS 
SIGA Technologies, Inc. 
4575 SW Research Way, Suite 110 
Corvallis, OR 97333 
Phone: 541-224-1305 
E-mail: eblum@siga.com  
 
Laboratory Data Managers 
Philip Marzinek, BS 
Frontier Science & Technology Research 
Foundation, Inc. 
4033 Maple Road 
Amherst, NY 14226 
Phone: 716-834-0900, ext. 7399 
E-mail: marzinek@frontierscience.org 
 
Kathleen Shepherd, MPH 
Frontier Science & Technology Research 
Foundation, Inc. 
4033 Maple Road 
Amherst, NY 14226 
Phone: 716-834-0900, ext. 7370 
E-mail: Kshepherd@frontierscience.org
Laboratory Specialists 
Grace Aldrovandi, MD 
ACTG Laboratory Center at UCLA  
University of California, Los Angeles 
675 Charles E. Young Drive South 
MacDonald Research Laboratory  
(MRL), 4-629 
Los Angeles, CA 90095 
Phone: 818-577-7034 
E-mail: gracea@mac.com 
 
Kathie Ferbas, PhD 
ACTG Laboratory Center at UCLA  
University of California, Los Angeles 
675 Charles E. Young Drive South 
MacDonald Research Laboratory  
(MRL), 4-629 
Los Angeles, CA 90095 
Phone: 310 825 7708 
Phone: 310-780-3639 (mobile) 
E-mail: kferbas@milabcentral.org 
 
Faith Landsman, BA 
ACTG Laboratory Center at UCLA 
University of California, Los Angeles  
10990 Wilshire Boulevard, Suite 260 
Los Angeles, CA 90024 
Phone: 323-806-8836 
E-mail: flandsman@milabcentral.org 
 
 

 
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STUDY MANAGEMENT 
 
All general questions concerning this protocol should be sent to actg.teamA5418@fstrf.org via 
e-mail. The appropriate team member will respond with a "cc" to actg.teamA5418@fstrf.org. A 
response should generally be received within 24 hours (Monday through Friday). 
 
Protocol E-mail Group 
Sites should contact the User Support Group at the Data Management Center (DMC) as soon 
as possible to have the relevant personnel at the site added to the actg.protA5418 e-mail group. 
Include the protocol number in the e-mail subject line.  
• 
Send an e-mail message to actg.user.support@fstrf.org.  
 
Clinical Management:  
For questions concerning entry criteria, toxicity management, concomitant medications, and co-
enrollment, contact the Clinical Management committee (CMC).  
• 
Send an e-mail message to actg.cmcA5418@fstrf.org. Include the protocol number, patient 
identification number (PID), and a brief relevant history. 
 
Laboratory 
For questions specifically related to immunologic, virologic, or pharmacologic laboratory tests, 
contact the Protocol Immunologist, Virologist, or Pharmacologist.  
• 
Send an e-mail message to actg.teamA5418@fstrf.org (ATTENTION: Cheryl Day/Alex 
Greninger, Christine Johnston/Davey Smith, and Jennifer Kiser/Edmund Capparelli, 
respectively). 
 
Data Management 
• 
For nonclinical questions about transfers, inclusion/exclusion criteria, electronic case report 
forms (eCRFs), randomization/registration, and other data management issues, contact the 
data manager. Completion guidelines for eCRFs and participant-completed CRFs can be 
downloaded from the FSTRF website at www.frontierscience.org. 
• 
For transfers, reference the Study Participant Transfer SOP 119, and contact Stephanie 
Caruso, Elizabeth Siciliano, and Alexander Watson directly.  
• 
For other questions, send an e-mail message to actg.teamA5418@fstrf.org (ATTENTION: 
Stephanie Caruso, Elizabeth Siciliano, and Alexander Watson).  
• 
Include the protocol number, PID, and a detailed question. 
 
Randomization/Participant Registration  
For randomization questions or problems and study identification number SID lists:  
• 
Send an e-mail message to rando.support@fstrf.org or call the DMC Randomization Desk at 
716-834-0900, extension 7301.  
 
DMC Portal and Medidata Rave Problems  
Contact DMC User Support. 
• 
Send an e-mail message to actg.user.support@fstrf.org or call 716-834-0900 x7302. 
 

 
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Protocol Document Questions 
For questions concerning the protocol document, contact the Clinical Trials Specialists.  
• 
Send an e-mail message to actg.teamA5418@fstrf.org (ATTENTION: Lara Hosey and 
Jhoanna Roa). 
 
Copies of the Protocol 
To request a hard copy of the protocol, send an e-mail message to ACTGNCC@dlhcorp.com. 
Electronic copies can be downloaded from the ACTG website at https://www.actgnetwork.org. 
 
Product Package Inserts and/or Investigator Brochures 
To request copies of product package inserts or investigator brochures, contact the DAIDS 
Regulatory Support Center (RSC) at RIC@tech-res.com or call 301-897-1708. 
 
Protocol Registration 
For protocol registration questions, send an e-mail message to Protocol@tech-res.com or call 
301-897-1707.  
 
Protocol Activation 
For questions related to protocol activation at U.S. sites contact the Clinical Trials Specialists.  
• 
Send an e-mail message to actg.teamA5418@fstrf.org (ATTENTION: Lara Hosey and 
Jhoanna Roa). 
 
For questions related to protocol activation at non-U.S. sites contact the ACTG Site 
Coordination Group.  
• 
Send an email message to actgsitecoordination@dlhcorp.com.  
 
Study Product 
For questions or problems regarding study product, dose, supplies, records, and returns contact 
the Protocol Pharmacists. 
• 
Send an e-mail message to Shawn Chiambah (shawn.chiambah@nih.gov) and Azizza 
Davis (azizza.davis@nih.gov) 
 
Study Drug Orders 
Call the Clinical Research Products Management Center (CRPMC) at 301-294-0741. 
 
IND (Investigational New Drug) Number or Questions  
For any questions related to the IND submission, contact the DAIDS RSC at Regulatory@tech-
res.com or call 301-897-1706. 
 
Expedited Adverse Event (EAE) Reporting/Questions  
Contact DAIDS through the RSC Safety Office at DAIDSRSCSafetyOffice@tech-res.com or call 
1-800-537-9979 or 301-897-1709; or fax 1-800-275-7619 or 301-897-1710.  
 

 
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Telephone Calls 
Sites are responsible for documenting telephone calls made to A5418 team members.  
• 
Send an e-mail message to actg.teamA5418@fstrf.org. 
 
Protocol-Specific Web Page 
Additional information about management of the protocol can be found on the protocol-specific 
web page (PSWP). 

 
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GLOSSARY OF PROTOCOL-SPECIFIC TERMS 
 
A-HRSI 
Anal Health-Related Symptom Index 
AUC 
area under the curve 
CD4  
cluster of differentiation 4  
CYP  
cytochrome P450  
DNA  
deoxyribonucleic acid  
DSMB  
Data and Safety Monitoring Board  
EA-IND 
expanded-access investigational new drug 
EC  
ethics committee  
FDA  
Food and Drug Administration  
GCP  
Good Clinical Practice  
HCV 
hepatitis C virus 
HIV  
human immunodeficiency virus  
HMPXV 
Human monkeypox virus 
IND  
investigational new drug (application)  
IRB  
institutional review board  
LPV 
lab processing chart 
MOP  
manual of procedures  
MVA  
modified vaccinia virus Ankara  
NIAID  
National Institute of Allergy and Infectious Diseases  
NIH 
National Institutes of Health  
OHRP  
Office for Human Research Protections  
OPXV  
orthopoxvirus  
PCR  
polymerase chain reaction  
PK  
pharmacokinetic  
PSWP 
protocol-specific web page 
PLWH 
persons living with HIV 
SAE  
serious adverse event  
SOE 
schedule of evaluations 
SUSAR  
serious and unexpected suspected adverse reaction  
WHO  
World Health Organization  
 
 

 
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SCHEMA 
 
A5418 
 
A Randomized, Placebo-Controlled, Double-Blinded Trial of the Safety and Efficacy of 
Tecovirimat for the Treatment of Human Monkeypox Virus Disease 
 
DESIGN 
Phase 3, randomized, placebo-controlled, double-blind trial of tecovirimat for the treatment of 
human monkeypox virus (HMPXV) disease. The study will also include a cohort of people who 
will receive open-label tecovirimat including people with protocol-defined severe HMPXV, 
pregnant and breastfeeding individuals, individuals less than 18 years of age, individuals on 
potent inducing concomitant medications, people with severe immune suppression or skin 
conditions placing them at higher risk for severe disease (see section 4.3).  
 
Participants with symptomatic HMPXV who do not meet criteria for the open-label cohort will be 
randomized in a 2:1 ratio to tecovirimat or matching placebo for 14 days. All participants will be 
followed through a combination of virtual assessments, in-person visits, and daily self-reports for 
resolution of clinical disease, specimen collection to assess viral clearance, and participant 
reported outcomes through day 57. Participants will have the option of completely remote 
participation. 
 
Participants who progress to severe disease post-randomization will be offered open-label 
tecovirimat. Participants who report severe pain from HMPXV will be offered open-label 
tecovirimat as early as 5 days post-randomization. 
 
The primary outcome measure is the time to clinical resolution defined as all skin lesions being 
scabbed, desquamated, or healed, and all visible mucosal lesions being healed. 
 
DURATION 
57 days  
 
SAMPLE SIZE 
530 Arms A+B (subject to re-estimation); Arm C sample size not specified 
 
POPULATION 
People with laboratory-confirmed or presumptive HMPXV disease with 1 or more skin or 
mucosal lesions or symptoms of mucosal lesions that are able to be followed for resolution and 
those with proctitis with or without mucosal lesions.  
 
STRATIFICATION  
Randomization (Arms A and B) will be stratified by duration of symptoms (≤5 or >5 days) and 
remote enrollment. Arm C will be non-randomized. 
 

 
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SCHEMA (Cont'd) 
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REGIMEN 
Arm A:  
• 
25 kg to <40 kg: Tecovirimat 400 mg by mouth within 30 minutes after food every 12 hours 
for 14 days 
• 
40 kg to <120 kg: Tecovirimat 600 mg by mouth within 30 minutes after food every 12 hours 
for 14 days 
• 
≥120 kg: Tecovirimat 600 mg by mouth within 30 minutes after food every 8 hours for 14 
days  
 
Arm B: Matching placebos for the doses described for Arm A 
 
Arm C: Open label tecovirimat at the doses described for Arm A plus the following for 
participants <25 kg: 
• 
<6 kg: Dosing based on weight (see Table 5.1-2)  
• 
6 kg to <13 kg: Tecovirimat 100 mg by mouth within 30 minutes after food every 12 hours for 
14 days 
• 
13 kg to <25 kg: Tecovirimat 200 mg by mouth within 30 minutes after food every 12 hours 
for 14 days  
  
 
 

 
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1.0 
HYPOTHESIS AND STUDY OBJECTIVES 
 
1.1 
Hypothesis 
 
Tecovirimat will lead to faster clinical resolution of HMPXV disease (all skin lesions 
scabbed, desquamated or healed and all visible mucosal lesions healed) compared to 
placebo. 
 
1.2 
Primary Objective 
 
To compare the clinical efficacy, as assessed by time to clinical resolution of skin and 
visible mucosal lesions, between participants with HMPXV randomized to tecovirimat 
versus placebo.  
 
1.3 
Secondary Objectives 
 
1.3.1 To compare pain scores between randomized arms.  
 
1.3.2 To compare rates of progression to severe HMPXV disease between randomized 
arms. 
 
1.3.3 To compare clearance of HMPXV between randomized arms in various 
compartments including blood, skin lesions, oropharynx, rectum, and genital 
secretions. 
 
1.3.4 To compare time to complete lesion healing between randomized arms. 
 
1.3.5 To compare participant-reported outcomes including adherence and EQ-5D-5L 
between randomized arms. 
 
1.3.6 To evaluate the safety of tecovirimat as compared to placebo. 
 
1.3.7 To describe time to lesion resolution, pain, clearance of HMPXV, time to 
complete lesion healing, participant-reported outcomes, and safety of tecovirimat 
in participants who receive open-label tecovirimat 
 
1.3.8 To determine the steady-state tecovirimat AUCtau and Ctau in children less than 
18 years of age. 
 
1.3.9 To evaluate the safety profile of 14 days of tecovirimat in children less than 18 
years of age. 
 
1.4 
Exploratory Objectives 
 
1.4.1 In a subset of participants, to define the natural history of HMPXV oral, rectal, vaginal, 
urine, and lesion shedding in the presence and absence of tecovirimat. 

 
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1.4.2 In a subset of participants, to determine virologic and immune correlates of 
disease severity. 
 
1.4.3 To describe lesion progression longitudinally over the study period. 
 
1.4.4 To investigate orthopoxvirus (OPXV) immunity and its impact on the course of 
HMPXV disease between tecovirimat and placebo groups. 
 
1.4.5 To assess genomic variability in MPXV isolated from participants based on 
geographic and clinical differences.  
 
1.4.6 To describe the presence of resistance at baseline and emergence of viral 
resistance during tecovirimat treatment.  
 
1.4.7 To describe the clinical efficacy of tecovirimat in various subgroups including 
those with shorter or longer duration of symptoms at baseline, people presenting 
with proctitis, and persons living with HIV. 
 
1.4.8 To explore the relationship between bacterial sexually transmitted infections 
(gonorrhea, chlamydia and syphilis), HSV, and HMPXV. 
 
1.4.9 To define the pharmacokinetic (PK) profile and PK-pharmacodynamic (PD) 
associations for tecovirimat in HMPXV. 
 
1.4.10 To assess the potential for drug interactions between tecovirimat and 
antiretrovirals among persons living with HIV (PLWH). 
 
1.4.11 To explore new HMPXV positivity among household contacts through to 28 days 
from start of investigational agent or placebo. 
 
1.4.12 To describe rates and patterns of recrudescent infection and disease. 
 
1.4.13  To describe the steady-state tecovirimat AUCtau and Ctau in pregnant participants. 
 
2.0 
INTRODUCTION 
 
2.1 
Background 
 
Human Monkeypox Virus (HMPXV) 
HMPXV is an enveloped double-stranded DNA virus that belongs to the Orthopoxvirus 
genus of the Poxviridae family, which also includes Variola and Vaccinia [Parker 2007]. 
The viral genome is composed of core, lateral bodies, outer membrane, and the outer 
lipoprotein envelope elements [Laliberte 2010]. There are two distinct genetic clades: the 
central African (Congo Basin) clade 1 and the West African clade 3. In general, clade 3 
infections cause a less severe disease than clade 1 [Bunge 2022]. Interestingly, isolates 
from the 2022 outbreak shared 40 mutations that distinguish it from its closest variant 

 
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[Isidro 2022; Figure 1]. Such variation may impact infectiousness, immune evasion, 
pathogenesis, and treatment susceptibility. 
 
Epidemiology and Recent Outbreak 
First discovered in laboratory monkeys in 1958, the primary carriers of monkeypox today 
are rodents. Zoonotic transmissions from infected animals are possible through animal 
bites, feces, or uncooked meat. Human to human transmission occurs from close 
physical contact with the virus entering through the oropharynx, nasopharynx, anorectal, 
or intradermal routes.  
 
Since Spring 2022, monkeypox has rapidly spread throughout the world, with 
more than 70,000 cases in 107 countries and more than 26,000 cases in the 
United States reported as of September 2022 [CDC 2022c]. This new outbreak 
has been concentrated among men who have sex with men (MSM) [Thornhill 
2022].  
 
HMPXV Infection and Disease 
In the HMPXV Clade 1 disease, the time from exposure to onset of symptoms ranges 
from 5 to 21 days, with a median time of onset of 7 days [Thornhill 2022]. The virus 
replicates at the inoculation site then spreads to regional lymph nodes. Following a 
period of initial viremia, the virus spreads to other body organs. HMPXV can be found in 
blood, semen, throat, rectum, and skin lesions (Figure 2.1-1) [Noe 2022]. Common 
symptoms include fever, headache, muscle aches, backache, swollen lymph nodes, 
malaise, fatigue, and pustular rash. Duration of symptoms is typically 2 to 4 weeks 
[Kumar 2022]. Symptoms usually include fevers, myalgias, and lymphadenopathy 
followed by a centrifugally appearing “pox” rash, often with numerous lesions. These 
lesions progress through the vesiculopustular to ulcerative stage and then 
spontaneously resolve. The disease caused by HMPXV can be rarely serious and life-
threatening, and most infections are self-limited. Previous studies of HMPXV in Central 
Africa, where people are often medically underserved, found a mortality up to 10% 
among people infected [Adler 2022]. 
 

 
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Figure 2.1-1: HMPXV genome copies per mL found in samples from two persons with 
active and symptomatic HMPXV infection (viral genome copies/mL of two participants 
averaged per sample type) [Noe 2022; Figure 2]. 
 
A recent report of 528 cases of HMPXV infection (Clade 3) from five continents, 16 
countries, and 43 clinical sites provides the most robust assessment of the current outbreak 
of HMPXV in MSM. Systemic features during the infection included fever (62%), lethargy 
(41%), myalgia (31%), headache (27%), and lymphadenopathy (56%). These systemic 
symptoms frequently preceded a generalized rash. In this case series, skin lesions were 
noted in 95%, and the most common sites were: anogenital area (73%); the trunk, arms, or 
legs (55%); the face (25%); and the palms and soles (10%). Among persons with skin 
lesions, 58% had lesions that were described as “vesiculopustular.” The number of lesions 
varied, and most persons had fewer than 10 lesions, and 54 presented with only a single 
genital ulcer. Mucosal lesions were reported in 41% of the persons. The anorectal mucosa 
involvement was the presenting symptom in 61 persons, which was associated with a 
combination of anorectal pain, proctitis, tenesmus, or diarrhea. The oropharyngeal mucosa 
involvement was reported as the initial symptoms in 26 persons, with symptoms including a 
combination of pharyngitis, odynophagia, epiglottitis, and oral or tonsillar lesions. Close to 
50% of cases are among PLWH, although clinical presentation was similar among persons 
with and without HIV. Sexually transmitted infections (STI) were reported at the time of 
HMPXV diagnosis in 109 of the 377 persons who were tested, gonorrhea (8%), chlamydia 
(5%), and syphilis (9%). Three new cases of HIV infection were identified. 
 
Seventy persons (13%) became hospitalized, most often for anorectal pain management 
(n=21) and treatment of soft-tissue superinfection (n=18). Other reasons for 
hospitalization included severe pharyngitis, which limited oral intake (n=5), treatment of 
eye lesions (n=2), acute kidney injury (n=2), myocarditis (n=2), and infection-control 
purposes (n=13). No difference in the frequency of hospitalization was observed based 
on presence of HIV. Additionally, almost all people with HIV were experiencing virologic 
control and immune reconstitution with antiretroviral therapy (median CD4 cell count of 
680 cells/mL). Despite some hospitalizations, there were no deaths reported in this 

 
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series; however, five deaths have been reported as of August 1, 2022 [Bisset 2022; 
University of Minnesota CIDRAP 2022]. 
 
Tecovirimat 
To date, most persons with HMPXV infection in the current pandemic have received only 
supportive and symptomatic care, but antivirals have been FDA approved for smallpox 
that should have activity against HMPXV [Adler 2022; Parker 2008]. One of these drugs, 
tecovirimat, is beginning clinical studies against HMPXV in Africa and Europe [ISARIC 
2022]. Tecovirimat was developed by SIGA Technologies, Inc. (SIGA) [SIGA 
Technologies, Inc. 2022]. Tecovirimat exerts antiviral activity on the exit of viral particles 
from an HMPXV-infected cell based on the viral p37 protein target, which is highly 
conserved across all species of orthopoxviruses, including those in clades 1 and 3 of 
HMPXV. Additionally, there are no mammalian homologs to p37. There are also no 
orthologous genes outside the Poxviridae family, therefore no off-target activity should 
be observed. In vivo efficacy studies of tecovirimat were conducted in non-human 
primates and rabbits, showing antiviral activity, and results from these studies were 
encouraging [Grosenbach 2018]. Also, safe administration of tecovirimat for treatment of 
HMPXV has been recently reported in some of the recent confirmed cases of HMPXV 
[Adler 2022; CDC 2022b]. 
 
Risks of Tecovirimat 
The safety of tecovirimat is currently being evaluated or will be evaluated in several trials 
of HMPXV disease, including an expanded–access IND (EA-IND) protocol being 
conducted by the U.S. CDC, although safety data are not yet available from these 
studies. The EA-IND protocol is not designed to yield data on efficacy and there is no 
control group included. Tecovirimat has not been studied in patients with smallpox 
disease, but it was studied in 359 healthy adults (18-79 years). Participants who 
received at least one 600 mg dose of tecovirimat were 59% female, 69% White, 28% 
Black/African American, 1% Asian, and 12% Hispanic or Latino ethnicity. Ten percent of 
the participants were 65 or older. Also, 336 participants received at least 23 of 28 doses 
of 600 mg tecovirimat in a twice daily regimen for 14 days. Most frequently reported 
adverse reactions were headache and nausea. See Table 2.1-1 adapted from [Gibson 
and Leibowitz 2019].  
 
Table 2.1-1: Adverse Reactions Reported in ≥2% of Healthy Adult Subjects Receiving at 
Least One Dose of Tecovirimat 600 mg 
Adverse Reaction 
Tecovirimat 600 mg 
n=359 (%) 
Placebo 
n=90 (%) 
Headache 
12 
8 
Nausea 
5 
4 
Abdominal pain 
2 
1 
Vomiting 
2 
0 
 
Children and HMPXV 
Historically HMPXV in endemic regions has involved children and adolescents. While the 
2022 HMPXV outbreak started primarily among adult MSM, secondary infections among 

 
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household contacts, including children, have been reported [Goodman 2022]. This is not 
unexpected as the household attack rate has been reported as high as 50% [Nolen 
2016] with a large number of those being childhood household contacts. For example, in 
a 2013 outbreak in the Democratic Republic of Congo the median age of case-patients 
was 10 years and 17.7% were under the age of 5 [Nolen 2016]. Once infected with 
HMPXV the clinical course appears similar to adults although children under age 8 may 
have more severe disease [Huhn 2005; Jezek 1987]. In the 2003 United States 
outbreak, 10 cases were in individuals less than 18 year of age and while overall 
severity was similar to that of adults there was an increase in pediatric patients (50%) 
requiring ICU admission [Huhn 2005]. In the 1980-1985 HMPXV outbreak in Zaire, 
children aged 14 and under made up 93% of cases with high mortality in those under 
age 4 (14.9%) and those aged 5-9 (6.5%) [Jezek 1987]. As with adults there is little 
known about the duration and sites of viral shedding among pediatric patients with 
HMPXV. 
 
Tecovirimat and Children 
No studies of tecovirimat have been conducted in pediatric patients and there are therefore no 
human data to assess the risk and benefits. Currently the CDC recommends treatment with 
tecovirimat for children under age 8 and those meeting the same severe disease or risk of 
severe disease criteria as adults [CDC 2022a]. Currently tecovirimat pharmacokinetics has not 
been evaluated in pediatric patients. The current pediatric dosing regimen is based on a 
population pharmacokinetic modeling and simulation approach that is expected to produce 
tecovirimat exposures comparable to those in adults [SIGA Technologies, Inc. 2018]. Based on 
the potential benefit and the critical need to establish optimal dosing, pediatric patients will be 
enrolled into Arm C (open label tecovirimat plus standard of care) to ensure access and to 
collect the data on the pharmacokinetic, safety, and efficacy of tecovirimat in this population. 
 
Pregnancy and HMPXV 
Given limited diagnostics and the austere environments in which the majority of 
monkeypox infections occur, data on monkeypox infection in pregnant and breastfeeding 
women are limited. However, case reports of HMPXV infected pregnant persons and 
reports from other orthopox infections including smallpox, cowpox, and vaccinia virus 
infection suggest that pregnant women potentially represent a high-risk population with 
increased risk of maternal and perinatal morbidity and mortality [Meaney-Delman 2022].  
  
Data on monkeypox infection in pregnancy is limited to five laboratory confirmed cases 
in the Democratic Republic of Congo (DRC). Four pregnant women with monkeypox 
infection were described in an observational study of 222 hospitalized patients who were 
isolated based on clinical suspicion of HMPXV infection and confirmed by polymerase 
chain reaction (PCR) [Khalil 2022; Mbala 2017; Meaney-Delman 2022]. While all four 
pregnant women survived, three of the four women who had moderate to severe 
monkeypox infection, by a WHO lesion number and activity-based severity score, 
experienced fetal demise, including two that occurred as first trimester miscarriages and 
one intrauterine fetal demise at 18 weeks gestation. While confirmatory testing of 
pregnancy tissues was not conducted in the two first trimester miscarriages, the 
intrauterine fetal demise had clinical, virological, histological, and serological evidence 
consistent with vertical transmission of HMPXV. The fetus displayed diffuse cutaneous 

 
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maculopapillary skin lesions on the abdomen, back, chest, and extremities including the 
palms and soles of the feet consistent with monkeypox infection. A rise in HMPX viral 
load from 102 copies/mL to 106 copies/mL was temporally associated with cessation of 
fetal movement. Monkeypox virus was found in amniotic fluid (2.6x107copies/mL), fetal 
tissue (1.7x107copies/mL), and umbilical cord vein blood (2.5x107copies/mL). The 
fourth pregnant woman experienced a mild monkeypox infection by WHO severity score 
which resulted in the live birth of a reportedly healthy neonate at term [Mbala 2017; 
Meaney-Delman 2022]. A fifth case of maternal monkeypox diagnosed in the second 
trimester was reported in Zaire in 1983 resulting in the delivery of a preterm neonate with 
a generalized rash consistent with congenital monkeypox infection, but no confirmatory 
testing was available. At 6 weeks of age, the infant subsequently died from malnutrition 
[Mbala 2017; Meaney-Delman 2022]. 
 
Tecovirimat and Pregnancy  
No studies of tecovirimat have been conducted in pregnant women, therefore there is no 
human data to establish the presence or absence of tecovirimat-associated risk in 
pregnancy. 
  
Reproduction studies in animals have found no embryofetal development toxicity in 
pregnant mice treated with tecovirimat at exposures up to 23 times higher than human 
exposure at the recommended human dose. Similarly, embryofetal development toxicity 
was not observed during organogenesis in rabbits at tecovirimat exposures less than 
human exposure at the recommended human dose.  
 
Based on the potential increased risk of maternal and fetal morbidity and mortality and 
the lack of embryofetal development toxicity in animal studies, pregnant woman, in any 
trimester and after a discussion of the risks associated with tecovirimat, will be enrolled 
into Arm C (open label tecovirimat plus standard of care) to ensure access to 
investigational therapeutics and to collect the data needed to establish the safety and 
efficacy of tecovirimat in this population [Birmingham Health Partners 2022]. The 
schedule of events will remain the same in both the double-blind randomized controlled 
trial and the open label pregnancy registry. 
 
Similarly, there are no available data on the effect of tecovirimat on milk production, the 
presence of the tecovirimat in human milk, and/or the effects on the breastfed child. 
When administered to lactating mice, tecovirimat was present in milk [SIGA 
Technologies 2022]. Since HMPXV is spread by close contact and neonates are at high 
risk for severe disease, women in the United States who are breastfeeding will be 
counseled to pump and discard breastmilk until all lesions have resolved, the scabs 
have fallen off and a fresh layer of intact skin has formed, consistent with CDC guidance 
[CDC 2022d]. 
 
Vaccination Against HMPXV 
Because HMPXV is closely related to the virus that causes smallpox, the smallpox 
vaccine can protect people from getting HMPXV. Past data from experiences in Africa 
suggests that the smallpox vaccine is at least 85% effective in preventing HMPXV 
infection [Jezek 1988]. There is one vaccine approved to prevent HMPXV-caused 

 
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disease, JYNNEOS. The JYNNEOS vaccine is based on the highly attenuated Modified 
Vaccinia Ankara (MVA) virus and is felt to be safer than other replicating smallpox 
vaccines [CDC 2022d]. MVA has demonstrated protective efficacy in animal models of 
HMPXV [SIGA Technologies, Inc. 2022], older human adults (56-80 years old) [CDC 
2022d], and persons living with HIV (PLWH) [CDC 2022d]. 
 
2.2 
Rationale 
 
Human Monkeypox virus is currently the cause of a multi-country outbreak and 
represents the most recent infectious threat to global public health. Given the dramatic 
increase in the numbers of infections (>28,000 in the past three months) and spread to 
more than 80 countries in which HMPXV is not considered endemic, the WHO declared 
a public health emergency of international concern [CDC 2022c; WHO 2022]. Along with 
preventative strategies including vaccination, contact tracing, and social mobilization, 
safe and effective therapeutics are urgently needed to improve clinical outcomes and 
control this and future outbreaks. 
 
While there are no therapeutics currently approved for HMPXV infection, tecovirimat has 
been FDA approved for use against another highly lethal Orthopox virus, variola virus, 
based on its efficacy against monkeypox virus infection of non-human primates (NHP) 
and rabbitpox in rabbits consistent with the FDA animal rule [Grosenbach 2018; Sherwat 
2022]. Case reports of antiviral efficacy in HMPXV-infected individuals treated with 
tecovirimat provide further support but are insufficient alone to demonstrate safety and 
efficacy in HMPXV infection [Adler 2022; Matias 2022; Rao 2022]. As a result, this 
randomized, double-blind, placebo controlled clinical trial is designed to provide safety 
and efficacy data on the use of tecovirimat in HMPXV infection. Ultimately, data from a 
rigorous placebo controlled RCT is needed to inform clinical care and accelerate 
regulatory pathways required to increase access to safe and effective therapeutics for 
people suffering in the current public health epidemic of international concern and for 
those in persistent threat of infection in endemic countries.  
 
Rationale for Placebo-Controlled Design 
Currently, there is no drug approved for HMPXV infection. Non-randomized, unblinded 
investigation of the efficacy of tecovirimat against HMPXV infection is encouraging, but the 
data are extremely limited (TPOXX, Siga) [Adler 2022; SIGA Technologies 2022]. In 2017, 
tecovirimat was approved by the FDA for the treatment of smallpox using a regulatory 
pathway known as the “animal rule.” This allows the FDA to approve a drug based on 
controlled studies in animals when studies in humans are not possible because of ethical 
issues or the rarity of the disease being studied [FDA 2018; FDA 2022].  
 
Additionally, the U.S. CDC currently recommends tecovirimat be used under an EA-IND 
for 14 days for patients with severe HMPXV infection or those who are at risk for severe 
HMPXV infection (SIGA’s Marketing Application) [CDC 2022b]. Since no randomized 
controlled clinical trial has yet evaluated the efficacy of tecovirimat for treatment of 
HMPXV, especially among MSM with clade 3 infection, this protocol will be conducted to 
gather additional data. 
 

 
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A randomized, placebo-controlled trial is the optimal design to show efficacy, especially 
when including subjective outcomes including resolution of skin lesions and pain. 
Convincing evidence of safety and efficacy will be critical to efforts to combat the disease 
around the world, especially if the epidemic generalizes to a world-wide endemic infection. 
However, the current fund of knowledge suggests the risk-benefit ratio favors access to 
tecovirimat. Indeed, the CDC has provided access to tecovirimat through an EA-IND. This 
study maximizes access to tecovirimat by using a 2:1 allocation ratio. The study also 
allows access to open-label tecovirimat should the disease progress or should participants 
experience severe pain post-randomization. The study also provides open-label 
tecovirimat for those at highest risk of complications such as those having facial lesions or 
ocular infection. 
 
Importantly, this RCT was developed in parallel with and will complement other clinical 
trials evaluating the safety and efficacy of tecovirimat in the treatment of HMPXV 
infection including the PALM007 trial in the Democratic Republic of Congo in which 
HMPXV infection is endemic, the PLATINUM study in the UK, a Canadian Clinical Trials 
Study, and the WHO Global Core Protocol which is an international adaptive multi-
country placebo-controlled therapeutics platform trial. 
 
Rationale for Open-Label Populations 
Access to tecovirimat is currently restricted to an EA-IND pathway for patients with 
severe HMPXV infection or those at risk for severe HMPXV infection. Even for patients 
that meet these criteria, regulatory challenges have limited access to tecovirimat. The 
inclusion of an open-label arm for specific high-risk patients and those with severe 
disease will not only increase access to tecovirimat but will enable the collection of data 
to inform safety and efficacy of this therapeutic. 
 
Pregnancy and Breastfeeding 
This trial will provide open-label tecovirimat to pregnant persons and persons who are 
breastfeeding. This rationale is described above. In addition, the approach to inclusions 
of this population is consistent with the ethical principles set forth by the Councils for 
International Organizations for Medical Sciences in collaboration with the World Health 
Organization (https://cioms.ch/wp-content/uploads/2017/01/WEB-CIOMS-
EthicalGuidelines.pdf). 
 
Highly Immunosuppressed Individuals (See section 4.3.2 for definition) 
Although data on HMPXV infection is lacking in immunocompromised persons, severe 
complications including progressive vaccinia [CDC 2009; Hopkins 2004; Lederman 2012] 
have been reported in immunocompromised individuals with smallpox infection and those 
who receive smallpox vaccination with the replication competent vaccinia virus.  
 
Suspected or Confirmed Ocular Involvement 
Corneal scarring and loss of vision represent one of the most significant and permanent 
complications of orthopox infection. Of 294 confirmed monkeypox infections followed in 
the DRC 2010-2013, 68 (23%) persons reported the presence of conjunctivitis among 
their symptoms [Reynolds 2017]. In a separate study of 338 persons with HMPXV in 
Zaire diagnosed between 1981 and 1986 [Jezek 1988; p 459], 10% of primary and 5% of 

 
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secondary cases were reported to have serious complications including “unilateral or 
bilateral blindness, weak vision, and deforming scars”.  
 
Skin Conditions Placing Individuals at a Higher Risk for Disseminated Infection 
Individuals with a history or presence of exfoliative skin conditions (eczema, atopic 
dermatitis, burns, impetigo, varicella zoster virus infection, psoriasis, or Darier disease 
[keratosis follicularis]) are potentially at higher risk for disseminated HMPXV infection. 
Eczema vaccinatum, a complication of smallpox vaccination that occurs in persons with 
exfoliative skin conditions, including those in complete remission at the time of 
vaccination, resulted in increased hospitalization and mortality [CDC 2007; Lane 1969; 
Reed 2012].  
 
Lesions Requiring Surgical Intervention and Hospitalization 
A small minority of persons with HMPXV during the current epidemic have experienced 
severe genital lesions (typically on the penile foreskin) that have extended beyond the 
subdermal layers and have required surgical debridement. Some participants have even 
required hospitalization. The inclusion of these small subsets into an open-label cohort 
will not appreciably impact the overall ability of the trial to rigorously test the efficacy and 
safety of tecovirimat and will perhaps reduce the likelihood of severe and long-term 
adverse outcomes for the study population in general. 
 
Children Under the Age of 18 
To date, tecovirimat has been approved for smallpox in all ages. However, it has only 
been studied for safety in adults, and pediatric PK used for dosing is based on modeling 
studies. Through this study, we will evaluate the PK and safety of tecovirimat in children 
less than 18 years. Tecovirimat is metabolized by uridine glucuronosyltransferase 
enzymes which are not fully functional at birth but rapidly increase in activity during the 
first few weeks to months of life [Kawade 1981; Krekels 2012]. Given this, initial 
tecovirimat doses for neonates <6kg are provided in Table 5.1-2. PK for each neonate 
will be used to inform dosing of subsequent neonates enrolled.  
 
People Receiving Potent Inducing Concomitant Medications 
There are very limited data on drug-drug interactions between tecovirimat and many 
concomitant medications. It is possible that strong inducing medications such as rifampin 
may decrease the exposure to tecovirimat by inducing UGT1A, it is not clear to what 
extent this will affect tecovirimat exposures. It appeared that tecovirimat was effective in 
animal models at lower-than-expected concentrations in humans [Grosenbach 2018]. 
Given the uncertainty, participants receiving these inducing medications will be placed in 
Arm C so that we can focus on determining the magnitude of interaction. This will provide 
important data to guide future use of tecovirimat, should it be found to be efficacious, and 
will help prioritize which additional drug-drug interaction studies are needed. 
 
Rationale for Additional Sampling Cohort 
Systematically collected data regarding the natural history of HMPXV dynamics in the 
current epidemic are urgently needed. The duration and quantity of viral shedding from 
rash, mucosal sites and blood will inform prevention messages and provide guidance for 
isolation among people with HMPXV. Understanding how viral shedding is impacted by 

 
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tecovirimat administration will help us understand the impact of more aggressive 
treatment with antivirals for all people with HMPXV and may have both individual and 
public health impacts through faster clearance of virus (analogous to HIV Treatment as 
Prevention). In addition, by collecting blood samples during infection and clearance of 
virus, we can study whether viremia and the development of the humoral and cellular 
immune response are associated with severity and duration of disease; through 
understanding correlates of disease severity, we can develop additional interventions 
and have better data to direct when to deploy medical countermeasures. 
 
There is little known about the duration and sites of viral shedding among people with 
HMPXV. A case series of 7 people with HMPXV infection in the UK in 2018-2021 
demonstrated detection of virus from multiple sites, including ulcerated skin lesions, 
upper respiratory tract secretions, blood and urine [Adler 2022]. Although shedding 
patterns were highly variable per patient, patients had HMPXV detected via PCR from 
ulcerated lesions, blood, and upper respiratory secretions for up to 28 days, with even 
more prolonged detection, particularly from upper respiratory tract secretions, among 
some participants. A second study enrolled 12 untreated participants from Spain in the 
context of the current global HMPXV outbreak. Samples were collected for up to 16 days 
post symptom onset from multiple sites including saliva, rectum, nasopharynx, semen, 
urine, and feces and tested for HMPXV by PCR [Peiró-Mestres 2022]. All participants 
had HMPXV shedding from saliva, and viral shedding was detected in most participants 
(>75%) from rectal, nasopharyngeal, semen, and urine sites. All participants had viral 
detection from at least one site at the time of last sample collection, suggesting 
prolonged viral shedding in the absence of antiviral therapy. 
 
Rationale for PK Sampling 
Pharmacokinetic data with tecovirimat were primarily generated in healthy volunteers. 
PK data in individuals with active disease are extremely limited. This study will determine 
the pharmacokinetics of tecovirimat using a combination of intensive and sparse 
sampling. A minimum of 24 participants in Arms A and B will undergo intensive PK 
sampling at steady state (day 8). Given the 2:1 randomization, it is expected that ~16 
participants will be on tecovirimat. Complete, evaluable intensive PK data are expected 
in ≥10 of these participants.  
 
Intensive PK will be performed in the first 8 pregnant participants enrolled in each 
trimester of pregnancy, at least the first 8 children in each weight band, individuals on 
potent inducing medications with the potential to lower tecovirimat exposures (these 
participants are encouraged but not required to participate in intensive PK sampling), 
and additional adult participants who agree to this sampling. The relationship between 
PK and response to tecovirimat will also be assessed.  
 
Anal Health-Related Symptom Index (A-HRSI) 
The Anal Health-Related Symptom Index (A-HRSI) will be administered to participants 
reporting proctitis at baseline. The A-HRSI was developed in a substudy of the ANCHOR 
study [NCT01946139 (https://clinicaltrials.gov/show/NCT01946139); Palefsky 2022] and 
included a four-phase process to establish content validity. Forty-one study participants who 
were eligible for ANCHOR were interviewed to inform the instrument developed and these 

 
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interviews were used to create a 23-item measure draft tool that was then tested in a 
second cohort of 45 participants eligible for ANCHOR in a process of cognitive interviewing. 
This process resulted in a 25-item content-valid measure of physical symptoms, physical 
impacts and psychological symptoms [Burkhalter 2018]. Reliability was assessed in 100 
ANCHOR participants across a 7–10-day timeframe, with Cronbach’s α in the fair to good 
range across the three domains (i.e., 0.79–0.82), indicating internal consistency for the 
measure [Atkinson 2019]. The test-retest reliability was good across each of the three 
domains (intraclass correlation coefficients = 0.80–0.84). Construct validity of the measure 
was then established in a fourth cohort of individuals enrolled in ANCHOR (n=303) who 
completed A-HRSI at a single time point, with the three-domain model (i.e., physical 
symptoms, physical impacts, psychological symptoms) confirmed via confirmatory factor 
analysis. These three domains strongly associated (Pearson’s r) with corresponding 
domains from the well-established MD Anderson Symptom Inventory and Functional 
Assessment of Cancer Therapy – General tools.  
 
3.0 
STUDY DESIGN 
 
This is a randomized, placebo-controlled, double-blind study to establish the efficacy of 
tecovirimat for the treatment of people with laboratory-confirmed or presumptive HMPXV 
disease. (See section 4.1.1 for the definitions of confirmed and presumptive 
disease.) Potential participants will be approached for informed consent and then 
assessed for eligibility.  
 
Participants should be assessed for the presence of HMPXV, the extent, duration and 
severity of disease, and the presence of any conditions necessitating enrollment into 
Arm C (open-label arm) as opposed to the randomized arms (Arms A and B). (See 
section 4.3 for the criteria for Arm C.) 
 
Enrollment of those with presumptive disease is allowed. For those with severe disease, 
enrollment based on presumptive diagnosis is strongly encouraged. Delaying enrollment 
for receipt of laboratory confirmation can be considered for those who have only mild 
symptoms whose confirmatory test results are expected within 24 hours.  
 
For participants who are enrolled (i.e., randomized to Arm A or B, or registered to Arm 
C) in person based on a presumptive HMPXV diagnosis, sites should send diagnostic 
specimens to the central laboratory for a clinical report as described in section 6.3.6 
whether or not there is a pending local test. Participants enrolled in person for whom 
both the local test (if one was obtained) and all clinically reported HMPXV tests from the 
central laboratory are negative should stop study drug. Follow up through remote or in 
person contact will occur 7 days after stopping study drug to assess for AEs. 
Participants randomized to Arms A and B will be replaced. If any of these tests are 
positive, then the person should complete the study as planned.  
 
For participants who are enrolled remotely, sites should verify that the local 
laboratory test confirmed HMPXV or verify that a local laboratory test confirming 
HMPXV is pending. No additional diagnostic testing is required. Participants 
enrolled remotely for whom the local HMPXV testing is negative should stop study 

 
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drug. Follow up through remote contact will occur 7 days after stopping study 
drug to assess for AEs. Participants randomized to Arms A and B will be replaced. 
 
Eligible and consented participants for the randomized arms (N=530) will be randomized 
2:1 to receive either tecovirimat or placebo (Arms A and B); participants with severe 
disease, significant skin conditions, participants with severe immune suppression (see 
section 4.3.2) will be enrolled to Arm C. Participants who are pregnant or breastfeeding 
will be enrolled into Arm C after discussion of the potential risks and benefits of 
tecovirimat. Participants less than 18 years of age will be enrolled to Arm C. Participants 
receiving a potent inducing concomitant medication will also be enrolled to Arm C.  
 
All participants will receive standard-of-care treatment according to local/site practice and 
suggested approaches to supportive care are described in a protocol manual of 
procedures (MOP). Randomization between Arms A and B will be stratified according to 
time since prodromal symptom onset (≤5 days or >5 days) and remote enrollment.  
 
Baseline evaluations for all adult participants and sexually active adolescents 
enrolled/followed in person will include an assessment for bacterial sexually transmitted 
infections, chronic viral hepatitis, and HIV testing as described in section 6.1 (Schedules of 
Evaluations). Participants with genital, anal, perianal, or perioral ulcerative lesions or 
proctitis should be tested for HSV if not done within 7 days prior to enrollment. This testing 
is available through the central laboratory to be used for clinical management. 
Participants enrolled remotely will be advised of the recommended STI testing and 
HIV testing (if not known to have HIV).  
 
Participants seen for in-person visits will have baseline samples for HMPXV collected 
including blood, oropharyngeal swabs, swabs of a representative lesion to be designated 
the “index lesion”, rectal swabs, eye fluid (if having suspected ocular infection) and self-
collected vaginal swabs (cisgender women and transgender men only). Participants with 
suspected HMPXV infection in the eye should be considered for referral to 
ophthalmology. Note there are specific recommendations for treating ocular HMPXV 
(see MOP). Participants seen in person agreeing to semen collection will be provided a 
kit for home collection.  
 
Participants enrolled remotely may elect to have follow up visits in person. In this 
event, these participants would sign the consent form for in person follow up. 
 
Participants enrolled in person may elect to have follow up visits remotely. In this 
event, participants will continue to follow the SOEs for in-person participants with 
evaluations that are required to be done in person marked as missed evaluations. 
Missed evaluations due to a remote visit are not protocol deviations. 
 
Regardless of whether participants are enrolled/followed in person or remotely, 
they should have a plan for accessing care for their monkeypox virus outside of 
the study, if necessary.  
 

 
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Once enrolled, study drug administration will begin according to study group assignment. 
Tecovirimat will be administered as described below (section 5.0). Study drug or placebo 
administration will be for 14 days. Participants should be counseled on how to avoid 
transmitting HMPXV to others. Participants who are enrolled/followed remotely will 
be sent the study product via mail or courier service.  
 
Participants who progress to develop one of the conditions for severe HMPXV disease 
(as defined in section 4.3.2) will have a visit to confirm progression. For participants 
enrolled/followed in person, this visit should be done in person, if feasible. For 
participants enrolled/followed remotely, this visit will be conducted remotely (i.e., 
via telemedicine) unless the participant prefers to come into the site. If severe 
disease is confirmed, participants will stop blinded study treatment and start a 14-day 
course of open-label tecovirimat.  
 
Participants reporting severe pain (7 or greater on the numerical rating scale) 5 days 
after randomization will have a visit to confirm indication for open-label tecovirimat. 
This includes participants who report persistent severe pain since baseline or 
pain that worsens and becomes severe. For participants enrolled/followed in 
person, this visit should be done in person, if feasible. For participants 
enrolled/followed remotely, this visit will be conducted remotely (i.e., via 
telemedicine) unless the participant prefers to come into the site. These 
participants will stop blinded study treatment and start a 14-day course of open-
label tecovirimat. Of note, participants randomized to Arm A who subsequently receive 
open-label tecovirimat will receive a total course of tecovirimat longer than 14 days. 
These participants will continue to be followed according to their original schedule of 
events. If participants become hospitalized, study staff should continue to follow the 
schedule of events as feasible. If in person visits for hospitalized participants are not 
possible, study staff should conduct remote assessments to ascertain study outcomes 
as allowed. 
  
Participants will self-monitor skin and/or mucosal lesions daily through 29 days or 
resolution (whichever comes first), complete a daily diary of symptoms and complete a 
daily numerical rating scale for pain assessment. Participants will be instructed on the 
criteria for lesion resolution. Participants will be requested to take serial photographs of 
lesions as described in the MOP, but these photographs are not required. If reporting 
lesion resolution, participants will be seen for a remote visit (or in person whichever is 
preferred by the participant) as soon as possible for study staff to confirm status.  
 
Participants enrolled/followed in person will be seen weekly through day 29 for 
assessment of HMPXV disease, safety assessments, HMPXV sampling similar to that 
described for entry, and swabbing of new HMPXV lesions. Participants will be seen at 
day 57 to assess for possible recrudescence of infection (i.e., new lesions occurring after 
initial resolution of disease.  
 

 
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Participants over the age of 18 in Arms A/B/C who are enrolled/followed in person will 
have the option to undergo additional mucosal and lesional viral sampling while on study 
drug in addition to optional PBMC collection, with the goal of having up to 100 
participants enrolled in this cohort. 
 
4.0 
SELECTION AND ENROLLMENT OF PARTICIPANTS 
 
4.1 
Inclusion Criteria (All participants; Arms A, B, and C) 
 
4.1.1 Laboratory-confirmed or presumptive HMPXV infection: 
 
Laboratory-confirmed HMPXV infection is defined as determined by PCR, 
culture, or antigen test obtained from a sample collected from a skin lesion, 
oropharynx, or rectal swab obtained within 7 days prior to study entry 
 
OR  
  
Presumptive diagnosis: 
• 
Skin lesion(s), mucosal lesion(s) or proctitis consistent with a high probability 
of HMPXV in the opinion of the site investigator 
AND 
• 
Sexual contact with 1 or more persons in the 21 days prior to symptom onset 
or close exposure to another person known to be infected with HMPXV.  
OR 
• 
Neonates (<4 weeks of age) born to mothers with monkeypox infection. 
These neonates are assumed to have monkeypox and no confirmatory 
testing is required. 
 
4.1.2 HMPXV illness of <14 days duration immediately prior to study entry. 
 
4.1.3 At least one active (not yet scabbed) skin lesion, mouth lesion, or proctitis with or 
without visible ulcers. 
 
4.1.4 Non-pregnant people of reproductive potential must agree to use at least one 
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: 
• 
Abstinence 
• 
Hormonal contraception 
• 
Male or female condom 
• 
Diaphragm or cervical cap with a spermicide 
• 
Intrauterine device 
 

 
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NOTE: Reproductive potential is defined as: 
• 
Participants who have reached menarche 
• 
Participants who have not been post-menopausal for at least 12 
consecutive months with follicle-stimulating hormone (FSH) ≥40 
IU/mL or 24 consecutive months if an FSH is not available 
• 
Participants who have not undergone surgical sterilization (e.g., 
hysterectomy, bilateral oophorectomy, bilateral tubal ligation, or 
bilateral salpingectomy)  
• 
For individuals with permanent infertility due to an alternate medical 
cause (e.g., Mullerian agenesis, androgen insensitivity), investigator 
discretion should be applied to determining study entry. 
 
4.1.5 Ability to provide informed consent (for those above the legal age of consent and 
those providing consent for minors) and assent (for those who have reached the 
age of assent, but not the legal age of consent), as allowed by local ethics 
committees.  
 
4.1.6 For participants to be enrolled/followed remotely, ability and willingness to 
participate in remote telehealth assessments (i.e., video visits). 
 
4.2 
Additional Inclusion Criteria for Arms A and B 
 
4.2.1 Age ≥18 years at the time of study entry. 
 
4.3 
Additional Inclusion Criteria for Arm C 
 
Participants who meet the above entry criteria (section 4.1) who also meet any of the 
following criteria will be registered to Arm C. 
 
4.3.1 Participants age <18 years at the time of study entry 
 
4.3.2 Those with severe HMPXV disease defined as having one or more of the 
following conditions: 
• 
Suspected or confirmed ocular involvement 
• 
Facial lesions on the malar, nose, or eyelid region 
• 
Confluent facial lesions 
• 
Hospitalization due to HMPXV infection or its complications 
• 
Lesions that require surgical intervention including debridement, urinary 
catheterization or sigmoidoscopy, or lesions extending below the dermis 
 
Those with or without severe disease and with one or more of the following will 
also be enrolled into Arm C: 
• 
Severe immunosuppression defined as: 
o HIV with CD4 <200 cells/mm3 or plasma HIV-1 RNA >1000 copies/mL 
o Leukemia 
o Lymphoma 

 
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o Generalized malignancy 
o Solid organ transplantation 
o Therapy with alkylating agents within 180 days prior to study entry 
o Antimetabolites within 180 days prior to study entry 
o Radiation therapy within 180 days prior to study entry 
o Tumor necrosis factor inhibitors within 180 days prior to study entry 
o High-dose corticosteroids (equivalent of 20 mg or greater of prednisone 
for at least 14 days) within 90 days prior to study entry 
o Being a recipient with hematopoietic stem cell transplant <24 months 
post-transplant or ≥24 months but with graft-versus-host disease or 
disease relapse, or having autoimmune disease with immunodeficiency 
as a clinical component) 
o Other severe immunosuppression in the opinion of the site investigator 
• 
Active skin conditions placing the person at higher risk for disseminated 
infection as defined as: 
o Atopic dermatitis  
o Active exfoliative skin condition(s) such as eczema, burns, impetigo, 
active varicella zoster virus infection, psoriasis, or Darier disease 
(keratosis follicularis) 
• 
Breastfeeding 
• 
Pregnancy  
• 
Receipt of potent inducers, including rifampin, rifapentine, rifabutin, St. John’s 
Wort, carbamazepine, phenytoin, phenobarbital, oxcarbazepine, or 
tipranavir/ritonavir  
• 
Current or planned use of another investigational drug at any point during 
tecovirimat/placebo dosing that would be predicted to have a significant drug-
drug interaction with tecovirimat therapeutics. 
 
4.4 
Exclusion Criteria (All participants; Arms A, B, and C) 
 
4.4.1 Prior or concomitant receipt of tecovirimat (e.g., under an alternative access 
mechanism). 
 
NOTE: Participants <18 years of age, pregnant, and/or breastfeeding in Arm 
C are allowed up to 3 days of tecovirimat immediately prior to entry. 
 
4.4.2 Planned initiation of intramuscular cabotegravir/rilpivirine during study drug 
administration or for two weeks following completion of study drug administration. 
Participants who are stable on long-acting intramuscular cabotegravir/rilpivirine 
may enroll.  
 
4.4.3 Participants who, in the judgement of the investigator, will be at significantly 
increased risk as a result of participation in the study. 
 
4.4.4 Participants who require intravenous dosing of tecovirimat. 
 

 
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4.5 
Study Enrollment Procedures 
 
4.5.1 Prior to implementation of this protocol, and any subsequent full version 
amendments, each site must have the protocol and the protocol consent form(s) 
approved, as appropriate, by the IRB of record as well as any required local 
institutional review board (IRB)/ethics committee (EC) approvals and any other 
applicable regulatory entity (RE). Upon receiving final approval, sites will submit 
all required protocol registration documents to the DAIDS Protocol Registration 
Office (DAIDS PRO) at the Regulatory Support Center (RSC). The DAIDS PRO 
will review the submitted protocol registration packet to ensure that all of the 
required documents have been received.  
 
Site-specific informed consent forms (ICFs) WILL be reviewed and approved by 
the DAIDS PRO, and sites will receive an Initial Registration Notification from the 
DAIDS PRO that indicates successful completion of the protocol registration 
process. A copy of the Initial Registration Notification should be retained in the 
site's regulatory files. 
 
Upon receiving final IRB/EC and any other applicable RE approvals for an 
amendment, sites should implement the amendment immediately. Sites are 
required to submit an amendment registration packet to the DAIDS PRO at the 
RSC. The DAIDS PRO will review the submitted protocol registration packet to 
ensure that all required documents have been received. Site-specific ICF(s) 
WILL NOT be reviewed or approved by the DAIDS PRO. Sites will receive an 
Amendment Registration Notification when the DAIDS PRO receives a complete 
registration packet. A copy of the Amendment Registration Notification should be 
retained in the site's regulatory files. 
 
For additional information on the protocol registration process and specific 
documents required for initial and amendment registrations, refer to the current 
version of the DAIDS Protocol Registration Manual.  
Participants from whom a signed informed consent has been obtained may be 
screened and enrolled, if they otherwise qualify. An ACTG Screening Checklist 
must be entered through the DMC Study Enrollment System.  
 
4.5.2 Consent Process 
 
If the potential participant is not of legal age to provide independent informed 
consent 
Written informed consent for study participation will be obtained from each 
potential participant’s parent or legal guardian before any study-specific 
procedures are performed. It is generally expected that the consent of one parent 
(or legal guardian) will be sufficient for child participation in this study. However, 
consenting requirements at each site will depend on the IRB/EC risk determination. 
 
When applicable per IRB/EC policies and procedures, written assent will also be 
obtained from the potential participant before any study-specific procedures are 

 
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performed. If the parent/guardian does not provide consent, or the potential 
participant does not provide assent when applicable, the potential participant will 
not be screened or enrolled. Minor participants who assent to the study and later 
withdraw that assent will not be maintained in the study against their will, even if 
their parent/guardian still wants them to participate. 
 
If the potential participant is of legal age or circumstance to provide independent 
informed consent or, if applicable per local regulations, is considered a minor 
who is legally able to provide informed consent 
Written informed consent for study participation will be obtained from each 
potential participant before any study-specific procedures are performed. 
 
4.5.3 Protocol Activation 
 
Prior to enrollment, sites must complete the Protocol Activation Checklist found 
on the ACTG Member website. This checklist must be approved prior to any 
screening of participants for enrollment.  
 
4.5.4 Randomization/Registration 
 
For participants from whom informed consent has been obtained, but who are 
deemed ineligible or who do not enroll into the initial protocol step, an ACTG 
Screening Failure Results form must be completed and keyed into the database.  
Participants who meet the enrollment criteria will be registered to the study 
according to standard ACTG DMC procedures.  
 
4.6 
Co-enrollment Guidelines  
 
• 
Sites in the U.S. are strongly encouraged to co-enroll participants enrolled/followed 
in person in A5128, “Plan for Obtaining Informed Consent to Use Stored Human 
Biological Materials for Currently Unspecified Analyses”, Co-enrollment in A5128 
does not require permission from the A5418 protocol chairs.  
• 
Sites outside of the U.S. are strongly encouraged to co-enroll participants 
enrolled/followed in person in A5243, “Plan for Obtaining Human Biological 
Samples at Non-U.S. Clinical Research Sites for Currently Unspecified Genetic 
Analyses“. Co-enrollment in A5243 does not require permission from the A5418 
protocol chairs. 
• 
Request for continued participation in non-interventional studies is not required. 
• 
For specific questions and approval for co-enrollment in other interventional studies, 
sites should first check the protocol-specific web page (PSWP) or contact the 
protocol team via e-mail as described in the Study Management section. 
 
5.0 
STUDY TREATMENT  
  
Study-provided treatment is defined as Tecovirimat or Placebo for Tecovirimat.  
  

 
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5.1 
Regimens and Duration 
  
Participants randomized to either Arm A or B to receive one of two regimens as shown in 
Table 5.1-1. Participants in Arm A and Arm B may change to a 14-day course of open 
label tecovirimat as described in section 3.0. Participants in Arm C will receive 
tecovirimat for 14 days as described in Table 5.1-1.  
 
Table 5.1-1: Treatment Regimens for Participants ≥6kg 
Arm 
Weight Band 
Dose 
Duration 
Arm A 
25 kg to less than 40 kg 
Tecovirimat 400 mg (2 capsules) 
every 12 hours 
14 days 
40 kg to less than 120 kg 
Tecovirimat 600 mg (3 capsules) 
every 12 hours 
14 days 
120 kg and over 
Tecovirimat 600 mg (3 capsules) 
every 8 hours 
14 days 
 
 
 
 
Arm B 
25 kg to less than 40 kg 
Placebo for Tecovirimat 400 mg 
(2 capsules) every 12 hours 
14 days 
40 kg to less than 120 kg 
Placebo for Tecovirimat  600 mg 
(3 capsules) every 12 hours 
14 days 
120 kg and over 
Placebo for Tecovirimat 600 mg 
(3 capsules) every 8 hours 
14 days 
 
 
 
 
Arm C 
Less than 6 kg 
See Table 5.1-2 
14 days 
6 kg to less than 13 kg 
Tecovirimat 100 mg (1/2 capsule) 
every 12 hours 
14 days 
13 kg to less than 25 kg 
Tecovirimat 200 mg (1 capsule) 
every 12 hours 
14 days 
25 kg to less than 40 kg 
Tecovirimat 400 mg (2 capsules) 
every 12 hours 
14 days 
40 kg to less than 120 kg 
Tecovirimat 600 mg (3 capsules) 
every 12 hours 
14 days 
120 kg and over 
Tecovirimat 600 mg (3 capsules) 
every 8 hours 
14 days 
 
Table 5.1-2: Initial Treatment Regimens for Participants <6kg  
Weight  
Dose 
Duration 
<3kg 
Tecovirimat 33.3 mg (3.3 mL) every 12 hours 
14 days 
3 to <6kg  
Tecovirimat 50 mg (5 mL) every 12 hours 
14 days 
 
Sites should contact the Clinical Management Committee (CMC) when enrolling children 
<6 kg. The available PK data will be discussed with the site investigator and the dose will 
be confirmed with the site. We are performing pharmacokinetic analyses in near real 
time for pediatric participants (results obtained approximately 1 week after shipment of 

 
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specimen). The initial dosing regimens are listed above. These doses will be updated (in 
the protocol MOP) based on available data as described in section 11.0. 
 
5.1.1 Dispensing 
 
Tecovirimat 33.3 mg: Administer as 33.3mg/3.3mL – 200mg capsule (20mg total 
dose) orally every 12 hours  
 
Tecovirimat 50 mg: Administer as one-quarter (1/4) – 200 mg (50 mg total dose) 
orally every 12 hours for participants older than 7 days)  
 
Tecovirimat 100 mg: Administer as one-half (1/2) – 200 mg (100 mg total dose) 
orally every 12 hours 
 
Tecovirimat 200 mg: Administer as one – 200 mg (200 mg total dose) orally 
every 12 hours 
 
Tecovirimat 400 mg/Placebo for Tecovirimat: Administer as two – 200 
mg/matching placebo capsules (400 mg total dose) orally every 12 hours 
 
Tecovirimat 600 mg/Placebo for Tecovirimat: Administer as three – 200 
mg/matching placebo capsules (600 mg total dose) orally every 12 hours 
 
Tecovirimat 600 mg/Placebo for Tecovirimat: Administer as three – 200 
mg/matching placebo capsule (600 mg total dose) orally every 8 hours (for 120kg 
and over) 
  
5.1.2 Administration 
  
Oral Therapy for Adults 
Tecovirimat capsules or placebo should be taken by mouth with a full glass of 
water within 30 minutes after eating a meal of moderate or high fat (ideally about 
600 calories and 25 grams of fat) in order to improve bioavailability. See MOP for 
a list of suggested meals meeting the caloric and fat criteria. Tecovirimat or 
placebo capsules can be opened and mixed in liquid for adults who cannot 
swallow capsules. Instructions for capsule opening and mixing are described in 
the MOP. 
 
  
Oral Therapy for Children 
For children <13kg, the contents of one- 200mg capsule should be mixed with 
20mL of water and a fraction of the water and drug mixture withdrawn to match 
the desired dosing. The prepared dose may be orally administered directly or 
further mixed with 1-2 teaspoons of liquid or soft food.  
 
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the desired dose should be mixed with 30mL of liquid (e.g., milk, chocolate 
milk, water) or soft food (e.g., apple sauce, yogurt).  
 
Instructions for capsule opening, mixing, and administration are described in the 
MOP. 
 
Children capable of taking tecovirimat with a meal will take the capsules 
within 30 minutes after eating a meal of moderate or high fat based on their age 
and weight in order to improve bioavailability. For younger children, we will 
investigate the PK based on their typical consumption including for those who are 
formula or breastfed.  
 
For children who may spit out a dose of study product or vomit within 15 minutes 
after taking study product, parents or guardians will be instructed to administer a 
replacement dose. If vomiting occurs more than 15 minutes after taking study 
product, a replacement dose should not be administered (the next scheduled 
dose should be taken as scheduled). 
 
Instructions for capsule opening and mixing are described in the MOP.  
 
 
Missed Dose 
If a dose of Tecovirimat or Placebo for Tecovirimat is missed, the participant 
should take the dose as soon as possible and anytime up to 8 hours prior to the 
next scheduled dose. If less than 8 hours remain before the next scheduled 
dose, the participant should not take the missed dose, and should resume dosing 
at the next scheduled dose.  
 
If the participant is scheduled for every 8-hour dosing and a dose of Tecovirimat 
or Placebo for Tecovirimat is missed, the participant should take the dose as 
soon as possible and anytime up to 6 hours prior to the next scheduled dose. If 
less than 6 hours remain before the next scheduled dose, the participant should 
not take the missed dose, and should resume dosing at the next scheduled dose.  
 
5.2 
Study Product Formulation and Storage 
  
5.2.1 Tecovirimat 
 
The oral formulation of Tecovirimat is provided as oral capsules containing white 
to off-white powder in orange and black hard gelatin capsules. Each capsule 
contains 200 mg of Tecovirimat active ingredient and comes in a   bottle 
containing 42 capsules. Tecovirimat capsules should be stored at room 
temperature at 20−25°C (68−77°F), with excursions permitted to 15−30°C 
(59−86°F) [see USP Controlled Room Temperature]. 
 
5.2.2 Placebo for Tecovirimat 
 
The oral formulation of the placebo for Tecovirimat is provided as oral capsules 

 
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containing white to off-white powder in orange and black hard gelatin capsules. 
The placebo comes in a bottle containing 42 capsules. Placebo for Tecovirimat 
should be stored at 20−25°C (68−77°F), [USP controlled room temperature].  
  
5.3 
Study Product Supply, Distribution, and Accountability 
  
5.3.1 Study Product Supply and Distribution 
 
Study products will be made available to sites through the NIAID Clinical Research 
Products Management Center (CRPMC). Upon successful completion of protocol 
registration procedures, the product may be obtained by the investigational 
pharmacist by following the instructions provided in the manual Pharmacy 
Guidelines and Instructions for DAIDS Clinical Trials Networks. 
 
All study products will be donated by SIGA.  
 
5.3.2 Study Product Accountability 
 
The investigational pharmacist is required to maintain complete records of all 
study products received from the NIAID CRPMC and subsequently dispensed. 
All study products must be stored in the investigational pharmacy. 
 
5.3.3 Final Disposition of Study Product 
 
For U.S. clinical research sites, all unused study product remaining at sites 
after the study is completed or terminated must be returned to the NIAID CRPMC 
(unless otherwise directed by the sponsor). Study products may also be returned 
to the CRPMC for other reasons, as requested by the sponsor. Investigational 
pharmacists will follow the relevant instructions for return of unused study 
products provided in the manual Pharmacy Guidelines and Instructions for 
DAIDS Clinical Trials Networks. 
 
At non-U.S. clinical research sites, the investigational pharmacist must 
follow the instructions in the Pharmacy Guidelines and Instructions for 
DAIDS Clinical Trials Networks for the destruction of unused study 
products remaining at the site. 
  
5.4 
Concomitant Medications 
 
Whenever a concomitant medication or study agent is initiated or a dose changed, 
investigators must review the concomitant medication’s and study agent’s most recent 
package insert, Investigator’s Brochure, or updated information from DAIDS to obtain the 
most current information on drug interactions, contraindications, and precautions.  
 

 
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5.4.1 Prohibited Medications 
 
Drug interaction data with tecovirimat are evolving. Study personnel are required to 
review the most updated interactions on the PSWP. There are no prohibited medications. 
 
5.4.2 Precautionary Medications 
 
Tecovirimat is a weak inducer of CYP3A and a weak inhibitor of CYP2C8 and 
CYP2C19. Participants taking drugs that are substrates of CYP3A should be 
monitored for reduced efficacy and participants who are taking drugs that are 
substrates for CYP2C8 and/or CYP2C19 should be monitored for side effects. 
Please see the PSWP for a table of CYP3A, CYP2C8, and CYP2C19 substrates 
which may be altered by tecovirimat.  
 
Avoid initiation of intramuscular cabotegravir/ritonavir during study drug 
administration and for two weeks following completion of study drug 
administration.  
 
Use of other antivirals with expected activity against HMPXV (i.e., cidofovir and 
brincidofovir) is strongly discouraged for Arms A and B. Sites should contact the 
CMC prior to use in Arms A and B.  
 
For those with severe immunosuppression, concomitant treatment with cidofovir 
or brincidofovir can be considered at the discretion of the local investigator. 
Please note that these medications are not provided by the study.  
 
An increase in dose for doravirine, rilpivirine, or maraviroc is not warranted, as it 
may lead to unnecessary confusion, dosing errors, and pill burden.  

 
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6.0 
CLINICAL AND LABORATORY EVALUATIONS 
 
6.1 
Schedule of Evaluations  
 
Table 6.1-1: Participants 18 Years of Age or Older; Arms A, B, and C – ENROLLED/FOLLOWED IN PERSON 
Evaluation 
Screening 
Entry (Day 1) 
Post-Entry Evaluations 
(Days) 
Confirmation of 
Lesion Resolution 
Confirmation of 
Disease 
Progression
6 
8 
15 
22 
29 
57 
Visit Windows (Days) 
-7 
 
± 1 
± 2 
± 2 
± 2 
± 4 
± 7 
 
 
Visit Location (R: Remote, P: In Person) 
 
 
R 
P 
P 
P 
P 
P 
P/R 
P 
Clinical Evaluations – see section 6.3.1 
Medical History 
X 
 
 
 
 
 
 
 
 
 
Medication History 
X 
 
 
 
 
 
 
 
 
 
Complete Physical Exam 
X 
 
 
 
 
 
 
 
 
 
Targeted Physical Exam 
 
X 
 
X 
X 
X 
X 
X 
(X) 
X 
Skin/HMPXV Assessment 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
Concomitant Medications 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
Study Treatment Modifications 
 
 
X 
X 
X 
 
 
 
 
 
Clinical/Safety/Laboratory Evaluations – see section 6.3.2 
Hematology 
 
X 
 
X 
 
 
 
 
 
 
Serum Chemistries 
 
X 
 
X 
 
 
 
 
 
 

 
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Evaluation 
Screening 
Entry (Day 1) 
Post-Entry Evaluations 
(Days) 
Confirmation of 
Lesion Resolution 
Confirmation of 
Disease 
Progression
6 
8 
15 
22 
29 
57 
Visit Windows (Days) 
-7 
 
± 1 
± 2 
± 2 
± 2 
± 4 
± 7 
 
 
Visit Location (R: Remote, P: In Person) 
 
 
R 
P 
P 
P 
P 
P 
P/R 
P 
Urine or Serum Pregnancy 
X 
 
 
Whenever pregnancy is suspected 
 
X 
Syphilis Serology with Reflex to Confirmatory 
Testing 
 
X 
 
 
 
 
 
 
 
 
Chlamydia and Gonorrhea (Swab) 
 
X 
 
 
 
 
 
 
 
 
Chlamydia and Gonorrhea (Urine) 
 
X 
 
 
 
 
 
 
 
 
HSV PCR Testing  
X 
 
 
 
 
 
 
 
 
 
Anti-HIV-1/HIV-2 
 
X 
 
 
 
 
 
 
 
 
HIV-1 RNA (for PLWH or on HIV PrEP) 
 
X 
 
 
 
 
 
 
 
 
Absolute CD4 (for PLWH) 
 
X 
 
 
 
 
 
 
 
 
HBsAg, Anti HBs, Anti HBc  
 
X 
 
 
 
 
 
 
 
 
Hepatitis C Virus Antibody with Reflex 
 
X 
 
 
 
 
 
 
 
 
HMPXV Diagnostic Skin Swab  
(Presumptive Diagnosis Only) 
X 
 
 
 
 
 
 
 
 
 
HMPXV Diagnostic Oral Swab  
(Presumptive Diagnosis Only) 
X 
 
 
 
 
 
 
 
 
 

 
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Evaluation 
Screening 
Entry (Day 1) 
Post-Entry Evaluations 
(Days) 
Confirmation of 
Lesion Resolution 
Confirmation of 
Disease 
Progression
6 
8 
15 
22 
29 
57 
Visit Windows (Days) 
-7 
 
± 1 
± 2 
± 2 
± 2 
± 4 
± 7 
 
 
Visit Location (R: Remote, P: In Person) 
 
 
R 
P 
P 
P 
P 
P 
P/R 
P 
HMPXV Diagnostic Rectal Swab  
(Presumptive Diagnosis Only) 
X 
 
 
 
 
 
 
 
 
 
Study Drug Administration – see section 6.3.3 
Study Drug Administration 
 
Daily on days 1 - 15 
 
 
 
 
 
Telephone Check 
 
 
X 
 
 
 
 
 
 
 
Open-Label Dispensing of Tecovirimat 
 
 
 
 
 
 
 
 
 
X 
Participant-Completed Evaluations – see section 6.3.4 
Participant-Completed Study Diary  
 
Daily self-assessment days 1 - 29 
 
 
 
Participant-Completed Pain Scale (NRS) 
X 
Daily self-assessment days 1 - 29 
 
 
 
Participant-Collected Photographs of Lesions 
(optional) 
 
Daily self-assessment days 1 - 29 
 
 
 
Participant-Completed Study Dosing Diary 
 
Daily on days 1 - 15 
 
 
 
 
 
Semen Collection (optional) 
 
X 
 
 
X 
 
 
X 
 
X 
Questionnaires – see section 6.3.5 
HMPXV Transmission Questionnaire 
 
X 
 
 
 
 
X 
 
 
 

 
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Evaluation 
Screening 
Entry (Day 1) 
Post-Entry Evaluations 
(Days) 
Confirmation of 
Lesion Resolution 
Confirmation of 
Disease 
Progression
6 
8 
15 
22 
29 
57 
Visit Windows (Days) 
-7 
 
± 1 
± 2 
± 2 
± 2 
± 4 
± 7 
 
 
Visit Location (R: Remote, P: In Person) 
 
 
R 
P 
P 
P 
P 
P 
P/R 
P 
Household Transmission Questionnaire 
 
X 
 
 
 
 
X 
X 
 
 
EQ-5D-5L Questionnaire 
 
X 
 
X 
X 
 
X 
 
 
 
Anal Health Related Symptom Index  
(if indicated) 
 
X 
X 
 
X 
 
 
X 
 
 
Samples Collected at Clinic – see section 6.3.6 
HMPXV Index/New Skin Lesion Swab  
 
X 
 
X 
X 
X 
X 
X 
 
X 
HMPXV Oral Swab 
 
X 
 
X 
X 
X 
X 
X 
 
X 
HMPXV Rectal Swab  
 
X 
 
X 
X 
X 
X 
X 
 
X 
HMPXV Vaginal Swab 
 
X 
 
X 
X 
X 
X 
X 
 
X 
Breastmilk Collection (breastfeeding only) 
 
X 
 
X 
X 
X 
X 
X 
 
 
Ocular Fluid (suspected eye disease only) 
 
X 
 
X 
X 
X 
X 
X 
 
X 
Whole Blood (HMPXV DNA) 
 
X 
 
X 
X 
X 
X 
X 
 
X 
Pharmacokinetic Samples - see section 6.3.7 
ARV Trough PK (Plasma ) 
(for participants on ARVs) 
 
X 
 
X  
X 
 
 
 
 
 

 
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Evaluation 
Screening 
Entry (Day 1) 
Post-Entry Evaluations 
(Days) 
Confirmation of 
Lesion Resolution 
Confirmation of 
Disease 
Progression
6 
8 
15 
22 
29 
57 
Visit Windows (Days) 
-7 
 
± 1 
± 2 
± 2 
± 2 
± 4 
± 7 
 
 
Visit Location (R: Remote, P: In Person) 
 
 
R 
P 
P 
P 
P 
P 
P/R 
P 
Sparse Tecovirimat PK 
 
 
 
X 
X 
 
 
 
 
X 
Intensive PK  
 
 
 
X 
 
 
 
 
 
 
Stored Samples – see section 6.3.8 
Stored Plasma and DBS 
 
X 
 
X 
X 
 
X 
X 
 
X 
Stored Serum 
 
X 
 
X 
X 
 
X 
X 
 
X 

 
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Table 6.1-2: Participants 18 Years of Age or Older; Arms A, B, and C – ENROLLED/FOLLOWED REMOTELY 
Evaluation 
Screening 
Entry (Day 1) 
Post-Entry Evaluations 
(Days) 
Confirmation of 
Lesion Resolution 
Confirmation of 
Disease Progression 
6 
8 
15 
22 
29 
57 
Visit Windows (Days) 
-7 
 
± 1 
± 2 
± 2 
± 2 
± 4 
± 7 
 
 
Clinical Evaluations – see section 6.3.1 
Capture from clinical care, if available 
Complete Physical Exam 
X 
 
 
 
 
 
 
 
 
 
Collect at the visit 
Medical History 
X 
 
 
 
 
 
 
 
 
 
Medication History 
X 
 
 
 
 
 
 
 
 
 
Skin/HMPXV Assessment 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
Concomitant Medications 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
Study Treatment Modifications 
 
 
X 
X 
X 
 
 
 
 
 
Clinical/Safety/Laboratory Evaluations – see section 6.3.2 
Capture from clinical care, if available 
Hematology 
 
X 
 
 
 
 
 
 
 
 
Serum Chemistries 
 
X 
 
 
 
 
 
 
 
 

 
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Evaluation 
Screening 
Entry (Day 1) 
Post-Entry Evaluations 
(Days) 
Confirmation of 
Lesion Resolution 
Confirmation of 
Disease Progression 
6 
8 
15 
22 
29 
57 
Visit Windows (Days) 
-7 
 
± 1 
± 2 
± 2 
± 2 
± 4 
± 7 
 
 
Urine or Serum Pregnancy 
X 
Any time pregnancy testing is performed 
 
X 
Syphilis Serology with Reflex to 
Confirmatory Testing 
 
X 
 
 
 
 
 
 
 
 
Chlamydia and Gonorrhea (Swab) 
 
X 
 
 
 
 
 
 
 
 
Chlamydia and Gonorrhea (Urine) 
 
X 
 
 
 
 
 
 
 
 
HSV PCR Testing  
X 
 
 
 
 
 
 
 
 
 
Anti-HIV-1/HIV-2 
 
X 
 
 
 
 
 
 
 
 
HIV-1 RNA (for PLWH or on HIV PrEP) 
 
X 
 
 
 
 
 
 
 
 
Absolute CD4 (for PLWH) 
 
X 
 
 
 
 
 
 
 
 
HBsAg, Anti HBs, Anti HBc  
 
X 
 
 
 
 
 
 
 
 
Hepatitis C Virus Antibody with Reflex 
 
X 
 
 
 
 
 
 
 
 
Study Drug Administration – see section 6.3.3 
Study Drug Administration 
 
Daily on days 1 - 15 
 
 
 
 
 
Telephone Check 
 
 
X 
 
 
 
 
 
 
 

 
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Evaluation 
Screening 
Entry (Day 1) 
Post-Entry Evaluations 
(Days) 
Confirmation of 
Lesion Resolution 
Confirmation of 
Disease Progression 
6 
8 
15 
22 
29 
57 
Visit Windows (Days) 
-7 
 
± 1 
± 2 
± 2 
± 2 
± 4 
± 7 
 
 
Open-Label Dispensing of Tecovirimat 
 
 
 
 
 
 
 
 
 
X 
Participant-Completed Evaluations – see section 6.3.4 
Participant-Completed Study Diary  
 
Daily self-assessment days 1 - 29 
 
 
 
Participant-Completed Pain Scale (NRS) 
X 
Daily self-assessment days 1 - 29 
 
 
 
Participant-Collected Photographs of 
Lesions (optional)  
 
At least twice a week 
 
 
 
Participant-Completed Study Dosing Diary 
 
Daily on days 1 - 15 
 
 
 
 
 
Questionnaires – see section 6.3.5 
HMPXV Transmission Questionnaire 
 
X 
 
 
 
 
X 
 
 
 
Household Transmission Questionnaire 
 
X 
 
 
 
 
X 
X 
 
 
EQ-5D-5L Questionnaire 
 
X 
 
X 
X 
 
X 
 
 
 
Anal Health Related Symptom Index  
(if indicated) 
 
X 
X 
 
X 
 
 
X 
 
 
Samples Collected – see section 6.6 
HMPXV Index/New Skin Lesion Swab  
 
X 
 
X 
New lesion occurring on 
day 6 or later 
 
 

 
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Table 6.1-3: Additional Sampling Cohort; Participants 18 Years of Age or Older – ENROLLED/FOLLOWED IN PERSON 
ONLY 
 
Evaluations on this schedule are IN ADDITION to those indicated in Table 6.1-1. 
 
Evaluation 
(see section 6.4) 
Entry (Day 1) 
Post-Entry Evaluations 
(Days) 
2 
3 
5 
8 
11 
15 
18 
22 
25 
29 
57 
Visit Windows (Days) 
 
± 1 
± 2 
± 2 
± 2 
± 2 
± 2 
± 2 
± 2 
± 2 
± 4 
± 7 
Visit Location (R: Remote, P: In Person) 
 
R 
P 
R 
P 
R 
P 
R 
P 
R 
P 
P 
Informed Consent for Additional 
Sampling 
X 
 
 
 
 
 
 
 
 
 
 
 
Teach Oral, Rectal, Vaginal, and Skin 
Lesion Swabs 
X 
 
 
 
 
 
 
 
 
 
 
 
HMPXV Oral Swab  
 
X 
X 
X 
 
X 
 
X 
 
X 
 
 
HMPXV Rectal Swab  
 
X 
X 
X 
 
X 
 
X 
 
X 
 
 
HMPXV Vaginal Swab 
 
X 
X 
X 
 
X 
 
X 
 
X 
 
 
HMPXV Index Skin Lesion Swab 
 
X 
X 
X 
 
X 
 
X 
 
X 
 
 
Return/Review Swabs 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Urine  
X 
 
X 
 
X 
 
X 
 
 
 
X 
 
Whole Blood for HMPXV DNA  
 
 
X 
 
 
 
 
 
 
 
 
 
Sparse Tecovirimat PK 
 
 
X 
 
 
 
 
 
 
 
 
 
Stored PBMCs (optional) 
X 
 
 
 
 
 
X 
 
 
 
 
X 

 
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Table 6.1-4: Participants Younger Than 18 Years of Age; Arm C – ENROLLED/FOLLOWED IN PERSON 
Evaluation 
 
(SA =  
perform only for  
sexually-active  
participants;  
X= perform for all participants) 
Screening 
Entry (Day 1) 
Post-Entry Evaluations 
(Days) 
Confirmation of 
Lesion Resolution 
Confirmation of 
Disease Progression 
6 
8 
15 
22 
29 
57 
Visit Windows (Days) 
-7 
 
± 1 
± 2 
± 2 
± 2 
± 4 
± 7 
 
 
Visit Location (R: Remote, P: In Person) 
 
 
R 
P 
P 
P 
P 
P 
P/R 
P 
Clinical Evaluations – see section 6.3.1 
Medical History 
X 
 
 
 
 
 
 
 
 
 
Medication History 
X 
 
 
 
 
 
 
 
 
 
Complete Physical Exam 
X 
 
 
 
 
 
 
 
 
 
Targeted Physical Exam 
 
X 
 
X 
X 
X 
X 
X 
 
X 
Skin/HMPXV Assessment 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
Concomitant Medications 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
Study Treatment Modifications 
 
 
X 
X 
X 
 
 
 
 
 
Safety or Clinical Laboratory  Evaluations – see section 6.3.2 
Hematology 
 
X 
 
X 
 
 
 
 
 
 
Serum Chemistries 
 
X 
 
X 
 
 
 
 
 
 
Urine or Serum Pregnancy Testing 
SA 
 
 
Whenever pregnancy is 
suspected 
 
 

 
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Evaluation 
 
(SA =  
perform only for  
sexually-active  
participants;  
X= perform for all participants) 
Screening 
Entry (Day 1) 
Post-Entry Evaluations 
(Days) 
Confirmation of 
Lesion Resolution 
Confirmation of 
Disease Progression 
6 
8 
15 
22 
29 
57 
Visit Windows (Days) 
-7 
 
± 1 
± 2 
± 2 
± 2 
± 4 
± 7 
 
 
Visit Location (R: Remote, P: In Person) 
 
 
R 
P 
P 
P 
P 
P 
P/R 
P 
Syphilis Serology with Reflex to Confirmatory 
Testing 
 
X 
 
 
 
 
 
 
 
 
Chlamydia and Gonorrhea (Swab) 
 
SA 
 
 
 
 
 
 
 
 
Chlamydia and Gonorrhea (Urine) 
 
SA 
 
 
 
 
 
 
 
 
HSV PCR Testing  
SA 
 
 
 
 
 
 
 
 
 
Anti-HIV-1/HIV-2 
 
SA 
 
 
 
 
 
 
 
 
HIV-1 RNA (for PLWH or on HIV PrEP) 
 
X 
 
 
 
 
 
 
 
 
Absolute CD4+ (for PLWH) 
 
X 
 
 
 
 
 
 
 
 
HBsAg, Anti HBs, Anti HBc  
 
SA 
 
 
 
 
 
 
 
 
Hepatitis C Virus Antibody with Reflex 
 
SA 
 
 
 
 
 
 
 
 
HMPXV Diagnostic Skin Swab  
(Presumptive Diagnosis Only) 
X 
 
 
 
 
 
 
 
 
 
HMPXV Diagnostic Oral Swab  
(Presumptive Diagnosis Only) 
X 
 
 
 
 
 
 
 
 
 

 
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Evaluation 
 
(SA =  
perform only for  
sexually-active  
participants;  
X= perform for all participants) 
Screening 
Entry (Day 1) 
Post-Entry Evaluations 
(Days) 
Confirmation of 
Lesion Resolution 
Confirmation of 
Disease Progression 
6 
8 
15 
22 
29 
57 
Visit Windows (Days) 
-7 
 
± 1 
± 2 
± 2 
± 2 
± 4 
± 7 
 
 
Visit Location (R: Remote, P: In Person) 
 
 
R 
P 
P 
P 
P 
P 
P/R 
P 
Study Drug Administration – see section 6.3.3 
Study Drug Administration 
 
Daily on days 1 - 15 
 
 
 
 
 
Telephone Check 
 
 
X 
 
 
 
 
 
 
 
Open-Label Dispensing of Tecovirimat 
 
 
 
 
 
 
 
 
 
X 
Participant-Completed Evaluations – see section 6.3.4  
Participant-Completed Study Diary  
 
Daily self-assessment days 1 - 29 
 
 
 
Participant-Completed Pain Scale 
X 
Daily self-assessment days 1 - 29 
 
 
 
Participant-Collected Photographs of Lesions 
(optional)  
 
Daily self-assessment days 1 - 29 
 
 
 
Participant-Completed Study Dosing Diary 
 
Daily on days 1 - 15 
 
 
 
 
 
Questionnaires – see section 6.3.5 
Household Transmission Questionnaire 
 
X 
 
 
 
 
X 
X 
 
 
Samples Collected at Clinic – see section 6.3.6 
HMPXV Index/New Skin Lesion Swab 
 
X 
 
X 
X 
X 
X 
X 
 
X 

 
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Evaluation 
 
(SA =  
perform only for  
sexually-active  
participants;  
X= perform for all participants) 
Screening 
Entry (Day 1) 
Post-Entry Evaluations 
(Days) 
Confirmation of 
Lesion Resolution 
Confirmation of 
Disease Progression 
6 
8 
15 
22 
29 
57 
Visit Windows (Days) 
-7 
 
± 1 
± 2 
± 2 
± 2 
± 4 
± 7 
 
 
Visit Location (R: Remote, P: In Person) 
 
 
R 
P 
P 
P 
P 
P 
P/R 
P 
HMPXV Oral Swab  
 
X 
 
X 
X 
X 
X 
X 
 
X 
Ocular Fluid (suspected eye disease only) 
 
X 
 
X 
X 
X 
X 
X 
 
X 
Whole Blood for HMPXV DNA 
 
X 
 
X 
X 
X 
X 
X 
 
X 
Pharmacokinetic Samples - see section 6.3.7 
ARV Trough PK (Plasma)  
(for participants on ARVs) 
 
X 
 
X  
X 
 
 
 
 
 
Sparse Tecovirimat PK  
 
(X) 
 
X 
X 
 
 
 
 
X 
Intensive PK  
 
 
 
X 
 
 
 
 
 
 
Stored Samples – see section 6.3.8 
Stored Serum 
 
X 
 
 
X 
 
 
 
 
X 
 

 
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Table 6.1-5: Participants Younger Than 18 Years of Age; Arm C – ENROLLED/FOLLOWED REMOTELY 
Evaluation 
Screening 
Entry (Day 1) 
Post-Entry Evaluations 
(Days) 
Confirmation of 
Lesion Resolution 
Confirmation of 
Disease Progression 
6 
8 
15 
22 
29 
57 
Visit Windows (Days) 
-7 
 
± 1 
± 2 
± 2 
± 2 
± 4 
± 7 
 
 
Clinical Evaluations – see section 6.3.1 
Capture from clinical care, if available 
Complete Physical Exam 
X 
 
 
 
 
 
 
 
 
 
Collect at the visit 
Medical History 
X 
 
 
 
 
 
 
 
 
 
Medication History 
X 
 
 
 
 
 
 
 
 
 
Skin/HMPXV Assessment 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
Concomitant Medications 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
Study Treatment Modifications 
 
 
X 
X 
X 
 
 
 
 
 
Clinical/Safety/Laboratory Evaluations – see section 6.3.2 
Capture from clinical care, if available 
Hematology 
 
X 
 
 
 
 
 
 
 
 
Serum Chemistries 
 
X 
 
 
 
 
 
 
 
 

 
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Evaluation 
Screening 
Entry (Day 1) 
Post-Entry Evaluations 
(Days) 
Confirmation of 
Lesion Resolution 
Confirmation of 
Disease Progression 
6 
8 
15 
22 
29 
57 
Visit Windows (Days) 
-7 
 
± 1 
± 2 
± 2 
± 2 
± 4 
± 7 
 
 
Urine or Serum Pregnancy 
X 
Any time pregnancy testing is performed 
 
X 
Study Drug Administration – see section 6.3.3 
Study Drug Administration 
 
Daily on days 1 - 15 
 
 
 
 
 
Telephone Check 
 
 
X 
 
 
 
 
 
 
 
Open-Label Dispensing of Tecovirimat 
 
 
 
 
 
 
 
 
 
X 
Participant-Completed Evaluations – see section 6.3.4 
Participant-Completed Study Diary  
 
Daily self-assessment days 1 - 29 
 
 
 
Participant-Completed Pain Scale (NRS) 
X 
Daily self-assessment days 1 - 29 
 
 
 
Participant-Collected Photographs of 
Lesions (optional) 
 
At least twice a week 
 
 
 
Participant-Completed Study Dosing Diary 
 
Daily on days 1 - 15 
 
 
 
 
 
Questionnaires – see section 6.3.5 
Household Transmission Questionnaire 
 
X 
 
 
 
 
X 
X 
 
 
Samples Collected – see section 6.6 
HMPXV Index/New Skin Lesion Swab  
 
X 
 
X 
New lesion occurring on 
Day 6 or later 
 
 

 
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6.2 
Timing of Evaluations 
 
6.2.1 Screening Evaluations  
 
Evaluations needed to determine eligibility and stratification for randomization to 
arms A or B or registration to Arm C must occur prior to the participant starting 
any study medications, treatments, or interventions. These assessments are 
included in the “Screening” column in the Schedule of Evaluations (SOE). 
 
Screening 
Screening evaluations to determine eligibility must be completed within 7 days 
prior to study entry unless otherwise specified. Screening evaluations will 
generally occur on the day of randomization with the possible exception of local 
HMPXV diagnostic testing. 
 
In addition to data being collected on participants who enroll into the study, 
demographic, clinical, and laboratory data on screening failures will be captured 
in a Screening Failure Results form and entered into the ACTG database.  
 
6.2.2 Entry Evaluations 
 
Entry evaluations can occur at the time of screening or the day of randomization 
or registration. Participants should begin treatment the same day as 
randomization. Treatment must begin within 3 days after randomization or 
registration. For those enrolled/followed remotely, treatment must begin 
within 5 days after randomization or registration. 
  
6.2.3 Post-Entry Evaluations 
 
On-Treatment/Post-Treatment Evaluations  
Evaluations should occur in the visit windows described in section 6.1. 
 
Study Completion Evaluations  
Day 57 evaluations will serve as the study completion evaluations. 
 
Confirmation of Disease Progression 
Participants in Arms A or B who develop severe disease (as defined in section 
4.3.2) should be seen in person or through telemedicine for a confirmation of 
disease progression visit. This can occur at any point after randomization. If 
severe disease is confirmed by study personnel, participants should stop blinded 
study treatment and start a 14-day course of open-label tecovirimat. Participants 
should continue to be followed according to the SOE. Participants do not change 
to Arm C. If these participants are hospitalized and the study staff are unable to 
conduct an in-person visit, study staff should make efforts to ensure access to 
open-label tecovirimat. Sites should continue to follow participants according to 
the SOE when able to do so. 

 
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If participants progress to severe disease after day 7 while on blinded study 
medication or after blinded study medication has stopped, the site investigator 
should contact the CMC to discuss management. 
 
Participants who report severe pain (7 or greater on the 11-point numerical rating 
scale) on day 6 or later should be seen in person or through telemedicine for a 
confirmation of disease progression visit. Participants should stop blinded study 
treatment and start a 14-day course of open-label tecovirimat. Participants 
should continue to be followed according to the SOE. Participants do not change 
to Arm C. 
 
Of note, participants randomized to Arm A who subsequently receive open-label 
tecovirimat will receive a total course of tecovirimat longer than 14 days. 
 
Confirmation of Lesion Resolution 
If a participant reports lesion resolution, then a remote or in-person visit should 
be performed as soon as possible to confirm lesion resolution. 
 
If the visit is done remotely, a targeted physical exam is not required. 
 
6.2.4 Discontinuation Evaluations 
 
Evaluations for Randomized or Registered Participants Who Do Not Start Study 
Treatment 
All eCRFs must be keyed for the period up to and including the entry visit. 
 
Premature Study Discontinuation Evaluations  
Evaluations performed at the participant’s last remote or in person visit will 
serve as the study discontinuation evaluations for participants who prematurely 
discontinue from the study; there are no additional premature discontinuation 
evaluations required. 
 
6.3 
Instructions for Evaluations (Arms A, B, and C) 
 
All clinical and laboratory information required by this protocol is to be present in the 
source documents. Sites must refer to the Source Document Guidelines on the DAIDS 
website for information about what must be included in the source document: 
https://www.niaid.nih.gov/sites/default/files/daids-sourcedocpolicy.pdf. 
 
All stated evaluations are to be recorded on the eCRF unless otherwise specified. Refer 
to section 7.0 for information on the DAIDS AE Grading Table and AE reporting of 
adverse events requirements. 
 

 
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6.3.1 Clinical Evaluations 
 
Medical History 
The medical history must include all signs and symptoms regardless of grade 
and all diagnoses identified by the ACTG criteria for clinical events and other 
diagnoses regardless of grade within the past 30 days.  
 
In addition, the following diagnoses should be recorded regardless of when the 
diagnosis was made: 
• 
HIV 
• 
Diagnoses listed in section 4.3.2 
 
Any allergies to any medications and their formulations must also be 
documented.  
 
Medication History 
A medication history must be present, including start and stop dates. The table 
below lists the medications that must be included in the history.  
 
Medication Category 
Complete History or Timeframe 
Antiretroviral therapy or 
pre-exposure prophylaxis 
Within 30 days prior to study entry 
Long-acting cabotegravir or rilpivirine 
Within one year prior to study entry 
Immune-based therapy, cancer 
therapy, immunosuppressants 
Within 90 days prior to study entry 
Prescription drugs (other) 
Within 14 days prior to entry 
Treatment for STIs 
Within 30 days prior to study entry 
Smallpox/HMPXV/MVA vaccine  
(childhood and recent receipt) 
Complete history 
Childhood vaccinations 
Within 30 days prior to study entry 
Prescription or over the counter 
medications or supplements listed in 
section 4.3.2 or section 5.4.2 
Within 30 days prior to study entry 
 
Complete Physical Examination 
A complete physical examination at screening for those seen in person 
should include at a minimum an examination of the skin, head, mouth, and neck; 
auscultation of the chest; cardiac examination; abdominal examination; 
examination of the lower extremities for edema. The complete physical 
examination will also include signs and symptoms, diagnoses, and vital signs 
(height, weight, temperature, pulse, and blood pressure). For those 
enrolled/followed remotely, sites should attempt to locate clinical care 
records including physical examinations. 
 

 
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Targeted Physical Examination 
A targeted physical examination is to include vital signs (weight, temperature, 
pulse, and blood pressure), and is to be driven by any previously identified or 
new adverse event, that the participant has experienced since the last visit or at 
this visit. This examination is not required for those enrolled/followed 
remotely. 
 
Post entry, see section 8.2 for collection requirements for pregnancy. 
 
Refer to section 7.2 for AE collection requirements.  
 
Skin/HMPXV Assessment 
This assessment will include: 
• 
A comprehensive skin assessment to locate all HMPXV skin lesions (see 
MOP for details). This assessment should include numbers of lesions, 
location of lesions (face, eyes, scalp, neck, arms, legs, trunk, penis, other 
genital area, vulva, buttock, perianus, and oropharynx) and description of 
lesions (including presence of bacterial superinfection). 
• 
Representative photos of lesions either in person or via telemedicine 
(optional) 
• 
Recording of the location of sampled lesions.  
• 
Designation of a lesion as the “Index Lesion” for the purposes of frequent 
sampling in the Additional Sampling cohort and for all participants to follow 
through the participant diary. 
• 
An examination of the lymph nodes (femoral, axillary, cervical) for in person 
assessments only. 
• 
An assessment for potential ocular complications including assessing for eye 
redness, eye pain, floaters, and any changes in vision.  
 
Concomitant Medications 
Post-entry, the following new and discontinued concomitant medications must be 
recorded: 
• 
Changes in ART 
• 
Treatment of STIs 
• 
Opioid use 
• 
Medications listed in section 4.3.2 or section 5.4.2.  
• 
Any prescription or over the counter medications initiated during the 14 days 
of study drug treatment 
• 
Other analgesics (e.g., acetaminophen, NSAIDS, topical analgesics) will be 
captured on Patient Diaries only 
• 
Medications or treatments with expected activity against HMPXV (e.g., 
cidofovir, brincidofovir, trifluridine eye drops) 
• 
Smallpox vaccination or vaccinia immune globulin 
 

 
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Study Treatment Modifications 
Record all study drug modifications, including initial doses, participant-initiated 
and/or protocol-mandated modifications, inadvertent and deliberate interruptions 
of more than two consecutive doses since the last visit. Record any permanent 
discontinuation of treatment. 
 
6.3.2 Laboratory Evaluations 
 
At screening/entry all laboratory values must be recorded. For participants 
enrolled/followed remotely, values from clinical care assessments should 
be entered if available. For post-entry assessments conducted during in 
person visits, record all laboratory values for AST, ALT, albumin, bilirubin (total 
and direct) regardless of grade; record abnormal laboratory findings as per 
section 7.2. 
 
Hematology 
Participants will have blood drawn for hemoglobin, hematocrit, WBC with 
differential, platelets, and RBC per the SOE. Samples must be tested by a 
laboratory that possesses a CLIA certification or equivalent (U.S. sites) or at any 
network-approved non-U.S. laboratory that operates in accordance with GCLP 
and participates in appropriate external quality assurance programs.  
 
For participants enrolled/followed remotely, values from clinical care 
assessments should be entered if available.  
 
At Entry/Day 1, blood should be drawn before study drug administration.  
  
Serum Chemistries 
Participants will have blood drawn for liver function tests (albumin, ALT, ALP, 
AST, total bilirubin, direct bilirubin, and total protein), and renal function tests 
(BUN, creatinine, potassium, and sodium) per the SOE. Samples must be tested 
by a laboratory that possesses a CLIA certification or equivalent (U.S. sites) or at 
any network-approved non-U.S. laboratory that operates in accordance with 
GCLP and participates in appropriate external quality assurance programs.  
 
For participants enrolled/followed remotely, values from clinical care 
assessments should be entered if available.  
  
At Entry/Day 1, blood should be drawn before study drug administration. 
  
Urine or Serum Pregnancy 
For participants of reproductive potential: Serum or urine b-HCG. (Urine test 
must have a sensitivity of ≤25 mIU/mL). Samples must be tested by a laboratory 
that possesses a CLIA certification or equivalent (U.S. sites) or at any network-
approved non-U.S. laboratory that operates in accordance with GCLP and 
participates in appropriate external quality assurance programs Pregnancy 
testing results must be obtained prior to randomization/registration. 

 
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Urine or serum pregnancy testing should be collected from clinical care if 
available but is not required for those followed remotely if it is not 
available. If pregnancy is suspected, then the participant is encouraged to 
obtain pregnancy testing.  
  
Post-screening, pregnancy testing should be done any time pregnancy is 
suspected. 
 
In the event of pregnancy occurring during the study, record pregnancy on an 
eCRF and record pregnancy outcome per section 8.2. 
 
Syphilis Serology with Reflex to Confirmatory Testing 
RPR or EIA will be performed in real time at a laboratory that possesses a CLIA 
certification or equivalent (U.S. sites) or at any network-approved non-U.S. 
laboratory that operates in accordance with GCLP and participates in appropriate 
external quality assurance programs. If the initial test yields positive results the 
alternate treponema test must be performed for confirmation. Positive syphilis 
tests should be treated locally with treatment of STIs captured on the CRF. 
Samples do not need to be repeated if they are available within 7 days prior to 
entry, but the results should be recorded on the CRF.  
 
For participants enrolled/followed remotely, values from clinical care 
assessments should be entered if available.  
 
Sites should provide appropriate STI treatment or refer as needed. 
 
Gonorrhea and Chlamydia (Swab) 
Oropharyngeal and rectal swabs (rectal swabs will only be done for participants ≥ 
18 years of age) for gonorrhea and chlamydia will be performed in real time using 
a nucleic acid amplification testing (NAAT) or culture. Samples must be tested by 
a laboratory that possesses a CLIA certification or equivalent (U.S. sites) or at 
any network-approved non-U.S. laboratory that operates in accordance with 
GCLP and participates in appropriate external quality assurance programs. 
Positive gonorrhea and chlamydia tests should be treated locally with treatment 
of STIs captured on the CRF. Samples do not need to be repeated if they are 
available within 7 days prior to entry, but the results should be recorded on the 
CRF.  
 
For participants enrolled/followed remotely, values from clinical care 
assessments should be entered if available.  
 
Sites should provide appropriate STI treatment or refer as needed. 
 
Gonorrhea and Chlamydia (Urine) 
Urine testing for gonorrhea and chlamydia will be performed in real time using a 
nucleic acid amplification testing (NAAT). Samples must be tested by a 
laboratory that possesses a CLIA certification or equivalent (U.S. sites) or at any 

 
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network-approved non-U.S. laboratory that operates in accordance with GCLP 
and participates in appropriate external quality assurance programs. Positive 
gonorrhea and chlamydia tests should be treated locally with treatment of STIs 
captured on the CRF. Samples do not need to be repeated if they are available 
within 7 days of entry, but the results should be recorded on the CRF.  
 
For participants enrolled/followed remotely, values from clinical care 
assessments should be entered if available.  
 
Sites should provide appropriate STI treatment or refer as needed. 
 
HSV Testing (if indicated) 
Swabs of genital, perianal, perioral or other ulcerative lesions suspicious for HSV 
should be swabbed and tested for HSV for participants with proctitis, swabs of 
the rectum should be obtained for HSV testing. Samples must be tested by a 
laboratory that possesses a CLIA certification or equivalent (U.S. sites) or at any 
network-approved non-U.S. laboratory that operates in accordance with GCLP 
and participates in appropriate external quality assurance programs. Sites may 
obtain testing through the central laboratory for this study, which will generate a 
clinical laboratory report that can be used for management of the participant. 
Samples do not need to be repeated if they are available within 7 days prior to 
entry, but the results should be recorded on the CRF.  
 
For participants enrolled/followed remotely, values from clinical care 
assessments should be entered if available.  
 
Sites should provide appropriate STI treatment or refer as needed. 
 
Anti-HIV-1/HIV-2 
HIV-1/HIV-2 antibody testing will be done at a laboratory that possesses a CLIA 
certification, waiver, or equivalent (U.S. sites) or at any network-approved non-
U.S. laboratory that operates in accordance with GCLP and participates in 
appropriate external quality assurance programs. Samples do not need to be 
repeated if they are available within 7 days prior to entry, but the results should 
be recorded on the CRF. For participants enrolled/followed remotely, values 
from clinical care assessments should be entered if available.  
 
Participants should be referred for treatment of HIV as required. 
 
HIV-1 RNA (for PLWH or on HIV PrEP) 
Participants with HIV and those on HIV pre-exposure prophylaxis should have 
plasma HIV-1 testing per the SOE. Samples must be tested by a laboratory that 
possesses a CLIA certification or equivalent (U.S. sites) or at any network-
approved non-U.S. laboratory that operates in accordance with GCLP and 
participates in VQA and is currently certified.  
 

 
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For participants enrolled/followed remotely, values from clinical care 
assessments should be entered if available.  
 
Absolute CD4 (for PLWH) 
Obtain absolute CD4 testing per the SOE from a laboratory that possesses a 
CLIA certification or equivalent (U.S. sites) or IQA certification (non-U.S. sites).  
 
For participants enrolled/followed remotely, values from clinical care 
assessments should be entered if available.  
 
HBsAg, Anti HBs, Anti HBc  
NOTE: Prior documentation of positive HBsAb is acceptable evidence that 
hepatitis B is not present. 
 
In the absence of documented positive HBsAb, obtain HBsAb, HBsAg, and 
HBcAb prior to study entry. Samples must be tested by a laboratory that 
possesses a CLIA certification or equivalent (U.S. sites) or at any network-
approved non-U.S. laboratory that operates in accordance with GCLP and 
participates in appropriate external quality assurance programs.  
 
For participants enrolled/followed remotely, values from clinical care 
assessments should be entered if available.  
 
Hepatitis C Virus (HCV) Antibody with Reflex 
Anti HCV with reflex to HCV RNA as part of screening/entry from a laboratory 
that possesses a CLIA certification or equivalent (U.S. sites) or at any network-
approved non-U.S. laboratory that operates in accordance with GCLP and 
participates in appropriate external quality assurance programs 
 
If Anti HCV is positive, HCV RNA should be performed by a laboratory that 
possesses a CLIA certification or equivalent (U.S. sites) or at any network-approved 
non-U.S. laboratory that operates in accordance with GCLP and participates in 
appropriate external quality assurance programs. Samples do not need to be 
repeated if they are available within 7 days prior to entry, but the results should be 
recorded on the CRF. 
 
For participants enrolled/followed remotely, values from clinical care 
assessments should be entered if available.  
 
HMPXV Diagnostic Swabs (Skin, Oral, Rectal) (Presumptive Diagnosis Only) 
Participants enrolled with laboratory-confirmed HMPXV do not need this testing.  
 
Participants seen in person who have a pending test obtained locally should send 
samples for diagnostic testing to the designated central laboratory testing in real-
time. This will generate a laboratory report that should be placed in the participant’s 
medical record. Up to 3 samples should be submitted: 1) swab of skin lesions: If 3 or 
more skin lesions are present, then up to 3 lesions should each be swabbed with a 

 
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unique swab and the 3 swabs placed together in one tube of viral transport media 
(see the Lab Processing Chart (LPC)). If one lesion is present, then only 1 swab 
should be obtained. If no lesions are present (e.g., isolated proctitis or mouth 
lesions), then only the other two samples should be submitted, 2) rectal swab (if 
reporting rectal symptoms), 3) oropharyngeal swab (if reporting mouth lesions, 
mouth pain or sore throat). 
 
NOTE: These specimens are in addition to the other specimens that are required 
by the protocol. For example, these participants will have skin lesion swabs sent 
for diagnostic testing in real time in addition to separate skin swabs sent for other 
protocol objectives to be batch tested. 
 
Participants enrolled in person for whom both the local test (if one was 
obtained) and all clinically reported HMPXV tests from the central 
laboratory are negative should stop study drug. Follow up through remote 
or in person contact will occur 7 days after stopping study drug to assess 
for AEs.  
 
For participants who are enrolled remotely, sites should verify that the 
local laboratory test confirmed HMPXV or verify that a local laboratory test 
confirming HMPXV is pending. No additional diagnostic testing is required. 
Participants enrolled remotely for whom the local HMPXV testing is 
negative should stop study drug. Follow up through remote contact will 
occur 7 days after stopping study drug to assess for AEs.  
 
6.3.3 Study Drug Administration 
 
Study Drug Administration 
Study drug will be self-administered for 14 days with the exception of intensive 
PK visits where participants will be instructed to hold the morning doses of study 
drug and bring study drug to the research center in the original container. 
 
Caregivers will assist with tecovirimat dosing for children who are unable to self-
administer the tecovirimat capsules and those who require opening of the 
tecovirimat capsules and dissolution in water. Instructions for opening capsules 
and preparing and administering the tecovirimat solution are provided in the 
MOP.  
 
Telephone Check  
Study staff will perform a telephone check per the SOE to assess participant’s 
symptoms and level of reported pain (on a numerical rating scale for adults and 
on a face scale for pediatric participants under the age of 18). 
 
Open-Label Administration of Tecovirimat 
Participants in Arms A and B reporting severe pain (7 or greater on the numerical 
rating scale) at day 6 will stop blinded study treatment and start a 14-day course 

 
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of open-label tecovirimat. Participants in Arms A and B who progress to severe 
disease as defined in section 4.3.2 will stop blinded study treatment and start a 
14-day course of open-label tecovirimat. These participants will be seen for an in-
person visit to confirm indication for open-label tecovirimat and to receive a 14-
day course of unblinded tecovirimat. These participants will continue to be 
followed per the SOE. 
 
6.3.4 Participant-Completed Evaluations 
 
Any evaluation listed as “participant completed” on the Schedule of Evaluations 
can be understood to be “participant or parent/guardian completed” in the case of 
pediatric participants requiring assistance.  
 
Participant-Completed Study Diary 
This will be completed per the SOE. The diary will collect the occurrence of new 
lesions, overall progress of lesions, clinical resolution (primary endpoint), and 
complete healing. The diary will track the progress of the designated “Index 
lesion” daily. This diary will collect the presence of specified HMPXV symptoms 
and the use of concomitant therapies to treat symptoms.  
 
Participant-Completed Pain Scale 
This will be a single item, the numeric rating scale for overall pain (on a 
numerical rating scale for adults and on a face scale [the Wong-Baker FACES 
Pain Rating Scale] for pediatric participants under the age of 18). 
 
Participant-Collected Photographs of Lesions (optional) 
Photographs of the index lesions, and other representative, new, or worrisome 
lesions will be obtained by participants per the SOE (see MOP for details). 
These photographs should be available to study staff to help determine whether 
clinical resolution has been achieved. Sites may be requested to submit certain 
photographs to the central database. 
 
Participant-Completed Study Dosing Diary 
This will be completed per the SOE. The dosing diary will collect the date 
and time of study drug doses. 
 
Semen Collection (Optional) 
Males will provide semen specimens as described in the MOP. 
 
6.3.5 Questionnaires 
 
Questionnaires are posted on the DMC Portal in the Forms Management Utility.  
 
HMPXV Transmission Questionnaire 
This questionnaire will assess HMPXV exposure and recent sexual activity.  
 

 
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Household Contact Questionnaire 
This questionnaire will ask about household contacts of participants and additional 
cases of HMPXV within the household. This questionnaire will be updated during the 
protocol to ascertain the new cases within the household during study follow-up. 
 
EQ-5D-5L Questionnaire 
Participants will be asked about symptoms and diagnoses experienced using the 
EQ-5D-5L instrument. 
 
Anal Health-Related Symptom Index (if indicated) 
The A-HRSI asks participants to rate the degree of prevalence or impact of their 
physical symptoms, physical impacts, or psychological symptoms. Items are 
averaged across each domain, with higher scores indicative of worse health-related 
quality of life (HRQoL). The measure takes approximately 6-10 minutes to complete in 
person or either via telephone-facilitated interview or participant completed electronic 
form. This will be done in participants reporting anal pain or proctitis at baseline.  
 
6.3.6 Samples Collected at Clinic (in person visits only) 
 
Oropharyngeal Swabs, Rectal Swabs, and/or Skin Lesion Swabs 
Oropharyngeal, rectal, and/or skin lesion swabs will be collected by site staff per 
the SOE (see MOP for details). Swabs will be collected for HMPXV testing, 
including viral levels, sequencing, and culture. For storage and shipping 
instructions, refer to the LPC. 
 
The skin lesion swabs should include the “Index Lesion”. This lesion will be 
swabbed throughout study follow-up.  
 
New skin lesions that have appeared since the participant’s last study visit should 
be swabbed (starting with in person visits after entry). 
 
At Entry/Day 1, the swabs should be collected prior to the first dose of 
investigational agent/placebo.  
 
Self-Collected Vaginal Swab 
Self-collected vaginal swabs (see MOP for details). Collect before any 
gynecologic exam with cervical cytology at visits where both procedures are 
scheduled. Swabs should not be obtained during the 14 days after any cervical 
or vaginal biopsy or procedure. For storage and shipping instructions, refer to the 
LPC. 
 
Breastmilk 
Lactating women will be asked to express breastmilk during study visits per the 
SOE, if able. For interpretation, this sample should be collected as close to the 
PK blood draw as possible at day 8 and 15.  
 

 
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For storage and shipping instructions, refer to the LPC. Any remaining expressed 
milk should be discarded.  
 
Ocular Fluid (For Eye Disease Only) 
For participants with ocular involvement with HMPXV (i.e., conjunctivitis, ocular 
lesion, vision change), collect tear fluid if possible (see MOP for details). If 
bilateral disease is present, then collect two independent samples. For storage 
and shipping instructions, refer to the LPC. 
 
Whole Blood for HMPXV DNA Levels 
Whole blood HMPXV DNA levels will be performed per the SOE. For storage and 
shipping instructions, refer to the LPC. 
 
6.3.7 Pharmacokinetics 
 
See the A5418 Lab Processing Chart for instructions on PK sample collection, 
processing, and shipment.  
 
ARV Trough PK (Plasma) 
Collected only from participants on ARVs. Trough samples for ARV PK will be 
obtained per the SOE. The time of prior ARV dosing for all ARV will be carefully 
recorded. If participant’s ARV regimen is twice daily, schedule the trough around 
the ARV metabolized by CYP3A4 (e.g., HIV protease inhibitors, cobicistat, 
maraviroc, NNRTIs). If an ARV trough is not possible because of evening dosing 
of daily ARV, attempt to obtain the samples at the same time post-ARV dose. For 
storage and shipping instructions, refer to the LPC. 
 
Sparse PK 
Entry/Day 1. The first 8 participants <6 kg will have a single blood draw 2-4 
hours after the first dose of study drug. This blood draw should only be 
performed if the participant is hospitalized and the blood draw will not 
result in exceeding maximum blood volume allowances. For storage and 
shipping instructions, refer to the LPC. 
 
Day 8. All participants not undergoing intensive PK will have a study drug trough 
obtained on day 8. This blood draw should occur 12 hours (+/- 2 hours) after 
study drug dosing for every 12-hour study product dosing and 8 hours (+/- 2 
hours) for every 8-hour study product dosing. Sparse PK sampling should be 
omitted if the participant has been off study drug >24 hours. The time of 
prior study product dosing should be carefully recorded. For storage and shipping 
instructions, refer to the LPC. 
 
Day 15. All participants will have a single blood sample obtained within 4 hours of 
study product administration. Sparse PK sampling should be omitted if the 
participant has been off study drug >24 hours. For storage and shipping 
instructions, refer to the LPC. 
 

 
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Confirmation of Disease Progression. Participants that complete this visit will 
have a single blood sample obtained. The time of prior study product dose will be 
carefully recorded. For storage and shipping instructions, refer to the LPC. 
 
Intensive Pharmacokinetics including Children, Pregnant Participants, and 
Individuals taking Potent Inducting Concomitant Medications   
A subset of participants will undergo intensive PK sampling per the SOE. The 
intensive PK visit should be performed within the protocol-specified window for day 8 
if feasible. However, the intensive PK can be performed as early as the 8th dose of 
study drug (1st sample prior to 8th dose and intensive sampling after the 8th dose) for 
logistical issues. This subset will include: 
• 
The first 8 pregnant persons enrolled in each trimester of pregnancy: 
o TM1: <13 weeks 
o TM2:  ≥13 weeks to <27 weeks 
o TM3:  ≥27 weeks 
• 
At least the first 8 children enrolled in each weight band:  
o Weight Band 1: <6 kg 
o Weight Band 2: 6 kg to <13 kg 
o Weight Band 3: 13 kg to <25 kg 
o Weight Band 4: 25 kg to <40 kg 
o Weight Band 5: ≥40 kg 
• 
Participants on potent inducers including rifampin, rifapentine, rifabutin, St. 
John’s Wort, carbamazepine, phenytoin, phenobarbital, oxcarbazepine, or 
tipranavir/ritonavir (these participants are encouraged but are not required to 
participate in intensive PK sampling) 
• 
Any additional participants ≥18 years of age that agree to participate in this 
sampling (goal 24 participants). 
 
Additional children may also undergo intensive PK sampling if, in the opinion of the 
protocol team, a confident determination regarding achievement of PK targets cannot be 
made based on the first 8 dose-evaluable children in a given weight band. The protocol 
team will provide frequent updates to all study sites via email regarding the number of 
dose-evaluable children enrolled in each weight band and will notify all sites when 
intensive PK sampling should be discontinued in each weight band. In the event that the 
protocol team determines that additional intensive PK sampling is required in a given 
weight band, all sites will be similarly notified. 
 
Site staff will contact participants the day before their intensive PK visit to assess 
their recent adherence, remind them of the evening dose, to hold the morning 
dose, and to bring their study drug in the original container with them to their PK 
visit.  
 
Participants will be asked to have nothing to eat or drink except for water for 8 
hours before their visit. They will arrive at the facility in the morning. They will 
have a blood sample drawn (pre-dose), eat a standardized meal, and then take 

 
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their study drug. Additional blood samples will be obtained at 1, 2, 3, 4, 6-, 8-, 
and 10-hours after dose of study drug. The intensive sampling will end at 8 hours 
for those taking study drug every 8 hours. Children who cannot fast for 8 hours 
are asked to fast for at least 2 hours prior to study drug administration. The time 
and type of last food should be recorded on the eCRF. Children will take the 
study drug with liquid or food appropriate for their age and size. The type of liquid 
or food consumed with the study drug will be recorded on the eCRF. 
 
For storage and shipping instructions, refer to the LPC. 
 
6.3.8 Stored Samples 
 
Stored Plasma and DBS (in person visits only) 
Blood plasma will be collected and stored for future testing, including but not 
limited to: 
• 
Immunologic studies including markers linked to systemic inflammation (IL-6, 
TNF-a), inflammasome activation (IL-1beta, IL-18), interferon pathways (IP-
10, type I interferon), neutrophil activation (MPO), monocyte activation 
(sCD14), as well as markers associated with coagulation or endothelial cell 
dysfunction (VWF, P-selectin, tissue factor) 
• 
HMPXV seroconversion and antibody titers (among seroconverters) 
• 
Additional quantitative HMPXV DNA 
• 
Full viral genome sequencing will be performed from select samples that are 
detectable for HMPXV DNA to assess for signs of viral evolution and resistance 
to the investigational agent or immune responses. If sequence analysis 
suggests viral escape from the investigational agent (e.g., mutations in putative 
binding regions or epitopes), then phenotypic analyses may be pursued. 
 
All Entry/Day 1 samples should be collected prior to the first dose of study drug. 
 
For storage and shipping instructions, refer to the LPC. 
  
Stored Serum (in person visits only) 
Blood sera will be collected and stored for future testing, including but not limited to: 
• 
Total and neutralizing antibody assays 
• 
In vitro phenotypic analysis of drug susceptibility to investigational agent or 
other agents 
 
All Entry/Day 1 samples should be collected prior to the first dose of study drug. 
 
For storage and shipping instructions, refer to the LPC. 
 

 
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6.4 
Instructions for Evaluations (Additional Sampling Cohort, in person visits only) 
 
6.4.1 Informed Consent for Additional Sampling 
 
Participants will provide consent for additional sampling. 
 
6.4.2 Participant-Collected Samples and Assessments 
 
Teach Oral, Rectal, Vaginal, and Index Lesion Swabs 
Participants will be instructed on at-home collection of oropharyngeal, rectal, 
vaginal, and index skin lesion swabs (see MOP for details). The index skin lesion 
will be identified at baseline and swabbed longitudinally. Swabs will be collected 
per the SOE. Documentation that these instructions took place will not be 
recorded on an eCRF. 
 
Oral, Rectal, Vaginal, and Index Lesion Swabs 
Swabs will be self-collected by the participants as instructed per the SOE. See 
MOP for details. Swabs will be stored at the participant’s home 
 
Return/Review Swabs 
Sites should remind participants of the need to return samples prior to the visit. 
Participants will return all samples stored at home at each in-person visit. For 
storage and shipping instructions, refer to the LPC. 
 
6.4.3 Sample Collection 
 
Urine 
Urine specimens will be obtained per the SOE. For storage and shipping 
instructions, refer to the LPC. 
 
Whole Blood for HMPXV DNA Levels 
Whole blood will be collected for HMPXV DNA per the SOE. For storage and 
shipping instructions, refer to the LPC. 
 
Sparse PK 
Day 3. Participants in the Additional Sampling cohort will have a single 
sparse/convenience blood sample obtained for PK. The time of prior study 
product dose will be carefully recorded. For storage and shipping instructions, 
refer to the LPC. 
 
Stored Peripheral Blood Mononuclear Cells (PBMCs) (optional) 
Blood will be collected for PBMC isolation per the SOE. For storage and shipping 
instructions, refer to the LPC. 
 
PBMCs will be collected only at select sites. Only sites certified by the IQA 
Cryopreservation PT Program at the Duke Human Vaccine Institute are required 
to collect PBMCs. Collection of PBMCs will be optional 

 
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PBMCs will be stored for future testing, which may include, but is not limited to, 
the following: 
• 
Cellular immune responses between treatment and control samples, 
including assessment of T-cell responses to HMXPV proteins  
• 
Cellular activation/exhaustion/memory differentiation phenotypes among innate or 
adaptive immune cells  
• 
Host genetics 
 
All Entry/Day 1 samples should be collected prior to the first dose of study drug. 
 
6.5 
Modifications for Participants under 18 Years of Age 
 
At entry, pediatric participants enrolled/followed in person will be assessed as being 
sexually active or not sexually active. 
 
Pediatric participants enrolled/followed in person will follow Table 6.1-4, with 
evaluations completed according to whether they are sexually active or not.  
 
Pediatric participants enrolled/followed remotely will follow Table 6.1-5.  
 
Pediatric laboratory evaluations and collections will vary according to weight band (see 
the LPC for details). 
 
6.6  
Virologic Assessments for Participants Enrolled/Followed Remotely 
 
Skin Lesion Swabs 
The index skin lesion will be swabbed by the participant at home at the times 
indicated in the SOE using the collection kit provided by the study (see MOP for 
details). In addition, the participant should swab a new skin lesion should one 
appear on day 6 or later. Only one new skin lesion should be swabbed. These 
samples may be omitted if testing kits/shipping kits are not available or if health 
ordinances preclude shipment of such samples by participants. Instructions for 
storage and shipment of samples will be provided to the participants. 
  
7.0 
ADVERSE EVENTS AND STUDY MONITORING 
 
7.1 
Definition of Adverse Events 
 
An adverse event (AE) is any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or diagnosis that occurs in a study participant during the 
conduct of the study REGARDLESS of the attribution (i.e., relationship of event to 
medical treatment/study product/device or procedure/intervention). This includes any 
occurrence that is new in onset or aggravated in severity or frequency from the baseline 
condition.  
 

 
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7.2 
Adverse Event Collection Requirements for This Protocol 
 
All AEs must be recorded on the eCRFs if any of the following criteria have been met: 
• 
All AEs that led to a change in study treatment/intervention regardless of grade 
• 
All AEs meeting SAE definition or EAE reporting requirement 
• 
All AEs Grade ≥3 
 
NOTE: SAEs or events meeting EAE reporting requirements should also be entered into 
the DAIDS Adverse Experience Reporting System (DAERS), an Internet-based reporting 
system. 
 
Serious Adverse Events (SAEs) 
An SAE is defined as any untoward medical occurrence that: 
• 
Results in death 
• 
Is life-threatening  
• 
Requires inpatient hospitalization or prolongation of existing hospitalization 
• 
Results in persistent or significant disability/incapacity  
• 
Is a congenital anomaly/birth defect 
• 
Is an important medical event that may not be immediately life-threatening or result 
in death or hospitalization but may jeopardize the patient or may require intervention 
to prevent one of the other outcomes listed in the definition above). 
 
7.3 
Expedited Adverse Event (EAE) Reporting to DAIDS 
 
7.3.1 Expedited Reporting of Adverse Events to DAIDS 
 
Requirements, definitions and methods for expedited reporting of Adverse 
Events (AEs) are outlined in Version 2.0 of the DAIDS EAE Manual, which is 
available on the RSC website at https://rsc.niaid.nih.gov/clinical-research-
sites/manual-expedited-reporting-adverse-events-daids.  
 
The DAIDS Adverse Experience Reporting System (DAERS), an internet-based 
reporting system, must be used for EAE reporting to DAIDS. In the event of 
system outages or technical difficulties, EAEs may be submitted using the DAIDS 
EAE Form. This form is available on the DAIDS RSC website at 
https://rsc.niaid.nih.gov/clinical-research-sites/paper-eae-reporting.  
 
For questions about DAERS, please contact NIAID CRMS Support at 
CRMSSupport@niaid.nih.gov. Please note that site queries may also be sent 
from within the DAERS application itself. 
 
For questions about expedited reporting, please contact the DAIDS RSC Safety 
Office at (DAIDSRSCSafetyOffice@tech-res.com). 
 

 
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7.3.2 Reporting Requirements for this Study 
 
• 
The SAE Reporting Category, as defined in Version 2.0 of the DAIDS EAE 
Manual, will be used for this study. 
• 
The study agents for which expedited reporting are required are:  
o Tecovirimat 
o Placebo for Tecovirimat 
 
7.3.3 Grading Severity of Events 
 
The Division of AIDS Table for Grading the Severity of Adult and Pediatric 
Adverse Events (DAIDS AE Grading Table), corrected Version 2.1, July 2017, 
must be used and is available on the DAIDS RSC website at 
https://rsc.niaid.nih.gov/clinical-research-sites/daids-adverse-event-grading-tables.  
 
7.3.4 Expedited AE Reporting Period 
 
• 
The expedited AE reporting period for this study is per the EAE manual. 
• 
After the protocol-defined AE reporting period, unless otherwise noted, only 
suspected, unexpected serious adverse reactions (SUSARs), as defined in 
Version 2.0 of the EAE Manual, will be reported to DAIDS if the study staff 
become aware of the events on a passive basis (from publicly available 
information). 
 
7.4 
Follow-up of Participants Reporting Adverse Events 
 
All AEs must be reported in detail on the appropriate page in the eCRF and followed to 
satisfactory resolution, until the investigator deems the event to be chronic or not 
clinically significant, the event is considered to be stable, or the participant is lost to 
follow-up. Study staff should obtain additional laboratory testing as needed to evaluate 
AE and confirm resolution. If an AE is ongoing at completion of participation in the study, 
only those that are investigational agent-related SAEs need continued follow-up to 
resolution or stability until 30 days past the last study visit. 
 
7.5 
Study Monitoring 
 
The protocol leadership team will monitor the conduct and safety of the study via regular 
summaries of accrual, study discontinuation, data completeness, and adverse events 
pooled over arms. 
 
The DAIDS Clinical Representative will review and assess select EAE reports for 
potential impact on the study participant safety and protocol conduct as per DAIDS 
policies, guidance documents, and SOPs as applicable.  
 
The study will be reviewed by a NIAID-appointed DSMB at least annually. Two interim 
efficacy reviews are planned at approximately 33% and 67% of total information (i.e., 

 
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when 119 and 238 participants experienced clinical resolution events) unless 
otherwise recommended by the DSMB. In the event that the study accrues at a 
slower pace than anticipated, the first safety review by the DSMB may occur 
approximately 6 months after the enrollment of the first study participant. An interim 
review may also be convened if a concern is identified by the DAIDS clinical 
representative, the study chairs, or study statistician in consultation with the team. See 
section 10.0 for statistical and other considerations related to interim monitoring. 
 
Detailed plans for study monitoring are outlined in a Study Monitoring Plan developed by the 
Statistical and Data Management Center (SDMC) prior to enrollment of the first participant. 
 
8.0 
CLINICAL MANAGEMENT ISSUES 
 
8.1 
Toxicity 
 
Overdose 
An overdose is any dose of study treatment given to a participant or taken by a 
participant that exceeds the dose described in the protocol. 
 
Any overdose must be reported within 24 hours (follow the directions described in the 
Study Management section). The overdose itself is not to be reported as an AE. 
However, any AEs associated with the overdose are to be reported on relevant AE/SAE 
sections in the eCRF. 
 
In the event of an overdose, the site investigator should: 
1. Contact the protocol team immediately 
2. Closely monitor the participant for any AE/SAE and laboratory abnormalities 
3. Obtain a plasma sample for PK analysis within 3 days of the date of the last dose of 
investigational agent/placebo if requested by the medical monitor 
4. Document the quantity of the excess dose as well as the duration of the overdose in 
the eCRF. 
 
Adverse Events 
It is possible that some participants will experience transient or prolonged AEs during the 
trial. To minimize the effects on the eventual evaluation of the safety and efficacy of 
study treatment, the following principles will be used to determine study drug 
discontinuation. 
 
Grade 1 or 2  
Participants who develop Grade 1 or 2 AE or toxicity felt to be related to study treatment 
may continue study treatment at the discretion of the site investigator with close follow 
up. If a participant chooses to discontinue study treatment, the site should notify the 
CMC within 72 hours. These participants will remain on study, off study treatment and 
have all evaluations performed per section 6.1 through completion of the study.  
 
Symptoms that may be related to HMPXV should prompt provision of or referral for 
supportive care (see MOP for details). 

 
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Grade 3 or 4 
Participants who develop a Grade 3 or 4 AE or toxicity thought by the site investigator to 
be related to study treatment should permanently discontinue study treatment and the 
site should consult with the CMC. The participant should be reevaluated weekly until the 
AE returns to Grade ≤2. These participants will remain on study, off study treatment and 
have all evaluations performed per section 6.1 through completion of the study.  
 
8.2 
Pregnancy  
 
Participants who are pregnant at the time of study entry will be assigned to Arm C.  
 
Participants who become pregnant while on study should continue evaluations according 
to the section 6.1. Participants who become pregnant prior to day 29 can request 
unblinding to help guide decision making about their treatment of HMPXV. 
 
At the end of the pregnancy, outcome and adverse events for participant and infant will 
be recorded on the outcome eCRF. If a participant has completed the study or chooses 
to discontinue from the study before the end of the pregnancy, then site staff should 
request permission to contact them regarding pregnancy outcomes at the end of 
pregnancy. If the information is obtained, pregnancy outcomes will be submitted on an 
eCRF at the end of the pregnancy.  
 
Participants will be asked to bring the infant for a study visit four weeks after birth for a 
physical exam.  
 
Participants who are enrolled/followed remotely will be asked to participate in a 
telemedicine visit to assess outcomes and to provide any relevant documentation 
of medical encounters to assess outcomes. 
 
8.3 
Breastfeeding 
 
Given that HMPXV is spread by close contact and neonates are at high risk for severe 
disease, the CDC recommends that breastfeeding should be delayed until all lesions have 
resolved, the scabs have fallen off and a fresh layer of intact skin has formed. 
 
At sites outside of the U.S. this is a more complex decision and the WHO recommends that 
breastfeeding practices be assessed on a case-by-case status accounting for the physical 
status of the mother and severity of disease. Protecting the child’s survival while maintaining 
the nutritional intake of the infant is the priority [WHO 2022]. International sites will make the 
decision regarding breastfeeding on a case-by-case basis accounting for local 
recommendations. 
 
9.0 
CRITERIA FOR DISCONTINUATION 
 
9.1 
Permanent and Premature Treatment Discontinuation 
 
• 
Drug-related toxicity (see section 8.1 Toxicity). 

 
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• 
Request by participant to terminate treatment. 
• 
Clinical reasons believed life-threatening by the physician, even if not addressed in 
the Toxicity section of the protocol. 
• 
Found to be HMPXV negative on all diagnostic tests. 
• 
Unable to take enteral medications. Intravenous formulations of tecovirimat may be 
obtained outside of the trial. 
• 
Receipt of tecovirimat through a mechanism outside the trial (participants should still 
continue to be followed on study/off treatment). 
 
9.2 
Premature Study Discontinuation 
 
• 
Request by the participant to withdraw. 
• 
Request of the primary care provider if she or he thinks the study is no longer in the 
best interest of the participant. 
• 
At the discretion of the IRB/EC, FDA, NIAID, Office for Human Research Protections (OHRP), 
other government agencies as part of their duties, investigator, or industry supporter.  
 
10.0 
STATISTICAL CONSIDERATIONS  
 
10.1 
General Design Issues 
 
A5418 is a randomized, placebo-controlled, double-blind study to establish the efficacy 
of tecovirimat for the treatment of individuals with laboratory-confirmed or presumptive 
HMPXV disease. Eligible participants will be randomized 2:1 to receive either tecovirimat 
or placebo for 14 days stratified according to time since prodromal symptom onset (≤5 
days or >5 days) and remote enrollment. Participants enrolled with presumptive 
HMPXV diseases with both negative results from local tests and diagnostic testing 
through the central laboratory will stop study drug and continue to be followed per the 
SOE for 7 days after stopping study drug. These participants, if enrolled in the 
randomized arms, will be replaced. 
 
Participants who progress to severe disease post-randomization as defined in section 
4.3.2 will stop blinded study treatment and start a 14-day course of open-label 
tecovirimat. Participants who report severe pain from HMPXV at day 6 should stop 
blinded study treatment and start a 14-day course of open-label tecovirimat. Participants 
who switch to open-label tecovirimat will be followed per the SOE for randomized arms.  
 
Participants will monitor skin lesions daily for 28 days after study entry with confirmation 
of the lesion resolution via remote or in person visit. Primary outcome measure is time to 
clinical resolution (all lesions scabbed, desquamated, or healed). Since primary outcome 
measure is only observable among participants with 1 or more skin or visible mucosal 
lesions that are able to be followed for resolution, participants who enroll with proctitis 
without any visible mucosal lesions or skin lesions will be excluded from the analysis of 
primary outcome measure.  
 

 
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Participants with severe disease, significant immunosuppression or skin conditions, who 
are pregnant, breastfeeding and children under age 18 will be enrolled to an open-label 
Arm C. 
 
10.1.1 
Estimand for Primary Objective 
 
Table 10.1.1-1: Estimand Description and Attributes for Primary Objective 1.2 
Estimand 
Description 
The instantaneous risk ratio of clinical resolution of skin or visible 
mucosal lesions among people with laboratory-confirmed 
monkeypox with 1 or more skin or visible mucosal lesions in those 
prescribed to Tecovirimat relative to no treatment 
Treatment 
Tecovirimat for 14 days 
Target Population People aged 18 or older with laboratory-confirmed HMPXV disease 
with 1 or more skin or visible mucosal lesions 
Variable(s) 
Time to clinical resolution up to 28 days 
Handling of 
Intercurrent 
Events 
All-cause death, treatment change due to disease progression 
or severe pain, use of other antivirals with expected activity 
against HMPXV: these events are considered competing 
events. Individuals experiencing these events will be retained 
in the risk set through 28 days under subdistribution hazard 
model (Composite strategy) 
Discontinuation of treatment for reasons other than disease 
progression or severe pain or death: all follow-up included 
regardless of treatment status (Treatment strategy) 
Population-Level 
Summary 
Measure 
Instantaneous risk ratio of Tecovirimat relative to no treatment 
 
10.1.2 
Estimand for Key Secondary Objective 
 
Table 10.1.2-1: Estimand Description and Attributes for Secondary Objective 
1.3.1 
Estimand 
Description 
The difference of the mean time-weighted average of pain 
intensity difference (pre-treatment - post treatment) over 5 days 
among people with laboratory-confirmed monkeypox who reported 
severe pain between those prescribed to Tecovirimat relative to no 
treatment 
Treatment 
Tecovirimat for 14 days 
Target Population People aged 18 or older with laboratory-confirmed HMPXV disease 
who reported severe pain (7-10 on the numerical rating scale) 

 
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Variable(s) 
Time-weighted average of pain intensity difference from pre-
treatment to each day post treatment over 5 days measured by 
11-point NRS 
Handling of 
Intercurrent 
Events 
All-cause death: all NRS measures included up to death (While on 
treatment strategy) 
Treatment change due to disease progression or severe pain: all 
NRS measures included up to treatment change (While on 
treatment strategy) 
Discontinuation of treatment for reasons other than disease 
progression or severe pain or death: all NRS measures included 
up to treatment discontinuation (While on treatment strategy) 
Population-Level 
Summary 
Measure 
Difference (Tecovirimat – no treatment) in mean time-weighted 
average of pain intensity difference over 5 days 
 
10.2 
Outcome Measures 
 
10.2.1 
Primary Outcome Measure 
 
Time to clinical resolution, defined as the first day on which all skin lesions are 
scabbed, desquamated or healed, and visible mucosal lesions are healed, up to 
28 days. 
 
10.2.2 
Secondary Outcome Measures 
 
10.2.2.1 Pain assessed by 11-point numerical rating scale for pain  
 
10.2.2.2 Development of severe HMPXV in those without severe HMPXV at 
baseline 
 
10.2.2.3 Levels of HMPXV in various compartments 
 
10.2.2.4 Time to complete lesion healing defined as all lesions being re-
epithelialized 
 
10.2.2.5 Self-reported adherence  
 
10.2.2.6 Summaries of Quality-of-life measures by EQ-5D-5L  
 
10.2.2.7 Occurrence of Grade 3 or greater adverse events 
 
10.2.2.8 All-cause mortality 
 
10.2.2.9 Tecovirimat blood concentrations in children less than 18 years of age 
 

 
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10.2.3 
Other Outcome Measures  
 
10.2.3.1 Frequency and quantity of HMPXV oral, rectal, vaginal, urine, and 
lesion shedding in the presence and absence of tecovirimat treatment  
 
10.2.3.2 HMPXV isolation by culture from oral, rectal, vagina and lesion in the 
presence and absence of tecovirimat  
 
10.2.3.3 Virologic and immunologic measurements that correlate with disease 
severity  
 
10.2.3.4 Number of lesions tracked longitudinally over the study period 
 
10.2.3.5 Cellular and humoral immune responses to OPXV that are 
associated with disease progression and clinical efficacy of 
tecovirimat 
 
10.2.3.6 Genomic variability in MPXV isolated from participants based on 
geographic and clinical differences 
 
10.2.3.7 Presence of resistance at baseline and emergence of viral resistance 
during tecovirimat treatment 
 
10.2.3.8 Summary measures of A-HRSI QoL assessment in participants 
reporting proctitis 
 
10.2.3.9 Presence of bacterial sexually transmitted infections 
 
10.2.3.10 Tecovirimat blood concentrations 
 
10.2.3.11 ARV blood concentrations 
 
10.2.3.12 Occurrence of new HMPXV positivity among household contacts 
 
10.2.3.13 Occurrence of lesions that occur after initial resolution of symptoms 
and skin lesions 
 
10.3 
Randomization and Stratification 
 
Eligible participants will be assigned using permuted block randomization in a 2:1 ratio to 
tecovirimat or placebo with dynamic institutional balancing to minimize imbalances at any 
clinical site. The randomization will be stratified by days from onset of symptoms (≤5 days or >5 
days) and remote enrollment.  
 

 
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10.4 
Sample Size and Accrual 
 
Sample size estimation is based on the comparison of the primary outcome measure “time 
to clinical resolution” using log-rank test. The two key determinants of power are the total 
number of lesion resolution events, E, and the treatment-to-control ratio of the 
instantaneous risk (hazard) of lesion resolution, θ. The number of events required to 
achieve power 1 −𝛽 to detect a ratio of θ using a two-tailed test with type I error rate 
α=0.05 is approximately 
 
𝐸= (1.96 + 𝑧𝛽)
2
{ln(𝜃)}2𝑞0𝑞1
,  
 
where 𝑧𝛽 is the 100(1 −𝛽)th percentile of the standard normal distribution and q0 and q1 
are the treatment allocation [Schoenfeld 1983]. 
  
Table 10.4.1 displays the numbers of events and participants needed to achieve 80% and 85% 
power with 2:1 allocation for various scenarios. In total, 357 participants with clinical resolution 
up to 28 days after randomization are needed to detect a 40% improvement in the instantaneous 
risk of clinical resolution as measured by the instantaneous risk 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 464 
participants.  
 
Note that the 77% event rate is used to determine the sample size as a conservative approach. 
Assuming the hypothesized instantaneous risk ratio of 1.4 is accurate, the event rate on the 
tecovirimat arm will be higher than 77%. It was also taken into consideration of participants 
switching to open-label tecovirimat due to disease progression or severe pain as these 
participants will be considered as not achieving the clinical resolution, hence potentially lower 
the event rate.  
 
A total sample size of 530 is planned while taking into account the following:  
• 
Two planned interim analyses 
• 
Potential loss to follow-up 
• 
Participants enrolled with proctitis without any skin or visible mucosal lesions  
• 
Participants switched to open-label tecovirimat due to disease progression or severe 
pain 
 

 
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Table 10.4-1: Number of Events and Participants Needed (assumed 77% will experience 
the event) to Have 80% and 85% Power with 2:1 Allocation before Accounting for 
Potential Drop-out  
Instantaneous 
Risk Ratio 
Scenario for 80% power 
Scenario for 85% power 
# Of  
Events Needed 
# Of 
Participants 
Needed 
# Of  
Events Needed 
# Of 
Participants 
Needed 
1.3 
514 
668 
587 
763 
1.4 
312 
406 
357 
464 
1.5 
215 
280 
246 
320 
 
Sample Size Re-Estimation 
Given the uncertainty of the event rate, a blinded sample size re-estimation will be conducted at 
the midpoint of the trial when 178 lesion resolution events have occurred (i.e., at 50% 
information). The blinded overall rate of events will be computed and used to determine whether 
the sample size should increase in order to reach the 357 total events needed to power the trial. 
For example, if the overall event rate is 60%, then the suggested number of participants would 
be 357/0.60 = 595 (before accounting for potential drop out). Because this is an event-driven 
trial, increasing the sample size the midway point will not change the planned timing of future 
interim analyses (since these are fixed based on the 357 events needed to power the trial) and 
will not require an update to any pre-specified interim monitoring bounds discussed below. Full 
details of the sample size re-estimation plan will be provided in the statistical analysis plan.  
 
Pain Intensity Reduction 
Pain intensity is assessed by participants using an 11-point NRS from 0=no pain to 
10=worst possible pain. Pain intensity scores were collected at Baseline (prior to treatment 
initiation, Day 1) and daily after for 28 days. Pain intensity difference is calculated by 
subtracting the pain intensity at each time point from the pain intensity at baseline. Positive 
numbers indicate a reduction in pain [maximum (max)=10 at each time point] and negative 
numbers indicate an increase in pain [minimum (min)=-10 at each time point]. Since the 
protocol requires participants to switch to open-label tecovirimat on Day 6 due to severe 
pain, the primary pain intensity difference will be summarized over the first 5 days after 
treatment initiation using an average summed pain intensity difference (SPID). The average 
SPID5d score is the time-weighted average of the pain intensity difference from Day 2 to 
Day 6, more specifically it is defined as the average of the sum of the pain intensity 
differences at each measurement multiplied by the duration in days since the previous 
measurement from Day 2 to Day 6. The range of average SPID5d is -10 to 10. 
Comparisons of the average SPID5d between the two randomized arms will use a two-
sample t-test.  
 
Conservatively assuming 50% of enrolled participants in Arms A and B reporting pain at 
baseline with approximately 10% reporting severe pain (7-10), and approximately 30% 
reporting moderate pain (4-6), N=213 (and separately in each pain category) are used 
as subpopulations for evaluating the pain reduction between the two randomized arms. 
The table below shows the effect size of the difference to be detected with at least 80% 
power using a two-sided t-test at 5% significance level. Any labeling claim based on pain 

 
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assessment as a secondary endpoint will be made only if the primary endpoint 
demonstrates statistically significant treatment effect on symptom resolution as a 
sequential testing strategy. This is to account for any potential multiplicity or type-I error 
inflation due to testing multiple endpoints. 
 
Table 10.4-2: Effect size to be detected with at least 80% power under various assumed SD. 
Pain Categories 
Reported at Baseline 
Tecovirimat 
(N) 
Placebo 
(N) 
SD* 
Difference to be 
Detected in SPID5d 
Severe 
36 
18 
1.5 
1.30 
 
 
 
2.0 
1.72 
Moderate 
106 
53 
1.5 
0.73 
 
 
 
2.0 
1.00 
Moderate/severe 
142 
71 
1.5 
0.63 
 
 
 
2.0 
0.85 
* SD estimated from Farrar, 2001.  
 
Sample Size Justification for Intensive Virologic Sampling Group 
With 100 participants undergoing intensive daily mucosal and lesional viral sampling, 
assuming 85% with evaluable measures (approximately 56 in tecovirimat group and 28 
in placebo group), the study will have at least 80% power to detect a difference of 0.7 
SD in time-weighted average of viral reduction in HMPXV log10 viral load from day 1 to 
day 15 between treatment groups using a 2-sided 5% t-test. For example, assuming the 
time-weighted average change in HMPXV from Day 1 to Day 15 in the placebo group 
will be -1.5 log10 copies/mL with a corresponding SD of 1, the study will have at least 
80% to detect a 0.7 log difference in time-weighted average change in log 10 viral load 
between the treatment groups.  
 
Accrual 
The study accrual rate will depend on the status of the monkeypox outbreak at each site, 
as estimated based on the number of sites, the study is expected to complete accrual of 
randomized groups in approximately 20 weeks with weekly enrollment projections below: 
 
Week 
Enrollment 
1 
3 
2 
5 
3 
8 
4 
13 
5 
21 
6 
34 
7-20 
34 
 
10.5 
Data and Safety Monitoring 
 
A NIAID-appointed Data and Safety Monitoring Board (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 

 
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evidence of a treatment benefit. The operation of the DSMB is governed by the NIAID 
DSMB Charter. 
 
10.5.1 
Interim Monitoring Guidelines 
 
The Lan-DeMets spending function analog of the O’Brien-Fleming boundaries will be 
used to monitor the primary outcome measure as a guide for the DSMB with an overall 
two-sided type-I error rate of 5%. Two interim efficacy analyses are planned at 
approximately 33% and 67% of total information unless otherwise recommended by the 
DSMB. The statistical analysis plan will provide a more detailed description of the 
stopping boundaries used for interim analyses. 
 
Table 10.5.1-1: Efficacy Boundaries Based on Planned Timing of Interim reviews using 
O’Brien-Fleming Spending Function 
Analysis 
Number of Participants with 
Lesion Resolution Events 
Efficacy Boundary 
Nominal α 
Level 
Interim #1 
119 
3.371 
0.0002 
Interim #2 
238 
2.511 
0.012 
Final 
357 
1.993 
0.046 
 
Efficacy boundaries estimated using East 6. 
 
In the absence of a significant difference between randomized groups that leads to 
termination of the randomized comparison, the study team believes that there is 
value in continuing the randomized comparison of tecovirimat versus placebo to 
full enrollment in order to obtain as much precision as possible and to provide 
maximal information to inform the field. 
 
The DSMB will monitor operational futility. With respect to operational futility, the 
DSMB may recommend modification to the study if the proportion of participants 
who switch to open-label tecovirimat due to disease progression or severe pain is 
unexpectedly high. As a benchmark, a switch rate to open-label tecovirimat of 
more than 20% would be cause for concern. In addition, the DSMB will monitor the 
loss to follow-up (LTFU) rate. As a benchmark, an overall LTFU rate in the 
randomized groups of more than 10% would be cause for concern. 
 
A separate unblinded statistical team will prepare these closed reports for 
DSMB review and recommendations. In considering its recommendations, the 
DSMB may also take into account the totality of the evidence from the trial data 
(including effects on secondary and other outcomes and in key participant 
subgroups) and any other information from external sources it considers 
relevant (e.g., results from other trials, emerging information on the nature of 
the disease and its epidemiology). For example, the DSMB might make 
recommendations based on substantial evidence for a difference between 
randomized arms in pain reduction or recommend modification to study  

 
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follow-up based on evidence of a difference in treatment effect between 
participants who were enrolled remotely versus in-person.  
 
10.6 
Analyses 
 
The following sections provide a brief overview of the analysis considerations. Prior to the 
start of enrollment, a detailed Statistical Analysis Plan fully delineates all planned statistical 
analyses. In the event of a DSMB recommendation to stop the trial for efficacy at interim 
review, full analysis and publication of the primary trial results will be prepared based on the 
frozen data for the DSMB meeting. Subsequent analyses (including a database prepared for 
future data-sharing requests) will be performed based on the final trial database including all 
final study termination visits. In the event of a DSMB recommendation to stop for operational 
futility, full analysis and publication of the primary trial results will be performed based on the 
final trial database including all final study termination visits 
 
Descriptive summaries of the distribution of continuous baseline variables will be presented 
in terms of percentiles (e.g., median, 25th and 75th percentiles), while discrete variables 
will be summarized in terms of frequencies and percentages. Statistical comparisons will be 
performed using two-sided significance tests with a 5% Type I error rate. 
 
The following study populations or analysis sets are used for addressing the study objectives. 
This terminology is used throughout this protocol and the Statistical Analysis Plan. 
 
Safety set for the randomized groups: all participants who (i) were randomized and (ii) 
take at least 1 dose of tecovirimat or placebo. 
 
Primary efficacy set for the randomized groups: all participants who (i) were randomized; 
(ii) with laboratory-confirmed monkeypox; (iii) with 1 or more skin or visible mucosal 
lesions that are able to be followed for resolution. 
 
Secondary efficacy set for the randomized groups: all participants who (i) were 
randomized; (ii) with laboratory-confirmed monkeypox.  
 
Open-label set: all participants who (i) enrolled to Arm C and (ii) take at least 1 dose of 
tecovirimat.  
 
10.6.1 Primary Outcome Measure 
 
Analysis of the time to clinical resolution will be restricted to the primary efficacy 
population for the randomized groups as defined above. As outlined in primary 
estimand 10.1.1, intercurrent events of all-cause death, use of other antivirals 
with expected activity against HMPXV, and disease progression or severe pain 
leading to treatment change will be considered as competing events under the 
subdistribution proportional hazard model (Fine and Gray, 1999) using a 
composite variable strategy. More specifically, those who died, used other 
antivirals with expected activity against HMPXV, or experienced disease 
progression or severe pain leading to treatment change will remain in the risk set 

 
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with their time to clinical resolution censored at 28 days. The intercurrent event of 
discontinuation of randomized treatment for reasons other than disease 
progression or severe pain or death will be treated using a treatment policy 
strategy where all follow-up is included regardless of treatment status. 
Instantaneous risk ratio of clinical resolution will be tested and estimated with its 
confidence interval using a subdistribution proportional hazards model. 
Cumulative incidence functions (CIFs) will be used to estimate the 
incidence of clinical resolution and tested between the two treatment 
groups using Gray’s test accounting for competing risk. For handling of 
missing data, participants’ losses to follow-up will be assumed as non-informative 
and will have their time to clinical resolution censored at the time of last 
evaluation of lesions.  
 
As a supportive analysis, cause-specific instantaneous risk ratio will be 
estimated to aid the understanding of the effect of tecovirimat on the 
incidence and the instantaneous risk of clinical resolution. For this 
analysis, all-cause death, use of antivirals with expected activity against 
HMPXV, and switching to open-label tecovirimat due to disease progression or 
severe pain will be censored at the time of event.  
 
Pre-specified subgroup analysis will be conducted for the primary outcome 
measure using the statistical test for interaction for the following: duration of 
symptoms (≤5 or >5 days), presence of moderate to severe pain (<7 or 7-10 on 
the 11-point NRS for pain), remote enrollment, receipt of monkeypox or 
smallpox vaccine, age, sex, and race. Additional subgroups may be identified 
and evaluated. Full details of planned subgroup analyses will be provided in the 
statistical analysis plan. 
 
10.6.2 Secondary Outcome Measure 
 
Unless otherwise specified, analyses of secondary outcome measures will use 
secondary efficacy population as defined above.  
 
Pain intensity reduction will be assessed using time-weighted average of sum 
pain intensity difference (SPID). Average SPID5d (SPID from study day 2 to day 
6) will be calculated in all enrolled participants. The primary analysis will be 
restricted to those who reported severe pain (NRS 7-10) at baseline. Calculation 
of SPID5d for participants who switched to open-label tecovirimat or discontinued 
randomized treatment prior to study day 6 will include NRS reported prior to 
open-label tecovirimat initiation or discontinuation of randomized treatment. 
Comparison between the randomized arms will use a two-sample t-test. Two-
sided 95% confidence interval on the difference between randomized groups will 
be calculated. Secondary analysis will compare the average SPID5d separately 
in those reported moderate or severe pain (NRS 4-10) at baseline and in all 
enrolled participants. Average SPID over the treatment period and absolute 
change from baseline to day 2 through day 6 will also be evaluated.  
 

 
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Time to complete lesion healing will be restricted to the primary efficacy population 
and analyzed using the same approach for the primary outcome measure.  
 
Development of severe HMPXV will be summarized by randomized groups and 
time to development of severe HMPXV will be analyzed using Kaplan-Meier 
methods.  
 
Levels of HMPXV will be summarized by randomized groups and by sampling 
locations. The proportion of participants with undetectable HMPXV at each 
evaluation time point will be estimated with 95% confidence intervals where 
appropriate and plotted over time. Comparisons between randomized groups will 
use a two-sample Z-test.  
 
Analysis of occurrence of grade 3 or greater adverse events will be limited to 
safety population as defined above. Grade 3 or greater adverse events will be 
tabulated by randomized groups and proportion of participants reporting such AE 
will be compared using a two-sample Z-test.  
 
All-cause mortality will be summarized by randomized groups and described in 
detail. Comparison of time to death between randomized groups will be made 
using a logrank test if there are enough events warrant such analysis.  
 
Self-reported adherence, summaries of quality-of-life measures by EQ-5D-5L, 
and summaries of A-HRSI QoL assessment will be summarized by randomized 
groups and compared using Wilcoxon rank-sum test or Chi-square test as 
appropriate.  
 
As Arm C is an open-label arm, analyses of all outcomes will be restricted to the 
open-label population as defined above and will be descriptive only.  
 
Please see section 11.0 for analyses of PK outcomes.  
 
Adjustment for Multiple Testing 
A hierarchical testing approach will be used to control the family-wise error rate 
across the primary outcome measure and the secondary pain outcome 
measure. Hypothesis testing will first be conducted for the primary outcome 
measure. If the null hypothesis is rejected at the nominal significance level 
derived as described in section 10.5.1, confirmatory analysis of the secondary 
pain outcome measures will be performed at the same nominal significance 
level; the Benjamini-Hochberg method will be used to account for 
multiplicity of testing of pain outcome measures. If the null hypothesis is not 
rejected, analysis of the secondary pain outcome measures will be considered 
exploratory and no formal conclusion will be drawn. Analysis of all other 
outcome measures will be considered supportive and no formal adjustment 
for multiplicity will be undertaken.  
 

 
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10.7 
Unblinding 
 
Planned Unblinding 
Participants will be unblinded at completion of the study. Please refer to ACTG SOP-123 
Unblinding Participants for details.  
 
Sudden/Unplanned Unblinding 
The decision to unblind one or more arms of an ongoing study is made by the team in 
conjunction with the relevant Scientific Committee and the Executive Committee. This can 
occur based on a recommendation from the DSMB or an SMC or the results of another 
trial (also see the DAIDS SOP “Termination of a Trial or a Single Treatment Arm”).  
 
If the decision is made to unblind, participants should be unblinded as soon as possible. 
Unblinding is conducted through the DMC, which sends treatment assignments to the 
sites soon after the unblinding decision. Every effort should be made by the sites to 
contact participants who have completed follow-up in order to explain the study results.  
 
When a treatment comparison is unblinded based on an interim analysis, the results of that 
interim analysis must be reported in publications. Data from visits that occurred before the 
interim review but that were not in the database at the data cutoff date have little potential for 
bias and may be reported with a comment. Data from visits that occurred after unblinding are 
potentially biased and must not be used if the intent is to claim that all the data are from a 
blinded study. In unblinding due to both “interim analysis” and the “other trial results” 
situations, if analyses are reported on clinical data or samples taken after the unblinding date, 
the conditions under which these data were gathered must be made clear in any publication. 
 
11.0 
PHARMACOLOGY PLAN 
 
The pharmacokinetics of tecovirimat have been established in healthy volunteers 
receiving 600 mg every 12 hours (shown in Table 11.0-1). Pharmacokinetic data with 
tecovirimat were primarily generated in healthy volunteers. PK data in individuals with 
active disease are extremely limited. This study will determine the pharmacokinetics of 
tecovirimat using a combination of intensive and sparse sampling. Intensive PK 
sampling will be optional for participants in Arms A/B, with a goal of having complete, 
evaluable PK profiles for 10 participants on active tecovirimat at day 8.  
 
Table 11.0-1: Tecovirimat Pharmacokinetics in Healthy Volunteers 
PK Parameter 
 
AUC (ng*hr/mL), mean (CV%) 
28,791 (35%) 
Cmax (ng/mL), mean (CV%) 
2106 (33%) 
Cmin (ng/mL), mean (CV%) 
587 (38%) 
Protein binding 
77-82% 
Half life 
20 hours 
CL/F (L/hr) 
31 
V/F (L) 
1030 
 

 
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The pharmacokinetics of tecovirimat have not been assessed in pregnant persons. 
Intensive PK sampling will be performed in the first 8 pregnant persons enrolled in each 
trimester. The PK will be compared with historical data and values obtained from 
participants intensively sampled in Arms A/B. 
 
There are very limited PK data for tecovirimat in children. Tecovirimat weight-band doses 
and administration methods for children in this study mirror those recommended by CDC for 
children ≥6 kg, but modeling and simulation indicated some refinements to dose and 
frequency for those <6 kg (described below). Intensive PK sampling will be performed in the 
first 8 children enrolled in each weight band. The weight bands are: (WB1 <6 kg, WB2 6 kg 
to <13 kg, WB3 13 kg to <25 kg, and WB4 25 kg to <40 kg, WB5 ≥40 kg) The PK in each 
weight band will be compared to historical data and values obtained from participants 
intensively samples in Arms A/B. Tecovirimat doses may be adjusted and additional 
intensive PK data performed if the PK, safety and efficacy data in the first 8 children suggest 
dose adjustments are needed. Sites must notify the CMC prior to initiating tecovirimat in 
children <6kg to verify the starting dose.  
 
Tecovirimat is metabolized by uridine glucuronosyl transferase (UGT) enzymes 1A1 and 
1A4. Tecovirimat is not a substrate for CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, 
CYP2D6 or CYP3A4. Tecovirimat is not a substrate for P-gp, BCRP, OATP1B1, or 
OATP1B3. Potent inducers such as rifampin, rifapentine, rifabutin, St. John’s Wort, 
carbamazepine, phenytoin, phenobarbital, oxcarbazepine, or tipranavir/ritonavir may lower 
exposures of tecovirimat. Participants on these potent inducers will enroll into Arm C and 
strongly encouraged to undergo intensive PK sampling.  
 
Tecovirimat is not an inhibitor of CYP1A2, CYP2D6, CYP2E1 or CYP3A4, and is not an 
inducer of CYP1A2. Tecovirimat inhibits BCRP in vitro, but is not an inhibitor of P-gp, 
OATP1B1 and OATP1B3, OAT1, OAT3, or OCT2. 
 
There are limited in vivo data on the drug interaction potential of tecovirimat. The potential 
for tecovirimat to act as a perpetrator in drug interactions has been evaluated in healthy 
volunteers using five CYP probe substrates: flurbiprofen (CYP2C9), bupropion (CYP2B6), 
repaglinide (CYP2C8), omeprazole (CYP2C19), and midazolam (CYP3A4). The AUC for 
flurbiprofen was not altered, indicating no impact on CYP2C9. Bupropion was minimally 
altered (16% reduction), indicating no significant impact of tecovirimat on CYP2B6 
substrates. However, AUCs of the other three drugs were altered. Repaglinide AUC was 
increased 29% and there was a high incidence of hypoglycemia with the combination. 
Omeprazole AUC was increased 73%, and while this is not a clinically significant impact 
for omeprazole, other CYP2C19 substrates with narrow therapeutic indices may have 
increased exposures. Midazolam AUC was reduced 32%, indicating tecovirimat has 
CYP3A induction potential. This is relevant for drugs that are substrates for CYP3A4 which 
may have reduced exposures and compromised therapeutic effects (e.g., HIV protease 
inhibitors, cobicistat, maraviroc, some NNRTIs). While a 30% reduction has historically 
been considered a clinically relevant threshold for reduced ARV exposures, newer ARV 

 
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have wider therapeutic indices and tecovirimat is administered for a relatively short 
duration (14 days). PWH are disproportionally affected by HMPXV and likely to receive 
tecovirimat in the absence of interaction data in practice and thus, this controlled clinical 
trial represents a unique and important opportunity to assess the interaction potential. This 
study will compare ARV concentrations with and without tecovirimat and measure HIV-1 
RNA during study drug administration. 
 
Selection of Pediatric Doses 
The tecovirimat doses selected for pediatric participants in this study include the FDA 
approved doses for older, larger children which had dosing down to 13kg. These doses 
were determined through extrapolation from adult PK data with the goal of achieving 
exposures comparable to the observed exposure from 600mg every 12 hours. A similar 
approach was taken to doses for pediatric patients less than 13 kg for this study. We 
used standard allometric scaling to extrapolate to lighter pediatric participants using the 
weight allometric exponent of 0.75 for CL and Q and 1.0 for V1 and V2. However, in 
addition to PK differences based on size, in newborns and young infants, immature 
metabolism also needs to be considered. Since tecovirimat is primarily eliminated 
through metabolism by the UGT1 family, we applied the ontogeny pattern of raltegravir 
metabolism, also a UGT1A substrate [Clark, 2019], in combination with allometric 
scaling to assess potential dosing regimens. Absorption was assumed to be similar to 
adults. The WHO weight band groups were used to the extent possible and median 
values from CDC NHANES growth data base used to link age and weight in simulations. 
 
The reported CL/F in adults is 31 L/h in the tecovirimat package insert. This projects an 
AUC0-24 at steady of 38.7 mcg*h/mL with 600mg given orally every 12 hours in adults 
(AUC=F*Dose/CL). This equates to an average concentration (Cave) at steady-state of 
1.6 mcg/mL (Cave= AUC/Dose Rate). The reported steady state trough on this dose is 
0.587 mcg/mL The CV for tecovirimat AUC, Cmax, and Cmin are reported to be between 
~30-40% thus the 10th percentile for Cave in adults is ~0.9 mcg/mL.  
 
FDA-approved tecovirimat doses in adults are well above the concentrations needed to 
prevent smallpox infection in the non-human primate model [Leeds, 2013]. The 3 
mg/kg/daily NHP dose was identified as the lowest efficacious dose using both Kaplan 
Meier and ROC analysis. This dose results in a steady-date AUC0-24 of ~3-4 mcg*h/mL 
(Cave=~0.15 mcg/mL). Thus, the adult human tecovirimat dose provides Cave 
exposures approximately ~10 times higher and uniformly greater than the average NHP 
exposure from the efficacious NHP dose of 3 mg/kg. 
 
The pediatric dosing regimens proposed are predicted to maintain Cave of 1-2 mcg/mL 
after the first week of life. These concentrations are several times above those shown to 
be effective for pox infection in primates, but safe in adults. Proposed doses include age 
and weight considerations for neonates to account for immature UGT1 metabolism. 
 

 
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11.1 
Pharmacology Objectives 
 
11.1.1 
To define the pharmacokinetic (PK) profile and PK-pharmacodynamic (PD) 
associations for tecovirimat in HMPXV. 
 
11.1.2 
To assess the potential for drug interactions between tecovirimat and 
antiretrovirals among PWH. 
 
11.1.3 
To determine the steady-state tecovirimat AUCtau and Ctau in children.  
 
11.1.4 
To describe PK of tecovirimat in pregnant persons. 
 
11.1.5 
To describe the PK of tecovirimat in persons receiving potent inducers rifampin, 
rifapentine, rifabutin, St. John’s Wort, carbamazepine, phenytoin, phenobarbital, 
oxcarbazepine, or tipranavir/ritonavir. 
 
11.2 
Pharmacology Study Design 
 
Participants will undergo PK testing per section 6.3.7. 
 
Non-Compartmental Tecovirimat PK Analysis of Intensive PK Data 
Intensive PK sampling will be performed in select participants (see section 6.3.7). From 
intensive PK samples, the following PK parameters will be observed or calculated via 
non-compartmental analysis:  
• 
Cmax is defined as the maximum concentration observed during the dosing interval.  
• 
Tmax is defined as the time at which Cmax occurs. 
• 
AUCtau, the area under the concentration-time curve over the dosing interval, will be 
calculated either using the linear or log-linear trapezoidal rule.  
• 
AUC0-inf, the area under the concentration-time curve from time 0 extrapolated to 
infinite time, will be calculated either using the linear or log-linear trapezoidal rule.  
• 
Apparent clearance (CL/F) will be calculated as dose divided by AUC0-inf. 
• 
Apparent terminal elimination half-life (t1/2) can be estimated using ln(2)/ke, where ke 
is the first-order rate constant and is obtained from the lambda z parameter 
calculated by standard pharmacokinetic software packages. 
• 
Ctau is defined as the concentration at the end of the dosing interval.  
 
Tecovirimat Population PK Modeling 
The tecovirimat PK parameter estimates derived from non-compartmental analysis will be 
used as prior initial estimates when constructing a population pharmacokinetic model of 
tecovirimat via nonlinear mixed effects modeling. Both sparse and intensive PK sampling 
data will be leveraged for model development. Several covariates will be evaluated in the 
model including disease severity, renal function, hepatic function, age, weight, sex, race 
(black vs. Non-black), pregnancy (yes/no), and inducing medications (yes/no). Phoenix 
(Certara) will be used for noncompartmental and population PK analysis. 
 

 
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Tecovirimat PK/PD Analysis 
To examine the association of tecovirimat exposure with clinical outcomes, participant-
specific estimates (from the population PK models) of tecovirimat clearance (or another 
PK parameter) will be used as independent variables in models of clinical outcomes as 
the dependent variable. Drug exposure parameter estimates may also be used as 
independent variables in models for the occurrence of selected toxicities. Further details 
will be provided in the PK SAP. 
 
Adherence may be used as predictor variable(s) in evaluations of associations with 
treatment response. 
 
PK in Pregnant Participants 
Tecovirimat PK in the pregnant participants will be determined using non-compartmental 
methods and summarized using descriptive statistics. The AUCtau and Ctau in pregnant 
women will be compared to these values in non-pregnant participants undergoing intensive 
PK in Arms A/B and historical data.  
 
PK in Children 
Geometric mean AUCtau and Ctau in each weight band will be compared to these values in 
participants undergoing intensive PK in Arms A/B and historical data. The relationship 
between tecovirimat AUCtau and Ctau quartiles and tecovirimat safety and efficacy will be 
examined in the first 8 children in each weight band. If the protocol team determines dose 
adjustments are needed, additional intensive PK may be performed on the adjusted doses. 
Initial tecovirimat doses for neonates are based on experience with raltegravir, another 
antiviral drug primarily metabolized by uridine glucuronosyltransferase enzymes. Initial 
tecovirimat starting doses for neonates are shown in Table 5.1-2. PK for each neonate will 
be used to inform dosing of subsequent neonates enrolled. 
 
ARV PK 
ARV PK will be compared within person with (Day 8 and 15) versus without tecovirimat 
(Entry). ARV will also be compared in persons on tecovirimat vs. Placebo. If there are 
insufficient numbers of participants on a particular ARV, we will evaluate classes of ARV in 
the population PK model covariates. If the ARV class reduces the objective function by 
3.84, this is analogous to a p<0.05 in a Chi square test. 
 
12.0 
DATA COLLECTION AND MONITORING  
 
12.1 
Records to Be Kept 
 
Electronic case report form (eCRF) screens will be made available to sites for data entry. 
Participants must not be identified by name on any data submitted to the DMC. 
Participants will be identified by the patient identification number (PID) and study 
identification number (SID) provided by the ACTG DMC upon randomization. 
 

 
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12.2 
Role of Data Management 
 
12.2.1 
Instructions concerning entering study data on eCRFs will be provided by the 
ACTG DMC. Each CRS is responsible for keying the data in a timely fashion. 
 
12.2.2 
It is the responsibility of the ACTG DMC to assure the quality of computerized 
data for each ACTG study. This role extends from protocol development to 
generation of the final study databases. 
 
12.3 
Clinical Site Monitoring and Record Availability 
 
Monitoring visits may be conducted on-site or remotely. Remote visits may include 
remote source document verification using methods specified for this purpose by NIAID. 
Remote monitoring visits may be performed in place of, or in addition to onsite visits to 
ensure the safety of study participants and data integrity [FDA 2021]. The site must 
make available study documents for site monitors to review utilizing a secure platform 
that is HIPAA and 21 CFR Part 11 compliant. The Data Management Center will 
configure Medidata Remove Source Review (RSR) and make it available to all sites. We 
encourage sites to use the DMC provided Medidata RSR platform but other potential 
platform options include: Veeva SiteVault, site-controlled SharePoint or cloud-based 
portal, and direct access to Electronic Medical Record (EMR). Other secure platforms 
that are 21 CFR Part 11 compliant may be utilized, as allowed by the DAIDS Office of 
Clinical Site Oversight (OCSO). 
 
13.0 
PARTICIPANTS 
 
13.1 
Institutional Review Board (IRB) Review and Informed Consent 
 
This protocol and the informed consent documents (Appendices I-IV) and any 
subsequent modifications will be reviewed and approved by the IRB or EC responsible 
for oversight of the study. A signed consent form will be obtained from the participant (or 
parent, legal guardian, or person with power of attorney for participants who cannot 
consent for themselves, such as those below the legal age of consent). The consent 
form will describe the purpose of the study, the procedures to be followed, and the risks 
and benefits of participation. A copy of the consent form will be given to the participant, 
parent, or legal guardian, and this fact will be documented in the participant’s record. 
 
13.2 
Participant Confidentiality 
 
All laboratory specimens, evaluation forms, reports, and other records that leave the site 
will be identified by coded number only to maintain participant confidentiality. All records 
will be kept locked. All computer entry and networking programs will be done with coded 
numbers only. Clinical information will not be released without written permission of the 
participant, except as necessary for monitoring by the ACTG, IRB/EC, FDA, NIAID, 
OHRP, other local, U.S., and international regulatory entities as part of their duties, or 
the industry supporter or designee.  
 

 
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13.3 
Study Discontinuation 
 
The study may be discontinued at any time by the ACTG, IRB/EC, FDA, NIAID, OHRP, 
other country-specific government agencies as part of their duties to ensure that 
research participants are protected, or the industry supporter. 
 
14.0 
PUBLICATION OF RESEARCH FINDINGS 
 
Publication of the results of this trial will be governed by ACTG policies. Any 
presentation, abstract, or manuscript will be made available for review by the industry 
supporter prior to submission.  
 
15.0 
BIOHAZARD CONTAINMENT 
 
The U.S. government does not consider the West African clade of monkeypox virus as 
meeting the definition of Category A infectious substance under the Hazardous Materials 
Regulations (HMR). Therefore, specimens and material suspected or confirmed to 
contain the West African clade of monkeypox virus can be shipped as UN 3373 
Biological Substance, Category B [CDC 2022].  
 
As the transmission of HIV and other blood-borne pathogens can occur through contact 
with contaminated needles, blood, and blood products, appropriate blood and secretion 
precautions will be employed by all personnel in the drawing of blood and shipping and 
handling of all specimens for this study, as currently recommended by the CDC and the 
National Institutes of Health. 
 
All dangerous goods and materials, including diagnostic specimens and infectious 
substances, must be transported using packaging mandated by CFR 42 Part 72. Please 
refer to instructions detailed in the International Air Transport Association (IATA) 
Dangerous Goods Regulations.  

 
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Mbala PK, Huggins JW, Riu-Rovira T, et al. Maternal and fetal outcomes among pregnant 
women with human monkeypox infection in the Democratic Republic of Congo. J Infect Dis 
2017;216:824-8. 
 
Meaney-Delman DM, Galang RR, Petersen BW, Jamieson DJ. A Primer on Monkeypox 
Virus for Obstetrician–Gynecologists. Diagnosis, Prevention, and Treatment. Obstet 
Gynocol 2022 Jul 11. doi: 10.1097/AOG.0000000000004909 
 
Noe S, Zange S, Seilmaier M, et al. Clinical and virological features of first human 
monkeypox cases in Germany. Infection 2022 Jul 11;1-6. doi: 10.1007/s15010-022-01874-z 
 
Nolen LD, Osadebe L, Katomba J, et al. Extended human-to-human transmission during a 
monkeypox outbreak in the Democratic Republic of the Congo. Emerg Infect Dis 
2016;22:1014-21. 

 
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Palefsky JM, Lee JY, Jay N, et al. Treatment of anal high-grade squamous intraepithelial lesions 
to prevent anal cancer. N Engl J Med 2022;386:2273-82. doi: 10.1056/NEJMoa2201048 
 
Parker S, Handley L, Buller RM. Therapeutic and prophylactic drugs to treat orthopoxvirus 
infections. Future Virol 2008;3:595-612. 
 
Parker S, Nuara A, Buller RML, Schultz DA. Human monkeypox: an emerging zoonotic 
disease. 2007;2(1):17-24. 
 
Peiró-Mestres A, Fuertes I, Camprubí-Ferrer D, et al.; Hospital Clinic de Barcelona 
Monkeypox Study Group. Frequent detection of monkeypox virus DNA in saliva, semen, and 
other clinical samples from 12 patients, Barcelona, Spain, May to June 2022. Eurosurveill 
2022;27(28):pii=2200503. https://doi.org/10.2807/1560-7917.ES.2022.27.28.2200503 
 
Prentice RL, Kalbfleisch JD, Peterson AV Jr, Flournoy N, Farewell VT, Breslow NE. The 
analysis of failure times in the presence of competing risks. Biometrics 1978;34:541-54. 
 
Rao AK, Schulte J, Chen TH, Hughes CM, et al. Monkeypox in a Traveler Returning from 
Nigeria - Dallas, Texas, July 2021. MMWR Morb Mortal Wkly Rep. 2022 Apr 8;71(14):509-
516. doi: 10.15585/mmwr.mm7114a1. PMID: 35389974; PMCID: PMC8989376.  
 
Reed JL, Scott DE, Bray M. Eczema vaccinatum. Clin Infect Dis 2012;54:832-40. 
 
Reynolds MG, McCollum AM, Nguete B, Lushima RS, 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;9:380. 
 
Schoenfeld DA. Sample-size formula for the proportional-hazards regression model. 
Biometrics 1983;39:499-503. 
 
Sherwat A, Brooks JT, Birnkrant D, Kim P. Tecovirimat and the treatment of monkeypox - 
past, present, and future considerations. N Engl J Med 2022 Aug 3. doi: 
10.1056/NEJMp2210125 
 
SIGA Technologies, Inc. TPOXX® (tecovirimat) Prescribing Information. Reference ID: 
4985981. Revised May 2022. Accessed at: 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/214518s000lbl.pdf 
 
Thornhill JP, Barkati S, Walmsley S, et al.; SHARE-net Clinical Group. Monkeypox Virus 
Infection in Humans across 16 Countries — April–June 2022. N Engl J Med 2022 July 21. 
doi: 10.1056/NEJMoa220 
 
University of Minnesota CIDRAP (Center for Infectious Disease Research and Policy). 
WHO: 14,000 Monkeypox cases worldwide, 5 deaths. July 20, 2022. Accessed at: 
https://www.cidrap.umn.edu/news-perspective/2022/07/who-14000-monkeypox-cases-
worldwide-5-deaths. 
 

 
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WHO. WHO Director-General declares the ongoing monkeypox outbreak a Public Health 
Emergency of International Concern. 23 July 2022. Accessed at: WHO Director-General 
declares the ongoing monkeypox outbreak a Public Health Emergency of International 
Concern 
 
WHO. Clinical management and infection prevention and control for monkeypox: Interim 
rapid response guidance. 10 June 2022. Accessed at: Clinical management and infection 
prevention and control for monkeypox: Interim rapid response guidance, 10 June 2022 
(who.int). 
 
 
 
 
 

 
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APPENDIX I: INFORMED CONSENT AND AUTHORIZATION TO USE AND DISCLOSE 
PROTECTED HEALTH INFORMATION FOR ADULTS AND PARTICIPANTS REACHING AGE 
OF MAJORITY (AOM) WHO ARE ENROLLED/FOLLOWED IN PERSON 
 
 
Sponsor / Study Title: 
  
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 Human 
Monkeypox Virus Disease” 
 
Protocol Number: 
 
A5418 
 
Principal Investigator: 
(Study Doctor) 
 
«PiFullName» 
 
Telephone: 
 
«IcfPhoneNumber» 
 
Address: 
«PiLocations» 
 
 
  
SUMMARY  
  
PURPOSE 
This is a research study and your participation in this study is voluntary. 
The purpose of this study is to evaluate how well tecovirimat works for the 
treatment of human monkeypox virus infection and if the study drug is 
safe in people. The study will also help us understand more about how 
human monkeypox causes disease and how the body fights off infection.  
STUDY  
DRUG 
Study drug will be either tecovirimat or placebo for tecovirimat. A placebo 
looks like a “real” drug but does not have any active drug in it. Twice as 
many people will receive the active drug in this study, so you are more 
likely to receive the active study drug. Tecovirimat or placebo for 
tecovirimat will be taken two or three times a day for 14 days. 
  
NUMBER OF  
PARTICIPANTS 
530 people will participate in this study and receive active study drug or 
placebo. Children, people who are pregnant, people with severe disease 
or severe skin conditions, people taking certain medications that may 
lower tecovirimat levels in the blood, and people whose immune systems 
are weakened will be in a separate group that receives tecovirimat with 
no possibility of receiving placebo – there is no limit to how many people 
will be assigned to this group.  
  
LENGTH OF  
STUDY 
 
Your participation in this study will last about 2 months. If you are 
pregnant, we will contact you periodically to see how your pregnancy 

 
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goes and to know the health of your child. We would also like you to bring 
your baby in for a study visit about 4 weeks after they are born so we can 
examine the baby. 
REQUIRED  
ACTIVITIES 
If you participate in this study, the following study procedures are 
required: 
• You will have physical exams 
• You will record your symptoms daily 
• You will provide blood and urine samples 
• You will provide (or a study team member will obtain) swabs of the 
sores on your skin, mouth, vagina, and rectum,  
• You will complete questionnaires about your symptoms 
 
RISKS  
The most common side effects people receiving tecovirimat have noticed 
are: 
• 
Headache  
• 
Nausea (feeling like you want to vomit) 
• 
Vomiting  
• 
Stomach pain  
  
BENEFITS  
We do not know if you will benefit from tecovirimat. Based on what we 
know about tecovirimat, the study drug may help to treat your infection 
and prevent it from getting worse, but we cannot make any guarantee.  
  
OTHER CHOICES  
There is no proven way to treat human monkeypox virus. You may 
benefit from supportive therapy (such as intravenous [IV] fluids, or 
medicine to control fever or pain) and antibiotics for any bacterial 
infections you may have. There may be other medications that your 
study doctor may consider using to treat your infection. Tecovirimat 
may be available outside this study. There may also be research 
studies looking at other new treatments for poxviruses.  
 
 
INTRODUCTION  
  
You are being asked to take part in this research study because: 
• 
You are known to have monkeypox virus or your healthcare providers suspect you have 
monkeypox virus  
• 
You have had symptoms for fewer than 14 days  
• 
You have at least one active, not yet scabbed lesion, or proctitis (inflammation of the lining 
of the rectum) or mouth sores 
  
This study is sponsored by the National Institutes of Health (NIH). The study doctor is in charge 
of this study at this site. Before you decide if you want to be a part of this study, we want you to 
know about the study.  
  

 
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This is a consent form. It gives you information about this study. The study staff will talk with you 
about this information. You are free to ask questions about this study at any time. If you agree to 
take part in this study, you will be asked to sign this consent form. You will get a copy to keep.  
 
 
WHY IS THIS STUDY BEING DONE?  
  
Monkeypox is caused by a virus. This virus is most often spread by close contact with 
someone who has monkeypox. Illness caused by monkeypox virus infection usually starts 
with a fever and feeling poorly before a rash begins. The rash looks like raised bumps 
and pus-filled blisters (called lesions). The lesions then crust, scab, and fall off after about 
2-4 weeks, sometimes leaving a scar. 
 
Since Spring 2022, monkeypox has rapidly spread throughout the world, with more than 
70,000 cases in 107 countries and more than 26,000 cases in the United States reported 
as of September 2022.  
 
Tecovirimat is a drug that may help to treat infections caused by pox viruses. Tecovirimat 
is approved by the Food and Drug Administration (FDA) to treat smallpox in adults and 
children, but its use in this study is considered investigational. An investigational use is 
one that has not been approved by the FDA. Tecovirimat has been approved based only 
on data from animals. We don’t know for sure if it works to treat any infections in people. 
The FDA has reviewed information on tecovirimat and determined that tecovirimat may 
help treat infection, including serious or potentially life-threatening disease, from 
poxviruses.  
 
Tecovirimat has been given safely to some people with monkeypox in the recent outbreak 
and is currently being studied in several ongoing studies outside of the U.S., but none of 
the studies have shown whether or not this study drug works to treat monkeypox. The 
safety of tecovirimat has been evaluated in a study with adult participants without 
monkeypox. Tecovirimat was generally safe and well tolerated – the risks are noted 
below.  
 
We are doing this study to see if tecovirimat is safe and whether it helps treat monkeypox 
in people. The study will also help us understand more about how human monkeypox 
causes disease and how the body fights off infection with monkeypox. 
 
 
WHAT DO I HAVE TO DO IF I AM IN THIS STUDY?  
 
Screening/Entry Visit 
If you would like to be in this study, after you have read and signed this consent form, you will 
have a visit to make sure you meet the requirements for joining the study.  
 
We will collect some demographic (for example, age, gender, race), clinical (for example, 
disease condition, diagnosis), and laboratory (for example, CD4 cell count and viral load if you 

 
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are living with HIV) information. We will collect this information even if you do not start study 
drug. 
 
At this visit: 
• 
You will have a physical exam and answer questions about your medical history and any 
medications you have taken recently.  
• 
You will have an exam of your skin to identify where you have monkeypox lesions. You will 
have to remove your clothes and wear a robe for this exam. Site staff will ask to take 
pictures of your skin lesions. You do not have to agree to have these pictures taken. 
You can participate in this study regardless of what you decide about having pictures 
taken. If you agree, these pictures will be used so that the study staff can follow how well 
your lesions are healing. These pictures will not be used for any other purpose without your 
written permission. If you have lesions on your face, it is possible that you will be able to be 
identified in these pictures. These pictures may be stored in your electronic medical 
record. If these pictures are stored in a study database, they will be stored securely with a 
code instead of your name. Please discuss how pictures are stored at your clinical 
research site. 
• 
If you can become pregnant (and you are not already pregnant), you will give a blood 
sample or urine sample for a pregnancy test.  
• 
Study staff will collect the following swabs: 
o Swabs from your skin, mouth/throat, and rectum if you do not have a lab diagnosis of 
monkeypox. The study doctor may be required by law to report the result of this test to 
the local health authorities. 
o Swabs of any lesions you have that may be caused by herpes 
• 
You will answer questionnaires about any pain your lesions may be causing you 
 
If you qualify for the study, you will have some more tests: 
• 
You will have blood drawn for the following tests:  
o HIV-1 testing. The study doctor may be required by law to report the result of this test to 
the local health authorities. 
o CD4 count (if you are living with HIV) 
o HIV viral load (if you are living with HIV) 
o Liver and kidney tests and blood counts 
o Tests for Hepatitis C, Hepatitis B (unless this information is in your medical records), and 
syphilis. The study doctor may be required by law to report the results of these tests to 
the local health authorities.  
o A test to measure concentrations of medicines used to treat or prevent HIV (if you are 
living with HIV or taking medications to prevent HIV infection) 
o Tests to see the levels of monkeypox virus in your blood 
o Stored blood for future study-required testing 
• 
You will be asked to give a urine sample for the following tests: 
o Tests for sexually transmitted infections. If you have a positive test for a sexually 
transmitted infection, you will be referred to your regular doctor for evaluation and 
treatment. You can join this study if you have a sexually transmitted infection. The study 
doctor may be required by law to report the result of these tests to the local health 
authority. 

 
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• 
If you are breastfeeding, we will ask you for a sample of your breastmilk 
• 
You will answer questionnaires about others who live in your home and whether they have 
monkeypox and how you are feeling 
• 
If you have eye disease from monkeypox or eye symptoms, study staff will place a strip of 
paper inside your lower eyelid to collect tears from you. You may also be given eyedrops to 
help treat eye disease. Please talk to the study staff, your primary care provider, or your 
eye doctor about this. These eyedrops are not provided by the study. 
• 
Study staff will take swabs for the following tests. The study doctor may be required by law 
to report the results of these tests to the local health authorities: 
o Swabs from the back of your throat and your rectum to test for gonorrhea and chlamydia 
o Swabs of from your skin, mouth and throat, rectum, and vagina (you will collect this 
swab yourself and give it to the study staff) for monkeypox testing 
• 
You will answer questionnaires about any recent sexual activity that you have had and any 
anal/rectal symptoms you may be having 
• 
If you qualify for the study, you will receive a study kit that includes: 
o Your study drugs. Tecovirimat or placebo for tecovirimat will be taken two or three times 
a day for 14 days. 
o Instructions on how to complete the study diary that you will complete at home to record 
how your skin lesions are doing, any symptoms that you are experiencing, and any pain 
that you are experiencing. We will also ask you to write down the date and time that you 
take your study drug. 
o Containers for any sample collections that you will do at home.  
 
Most people will be randomly assigned (like flipping a coin or rolling dice) to a study group. You 
and the study staff will not be able to choose which study treatment group you are in. You and 
the study staff will not know whether you are receiving active study drug or placebo. Twice as 
many people will receive active study drug as receive placebo in this study, so you are twice as 
likely to receive “real” study drug.  
 
Some people will be assigned to receive tecovirimat instead of being randomly assigned to a 
study group. If you belong to one of the groups below, you will receive tecovirimat – there is no 
chance you will receive placebo. 
• 
Participants under 18 
• 
People who are pregnant or breastfeeding 
• 
People with severe skin disease 
• 
People with a severely suppressed immune system 
• 
People with monkeypox disease in their eye or on their face (cheeks, nose, eyelid) 
• 
People with severe monkeypox lesions that have to be treated surgically 
• 
People who have to be hospitalized due to their monkeypox infection 
• 
People taking medicines that may reduce tecovirimat levels including rifampin, rifapentine, 
rifabutin, St. John’s Wort, carbamazepine, phenytoin, phenobarbital, oxcarbazepine, or 
tipranavir/ritonavir 
 
If you join the study at an in-person visit, you should continue to be seen in person if 
possible, however visits may occur through telemedicine if needed. 
 

 
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Study Visit on Day 6 
At this visit: 
• 
The study staff will contact you by phone or via telemedicine to ask about any symptoms 
you are experiencing and any pain that you might be experiencing. 
• 
Study staff will ask if you are taking your study drugs as directed. 
• 
You will answer questionnaires about your anal/rectal health. 
 
Study Visits on Days 8, 15, 22, 29, 57 
At these visits: 
• 
You will have a brief physical exam and answer questions about any medications you are 
taking. 
• 
You will have an exam of your skin to identify where you have monkeypox lesions. Study 
staff will take pictures of your skin lesions. 
• 
You will answer questionnaires about recent sex you may have had (day 29) and whether 
people in your household have monkeypox (day 29 and 57), your quality of life (days 8, 15, 
and 29), and anal/rectal health (days 15 and 57). 
• 
Study staff will collect the following swabs: 
o Swabs of your skin, mouth and throat, rectum, and vagina (you will collect this swab 
yourself and give it to the study staff) for monkeypox testing 
o If the study staff thinks you have monkeypox in your eye or you have eye symptoms, a 
small strip of paper will be placed in your lower eyelid to collect tear fluid. 
• 
If you are breastfeeding, we will collect a sample of your breastmilk  
• 
You will have blood drawn for the following tests:  
o Routine safety tests (liver and kidney tests and blood counts) (day 8) 
o Blood tests to see the levels of monkeypox virus in your blood  
o Blood tests to see how your body processes the study drugs and other medications you 
take that may interact with study drug (these tests are called pharmacokinetic [PK] tests 
(days 8 and 15) 
o A test to measure concentrations of medicines used to treat or prevent HIV (if you are 
living with HIV or taking medications to prevent HIV infection) (days 8 and 15) 
Stored blood for future study-required testing (days 8, 15, 29, and 57) 
• You may have a series of blood draws to see how your body processes the study drugs 
(these tests are called intensive PK tests) (day 8). These tests are required for some 
participants. The study staff at your site can tell you if you will have to have these tests. If 
you have these tests, you will be asked to have nothing to eat or drink except for water for 8 
hours before your visit. You will be arrive at the facility in the morning and will remain there 
for 8-12 hours, depending on how often you take your study drug. You will have a blood 
sample drawn, eat a standardized meal provided by the site, and then you will take your 
study drug. Additional blood samples will be obtained at 1, 2, 3, 4, 6-, 8-, and 10-hours after 
your dose of study drug. On the day of the visit, we will place a small plastic tube (like a 
“drip”) in your arm. The tube is attached to a plastic needle. The tube will stay in your arm 
until all the blood draws are done. We use the tube so we do not have to stick you with a 
needle each time blood is drawn. 
 

 
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Study Evaluations to Complete at Home 
In addition to study visits at the clinic, you will have to complete some study evaluations at 
home: 
• 
Complete your study diary and pain rating every day on days 1-29 
• 
If you are able to and you agree, you will take a photograph of your lesions on days 1-29 so 
you can show them to the study staff to track how your lesions are healing 
• 
If you agree to provide a semen sample, you will receive specimen containers for this 
purpose. You will masturbate into the container on the morning of your day 1, day 15, and 
day 57 study visits and bring the sample with you to your study visit. 
 
Additional Study Visits 
You will have extra study visits if your monkeypox disease gets worse or if your lesions heal up. 
If you need to report to the site that your lesions have healed, this visit may be done remotely 
(over the phone or via telemedicine systems approved for use at your site). 
 
Early Discontinuation 
If at any point in the study you want to stop participating in the study, you must contact the site 
immediately. If you choose to withdraw consent, no additional samples will be collected and no 
new information will be collected. Any samples that have not been analyzed prior to your 
withdrawal of consent will be destroyed, but any information from any samples already analyzed 
will still be used.  
 
 
ARE THERE ANY TESTS THAT ARE OPTIONAL? 
 
Some people in this study are required to have the intensive PK tests described above. Even if 
you are not required to, you may be asked to have the intensive PK tests.  
 
____ (initials) I understand and I agree to participate in this procedure 
 
OR  
 
____ (initials) I understand but I do not agree to participate in this procedure 
 
  

 
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QUICK SUMMARY OF EVALUATIONS 
 
  
Screening/ 
Day 1 
 
Day 
6 
Day 
8 
Day 
15 
Day 
22 
Day 
29 
Day 
57 
Lesion 
Resolution 
Disease 
Progression 
Physical Exam  
X 
 
X 
X 
X 
X 
X 
X 
X 
Telephone Check 
 
X 
 
 
 
 
 
 
 
Blood Drawn 
X 
 
X 
X 
X 
X 
X 
 
X 
Urine Collected 
X 
 
 
 
 
 
 
 
 
Intensive PK 
 
 
X 
 
 
 
 
 
 
Swabs Collected 
X 
 
X 
X 
X 
X 
X 
 
X 
Questionnaires 
X 
X 
X 
X 
 
X 
X 
 
X 
Semen Sample 
(optional) 
X 
 
 
X 
 
 
X 
 
X 
Study Diary/Self 
Assessments 
Days 1-29 
  
  
  
 
 
WHAT IF I AM IN PAIN OR MY MONKEYPOX VIRUS GETS WORSE? 
 
If you become more ill from monkeypox or you develop new skin lesions on your face, please 
contact the study staff. You may be able to start tecovirimat without the possibility of placebo. 
You may also be able to start tecovirimat without the possibility of placebo if you have severe 
pain for 5 days after starting the study. 
 
 
WILL I RECEIVE THE RESULTS OF ANY TESTS? 
 
You will receive the results of routine lab tests (for example, blood counts, liver and 
kidney tests, pregnancy test, testing for sexually transmitted diseases and HIV, HIV 
viral load, CD4 count) that are performed at the study visits. You will be told of the 
monkeypox results from swabs taken from skin lesions, rectal swab, and mouth swab.  
 
Some of the blood that is collected from you will be stored and tested later. Some of these tests 
may be done after you are done with the study, and other tests are not yet approved by the FDA 
and are still considered “research” tests. For these reasons, you will not receive the results of: 
• 
Monkeypox testing from areas other than skin lesions, mouth, and rectum 
• 
Monkeypox testing after entry 
• 
Tests of your immune response to monkeypox 
• 
Tests of blood concentrations of tecovirimat or other medicines 
 
You will be told of any new information learned during the course of the study that might cause 
you to change your mind about staying in the study. At the end of the study, you will be told 
when study results may be available and how to learn about them. As with all studies, if we find 
out important information that may affect your care, you will be provided with those results. 
 

 
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CAN I CHOOSE THE TYPES OF RESEARCH THAT MY SAMPLES AND INFORMATION ARE 
USED FOR?  
  
Some of your blood will be stored and used for study-required pharmacologic, immunologic, and 
virologic testing.  
  
Identifiers will be removed from your samples and from any private information that has been 
collected about you. This means that no one looking at the labels or at other information will be 
able to know that the samples or information came from you.  
  
The tests described above are required by this study. If you do not agree to the storage or 
testing that has been described above, you should not join this study.  
 
Please refer to Attachment A to consent for use of your samples in other studies.  
 
 
COMMERCIAL PROFIT 
 
Your biospecimens collected during this study may be used for commercial profit (even if 
identifiers are removed) and you will not share in this profit. 
  
  
HOW MANY PEOPLE WILL TAKE PART IN THIS STUDY?  
  
530 people will participate in this study and receive active study drug or placebo.  
 
There is a third group of people (including participants under 18, people who are pregnant or 
breastfeeding, people with severe disease, people taking certain medicines that may interact 
with tecovirimat, and people whose immune systems are weakened by other infections) who will 
be assigned to active study drug with no possibility of receiving placebo – there is no limit to 
how many people will be assigned to this group.  
  
  
HOW LONG WILL I BE IN THIS STUDY?  
  
You will be in this study for about two months (60 days).  
 
  
WHY WOULD THE STUDY DOCTOR TAKE ME OFF THIS STUDY EARLY?  
  
The study doctor may need to take you off the study early without your permission if:  
• 
The study is stopped or cancelled  
• 
Your primary care doctor thinks that this study is no longer in your best interest and they 
request that you stop participating 
  
The study doctor may also need to take you off the study drug(s) without your permission if:  
• 
Continuing the study drug may be harmful to you  

 
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• 
You need a treatment that you may not take while on the study  
• 
You are not able to take the study drug as required by the study  
 
 
WHAT HAPPENS WHEN I FINISH THE STUDY? 
 
After you have completed your study participation, the study will not be able to continue to 
provide you with the study drug you received on the study. If continuing to take this or similar 
drugs/agents would be of benefit to you, the study staff will discuss how you may be able to 
obtain them. 
 
 
WHAT ARE THE RISKS OF THE STUDY?  
  
The drug used in this study may have side effects, some of which are listed below. Please note 
that these lists do not include all the side effects seen with this study drug. These lists include 
the more serious or common side effects with a known or possible relationship. If you have 
questions concerning the additional study drug side effects, please ask the study staff at your 
site.  
  
There is a risk of serious and/or life-threatening side effects when non-study medications are 
taken with the study drugs. For your safety, you must tell the study doctor or study nurse about 
all medications you are taking before you start the study and also before starting any new 
medications while on the study. Also, you must tell the study doctor or study nurse before 
enrolling in any other clinical trials while on this study.  
  
The risks of tecovirimat in people with smallpox or other poxviruses are not known. 
Tecovirimat has not been studied in people with weak immune systems, the elderly, or 
children. Tecovirimat 600 mg capsules were tested in 359 healthy adults, including 336 
healthy adults who received tecovirimat capsules twice a day for 14 days. Tecovirimat for 
injection was also tested in 26 healthy adults. No serious problems occurred in any of the 
participants in these studies.  
  
During the 2022 monkeypox outbreak in the U.S., tecovirimat capsules have also been 
given to more than 230 people with poxvirus infection, including people with monkeypox, 
as of July 2022; side effects are being monitored but no serious problems with tecovirimat 
have been reported so far. Still, tecovirimat may cause some adverse events (side 
effects). There also may be other adverse events that we cannot predict. The most 
common adverse events in people who have taken tecovirimat were:  
• 
Headache  
• 
Nausea  
• 
Vomiting  
• 
Stomach pain  
  
As with any medication, there is a potential risk of an allergic reaction. An allergic reaction 
after receiving tecovirimat could include:  

 
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• 
Rash 
• 
Difficulty breathing 
• 
Wheezing 
• 
Sudden drop in blood pressure causing dizziness or fainting  
• 
Swelling (around the mouth, throat, or eyes)  
• 
Fast pulse 
• 
Sweating 
 
Risks of Drug Interactions 
There are drug interactions with tecovirimat. Tecovirimat can lower or raise the 
concentrations of other medicines in your blood. When the blood concentrations of other 
medicines are lower, the other medicines may not work as well. When the blood 
concentrations of other medicines are raised, the other medicines may cause more side 
effects. Other medicines may also lower or raise the tecovirimat concentrations in the blood. 
To minimize the risk for drug interactions, it is important to review all of your prescription and 
over-the- counter medicines and dietary and herbal supplements with study personnel. It is 
also important to notify study personnel before you start any new prescription or over-the- 
counter medicines and dietary and herbal supplements while taking the study drug.  
  
Risks of Blood Draw  
Having blood drawn may cause some discomfort, bleeding, bruising, and/or swelling where the 
needle enters the body, and in rare cases it may result in fainting. There is a small risk of 
infection.  
  
Risks of Anal Swabs, Mouth Swabs, Skin Swabs, and Vaginal Swabs  
These can be uncomfortable and occasionally there can be some bleeding. If you are having 
pain in the rectum, there may be significant pain with the anal swab.  
 
Questionnaires 
You may be embarrassed by the detailed questions about sex and your anal health. 
 
Loss of Privacy - Photographs of Participant’s Face 
You may have photographs of your face or areas of your skin that have distinctive markings 
such as tattoos taken for this study. It is possible that these photographs may be 
recognizable and your identity may be known. All photographs taken during the study will be 
stored in your electronic medical record or will be stored with a code instead of your name. 
 
Risks of Starting the Study Before Your Monkeypox Virus is Confirmed by a Lab 
There are other things that can cause lesions on your skin, but we want you to start the study as 
soon as possible, so we will let you begin study drug even if your skin lesions have not been 
tested by a lab and confirmed to be monkeypox. There is a chance that your lab tests will show 
that you do not have monkeypox, so there is a risk that you will have taken study drug and 
participated in study tests when you do not have monkeypox.  
 
The study doctors at your site will use their best judgement to make sure that this does not 
happen, but if it does happen you will stop taking the study drug and the study staff at your 

 
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study site will check on you in 7 days to make sure that you do not have any side effects 
before you leave the study. 
 
 
ARE THERE RISKS RELATED TO PREGNANCY AND BREASTFEEDING?  
 
Tecovirimat has not been studied in pregnant or nursing people. It is not known if giving 
tecovirimat to a pregnant person would hurt the unborn child. Tecovirimat has been tested 
on pregnant mice and rabbits. There were no serious problems in the unborn animals. 
Poxviruses during pregnancy can cause serious harm to the pregnant person and unborn 
baby.  
 
In animal studies, tecovirimat was present in animal milk. When a drug is present in 
animal milk it is likely to be present in human milk. Because of the potential for virus 
transmission through direct contact with the breastfed infant, breastfeeding is not 
recommended while the nursing individual has active lesions. A lactating person should 
consider pausing breastfeeding and consider pumping and discarding breast milk during 
the study. 
 
If you can get pregnant but are not pregnant when you join the study and you are engaging in 
sexual activity that could lead to pregnancy, you must agree to use at least one effective 
method of contraception from the time you join the study until you are finished with the study. 
Effective methods of contraception are hormonal contraceptives (injected or in pills), male or 
female condoms, diaphragm or cervical cap with a spermicide, or an intrauterine device (an 
IUD). Abstinence (agreeing not to have sex) is also allowed as a way to prevent pregnancy. 
 
If at any point during the study you think you may be pregnant, you should let the study staff at 
your site know so that a pregnancy test can be done. 
 
If you are pregnant or become pregnant while on study, the study staff would like to obtain 
information from you about the outcome of the pregnancy (even if it is after your participation in 
the study ends). We would also like you to bring your baby in for a study visit about 4 weeks 
after they are born so we can examine the baby.  
 
 
ARE THERE BENEFITS TO TAKING PART IN THIS STUDY?  
  
We do not know for certain if you will benefit from tecovirimat. Based on what we know 
about tecovirimat, the study drug may help to treat your infection and prevent it from 
getting worse, but we cannot make any guarantee. 
  
  
WHAT OTHER CHOICES DO I HAVE BESIDES THIS STUDY?  
  
There is no proven way to treat poxviruses, but research is ongoing. You may benefit from 
supportive therapy (such as IV fluids, or medicine to control fever or pain) and antibiotics for 
any bacterial infections you may have. There may be other medications that your study doctor 

 
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may consider using to treat your infection. Tecovirimat may be available outside this study. 
There may also be research studies looking at other new treatments for poxviruses.  
  
Please talk to your study doctor about these and other choices available to you. Your study 
doctor will explain the risks and benefits of these choices.  
  
  
WHAT ABOUT CONFIDENTIALITY?  
  
We will do everything we can to protect your privacy. In addition to the efforts of the study staff 
to help keep your personal information private, we have gotten a Certificate of Confidentiality 
from the U.S. Federal Government. This certificate means that researchers cannot be forced to 
tell people who are not connected with this study, such as the court system, about your 
participation. The researchers with this Certificate may not disclose or use information, 
documents, or biospecimens that may identify you in any federal, state, or local civil, criminal, 
administrative, legislative, or other action, suit, or proceeding, or be used as evidence, for 
example, if there is a court subpoena, unless you have consented for this use. Information, 
documents, or biospecimens protected by this Certificate cannot be disclosed to anyone else 
who is not connected with the research except, if there is a federal, state, or local law that 
requires disclosure (see below); if you have consented to the disclosure, including for your 
medical treatment; or if it is used for other scientific research, as allowed by federal regulations 
protecting research participants.  
 
The Certificate cannot be used to refuse a request for information from personnel of the United 
States federal or state government agency sponsoring the project that is needed for auditing or 
program evaluation by the agency which is funding this project or for information that must be 
disclosed in order to meet the requirements of the federal Food and Drug Administration (FDA). 
You should understand that a Certificate of Confidentiality does not prevent you from voluntarily 
releasing information about yourself or your involvement in this research. If you want your 
research information released to an insurer, medical care provider, or any other person not 
connected with the research, you must provide consent to allow the researchers to release it. 
  
Having a Certificate of Confidentiality does not prevent you from releasing information about 
yourself and your participation in the study. The Certificate of Confidentiality will not be used to 
prevent disclosure for any purpose you have consented to in this informed consent document. 
  
Even with the Certificate of Confidentiality, if the study staff learns of possible child abuse and/or 
neglect or a risk of harm to yourself or others, we will be required to tell the proper authorities. 
  
Your records may be reviewed by the U.S. Food and Drug Administration (FDA), the AIDS 
Clinical Trials Group (ACTG), the U.S. Office for Human Research Protections (OHRP), or other 
local, U.S., and international regulatory entities as part of their duties, Advarra  Institutional 
Review Board (IRB) (a committee that protects the rights and safety of participants in research), 
National Institutes of Health (NIH), study staff, study monitors, drug companies supporting this 
study, and their designees.  
 
  

 
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Also, any publication of this study will not use your name or identify you personally. 
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by 
U.S. law. This Web site will not include information that can identify you. At most, the Web site 
will include a summary of the results. You can search this Web site at any time.  
  
  
WHAT ARE THE COSTS TO ME?  
  
The study will pay for research-related tests and assessments. Taking part in this study may 
lead to added costs to you and your insurance company. In some cases, it is possible that your 
insurance company will not pay for these costs because you are taking part in a research study. 
 
 
WILL I RECEIVE ANY PAYMENT?  
  
«Compensation» 
 
You will be paid up to a total of $xx.xx if you complete this study. You will be paid for the visits 
you complete according to the following schedule: 
$xx.xx for Visits xxx.  
$xx.xx for Visits xxx.  
$xx.xx for Visits xxx.  
 
If you do not complete the study, for any reason, you will be paid for each study visit you do 
complete.  
 
You will be paid ___________ [“following each completed visit”, “monthly”, “quarterly”, “at the 
end of your participation in the research study”, “following each completed visit or at the end of 
your participation in the research study, whichever you prefer”]. 
 
If you have any questions regarding your compensation for participation, please contact the 
study staff.  
 
 
WHAT HAPPENS IF I AM INJURED?  
  
If you are injured as a result of being in this study, you will be given immediate treatment for 
your injuries. There is no program for compensation through the NIH. The cost for this treatment 
will be charged to you or your insurance company. 
You will not be giving up any of your legal rights by signing this consent form.  
  
  
WHAT ARE MY RIGHTS AS A RESEARCH PARTICIPANT?  
  
Taking part in this study is completely voluntary. You may choose not to take part in this study 
or leave this study at any time. Your decision will not have any impact on your participation in 

 
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other studies conducted by NIH and will not result in any penalty or loss of benefits to which you 
are otherwise entitled.  
  
We will tell you about new information from this or other studies that may affect your health, 
welfare, or willingness to stay in this study. If you want the results of the study, let the study staff 
know.  
  
  
WHOM TO CONTACT ABOUT THIS STUDY 
 
During the study, if you experience any medical problems, suffer a research-related injury, or 
have questions, concerns or complaints about the study such as: 
• 
Whom to contact in the case of a research-related injury or illness; 
• 
Payment or compensation for being in the study, if any; 
• 
Your responsibilities as a research participant; 
• 
Eligibility to participate in the study; 
• 
The study doctor’s or study site’s decision to withdraw you from participation; 
• 
Results of tests and/or procedures; 
 
Please contact the study doctor at the telephone number listed on the first page of this consent 
document.  
 
If you seek emergency care, or hospitalization is required, alert the treating physician that you 
are participating in this research study.  
 
An institutional review board (IRB) is an independent committee established to help protect the 
rights of research participants. If you have any questions about your rights as a research 
participant, contact: 
• 
By mail: 
Study Subject Adviser 
Advarra IRB 
6100 Merriweather Dr., Suite 600 
Columbia, MD 21044 
• 
or call toll free:    877-992-4724 
• 
or by email: adviser@advarra.com 
 
Please reference the following number when contacting the Study Subject Adviser: Pro00065749. 

 
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SIGNATURE PAGE  
  
If you have read this consent form (or had it explained to you), all your questions have been 
answered and you agree to take part in this study, please sign your name below.  
  
 
_______________________  
_________________________________________  
Participant’s Name (print) 
 
Signature and Date  
  
  
  
  
______________________  
___________________________________________  
Study Staff Conducting 
 
Signature and Date  
Consent Discussion (print) 
  
  
_____________________ 
 
____________________________________________ 
Witness’s Name (print) 
 
Signature and Date  
(As appropriate)  
 
 
FOR CHILDREN WHO BECOME ADULTS  
 
I have been told that my parents/legal guardian agreed for me to participate in this research 
study as a minor. I have read and understand the information in this informed consent 
document. I have had an opportunity to ask questions and all of my questions have been 
answered to my satisfaction. I voluntarily agree to continue to participate in this study until I 
decide otherwise. I do not give up any of my legal rights by signing and dating this consent 
document. I will receive a copy of this signed and dated consent document. 
  
  
_______________________  
_________________________________________  
Participant’s Name (print) 
 
Signature and Date  
 
 

 
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AUTHORIZATION TO USE AND DISCLOSE PROTECTED HEALTH INFORMATION 
  
If you decide to be in this study, the study doctor and study staff will use and share health data 
about you to conduct the study. Health data may include: 
• 
Your name. 
• 
Address. 
• 
Phone number. 
• 
Date of birth. 
• 
Medical history. 
• 
Information from your study visits, including all test results.  
  
Health data may come from your study records or from existing records kept by your doctor or 
other health care workers.  
  
For this study, the study staff may share health data about you with authorized users. 
Authorized users may include: 
• 
Representatives of University of California, Los Angeles (UCLA) and National Institute of 
Allergy and Infectious Diseases (NIAID). 
• 
Representatives of ACTG. 
• 
Representatives of Advarra IRB (an Institutional Review Board that reviews this study). 
• 
The Food and Drug Administration (FDA) and other U.S. federal and state agencies. 
• 
Government agencies to whom certain diseases (like HIV, hepatitis, and STDs) must be 
reported. 
• 
Governmental agencies of other countries. 
• 
Outside individuals and companies, such as laboratories and data storage companies, that 
work with the researchers and sponsor and need to access your information to conduct this 
study. 
• 
Other research doctors and medical centers participating in this study, if applicable.  
• 
A data safety monitoring board which oversees this study, if applicable. 
  
Your health data will be used to conduct and oversee the research, including for instance: 
• 
To see if the study drug works and is safe. 
• 
To compare the study drug to other drugs. 
• 
For other research activities related to the study drug. 
  
Once your health data has been shared with authorized users, it may no longer be protected by 
federal privacy law and could possibly be used or disclosed in ways other than those listed here.  
  
Your permission to use and share health data about you will end in 50 years unless you revoke 
it (take it back) sooner.  
  
You may revoke (take back) your permission to use and share health data about you at any 
time by writing to the study doctor at the address listed on the first page of this form. If you do 
this, you will not be able to stay in this study. No new health data that identifies you will be 
gathered after your written request is received. However, health data about you that has already 
been gathered may still be used and given to others as described in this form.  

 
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Your right to access your health data in the study records will be suspended during the study to 
keep from changing the study results. When the study is over, you can access your study health 
data. 
  
If you decide not to sign and date this form, you will not be able to take part in the study. 
 
 
 
 

 
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STATEMENT OF AUTHORIZATION 
 
I have read this form and its contents were explained. My questions have been answered. I 
voluntarily agree to allow study staff to collect, use and share my health data as specified in this 
form. I will receive a signed and dated copy of this form for my records. I am not giving up any of 
my legal rights by signing and dating this form.  
  
  
______________________           ____________________________ 
Participant’s Name (print)               Signature and Date 
  
  
_____________________             ____________________________ 
Witness’s Name (print)                   Signature and Date 
  
  
FOR CHILDREN WHO BECOME ADULTS  
 
I have been told that my parents/legal guardian agreed to the use and disclosure of my 
Protected Health Information as outlined in this document. I have read and understand the 
information in this authorization. I have had an opportunity to ask questions and all of my 
questions have been answered to my satisfaction. I continue to authorize the use and disclosure 
of my Protected Health Information. I will receive a copy of this signed and dated authorization. 
  
____________________________________               
Participant’s Printed Name  
  
  
____________________________________        __________ 
Participant’s Signature                                               Date 
 
 

 
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APPENDIX II: INFORMED CONSENT AND AUTHORIZATION TO USE AND DISCLOSE 
PROTECTED HEALTH INFORMATION FOR ADULTS AND PARTICIPANTS REACHING 
AGE OF MAJORITY (AOM) WHO ARE ENROLLED/FOLLOWED REMOTELY 
 
 
Sponsor / Study Title: 
  
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 Human Monkeypox Virus Disease” 
 
Protocol Number: 
 
A5418 
 
Principal Investigator: 
(Study Doctor) 
 
«PiFullName» 
 
Telephone: 
 
«IcfPhoneNumber» 
 
Address: 
«PiLocations» 
 
 
 
SUMMARY  
 
PURPOSE 
This is a research study and your participation in this study is 
voluntary. The purpose of this study is to evaluate how well 
tecovirimat works for the treatment of human monkeypox virus 
infection and if the study drug is safe in people. The study will also 
help us understand more about how human monkeypox causes 
disease and how the body fights off infection.  
STUDY  
DRUG 
Study drug will be either tecovirimat or placebo for tecovirimat. A 
placebo looks like a “real” drug but does not have any active drug in 
it. Twice as many people will receive the active drug in this study, so 
you are more likely to receive the active study drug. Tecovirimat or 
placebo for tecovirimat will be taken two or three times a day for 14 
days. 
 
NUMBER OF  
PARTICIPANTS 
530 people will participate in this study and receive active study 
drug or placebo. Children, people who are pregnant, people with 
severe disease or severe skin conditions, people taking certain 
medications that may lower tecovirimat levels in the blood, and 
people whose immune systems are weakened will be in a separate 
group that receives tecovirimat with no possibility of receiving 
placebo – there is no limit to how many people will be assigned to 
this group.  
 

 
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LENGTH OF  
STUDY 
 
Your participation in this study will last about 2 months. If you are 
pregnant, we will contact you periodically to see how your 
pregnancy goes and to know the health of your child.  
REQUIRED  
ACTIVITIES 
If you participate in this study, the following study procedures are 
required: 
• You will record your symptoms daily 
• You will provide swabs of the sores on your skin  
• You will complete questionnaires about your symptoms 
 
RISKS  
The most common side effects people receiving tecovirimat have 
noticed are: 
• 
Headache  
• 
Nausea (feeling like you want to vomit) 
• 
Vomiting  
• 
Stomach pain  
 
BENEFITS  
We do not know if you will benefit from tecovirimat. Based on what 
we know about tecovirimat, the study drug may help to treat your 
infection and prevent it from getting worse, but we cannot make any 
guarantee.  
 
OTHER CHOICES  
There is no proven way to treat human monkeypox virus. You may 
benefit from supportive therapy (such as intravenous [IV] fluids, 
or medicine to control fever or pain) and antibiotics for any 
bacterial infections you may have. There may be other 
medications that your study doctor may consider using to treat 
your infection. Tecovirimat may be available outside this study. 
There may also be research studies looking at other new 
treatments for poxviruses.  
 
 
INTRODUCTION  
 
You are being asked to take part in this research study because: 
• 
You are known to have monkeypox virus or your healthcare providers suspect you 
have monkeypox virus  
• 
You have had symptoms for fewer than 14 days  
• 
You have at least one active, not yet scabbed lesion, or proctitis (inflammation of the 
lining of the rectum) or mouth sores 
 
This study is sponsored by the National Institutes of Health (NIH). The study doctor is in 
charge of this study at this site. Before you decide if you want to be a part of this study, 
we want you to know about the study.  
 

 
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This is a consent form. It gives you information about this study. The study staff will talk 
with you about this information. You are free to ask questions about this study at any 
time. If you agree to take part in this study, you will be asked to sign this consent form. 
You will get a copy to keep.  
 
 
WHY IS THIS STUDY BEING DONE?  
 
Monkeypox is caused by a virus. This virus is most often spread by close contact 
with someone who has monkeypox. Illness caused by monkeypox virus infection 
usually starts with a fever and feeling poorly before a rash begins. The rash looks 
like raised bumps and pus-filled blisters (called lesions). The lesions then crust, 
scab, and fall off after about 2-4 weeks, sometimes leaving a scar. 
 
Since Spring 2022, monkeypox has rapidly spread throughout the world, with more 
than 70,000 cases in 107 countries and more than 26,000 cases in the United States 
reported as of September 2022.  
 
Tecovirimat is a drug that may help to treat infections caused by pox viruses. 
Tecovirimat is approved by the Food and Drug Administration (FDA) to treat 
smallpox in adults and children, but its use in this study is considered 
investigational. An investigational use is one that has not been approved by the 
FDA. Tecovirimat has been approved based only on data from animals. We don’t 
know for sure if it works to treat any infections in people. The FDA has reviewed 
information on tecovirimat and determined that tecovirimat may help treat infection, 
including serious or potentially life-threatening disease, from poxviruses.  
 
Tecovirimat has been given safely to some people with monkeypox in the recent 
outbreak and is currently being studied in several ongoing studies outside of the 
U.S., but none of the studies have shown whether or not this study drug works to 
treat monkeypox. The safety of tecovirimat has been evaluated in a study with 
adult participants without monkeypox. Tecovirimat was generally safe and well 
tolerated – the risks are noted below.  
 
We are doing this study to see if tecovirimat is safe and whether it helps treat 
monkeypox in people. The study will also help us understand more about how 
human monkeypox causes disease and how the body fights off infection with 
monkeypox. 
 
 
WHAT DO I HAVE TO DO IF I AM IN THIS STUDY?  
 
Screening/Entry Visit 
If you would like to be in this study, after you have read and signed this consent form, 
you will have a visit to make sure you meet the requirements for joining the study. This 
visit will be done via telemedicine. 

 
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We will collect some demographic (for example, age, gender, race), clinical (for example, 
disease condition, diagnosis), and laboratory (for example, CD4 cell count and viral load 
if you are living with HIV) information. We will collect this information even if you do not 
start study drug. 
 
At this visit: 
• 
You will answer questions about your medical history and any medications you have 
taken recently.  
• 
You will have an exam of your skin to identify where you have monkeypox lesions. 
You may have to remove some of your clothes for this exam. Site staff will ask to take 
pictures of your skin lesions. You do not have to agree to have these pictures taken. 
You can participate in this study regardless of what you decide about having pictures 
taken. If you agree, these pictures will be used so that the study staff can follow how 
well your lesions are healing. These pictures will not be used for any other purpose 
without your written permission. If you have lesions on your face, it is possible that 
you will be able to be identified in these pictures. These pictures may be stored in 
your electronic medical record. If these pictures are stored in a study database, they 
will be stored securely with a code instead of your name. Please discuss how 
pictures are stored at your clinical research site. 
• 
You will answer questionnaires about any pain your lesions may be causing you 
• 
If it is available in your medical records, we will record the results from your latest 
physical exam, any recent testing you have had for herpes virus, and results from any 
recent pregnancy test.  
 
If you qualify for the study, you will have some more tests: 
• 
You will be advised to obtain testing for sexually transmitted infections outside of 
the study as indicated. If you are found to have an STI or HIV, you will be referred for 
treatment or study staff will provide appropriate treatment.  
• 
You will answer questionnaires about others who live in your home and whether 
they have monkeypox and how you are feeling 
• 
If you have eye disease from monkeypox or eye symptoms, study staff will ask you 
to be seen by an eye doctor outside of the study 
• 
You will answer questionnaires about any recent monkeypox exposure, any recent 
sexual activity that you have had, and any anal/rectal symptoms you may be having 
• 
If they are available in your medical records, we will record the results from recent 
bloodwork you had, recent testing for sexually transmitted infections, recent testing 
for hepatitis, recent testing for HIV, and recent CD4 and viral load testing (if you are 
living with HIV) 
• 
If you qualify for the study, a study kit will be delivered to you that includes: 
o Your study drugs. Tecovirimat or placebo for tecovirimat will be taken two or three 
times a day for 14 days. The study drugs may arrive in a separate shipment. 
o Instructions on how to complete the study diary that you will complete at home to 
record how your skin lesions are doing, any symptoms that you are experiencing, 
and any pain that you are experiencing. We will also ask you to write down the 
date and time that you take your study drug. 

 
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o Containers for any sample collections that you will do at home. 
 
Most people will be randomly assigned (like flipping a coin or rolling dice) to a study 
group. You and the study staff will not be able to choose which study treatment group 
you are in. You and the study staff will not know whether you are receiving active study 
drug or placebo. Twice as many people will receive active study drug as receive placebo 
in this study, so you are twice as likely to receive “real” study drug.  
 
Some people will be assigned to receive tecovirimat instead of being randomly assigned 
to a study group. If you belong to one of the groups below, you will receive tecovirimat – 
there is no chance you will receive placebo. 
• 
Participants under 18 
• 
People who are pregnant or breastfeeding 
• 
People with severe skin disease 
• 
People with a severely suppressed immune system 
• 
People with monkeypox disease in their eye or on their face (cheeks, nose, eyelid) 
• 
People with severe monkeypox lesions that have to be treated surgically 
• 
People who have to be hospitalized due to their monkeypox infection 
• 
People taking medicines that may reduce tecovirimat levels including rifampin, 
rifapentine, rifabutin, St. John’s Wort, carbamazepine, phenytoin, phenobarbital, 
oxcarbazepine, or tipranavir/ritonavir 
 
If you join the study remotely, we expect that all of your visits will be done remotely, but 
you may elect to have follow up visits in person. In this event, you would sign the 
consent form for in person follow up. 
 
Study Visit on Day 6 
At this visit: 
• 
The study staff will contact you by phone or via telemedicine to ask about any 
symptoms you are experiencing and any pain that you might be experiencing. 
• 
Study staff will ask if you are taking your study drugs as directed. 
• 
You will answer questionnaires about your anal/rectal health. 
 
Study Visits on Days 8, 15, 22, 29, 57 
These visits will be conducted via telemedicine. At these visits: 
• 
You will answer questions about any medications you are taking. 
• 
You will have an exam of your skin to identify where you have monkeypox lesions. 
Study staff will ask you take pictures of your skin lesions or they will take pictures via 
telemedicine.  
• 
You will answer questionnaires about recent sex you may have had (day 29) and 
whether people in your household have monkeypox (day 29 and 57), your quality of 
life (days 8, 15, and 29), and anal/rectal health (days 15 and 57). 
 

 
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Study Evaluations to Complete at Home 
In addition to the telemedicine visits, you will have to complete additional study 
evaluations at home: 
• 
Complete your study diary and pain rating every day on days 1-29 
• 
If you are able to and you agree, you will take photographs of your skin lesions at 
least twice a week so you can show them to the study staff to track how your lesions 
are healing 
• 
On the day you start the study and again on Day 8 you will be asked to take swabs of 
your skin for monkeypox testing. You will return these samples to the testing lab via 
mail or courier service. These samples may be omitted if testing/shipping kits are not 
available or if health laws where you live do not allow you to ship the samples. 
• 
If a new lesion appears on your skin on or after day 6, you will be asked to take a 
swab of the new lesion for monkeypox testing. You will send the swab to the testing 
laboratory.  
 
Additional Study Visits 
You will have extra telemedicine visits if your monkeypox disease gets worse or if your 
lesions heal up. If your monkeypox disease gets worse you may also choose to come 
into the site to see the site staff in person if you would prefer. 
 
Early Discontinuation 
If at any point in the study you want to stop participating in the study, you must contact 
the site immediately. If you choose to withdraw consent, no additional samples will be 
collected and no new information will be collected. Any samples that have not been 
analyzed prior to your withdrawal of consent will be destroyed, but any information from 
any samples already analyzed will still be used.  
 
 
QUICK SUMMARY OF EVALUATIONS 
 
 
Screening/ 
Day 1 
 
Day 
6 
Day 
8 
Day 
15 
Day 
22 
Day 
29 
Day 
57 
Lesion 
Resolution 
Disease 
Progression 
Skin Exam via 
Telemedicine 
X 
 
X 
X 
X 
X 
X 
X 
X 
Swabs Collected 
X 
 
X 
 
 
 
 
 
 
Questionnaires 
X 
X 
X 
X 
 
X 
X 
 
X 
Study Diary/Self 
Assessments 
Days 1-29 
 
 
 
 
 
WHAT IF I AM IN PAIN OR MY MONKEYPOX VIRUS GETS WORSE? 
 
If you become more ill from monkeypox or you develop new skin lesions on your face, 
please contact the study staff. You may be able to start tecovirimat without the 

 
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possibility of placebo. You may also be able to start tecovirimat without the possibility of 
placebo if you have severe pain for 5 days after starting the study. 
 
 
WILL I RECEIVE THE RESULTS OF ANY TESTS? 
 
Testing of the swabs that you collect may be done after you are done with the study. For 
this reason, you will not receive these results. 
You will be told of any new information learned during the course of the study that might 
cause you to change your mind about staying in the study. At the end of the study, you 
will be told when study results may be available and how to learn about them. As with all 
studies, if we find out important information that may affect your care, you will be 
provided with those results. 
 
 
CAN I CHOOSE THE TYPES OF RESEARCH THAT MY SAMPLES AND INFORMATION 
ARE USED FOR?   
 
The tests described above are required by this study. If you do not agree to the storage 
or testing that has been described above, you should not join this study.  
 
Please refer to Attachment A to consent for use of your samples in other studies.  
 
 
COMMERCIAL PROFIT 
 
Your biospecimens collected during this study may be used for commercial profit (even 
if identifiers are removed) and you will not share in this profit. 
 
 
HOW MANY PEOPLE WILL TAKE PART IN THIS STUDY?  
 
530 people will participate in this study and receive active study drug or placebo.  
 
There is a third group of people (including participants under 18, people who are 
pregnant or breastfeeding, people with severe disease, people taking certain medicines 
that may interact with tecovirimat, and people whose immune systems are weakened by 
other infections) who will be assigned to active study drug with no possibility of 
receiving placebo – there is no limit to how many people will be assigned to this group.  
 
 
HOW LONG WILL I BE IN THIS STUDY?  
 
You will be in this study for about two months (60 days).  
 
 
WHY WOULD THE STUDY DOCTOR TAKE ME OFF THIS STUDY EARLY?  

 
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The study doctor may need to take you off the study early without your permission if:  
• 
The study is stopped or cancelled  
• 
Your primary care doctor thinks that this study is no longer in your best interest and 
they request that you stop participating 
 
The study doctor may also need to take you off the study drug(s) without your 
permission if:  
• 
Continuing the study drug may be harmful to you  
• 
You need a treatment that you may not take while on the study  
• 
You are not able to take the study drug as required by the study  
 
 
WHAT HAPPENS WHEN I FINISH THE STUDY? 
 
After you have completed your study participation, the study will not be able to continue 
to provide you with the study drug you received on the study. If continuing to take this or 
similar drugs/agents would be of benefit to you, the study staff will discuss how you may 
be able to obtain them. 
 
 
WHAT ARE THE RISKS OF THE STUDY?  
 
The drug used in this study may have side effects, some of which are listed below. 
Please note that these lists do not include all the side effects seen with this study drug. 
These lists include the more serious or common side effects with a known or possible 
relationship. If you have questions concerning the additional study drug side effects, 
please ask the study staff at your site.  
 
There is a risk of serious and/or life-threatening side effects when non-study medications 
are taken with the study drugs. For your safety, you must tell the study doctor or study 
nurse about all medications you are taking before you start the study and also before 
starting any new medications while on the study. Also, you must tell the study doctor or 
study nurse before enrolling in any other clinical trials while on this study.  
 
The risks of tecovirimat in people with smallpox or other poxviruses are not known. 
Tecovirimat has not been studied in people with weak immune systems, the elderly, 
or children. Tecovirimat 600 mg capsules were tested in 359 healthy adults, 
including 336 healthy adults who received tecovirimat capsules twice a day for 14 
days. Tecovirimat for injection was also tested in 26 healthy adults. No serious 
problems occurred in any of the participants in these studies.  
 
During the 2022 monkeypox outbreak in the U.S., tecovirimat capsules have also 
been given to more than 230 people with poxvirus infection, including people with 
monkeypox, as of July 2022; side effects are being monitored but no serious 
problems with tecovirimat have been reported so far. Still, tecovirimat may cause 
some adverse events (side effects). There also may be other adverse events that we 

 
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cannot predict. The most common adverse events in people who have taken 
tecovirimat were:  
• 
Headache  
• 
Nausea  
• 
Vomiting  
• 
Stomach pain  
 
As with any medication, there is a potential risk of an allergic reaction. An allergic 
reaction after receiving tecovirimat could include:  
• 
Rash 
• 
Difficulty breathing 
• 
Wheezing 
• 
Sudden drop in blood pressure causing dizziness or fainting  
• 
Swelling (around the mouth, throat, or eyes)  
• 
Fast pulse 
• 
Sweating 
 
Risks of Drug Interactions 
There are drug interactions with tecovirimat. Tecovirimat can lower or raise the 
concentrations of other medicines in your blood. When the blood concentrations of 
other medicines are lower, the other medicines may not work as well. When the blood 
concentrations of other medicines are raised, the other medicines may cause more 
side effects. Other medicines may also lower or raise the tecovirimat concentrations 
in the blood. To minimize the risk for drug interactions, it is important to review all of 
your prescription and over-the- counter medicines and dietary and herbal 
supplements with study personnel. It is also important to notify study personnel 
before you start any new prescription or over-the- counter medicines and dietary and 
herbal supplements while taking the study drug.  
 
Risks of Skin Swabs  
These can be uncomfortable and occasionally there can be some bleeding.  
 
Questionnaires 
You may be embarrassed by the detailed questions about sex and your anal health. 
 
Loss of Privacy - Photographs of Participant’s Face 
You may have photographs taken for this study of your face or areas of your skin that 
have distinctive markings such as tattoos. It is possible that these photographs may be 
recognizable and your identity may be known. All photographs taken during the study 
will be stored in your electronic medical record or will be stored with a code instead of 
your name. 
 
Risks of Starting the Study Before Your Monkeypox Virus is Confirmed by a Lab 
There are other things that can cause lesions on your skin, but we want you to start the 
study as soon as possible, so we will let you begin study drug even if your skin lesions 
have not been tested by a lab and confirmed to be monkeypox. There is a chance that 

 
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your lab tests will show that you do not have monkeypox, so there is a risk that you will 
have taken study drug and participated in study tests when you do not have monkeypox.  
 
The study doctors at your site will use their best judgement to make sure that this does 
not happen, but if it does happen you will stop taking the study drug and the study staff 
at your study site will check on you in 7 days to make sure that you do not have any side 
effects before you leave the study. 
 
Risks of Participating in the Study through Telemedicine 
Study providers are not able to fully examine you through telemedicine. It is possible that 
their assessment is not complete or not as accurate as an in-person visit. You are 
encouraged to see local providers in person if you have concerns about your health. 
 
 
ARE THERE RISKS RELATED TO PREGNANCY AND BREASTFEEDING?  
 
Tecovirimat has not been studied in pregnant or nursing people. It is not known if 
giving tecovirimat to a pregnant person would hurt the unborn child. Tecovirimat 
has been tested on pregnant mice and rabbits. There were no serious problems in 
the unborn animals. Poxviruses during pregnancy can cause serious harm to the 
pregnant person and unborn baby.  
 
In animal studies, tecovirimat was present in animal milk. When a drug is present in 
animal milk it is likely to be present in human milk. Because of the potential for 
virus transmission through direct contact with the breastfed infant, breastfeeding is 
not recommended while the nursing individual has active lesions. A lactating 
person should consider pausing breastfeeding and consider pumping and 
discarding breast milk during the study. 
 
If you can get pregnant but are not pregnant when you join the study and you are 
engaging in sexual activity that could lead to pregnancy, you must agree to use at least 
one effective method of contraception from the time you join the study until you are 
finished with the study. Effective methods of contraception are hormonal contraceptives 
(injected or in pills), male or female condoms, diaphragm or cervical cap with a 
spermicide, or an intrauterine device (an IUD). Abstinence (agreeing not to have sex) is 
also allowed as a way to prevent pregnancy. 
 
If at any point during the study you think you may be pregnant, you should let the study 
staff at your site know. You are encouraged to obtain pregnancy testing if you believe 
you may be pregnant.  
 
If you are pregnant or become pregnant while on study, the study staff would like to 
obtain information from you about the outcome of the pregnancy (even if it is after your 
participation in the study ends).  
 
 

 
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ARE THERE BENEFITS TO TAKING PART IN THIS STUDY?  
 
We do not know for certain if you will benefit from tecovirimat. Based on what we 
know about tecovirimat, the study drug may help to treat your infection and 
prevent it from getting worse, but we cannot make any guarantee. 
 
 
WHAT OTHER CHOICES DO I HAVE BESIDES THIS STUDY?  
 
There is no proven way to treat poxviruses, but research is ongoing. You may benefit 
from supportive therapy (such as IV fluids, or medicine to control fever or pain) and 
antibiotics for any bacterial infections you may have. There may be other medications 
that your study doctor may consider using to treat your infection. Tecovirimat may be 
available outside this study. There may also be research studies looking at other new 
treatments for poxviruses.  
 
Please talk to your study doctor about these and other choices available to you. Your 
study doctor will explain the risks and benefits of these choices.  
 
 
WHAT ABOUT CONFIDENTIALITY?  
 
We will do everything we can to protect your privacy. In addition to the efforts of the 
study staff to help keep your personal information private, we have gotten a Certificate of 
Confidentiality from the U.S. Federal Government. This certificate means that 
researchers cannot be forced to tell people who are not connected with this study, such 
as the court system, about your participation. The researchers with this Certificate may 
not disclose or use information, documents, or biospecimens that may identify you in 
any federal, state, or local civil, criminal, administrative, legislative, or other action, suit, 
or proceeding, or be used as evidence, for example, if there is a court subpoena, unless 
you have consented for this use. Information, documents, or biospecimens protected by 
this Certificate cannot be disclosed to anyone else who is not connected with the 
research except, if there is a federal, state, or local law that requires disclosure (see 
below); if you have consented to the disclosure, including for your medical treatment; or 
if it is used for other scientific research, as allowed by federal regulations protecting 
research participants.  
 
The Certificate cannot be used to refuse a request for information from personnel of the 
United States federal or state government agency sponsoring the project that is needed 
for auditing or program evaluation by the agency which is funding this project or for 
information that must be disclosed in order to meet the requirements of the federal Food 
and Drug Administration (FDA). You should understand that a Certificate of 
Confidentiality does not prevent you from voluntarily releasing information about 
yourself or your involvement in this research. If you want your research information 
released to an insurer, medical care provider, or any other person not connected with the 
research, you must provide consent to allow the researchers to release it. 
  

 
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Having a Certificate of Confidentiality does not prevent you from releasing information 
about yourself and your participation in the study. The Certificate of Confidentiality will 
not be used to prevent disclosure for any purpose you have consented to in this 
informed consent document. 
  
Even with the Certificate of Confidentiality, if the study staff learns of possible child 
abuse and/or neglect or a risk of harm to yourself or others, we will be required to tell the 
proper authorities. 
 
Your records may be reviewed by the U.S. Food and Drug Administration (FDA), the AIDS 
Clinical Trials Group (ACTG), the U.S. Office for Human Research Protections (OHRP), or 
other local, U.S., and international regulatory entities as part of their duties, Advarra  
Institutional Review Board (IRB) (a committee that protects the rights and safety of 
participants in research), National Institutes of Health (NIH), study staff, study monitors, 
drug companies supporting this study, and their designees.  
 
Also, any publication of this study will not use your name or identify you personally. 
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as 
required by U.S. Law. This Web site will not include information that can identify you. At 
most, the Web site will include a summary of the results. You can search this Web site at 
any time.  
 
 
WHAT ARE THE COSTS TO ME?  
 
The study will pay for research-related tests and assessments. Taking part in this study 
may lead to added costs to you and your insurance company. In some cases, it is 
possible that your insurance company will not pay for these costs because you are 
taking part in a research study. If you go to a clinic other than your site clinic for STI 
testing, pregnancy testing, or other testing, the study will not pay for this testing.  
 
 
WILL I RECEIVE ANY PAYMENT?  
 
«Compensation» 
 
You will be paid up to a total of $xx.xx if you complete this study. You will be paid for the 
visits you complete according to the following schedule: 
$xx.xx for Visits xxx.  
$xx.xx for Visits xxx.  
$xx.xx for Visits xxx.  
 
If you do not complete the study, for any reason, you will be paid for each study visit you 
do complete.  
 
You will be paid ___________ [“following each completed visit”, “monthly”, “quarterly”, 

 
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“at the end of your participation in the research study”, “following each completed visit 
or at the end of your participation in the research study, whichever you prefer”]. 
 
If you have any questions regarding your compensation for participation, please contact 
the study staff.  
 
 
WHAT HAPPENS IF I AM INJURED?  
 
If you are injured as a result of being in this study, you will be given immediate treatment 
for your injuries. There is no program for compensation through the NIH. The cost for 
this treatment will be charged to you or your insurance company. 
 
You will not be giving up any of your legal rights by signing this consent form.  
 
 
WHAT ARE MY RIGHTS AS A RESEARCH PARTICIPANT?  
 
Taking part in this study is completely voluntary. You may choose not to take part in this 
study or leave this study at any time. Your decision will not have any impact on your 
participation in other studies conducted by NIH and will not result in any penalty or loss 
of benefits to which you are otherwise entitled.  
 
We will tell you about new information from this or other studies that may affect your 
health, welfare, or willingness to stay in this study. If you want the results of the study, 
let the study staff know.  
 
 
WHOM TO CONTACT ABOUT THIS STUDY 
 
During the study, if you experience any medical problems, suffer a research-related 
injury, or have questions, concerns or complaints about the study such as: 
• 
Whom to contact in the case of a research-related injury or illness; 
• 
Payment or compensation for being in the study, if any; 
• 
Your responsibilities as a research participant; 
• 
Eligibility to participate in the study; 
• 
The study doctor’s or study site’s decision to withdraw you from participation; 
• 
Results of tests and/or procedures; 
 
Please contact the study doctor at the telephone number listed on the first page of this 
consent document.  
 
If you seek emergency care, or hospitalization is required, alert the treating physician 
that you are participating in this research study.  
 
An institutional review board (IRB) is an independent committee established to help 

 
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protect the rights of research participants. If you have any questions about your rights as 
a research participant, contact: 
• 
By mail: 
Study Subject Adviser 
Advarra IRB 
6100 Merriweather Dr., Suite 600 
Columbia, MD 21044 
• 
or call toll free:    877-992-4724 
• 
or by email:  adviser@advarra.com 
 
Please reference the following number when contacting the Study Subject Adviser: 
Pro00065749. 
 

 
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SIGNATURE PAGE  
 
If you have read this consent form (or had it explained to you), all your questions have 
been answered and you agree to take part in this study, please sign your name below.  
 
 
_______________________  
_________________________________________  
Participant’s Name (print)  
Signature and Date  
 
 
 
 
______________________  
___________________________________________  
Study Staff Conducting 
 
Signature and Date  
Consent Discussion (print) 
 
 
_____________________ 
 
____________________________________________ 
Witness’s Name (print) 
 
Signature and Date  
(As appropriate)  
 
 
FOR CHILDREN WHO BECOME ADULTS  
 
I have been told that my parents/legal guardian agreed for me to participate in this 
research study as a minor. I have read and understand the information in this informed 
consent document. I have had an opportunity to ask questions and all of my questions 
have been answered to my satisfaction. I voluntarily agree to continue to participate in 
this study until I decide otherwise. I do not give up any of my legal rights by signing and 
dating this consent document. I will receive a copy of this signed and dated consent 
document. 
  
  
_______________________  
_________________________________________  
Participant’s Name (print)  
Signature and Date  
 
 

 
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AUTHORIZATION TO USE AND DISCLOSE PROTECTED HEALTH INFORMATION 
  
If you decide to be in this study, the study doctor and study staff will use and share 
health data about you to conduct the study. Health data may include: 
• 
Your name. 
• 
Address. 
• 
Phone number. 
• 
Date of birth. 
• 
Medical history. 
• 
Information from your study visits, including all test results.  
  
Health data may come from your study records or from existing records kept by your 
doctor or other health care workers.  
  
For this study, the study staff may share health data about you with authorized users. 
Authorized users may include: 
• 
Representatives of University of California, Los Angeles (UCLA) and National Institute 
of Allergy and Infectious Diseases (NIAID). 
• 
Representatives of ACTG. 
• 
Representatives of Advarra IRB (an Institutional Review Board that reviews this 
study). 
• 
The Food and Drug Administration (FDA) and other U.S. federal and state agencies. 
• 
Government agencies to whom certain diseases (like HIV, hepatitis, and STDs) must 
be reported. 
• 
Governmental agencies of other countries. 
• 
Outside individuals and companies, such as laboratories and data storage 
companies, that work with the researchers and sponsor and need to access your 
information to conduct this study. 
• 
Other research doctors and medical centers participating in this study, if applicable.  
• 
A data safety monitoring board which oversees this study, if applicable. 
  
Your health data will be used to conduct and oversee the research, including for 
instance: 
• 
To see if the study drug works and is safe. 
• 
To compare the study drug to other drugs. 
• 
For other research activities related to the study drug. 
  
Once your health data has been shared with authorized users, it may no longer be 
protected by federal privacy law and could possibly be used or disclosed in ways other 
than those listed here.  
  
Your permission to use and share health data about you will end in 50 years unless you 
revoke it (take it back) sooner.  
  
You may revoke (take back) your permission to use and share health data about you at 
any time by writing to the study doctor at the address listed on the first page of this form. 

 
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If you do this, you will not be able to stay in this study. No new health data that identifies 
you will be gathered after your written request is received. However, health data about 
you that has already been gathered may still be used and given to others as described in 
this form.  
  
Your right to access your health data in the study records will be suspended during the 
study to keep from changing the study results. When the study is over, you can access 
your study health data. 
  
If you decide not to sign and date this form, you will not be able to take part in the study. 
 
 
 
 

 
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STATEMENT OF AUTHORIZATION 
 
I have read this form and its contents were explained. My questions have been answered. 
I voluntarily agree to allow study staff to collect, use and share my health data as 
specified in this form. I will receive a signed and dated copy of this form for my records. I 
am not giving up any of my legal rights by signing and dating this form.  
  
  
______________________           ____________________________ 
Participant’s Name (print)               Signature and Date 
  
  
_____________________             ____________________________ 
Witness’s Name (print)                   Signature and Date 
  
  
FOR CHILDREN WHO BECOME ADULTS  
 
I have been told that my parents/legal guardian agreed to the use and disclosure of my 
Protected Health Information as outlined in this document. I have read and understand 
the information in this authorization. I have had an opportunity to ask questions and all 
of my questions have been answered to my satisfaction. I continue to authorize the use 
and disclosure of my Protected Health Information. I will receive a copy of this signed 
and dated authorization. 
  
____________________________________               
Participant’s Printed Name  
  
  
____________________________________             __________ 
Participant’s Signature                                              Date 
 
 

 
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ATTACHMENT A: CONSENT FOR USE OF SAMPLES IN OTHER STUDIES FOR ADULTS 
AND PARTICIPANTS REACHING AGE OF MAJORITY (AOM) 
 
Everything in the main study consent form you signed before still applies to your participation 
in this study unless otherwise noted in this form. 
 
When samples are no longer needed for this study, the ACTG may want to use them in other 
studies and share them with other researchers. These samples are called “extra samples.” 
The ACTG will only allow your extra samples to be used in other studies if you agree to this. 
If you have any questions, please ask.  
  
Identifiers will be removed from your samples and from any private information that has been 
collected about you. This means that no one looking at the labels or at other information will 
know that the samples or information came from you.  
  
Extra samples are stored in a secure central place called a repository. Your samples will be 
stored in the ACTG repository located in the United States.  
  
There is no limit on how long your extra samples will be stored.  
  
When a researcher wants to use your samples and information, their research plan must be approved 
by the ACTG. Also, the researcher’s institutional review board (IRB) or ethics committee (EC) will 
review their plan. IRBs/ECs protect the rights and well-being of people in research. If the research plan 
is approved, the ACTG will send your samples to the researcher’s location. This means that 
researchers who are not part of the study team may use your samples without asking you again for 
your consent.  
 
You will not be paid for your samples. Also, a researcher may make a new scientific discovery or product 
based on the use of your samples. If this happens, there is no plan to share any money with you.  
  
You may withdraw your consent for research on your extra samples at any time and the 
specimens will be discarded.  
 
Please choose the response that matches what you want by putting your initials in the space 
provided. Please ask the study staff any questions that you have before you indicate your 
selection. 
 
Research without Human Genetic Testing 
If you agree, your extra samples may be stored (with usual protection of your identity) and used 
for ACTG-approved research that does not include human genetic testing. 
 
____ (initials) I understand and I agree to this storage and possible use of my samples 
 
OR 
 
____ (initials) I understand but I do not agree to this storage and possible use of my samples 
 

 
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Research with Human Genetic Testing  
The ACTG has two studies that collect samples for genetic testing.  
 
If you live in the U.S., this study is called ACTG A5128, Plan for Obtaining Informed Consent to 
Use Stored Human Biological Materials for Currently Unspecified Analyses. 
 
If you live outside of the U.S., this study is called ACTG A5243, Plan for Obtaining Human 
Biological Samples at Non-U.S. Clinical Research Sites for Currently Unspecified Genetic 
Analyses. 
 
Your site might ask you if you would like to participate in this study if it is being done where you 
live. If you would like to participate, you will sign and date a separate consent form. 
 
Your extra samples will not be used for human genetic testing unless you sign and date a 
consent form for A5128 or A5243.  
 
 

 
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SIGNATURE PAGE  
  
If you have read this consent form (or had it explained to you), all your questions have been 
answered and you agree to take part in this study, please sign your name below.  
  
  
 _______________________ __________________________________________  
Participant’s Name (print) 
 
Signature and Date  
  
   
______________________  
___________________________________________  
Study Staff Conducting 
 
Signature and Date  
Consent Discussion (print)   
  
  
______________________  
__________________________________________  
Witness’s Name (print) 
 
Signature and Date  
 
 
FOR CHILDREN WHO BECOME ADULTS  
 
I have been told that my parents/legal guardian agreed for me to participate in this research 
study as a minor. I have read and understand the information in this informed consent 
document. I have had an opportunity to ask questions and all of my questions have been 
answered to my satisfaction. I voluntarily agree to continue to participate in this study until I 
decide otherwise. I do not give up any of my legal rights by signing and dating this consent 
document. I will receive a copy of this signed and dated consent document. 
  
  
_______________________  
__________________________________________  
Participant’s Name (print) 
 
Signature and Date  
 
 

 
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APPENDIX III: INFORMED CONSENT  TO PARTICIPATE IN ADDITIONAL SAMPLING FOR 
ADULT PARTICIPANTS WHO ARE ENROLLED/FOLLOWED IN PERSON 
  
Sponsor / Study Title: 
  
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 Human 
Monkeypox Virus Disease” 
 
Protocol Number: 
 
A5418 
 
Principal Investigator: 
(Study Doctor) 
 
«PiFullName» 
 
Telephone: 
 
«IcfPhoneNumber» 
 
Address: 
«PiLocations» 
 
 
The optional procedures and sample collections described below will advance the scientific 
goals of this study but will offer no direct benefit to participants. Neither you nor your primary 
care doctor will receive any results from these procedures because these tests are for research 
purposes only. You can still be in this study even if you choose not to participate in the optional 
procedures. Even if you choose to participate in the optional procedures at this time, you may 
withdraw your consent at any time during the study.  
 
 
WHAT DO I HAVE TO DO IF I PARTICIPATE IN THE ADDITIONAL SAMPLING?  
 
If you agree, you will have the evaluations described below in addition to the evaluations that 
were described in the previous consent form. Everything in the main study consent form you 
signed before still applies to your participation in this study unless otherwise noted in this form. 
 
Screening/Entry Visit 
• 
You will provide a urine sample 
• 
Study staff will teach you how to collect oral swabs, anogenital swabs (the area around your 
anus and genitals), and swabs of monkeypox lesions on your skin 
 
Study Evaluations to Complete at Home 
• 
On days 2, 5, 11, 18, and 25 you will collect swabs from the back of the throat, rectum, 
vagina, and skin lesions 
 

 
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Day 3 
This is an extra visit that you will have only if you are in the additional sampling group. At this 
visit: 
• 
You will provide a urine sample 
• 
You will have blood drawn 
• 
You will return the swabs you have taken at home 
• 
You will have swabs from the back of the throat, skin lesions, rectum and vagina (you will 
collect this swab yourself and give it to the study staff) 
 
Days 8, 15, 22, 29 
• 
You will return the swabs you have taken at home 
• 
You will provide a urine sample (days 8, 15, and 29) 
 
 
ARE THERE ANY PROCEDURES THAT ARE OPTIONAL? 
 
If you agree, you will have an extra blood drawn on the day you enter the study and on days 
15 and 57. This blood will be used to collect a type of cells called peripheral blood 
mononuclear cells (PBMCs).  
 
 
You can still be a part of the additional sampling group even if you do not agree to provide 
PBMCs.  
 
____ (initials) I understand and I agree to provide PBMCs. 
 
OR  
 
____ (initials) I understand but I do not agree to provide PBMCs.  
 
 
 

 
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QUICK SUMMARY OF ADDITIONAL SAMPLING 
 
 Remember that you will have these additional sampling procedures done in addition 
to the procedures described in the main consent form that you signed.  
 
 
 
 
 
 
  
Screening
/ Day 1 
Day 
2 
Day 
3 
Day 
5 
Day 
8 
Day 
11 
Day 
15 
Day 
18 
Day 
22 
Day 
25 
Day 
29 
Day 
57 
Blood Drawn 
 
 
X 
 
 
 
 
 
 
 
 
 
Urine Collected 
X 
 
X 
 
X 
 
X 
 
 
 
X 
 
Stored PBMCs 
(optional) 
X 
 
 
 
 
 
X 
 
 
 
 
X 
Self Collected 
Swabs 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
Return Swabs 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 

 
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SIGNATURE PAGE  
  
If you have read this consent form (or had it explained to you), all your questions have been 
answered and you agree to take part in this study, please sign your name below.  
  
  
 _______________________ 
__________________________________________  
Participant’s Name (print) 
 
Signature and Date  
  
  
 
______________________  
___________________________________________  
Study Staff Conducting 
 
Signature and Date  
Consent Discussion (print) 
  
 
 ______________________  
__________________________________________  
Witness’s Name (print) 
 
Signature and Date  
(As appropriate)  
  
  
 
 
 

 
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APPENDIX IV: INFORMED CONSENT AND AUTHORIZATION TO USE AND DISCLOSE 
PROTECTED HEALTH INFORMATION FOR PARENTS/LEGAL GUARDIANS OF CHILDREN 
WHO ARE ENROLLED/FOLLOWED IN PERSON 
  
  
Sponsor / Study Title: 
  
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 Human 
Monkeypox Virus Disease” 
 
Protocol Number: 
 
A5418 
 
Principal Investigator: 
(Study Doctor) 
 
«PiFullName» 
 
Telephone: 
 
«IcfPhoneNumber» 
 
Address: 
«PiLocations» 
 
 
SUMMARY  
  
PURPOSE 
This is a research study and your child’s participation in this study is 
voluntary. The purpose of this study is to evaluate how well tecovirimat 
works for the treatment of human monkeypox virus infection and if the 
study drug is safe in people. The study will also help us understand more 
about how human monkeypox causes disease, how the body fights off 
infection, and how to dose tecovirimat in children. 
 
STUDY GROUPS 
There are different groups in this study. Arm A will take the tecovirimat 
study drug, Arm B will take a placebo. A placebo looks like a “real” drug 
but does not have any active drug in it. Participants will be randomly 
assigned to Arm A or Arm B (like flipping a coin or rolling dice).  
 
All participants in Arm C will take tecovirimat, without any chance of 
getting the placebo. Children under 18 years of age will be in Arm C and 
receive tecovirimat. 
 
STUDY  
DRUG 
The study drug will be tecovirimat. Tecovirimat will be taken two or 
three times a day for 14 days.  
NUMBER OF  
PARTICIPANTS 
There is no limit to how many children will enroll in this study.  
  

 
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LENGTH OF  
STUDY  
Your child’s participation in this study will last about 2 months. If they 
become pregnant, we will contact you periodically to see how their 
pregnancy goes and to know the health of their child. We would also like 
them to bring their baby in for a study visit about 4 weeks after they are 
born so we can examine the baby. 
  
REQUIRED  
ACTIVITIES 
If your child is in this study, the following study procedures are required 
• They will have physical exams 
• You or your child will record their symptoms daily 
• They will provide blood and urine samples 
• A study team member will obtain swabs of the sores on their skin and 
a swab of their throat 
• You or your child will complete questionnaires about their symptoms 
 
RISKS  
The most common side effects people receiving tecovirimat have 
noticed are: 
• 
Headache  
• 
Nausea (feeling like you want to vomit) 
• 
Vomiting  
• 
Stomach pain  
  
BENEFITS  
We do not know if your child will benefit from tecovirimat. Based on what 
we know about tecovirimat, the study drug may help to treat their infection 
and prevent it from getting worse, but we cannot make any guarantee.  
  
OTHER CHOICES  
There is no proven way to treat human monkeypox virus. Your child 
may benefit from supportive therapy (such as intravenous [IV] fluids, or 
medicine to control fever or pain) and antibiotics for any bacterial 
infections they may have. There may be other medications that your 
child’s study doctor may consider using to treat their infection. 
Tecovirimat may be available outside this study. There may also be 
research studies looking at other new treatments for poxviruses.  
 
 
INTRODUCTION  
  
This form is for the parent or legal guardian of a child or adolescent who is being asked to 
participate in this research study. In this form, participants are referred to as “children” even 
though they may be older teenagers.  
 
You are being asked for your child to take part in this research study because they: 
• 
Have confirmed or suspected monkeypox virus  
• 
They have had symptoms for fewer than 14 days  

 
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• 
They have at least one active, not yet scabbed lesion in the skin, a sore in the mouth or 
proctitis (inflammation of the lining of the rectum)  
  
This study is sponsored by the National Institutes of Health (NIH). The study doctor is in charge 
of this study at this site. Before you decide if you want to be a part of this study, we want you to 
know about the study.  
  
This is a consent form. It gives you information about this study. The study staff will talk with you 
about this information. You are free to ask questions about this study at any time. If you agree 
for your child to take part in this study, you will be asked to sign this consent form. You will get a 
copy to keep.  
  
 
WHY IS THIS STUDY BEING DONE?  
  
Monkeypox is caused by a virus. This virus is most often spread by close contact with 
someone who has monkeypox. Illness caused by monkeypox virus infection usually starts 
with a fever and feeling poorly before a rash begins. However, the rash may begin without 
other symptoms. The rash looks like raised bumps and pus-filled blisters (called lesions). 
They usually crust, scab, and fall off after about 2-4 weeks, sometimes leaving a scar. 
 
Since Spring 2022, monkeypox has rapidly spread throughout the world, with more than 
70,000 cases in 107 countries and more than 26,000 cases in the United States reported 
as of September 2022.  
  
Tecovirimat is a drug that may help to treat infections caused by pox viruses. Tecovirimat is 
approved by the Food and Drug Administration (FDA) to treat smallpox in adults and children, 
but its use in this study is considered investigational. An investigational use is one that has not 
been approved by the FDA. Tecovirimat has been approved based only on data from animals. 
We don’t know for sure if it works to treat any infections in people. The FDA has reviewed 
information on tecovirimat and determined that tecovirimat may help treat infection, including 
serious or potentially life-threatening disease, from poxviruses.  
 
Tecovirimat has been given safely to some people with monkeypox in the recent outbreak 
and is currently being studied in several ongoing studies outside of the U.S., but none of 
the studies have shown whether or not this study drug works to treat monkeypox. The 
safety of tecovirimat has been evaluated in a study with adult participants without 
monkeypox. Tecovirimat was generally safe and well tolerated – the risks are noted 
below.  
  
We are doing this study to see if tecovirimat is safe and whether it helps treat monkeypox 
in people. The study will also help us understand more about how human monkeypox 
causes disease and how the body fights off infection. This study will help us understand 
how much tecovirimat to give children to treat monkeypox. 
 

 
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WHAT DOES MY CHILD HAVE TO DO IF THEY ARE IN THIS STUDY?  
 
Screening/Day 1 Visit 
If you would like your child to be in this study, after you have read and signed this consent form, 
your child will have a screening visit to make sure they meet the requirements for joining the study.  
 
We will collect some demographic (for example, age, gender, race), clinical (for example, 
disease condition, diagnosis), and laboratory (for example, CD4 cell count and viral load if your 
child is living with HIV) information. We will collect this information even if your child does not 
join this study. 
 
At this visit: 
• 
Your child will have a physical exam and answer questions about their medical history and 
any medications they have taken recently.  
• 
Your child will have an exam of their skin to identify where they have monkeypox lesions. 
Your child will have to remove their clothes and wear a robe for this exam. Site staff will ask 
to take pictures of your child’s skin lesions. Your child does not have to agree to have 
these pictures taken. Your child can participate in this study regardless of what they 
decide about having pictures taken. If your child agrees, these pictures will be used so 
that the study staff can follow how well their lesions are healing. These pictures will not be 
used for any other purpose without your child’s written permission. If your child has lesions 
on their face, it is possible that they will be able to be identified in these pictures. These 
pictures may be stored in your child’s electronic medical record. If these pictures are 
stored in a study database, they will be stored securely with a code instead of your child’s 
name. Please discuss how pictures are stored at your child’s clinical research site. 
• 
Study staff will collect the following swabs: 
o Swabs from your child’s skin and mouth/throat if they do not have a lab diagnosis of 
monkeypox. The study doctor may be required by law to report the result of this test to 
the local health authorities. 
• 
Your child will answer questionnaires about any pain their lesions may be causing. 
• 
Your child may have blood drawn 2-4 hours after their first dose of study drug to test 
the levels of drug in their blood. This test is required for some participants. The study 
staff at your site can tell your child if they will have to have this test. 
 
There are some tests that we will only do at this study visit if your child is sexually active: 
• 
If your child can become pregnant (and is not already pregnant), they will give a blood 
sample or urine sample for a pregnancy test 
• 
Study staff will take swabs for the following tests: 
o Swabs of any lesions your child has that may be caused by herpes 
 
If your child qualifies for the study, they will have some more tests: 
• 
Your child will have blood drawn for the following tests:  
o Liver and kidney tests and blood counts 
o A test to measure concentrations of medicines used to treat or prevent HIV (if they are 
living with HIV or taking medications to prevent HIV infection) 
o CD4 count (if they are living with HIV) 

 
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o HIV viral load (if they are living with HIV) 
o Tests for syphilis. The study doctor may be required by law to report the result of these 
tests to the local health authorities 
o Tests to see the levels of monkeypox virus in their blood 
o Stored blood for future study-required testing 
• 
Your child will answer questionnaires about others who live in their home and whether these 
household members have monkeypox 
• 
Study staff will take swabs for the following tests: 
o Swabs of your child’s skin, mouth, and throat for monkeypox testing 
• 
If your child has eye disease from monkeypox or eye symptoms, study staff will place a strip 
of paper inside their lower eyelid to collect tears. Your child may also be given eyedrops to 
help treat eye disease. Please talk to the study staff, your child’s primary care provider, or 
your child’s eye doctor about this. These eyedrops are not provided by the study. 
• 
If your child qualifies for the study, they will receive a study kit that includes: 
o Their study drugs. Tecovirimat or placebo for tecovirimat will be taken two or three 
times a day for 14 days.. If you child spits out a dose of study drug or vomits within 15 
minutes after taking their study drug, they should take a replacement dose. If your child 
spits up or vomits more than 15 minutes after taking their study drug, a replacement 
dose should not be given (the next dose should be taken as scheduled). 
o Instructions on how to complete the study diary that they will complete at home to record 
how their skin lesions are doing, any symptoms that they are experiencing, and any pain 
that they are experiencing. We will also ask your child to write down the date and time 
that they take their study drug. 
 
There are some tests that will only be done at this study visit if your child qualifies for the study 
and is sexually active: 
• 
Your child will have blood drawn for the following tests. The study doctor may be required by 
law to report the result of these tests to the local health authorities   
o Tests for Hepatitis C  
o Tests for Hepatitis B (unless this information is in their medical records) 
o HIV-1 testing  
• 
Your child will be asked to give a urine sample for the following tests: 
o Tests for sexually transmitted infections. If your child has a positive test for a sexually 
transmitted infection, they will be referred to their regular doctor for evaluation and 
treatment. Your child can join this study if they have a sexually transmitted infection. The 
study doctor may be required by law to report the result of these tests to the local health 
authorities. 
• 
Study staff will take swabs for the following tests. The study doctor may be required by law 
to report the result of these tests to the local health authorities.  
o Swabs from the back of your child’s throat to test for gonorrhea and chlamydia. 
 
If your child joins the study at an in-person visit, they should continue to be seen in 
person if possible, however visits may occur through telemedicine if needed. 
 

 
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Study Visit on Day 6 
At this visit: 
• 
The study staff will contact your child by phone or via telemedicine to ask about any 
symptoms they are experiencing and any pain that they might be experiencing.  
• 
Study staff will ask your child if they are taking their study drugs as directed. 
 
Study Visits on Days 8, 15, 22, 29, 57 
At these visits: 
• 
Your child will have a brief physical exam and answer questions about any medications they 
are taking. 
• 
Your child will have an exam of their skin to identify where they have monkeypox lesions. 
Study staff will take pictures of their skin lesions.  
• 
Your child will answer questionnaires about whether people in their household have 
monkeypox (day 29 and 57).  
• 
Study staff will collect the following swabs: 
o Swabs of your child’s skin, mouth, and throat for monkeypox testing 
• 
If the study staff thinks your child has monkeypox in their eye or they have eye symptoms, a 
small strip of paper will be placed in their lower eyelid to collect tears. 
• 
Your child will have blood drawn for the following tests:  
o Routine safety tests (liver and kidney tests and blood counts) (day 8) 
o Blood tests to see the levels of monkeypox virus in their blood  
o Blood tests to see how their body processes the study drugs and other medications they 
take that may interact with study drug (these tests are called pharmacokinetic [PK] tests 
(days 8 and 15) 
o A test to measure concentrations of medicines used to treat or prevent HIV (if they are 
living with HIV or taking medications to prevent HIV infection) (day 8 and 15) 
o Stored blood for future study-required testing (day 15) 
• 
Your child may have a series of blood draws to see how their body processes the study 
drugs (these tests are called intensive PK tests) (day 8). These tests are required for some 
participants. The study staff at your site can tell your child if they will have to have these 
tests. If your child has these tests, they will be asked to have nothing to eat or drink except 
for water for 2-8 hours before their visit. They will arrive at the facility in the morning and will 
remain there for 8-12 hours, depending on how often they take their study drug. They will 
have a blood sample drawn, eat a meal appropriate to their age and size, and then they will 
take their study drug. Additional blood samples will be obtained at 1, 2, 3, 4, 6-, 8-, and 10-
hours after their dose of study drug. On the day of the visit, we will place a small plastic tube 
(like a “drip”) in your child’s arm. The tube is attached to a plastic needle. The tube will stay 
in your child’s arm until all the blood draws are done. We use the tube so we do not have to 
stick your child with a needle each time blood is drawn. 
 
Study Evaluations to Complete at Home 
In addition to study visits at the clinic, your child will have to complete some study evaluations at 
home: 
• 
Complete their study diary and pain rating every day on days 1-29 
• 
If you are able to and you agree, you will take a photograph of your child’s lesions on days 
1-29 so you can show them to the study staff to track how your child’s lesions are healing.  

 
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Additional Study Visits 
Your child will have extra study visits if their monkeypox disease gets worse or if their lesions 
heal up. If you need to report to the site that your child’s lesions have healed, this visit may be 
done remotely (over the phone or via telemedicine systems approved for use at your site). 
 
Early Discontinuation 
If at any point in the study you or your child want your child to stop participating in the study, you 
must contact the site immediately. If you choose to withdraw consent, no additional samples will 
be collected and no new information will be collected. Any samples that have not been analyzed 
prior to your withdrawal of consent will be destroyed, but any information from any samples 
already analyzed will still be used.  
 
 
QUICK SUMMARY OF EVALUATIONS 
 
 
Screening/ 
Day 1 
Day 
6 
Day 
8 
Day 
15 
Day 
22 
Day 
29 
Day 
57 
Lesion 
Resolution 
Disease 
Progression 
Physical Exam 
X 
 
X 
X 
X 
X 
X 
X 
X 
Telephone Check 
 
X 
 
 
 
 
 
 
 
Blood Drawn 
X 
 
X 
X 
X 
X 
X 
 
X 
Urine Collected 
X 
 
 
 
 
 
 
 
 
Intensive PK 
 
 
X 
 
 
 
 
 
 
Swabs Collected 
X 
 
X 
X 
X 
X 
X 
 
X 
Questionnaires 
X 
X 
X 
X 
 
X 
X 
 
X 
Study Diary/Self 
Assessments 
Days 1-29 
 
 
 
 
 
WILL MY CHILD RECEIVE THE RESULTS OF ANY TESTS? 
 
You and your child will receive the results of routine lab tests (for example, blood 
counts, liver and kidney tests, pregnancy test (if your child is sexually active), testing 
for sexually transmitted diseases (if your child is sexually active), HIV viral load and  
CD4 count (if your child is living with HIV) that are performed at the study visits. You 
will be told of the monkeypox results from swabs taken from skin lesions. 
 
Some of the blood that is collected from your child will be stored and tested later. Some of these 
tests may be done after you child is done with the study, and other tests are not yet approved by 
the FDA and are still considered “research” tests. For these reasons, you and your child will not 
receive the results of: monkeypox testing from areas other than skin lesions, immune response 
to monkeypox, or blood concentrations of tecovirimat. 
 
You and your child will be told of any new information learned during the course of the study 
that might cause you to change your mind about staying in the study. At the end of the study, 

 
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you and your child will be told when study results may be available and how to learn about 
them. As with all studies, if we find out important information that may affect your child’s care, 
you and your child will be provided with those results. 
 
 
CAN I CHOOSE THE TYPES OF RESEARCH THAT MY CHILD’S SAMPLES AND 
INFORMATION ARE USED FOR?  
  
Some of your child’s blood will be stored and used for study-required tests that measure the 
amount of tecovirimat in the blood, how your child’s immune system is fighting off monkeypox 
and how long monkeypox lasts in your child.  
  
Identifiers will be removed from your child’s samples and from any private information that has 
been collected about your child. This means that no one looking at the labels or at other 
information will be able to know that the samples or information came from your child.  
  
The tests described above are required by this study. If you do not agree to the storage or 
testing that has been described above, you should not give permission for your child join this 
study.  
  
Please refer to Attachment B to consent for use of your child’s samples in other studies.  
 
 
COMMERCIAL PROFIT 
 
Your child’s biospecimens collected during this study may be used for commercial profit (even if 
identifiers are removed) and your child will not share in this profit. 
 
  
HOW MANY PEOPLE WILL TAKE PART IN THIS STUDY?  
  
There is no limit to how many children will be in Arm C. 
 
 
HOW LONG WILL MY CHILD BE IN THIS STUDY?  
  
Your child will be in this study for about two months (60 days).  
 
  
WHY WOULD THE STUDY DOCTOR TAKE MY CHILD OFF THIS STUDY EARLY?  
  
The study doctor may need to take your child off the study early without your permission if:  
• 
The study is stopped or cancelled  
• 
Your child’s primary care doctor thinks that this study is no longer in your child’s best interest 
and they request that your child stop participating 
 

 
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The study doctor may also need to take your child off the study drug(s) without your permission if:  
• 
Continuing the study drug may be harmful to your child  
• 
Your child needs a treatment that they may not take while on the study  
• 
Your child is not able to take the study drug as required by the study  
 
 
WHAT HAPPENS WHEN MY CHILD FINISHES THE STUDY? 
 
After your child has completed the study, the study will not be able to continue to provide your 
child with the study drug they received on the study. If continuing to take this or similar drugs 
would be of benefit to your child, the study staff will discuss how you may be able to obtain them. 
  
 
WHAT ARE THE RISKS OF THE STUDY?  
  
The drug used in this study may have side effects, some of which are listed below. Please note 
that these lists do not include all the side effects seen with this study drug. These lists include the 
more serious or common side effects with a known or possible relationship. If you have questions 
concerning the additional study drug side effects please ask the study staff at your site.  
  
There is a risk of serious and/or life-threatening side effects when non-study medications are 
taken with the study drugs. For your child’s safety, you and your child must tell the study doctor 
or study nurse about all medications your child is taking before they start the study and also 
before starting any new medications while on the study. Also, you and your child must tell the 
study doctor or study nurse before enrolling in any other clinical trials while on this study.  
  
The risks of tecovirimat in people with smallpox or other poxviruses are not known. 
Tecovirimat has not been studied in people with weak immune systems, the elderly, or 
children and unanticipated side effects may occur. Tecovirimat 600 mg capsules were 
tested in 359 healthy adults, including 336 healthy adults who received tecovirimat 
capsules twice a day for 14 days. Tecovirimat for injection was also tested in 26 healthy 
adults. No serious problems occurred in any of the participants in these studies.  
  
During the 2022 monkeypox outbreak in the U.S., tecovirimat capsules have also been 
given to more than 230 people with poxvirus infection, including people with monkeypox, 
as of July 2022; side effects are being monitored but no serious problems with tecovirimat 
have been reported so far. Still, tecovirimat may cause some adverse events (side 
effects). There also may be other adverse events that we cannot predict. The most 
common adverse events in people who have taken tecovirimat were:  
• 
Headache  
• 
Nausea  
• 
Vomiting  
• 
Stomach pain  
 

 
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As with any medication, there is a potential risk of an allergic reaction. An allergic reaction 
after receiving tecovirimat could include: 
• 
Rash 
• 
Difficulty breathing 
• 
Wheezing 
• 
Sudden drop in blood pressure causing dizziness or fainting 
• 
Swelling (around the mouth, throat, or eyes) 
• 
Fast pulse 
• 
Sweating.  
 
Risks of Drug Interactions 
There are drug interactions with tecovirimat. Tecovirimat can lower or raise the 
concentrations of other medicines in your blood. When the blood concentrations of other 
medicines are lower, the other medicines may not work as well. When the blood 
concentrations of other medicines are raised, the other medicines may cause more side 
effects. Other medicines may also lower or raise the tecovirimat concentrations in the blood. 
To minimize the risk for drug interactions, it is important to review all of your child’s 
prescription and over-the- counter medicines and dietary and herbal supplements with study 
personnel. It is also important to notify study personnel before your child starts any new 
prescription or over-the-counter medicines and dietary and herbal supplements while taking 
the study drug.  
 
Risks of Blood Draw  
Having blood drawn may cause some discomfort, bleeding, bruising, and/or swelling where the 
needle enters the body, and in rare cases it may result in fainting. There is a small risk of infection. 
 
Risks of Mouth and Skin Swabs  
These can be uncomfortable and occasionally there can be some bleeding.  
 
Questionnaires 
You or your child may be embarrassed by the questions about sex. 
 
Loss of Privacy - Photographs of Participant’s Face 
Your child may have photographs taken for this study of their face or areas of their skin that 
have distinctive markings such as tattoos. It is possible that these photographs may be 
recognizable and their identity may be known. All photographs taken during the study will be 
stored in your child’s electronic medical record or will be stored with a code instead of 
their name.  
 
Risks of Your Child Starting the Study Before Their Monkeypox Virus is Confirmed by a Lab 
There are other things that can cause lesions on your child’s skin, but we want your child to start 
the study as soon as possible, so we will let them begin study drug even if their skin lesions 
have not been tested by a lab and confirmed to be monkeypox. There is a chance that your 
child’s lab tests will show that they do not have monkeypox, so there is a risk that they will have 
taken study drug and participated in study tests when they do not have monkeypox.  
 

 
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The study doctors at your child’s site will use their best judgement to make sure that this does 
not happen, but if it does happen your child will stop taking the study drug and the study staff 
at your study site will check on your child in 7 days to make sure that they do not have any 
side effects before they leave the study. 
 
 
ARE THERE RISKS RELATED TO PREGNANCY AND BREASTFEEDING?  
 
Tecovirimat has not been studied in pregnant or nursing people. It is not known if giving 
tecovirimat to a pregnant person would hurt the unborn child. Tecovirimat has been tested 
on pregnant mice and rabbits. There were no serious problems in the unborn animals. 
Poxviruses during pregnancy can cause serious harm to the pregnant person and unborn 
baby.  
 
In animal studies, tecovirimat was present in animal milk. When a drug is present in animal milk it 
is likely to be present in human milk. Because of the potential for virus transmission through 
direct contact with the breastfed infant, breastfeeding is not recommended while the nursing 
individual has active lesions. A lactating person should consider pausing breastfeeding and 
consider pumping and discarding breast milk during study treatment. 
 
If your child can get pregnant but is not pregnant when they join the study and they are 
engaging in sexual activity that could lead to pregnancy, they must agree to use at least one 
effective method of contraception from the time they join the study until they are finished with 
the study. Effective methods of contraception are hormonal contraceptives (injected or in pills), 
male or female condoms, diaphragm or cervical cap with a spermicide, or an intrauterine device 
(an IUD). Abstinence (agreeing not to have sex) is also allowed as a way to prevent pregnancy. 
 
If at any point during the study you think your child may be pregnant, you should let the study 
staff at your site know so that a pregnancy test can be done. 
 
If your child is pregnant or they become pregnant while on study, the study staff would like to 
obtain information from your child about the outcome of the pregnancy (even if it is after their 
participation in the study ends). We would also like them to bring the baby in for a study visit 
about 4 weeks after they are born so we can examine the baby. 
 
 
ARE THERE BENEFITS TO TAKING PART IN THIS STUDY?  
  
We do not know for certain if your child will benefit from tecovirimat. Based on what we 
know about tecovirimat, the study drug may help to treat their infection and prevent it 
from getting worse, but we cannot make any guarantee. 
  
 
WHAT OTHER CHOICES DOES MY CHILD HAVE BESIDES THIS STUDY?  
  
There is no proven way to treat poxviruses, but research is ongoing. Your child may benefit 
from supportive therapy (such as IV fluids, or medicine to control fever or pain) and antibiotics 

 
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for any bacterial infections they may have. There may be other medications that your child’s 
study doctor may consider using to treat their infection. There may also be research studies 
looking at other new treatments for poxviruses.  
  
Please talk to your study doctor about these and other choices available to your child. Your 
study doctor will explain the risks and benefits of these choices.  
 
 
WHAT ABOUT CONFIDENTIALITY?  
  
We will do everything we can to protect your child’s privacy. In addition to the efforts of the study 
staff to help keep your child’s personal information private, we have gotten a Certificate of 
Confidentiality from the U.S. Federal Government. This certificate means that researchers 
cannot be forced to tell people who are not connected with this study, such as the court system, 
about your child’s participation. The researchers with this Certificate may not disclose or use 
information, documents, or biospecimens that may identify your child in any federal, state, or 
local civil, criminal, administrative, legislative, or other action, suit, or proceeding, or be used as 
evidence, for example, if there is a court subpoena, unless you have consented for this use. 
Information, documents, or biospecimens protected by this Certificate cannot be disclosed to 
anyone else who is not connected with the research except, if there is a federal, state, or local 
law that requires disclosure (see below); if you have consented to the disclosure, including for 
your child’s medical treatment; or if it is used for other scientific research, as allowed by federal 
regulations protecting research participants. 
 
The Certificate cannot be used to refuse a request for information from personnel of the United 
States federal or state government agency sponsoring the project that is needed for auditing or 
program evaluation by the agency which is funding this project or for information that must be 
disclosed in order to meet the requirements of the federal Food and Drug Administration (FDA). 
You should understand that a Certificate of Confidentiality does not prevent you from voluntarily 
releasing information about your child or your child’s involvement in this research. If you want 
your child’s research information released to an insurer, medical care provider, or any other 
person not connected with the research, you must provide consent to allow the researchers to 
release it. 
  
Having a Certificate of Confidentiality does not prevent you or your child from releasing 
information about your child and your child’s participation in the study. The Certificate of 
Confidentiality will not be used to prevent disclosure for any purpose you have consented to in 
this informed consent document. 
  
Even with the Certificate of Confidentiality, if the study staff learns of possible child abuse and/or 
neglect or a risk of harm to yourself or others, we will be required to tell the proper authorities. 
 
Your child’s records may be reviewed by the U.S. Food and Drug Administration (FDA), the 
AIDS Clinical Trials Group (ACTG), the U.S. Office for Human Research Protections (OHRP), or 
other local, U.S., and international regulatory entities as part of their duties, Advarra Institutional 
Review Board (IRB) (a committee that protects the rights and safety of participants in research), 

 
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National Institutes of Health (NIH), study staff, study monitors, drug companies supporting this 
study, and their designees.  
 
Also, any publication of this study will not use your child’s name or identify them personally. 
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by 
U.S. Law. This Web site will not include information that can identify you. At most, the Web site 
will include a summary of the results. You can search this Web site at any time.  
  
 
WHAT ARE THE COSTS TO MY CHILD?  
  
The study will pay for research-related tests and assessments. Taking part in this study may 
lead to added costs to your child and your insurance company. In some cases, it is possible that 
your insurance company will not pay for these costs because your child is taking part in a 
research study.  
 
 
WILL MY CHILD RECEIVE ANY PAYMENT?  
  
Compensation 
 
You child will be paid up to a total of $xx.xx if they complete this study. You child will be paid for 
the visits they complete according to the following schedule: 
$xx.xx for Visits xxx.  
$xx.xx for Visits xxx.  
$xx.xx for Visits xxx.  
 
If your child does not complete the study, for any reason, they will be paid for each study visit 
they do complete.  
 
Your child will be paid ___________ [“following each completed visit”, “monthly”, “quarterly”, “at 
the end of their participation in the research study”, “following each completed visit or at the end 
of their participation in the research study, whichever you prefer”]. 
 
If you have any questions regarding your child’s compensation for participation, please contact 
the study staff.  
 
 
WHAT HAPPENS IF MY CHILD IS INJURED?  
  
If your child is injured as a result of being in this study, they will be given immediate treatment 
for their injuries. There is no program for compensation through the NIH. The cost for this 
treatment will be charged to you or your insurance company. 
  
You will not be giving up any of your legal rights by signing this consent form.  
  

 
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WHAT ARE MY CHILD’S RIGHTS AS A RESEARCH PARTICIPANT?  
  
Taking part in this study is completely voluntary. You or your child may choose not to take part 
in this study or leave this study at any time. You or your child’s decision will not have any impact 
on your or your child’s participation in other studies conducted by NIH and will not result in any 
penalty or loss of benefits to which you or your child are otherwise entitled.  
  
We will tell you about new information from this or other studies that may affect your child’s 
health, welfare, or willingness to stay in this study. If you want the results of the study, let the 
study staff know.  
 
 
WHOM TO CONTACT ABOUT THIS STUDY 
 
During the study, if your child experiences any medical problems, suffers a research-related 
injury, or has questions, concerns or complaints about the study such as: 
• 
Whom to contact in the case of a research-related injury or illness; 
• 
Payment or compensation for being in the study, if any; 
• 
Their responsibilities as a research participant; 
• 
Eligibility to participate in the study; 
• 
The study doctor’s or study site’s decision to withdraw your child from participation; 
• 
Results of tests and/or procedures; 
 
Please contact the study doctor at the telephone number listed on the first page of this consent 
document.  
 
If you seek emergency care, or hospitalization is required, alert the treating physician that your 
child is participating in this research study.  
 
An institutional review board (IRB) is an independent committee established to help protect the 
rights of research participants. If you have any questions about your child’s rights as a research 
participant, contact: 
• 
By mail: 
Study Subject Adviser 
Advarra IRB 
6100 Merriweather Dr., Suite 600 
Columbia, MD 21044 
• 
or call toll free:    877-992-4724 
• 
or by email: adviser@advarra.com 
 
Please reference the following number when contacting the Study Subject Adviser: Pro00065749. 
 
 

 
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SIGNATURE PAGE  
 
If you have read this consent form (or had it explained to you), all your questions have been 
answered and you agree for your child to take part in this study, please sign your name below.  
 
 
 
 
 
 
 
 
 
 
 
Name of Child or Adolescent 
(print) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Name of Parent or Legal Guardian Parent or Legal Guardian Signature  Date 
(print) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Name of Witness 
 
 
Witness Signature 
 
 
Date 
(if applicable, print) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Staff Conducting 
 
Study Staff Signature  
 
Date 
Consent Process Name (print) 
 
 
 

 
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AUTHORIZATION TO USE AND DISCLOSE PROTECTED HEALTH INFORMATION 
  
If you decide for your child to be in this study, the study doctor and study staff will use and share 
health data about your child to conduct the study. Health data may include: 
• 
Your child’s name. 
• 
Address. 
• 
Phone number. 
• 
Date of birth. 
• 
Medical history. 
• 
Information from your child’s study visits, including all test results.  
  
Health data may come from your child’s study records or from existing records kept by your 
child’s doctor or other health care workers.  
  
For this study, the study staff may share health data about you with authorized users. 
Authorized users may include: 
• 
Representatives of University of California, Los Angeles (UCLA) and National Institute of 
Allergy and Infectious Diseases (NIAID). 
• 
Representatives of ACTG. 
• 
Representatives of Advarra IRB (an Institutional Review Board that reviews this study). 
• 
The Food and Drug Administration (FDA) and other U.S. federal and state agencies. 
• 
Government agencies to whom certain diseases (like HIV, hepatitis, and STDs) must be 
reported. 
• 
Governmental agencies of other countries. 
• 
Outside individuals and companies, such as laboratories and data storage companies, that 
work with the researchers and sponsor and need to access your information to conduct this 
study. 
• 
Other research doctors and medical centers participating in this study, if applicable.  
• 
A data safety monitoring board which oversees this study, if applicable. 
  
Your child’s health data will be used to conduct and oversee the research, including for 
instance: 
• 
To see if the study drug works and is safe. 
• 
To compare the study drug to other drugs. 
• 
For other research activities related to the study drug. 
  
Once your child’s health data has been shared with authorized users, it may no longer be 
protected by federal privacy law and could possibly be used or disclosed in ways other than 
those listed here.  
  
Your permission to use and share health data about your child will end in 50 years unless you 
revoke it (take it back) sooner.  
  
You may revoke (take back) your permission to use and share health data about your child at 
any time by writing to the study doctor at the address listed on the first page of this form. If you 
do this, your child will not be able to stay in this study. No new health data that identifies your 

 
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child will be gathered after your written request is received. However, health data about your 
child that has already been gathered may still be used and given to others as described in this 
form.  
  
Your right to access your child’s health data in the study records will be suspended during the 
study to keep from changing the study results. When the study is over, you can access your 
child’s study health data. 
  
If you decide not to sign and date this form, your child will not be able to take part in the study. 
 
  
 
 

 
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STATEMENT OF AUTHORIZATION 
 
I have read this form and its contents were explained. My questions have been answered. I 
voluntarily agree to allow study staff to collect, use and share my child’s health data as specified 
in this form. I will receive a signed and dated copy of this form for my records. I am not giving up 
any of my or my child’s legal rights by signing and dating this form.  
  
 
_____________________________   
Name of Child or Adolescent (print) 
 
  
______________________           ____________________________ 
Name of Parent of Legal  
        Parent of Legal Guardian  
Guardian (print)                
        Signature and Date 
 
  
_____________________             ____________________________ 
Name of Witness 
    Witness Signature and Date 
(if applicable) (print)                    
  
 
 

 
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APPENDIX V: INFORMED CONSENT AND AUTHORIZATION TO USE AND DISCLOSE 
PROTECTED HEALTH INFORMATION FOR PARENTS/LEGAL GUARDIANS OF CHILDREN 
WHO ARE ENROLLED/FOLLOWED REMOTELY 
 
 
Sponsor / Study Title: 
  
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 Human Monkeypox Virus Disease” 
 
Protocol Number: 
 
A5418 
 
Principal Investigator: 
(Study Doctor) 
 
«PiFullName» 
 
Telephone: 
 
«IcfPhoneNumber» 
 
Address: 
«PiLocations» 
 
 
SUMMARY  
 
PURPOSE 
This is a research study and your child’s participation in this study 
is voluntary. The purpose of this study is to evaluate how well 
tecovirimat works for the treatment of human monkeypox virus 
infection and if the study drug is safe in people. The study will also 
help us understand more about how human monkeypox causes 
disease, how the body fights off infection, and how to dose 
tecovirimat in children. 
 
STUDY GROUPS 
There are different groups in this study. Arm A will take the 
tecovirimat study drug, Arm B will take a placebo. A placebo looks 
like a “real” drug but does not have any active drug in it. 
Participants will be randomly assigned to Arm A or Arm B (like 
flipping a coin or rolling dice).  
 
All participants in Arm C will take tecovirimat, without any chance of 
getting the placebo. Children under 18 years of age will be in Arm C 
and receive tecovirimat. 
 
STUDY  
DRUG 
The study drug will be tecovirimat. Tecovirimat will be taken two or 
three times a day for 14 days.. 
 

 
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NUMBER OF  
PARTICIPANTS 
There is no limit to how many children will enroll in this study.  
 
LENGTH OF  
STUDY  
Your child’s participation in this study will last about 2 months. If 
they become pregnant, we will contact you periodically to see how 
their pregnancy goes and to know the health of their child.  
 
REQUIRED  
ACTIVITIES 
If your child is in this study, the following study procedures are 
required 
• You or your child will record their symptoms daily 
• They will provide swabs of the sores on their skin  
• You or your child will complete questionnaires about their 
symptoms 
 
RISKS  
The most common side effects people receiving tecovirimat 
have noticed are: 
• 
Headache  
• 
Nausea (feeling like you want to vomit) 
• 
Vomiting  
• 
Stomach pain  
 
BENEFITS  
We do not know if your child will benefit from tecovirimat. Based on 
what we know about tecovirimat, the study drug may help to treat 
their infection and prevent it from getting worse, but we cannot 
make any guarantee.  
 
OTHER CHOICES  
There is no proven way to treat human monkeypox virus. Your 
child may benefit from supportive therapy (such as intravenous 
[IV] fluids, or medicine to control fever or pain) and antibiotics for 
any bacterial infections they may have. There may be other 
medications that your child’s study doctor may consider using to 
treat their infection. Tecovirimat may be available outside this 
study. There may also be research studies looking at other new 
treatments for poxviruses.  
 
 
INTRODUCTION  
 
This form is for the parent or legal guardian of a child or adolescent who is being asked 
to participate in this research study. In this form, participants are referred to as 
“children” even though they may be older teenagers.  
 
You are being asked for your child to take part in this research study because they: 
• 
Have confirmed or suspected monkeypox virus  

 
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• 
They have had symptoms for fewer than 14 days  
• 
They have at least one active, not yet scabbed lesion in the skin, a sore in the mouth 
or proctitis (inflammation of the lining of the rectum)  
 
This study is sponsored by the National Institutes of Health (NIH). The study doctor is in 
charge of this study at this site. Before you decide if you want to be a part of this study, 
we want you to know about the study.  
 
This is a consent form. It gives you information about this study. The study staff will talk 
with you about this information. You are free to ask questions about this study at any 
time. If you agree for your child to take part in this study, you will be asked to sign this 
consent form. You will get a copy to keep.  
 
 
WHY IS THIS STUDY BEING DONE?  
 
Monkeypox is caused by a virus. This virus is most often spread by close contact 
with someone who has monkeypox. Illness caused by monkeypox virus infection 
usually starts with a fever and feeling poorly before a rash begins. However, the rash 
may begin without other symptoms. The rash looks like raised bumps and pus-filled 
blisters (called lesions). They usually crust, scab, and fall off after about 2-4 weeks, 
sometimes leaving a scar. 
 
Since Spring 2022, monkeypox has rapidly spread throughout the world, with more 
than 70,000 cases in 107 countries and more than 26,000 cases in the United States 
reported as of September 2022.  
 
Tecovirimat is a drug that may help to treat infections caused by pox viruses. 
Tecovirimat is approved by the Food and Drug Administration (FDA) to treat smallpox in 
adults and children, but its use in this study is considered investigational. An 
investigational use is one that has not been approved by the FDA. Tecovirimat has been 
approved based only on data from animals. We don’t know for sure if it works to treat 
any infections in people. The FDA has reviewed information on tecovirimat and 
determined that tecovirimat may help treat infection, including serious or potentially life-
threatening disease, from poxviruses.  
 
Tecovirimat has been given safely to some people with monkeypox in the recent 
outbreak and is currently being studied in several ongoing studies outside of the 
U.S., but none of the studies have shown whether or not this study drug works to 
treat monkeypox. The safety of tecovirimat has been evaluated in a study with 
adult participants without monkeypox. Tecovirimat was generally safe and well 
tolerated – the risks are noted below.  
 
We are doing this study to see if tecovirimat is safe and whether it helps treat 
monkeypox in people. The study will also help us understand more about how 
human monkeypox causes disease and how the body fights off infection. This 

 
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study will help us understand how much tecovirimat to give children to treat 
monkeypox. 
 
 
WHAT DOES MY CHILD HAVE TO DO IF THEY ARE IN THIS STUDY?  
 
Screening/Day 1 Visit 
If you would like your child to be in this study, after you have read and signed this 
consent form, your child will have a screening visit to make sure they meet the 
requirements for joining the study. This visit will be done via telemedicine. 
 
We will collect some demographic (for example, age, gender, race), clinical (for example, 
disease condition, diagnosis), and laboratory (for example, CD4 cell count and viral load 
if your child is living with HIV) information. We will collect this information even if your 
child does not join this study. 
 
At this visit: 
• 
Your child will answer questions about their medical history and any medications 
they have taken recently.  
• 
Your child will have an exam of their skin to identify where they have monkeypox 
lesions. Your child will may have to remove some of their clothes for this exam. Site 
staff will ask to take pictures of your child’s skin lesions. Your child does not have to 
agree to have these pictures taken. Your child can participate in this study regardless 
of what they decide about having pictures taken. If your child agrees, these pictures 
will be used so that the study staff can follow how well their lesions are healing. 
These pictures will not be used for any other purpose without your child’s written 
permission. If your child has lesions on their face, it is possible that they will be able 
to be identified in these pictures. These pictures may be stored in your child’s 
electronic medical record. If these pictures are stored in a study database, they will 
be stored securely with a code instead of your child’s name. Please discuss how 
pictures are stored at your child’s clinical research site. 
• 
Your child will answer questionnaires about any pain their lesions may be causing.  
• 
If your child has eye disease from monkeypox or eye symptoms, study staff will ask 
you to have your child be seen by an eye doctor outside of the study. 
• 
If they are available in their medical records, we will record the results from your 
child’s latest physical exam and results from any recent pregnancy test.  
 
There are some tests that we will only request at this study visit if your child is sexually 
active: 
• 
Your child will be advised to obtain testing for sexually transmitted infections outside 
of the study as indicated. If your child is found to have an STI or HIV, they will be 
referred for treatment or study staff will provide appropriate treatment. 
 

 
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There are some tests that will only be done at this study visit if your child qualifies for 
the study: 
• 
Your child will answer questionnaires about others who live in their home and 
whether these household members have monkeypox. 
• 
If they are available in your medical records, we will record the results from recent 
blood tests your child had. 
• 
If your child qualifies for the study, a study kit will be delivered to them that includes: 
o Their study drugs. Tecovirimat will be taken two or three times a day for 14 days. 
If you child spits out a dose of study drug or vomits within 15 minutes after taking 
their study drug, they should take a replacement dose. If your child spits up or 
vomits more than 15 minutes after taking their study drug, a replacement dose 
should not be given (the next dose should be taken as scheduled). 
o Instructions on how to complete the study diary that they will complete at home to 
record how their skin lesions are doing, any symptoms that they are experiencing, 
and any pain that they are experiencing. We will also ask your child to write down 
the date and time that they take their study drug. 
o Containers for any sample collections that your child will do at home. 
 
If your child joins the study remotely, we expect that all of their visits will be done 
remotely, but they may elect to have follow up visits in person. In this event, they would 
sign the consent form for in person follow up. 
 
Study Visit on Day 6 
At this visit: 
• 
The study staff will contact your child by phone or via telemedicine to ask about any 
symptoms they are experiencing and any pain that they might be experiencing.  
• 
Study staff will ask your child if they are taking their study drugs as directed. 
 
Study Visits on Days 8, 15, 22, 29, 57 
These visits will be conducted via telemedicine. At these visits: 
• 
Your child will answer questions about any medications they are taking. 
• 
Your child will have an exam of their skin to identify where they have monkeypox 
lesions. Study staff will ask you to take pictures of their skin lesions or they will take 
pictures via telemedicine.  
• 
Your child will answer questionnaires about whether people in their household have 
monkeypox (day 29 and 57).  
 
Study Evaluations to Complete at Home 
In addition to the telemedicine visits, your child will have to complete additional study 
evaluations at home: 
• 
Complete their study diary and pain rating every day on days 1-29 
• 
If you are able to and you and your child agree, you will take photographs of your 
child’s lesions at least twice a week so you can show them to the study staff to track 
how your child’s lesions are healing.  
• 
On the day that they enter the study and again on day 8 your child will be asked to 
take swabs of their skin for monkeypox testing. You will return these samples to the 

 
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testing lab via mail or courier service. These samples may be omitted if 
testing/shipping kits are not available or if health laws where you live do not allow 
you to ship the samples. If a new lesion appears on your child’s skin on or after day 6, 
they will be asked to take a swab of the new lesion for monkeypox testing. You will 
send the swab to the testing laboratory.  
 
Additional Study Visits 
Your child will have extra telemedicine visits if their monkeypox disease gets worse or if 
their lesions heal up. If you need to report to the site that your child’s lesions have 
healed, this visit may be done remotely (over the phone or via telemedicine systems 
approved for use at your site). If your child’s monkeypox disease gets worse they may 
also choose to come into the site to see the site staff in person if they would prefer. 
 
Early Discontinuation 
If at any point in the study you or your child want your child to stop participating in the 
study, you must contact the site immediately. If you choose to withdraw consent, no 
additional samples will be collected and no new information will be collected. Any 
samples that have not been analyzed prior to your withdrawal of consent will be 
destroyed, but any information from any samples already analyzed will still be used.  
 
 
QUICK SUMMARY OF EVALUATIONS 
 
 
Screening/ 
Day 1 
 
Day 
6 
Day 
8 
Day 
15 
Day 
22 
Day 
29 
Day 
57 
Lesion 
Resolution 
Disease 
Progression 
Skin Exam via 
Telemedicine 
X 
 
X 
X 
X 
X 
X 
X 
X 
Swabs Collected 
X 
 
X 
 
 
 
 
 
 
Questionnaires 
X 
X 
X 
X 
 
X 
X 
 
X 
Study Diary/Self 
Assessments 
Days 1-29 
  
  
  
 
 
WILL MY CHILD RECEIVE THE RESULTS OF ANY TESTS? 
 
Testing of the swabs that you collect may be done after you are done with the study. For 
this reason, you will not receive these results. 
 
You and your child will be told of any new information learned during the course of the 
study that might cause you to change your mind about staying in the study. At the end of 
the study, you and your child will be told when study results may be available and how to 
learn about them. As with all studies, if we find out important information that may affect 
your child’s care, you and your child will be provided with those results. 
 
 

 
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CAN I CHOOSE THE TYPES OF RESEARCH THAT MY CHILD’S SAMPLES AND 
INFORMATION ARE USED FOR?  
 
The tests described above are required by this study. If you do not agree to the storage 
or testing that has been described above, you should not give permission for your child 
join this study.  
 
Please refer to Attachment B to consent for use of your child’s samples in other studies.  
 
 
COMMERCIAL PROFIT 
 
Your child’s biospecimens collected during this study may be used for commercial profit 
(even if identifiers are removed) and your child will not share in this profit. 
 
 
HOW MANY PEOPLE WILL TAKE PART IN THIS STUDY?  
 
There is no limit to how many children will be in Arm C. 
 
 
HOW LONG WILL MY CHILD BE IN THIS STUDY?  
 
Your child will be in this study for about two months (60 days).  
 
 
WHY WOULD THE STUDY DOCTOR TAKE MY CHILD OFF THIS STUDY EARLY?  
 
The study doctor may need to take your child off the study early without your permission 
if:  
• 
The study is stopped or cancelled  
• 
Your child’s primary care doctor thinks that this study is no longer in your child’s 
best interest and they request that your child stop participating 
 
The study doctor may also need to take your child off the study drug(s) without your 
permission if:  
• 
Continuing the study drug may be harmful to your child  
• 
Your child needs a treatment that they may not take while on the study  
• 
Your child is not able to take the study drug as required by the study  
 
 
WHAT HAPPENS WHEN MY CHILD FINISHES THE STUDY? 
 
After your child has completed the study, the study will not be able to continue to provide 
your child with the study drug they received on the study. If continuing to take this or 

 
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similar drugs would be of benefit to your child, the study staff will discuss how you may 
be able to obtain them. 
 
 
WHAT ARE THE RISKS OF THE STUDY?  
 
The drug used in this study may have side effects, some of which are listed below. Please 
note that these lists do not include all the side effects seen with this study drug. These lists 
include the more serious or common side effects with a known or possible relationship. If 
you have questions concerning the additional study drug side effects please ask the study 
staff at your site.  
 
There is a risk of serious and/or life-threatening side effects when non-study medications 
are taken with the study drugs. For your child’s safety, you and your child must tell the 
study doctor or study nurse about all medications your child is taking before they start 
the study and also before starting any new medications while on the study. Also, you and 
your child must tell the study doctor or study nurse before enrolling in any other clinical 
trials while on this study.  
 
The risks of tecovirimat in people with smallpox or other poxviruses are not known. 
Tecovirimat has not been studied in people with weak immune systems, the elderly, 
or children and unanticipated side effects may occur. Tecovirimat 600 mg capsules 
were tested in 359 healthy adults, including 336 healthy adults who received 
tecovirimat capsules twice a day for 14 days. Tecovirimat for injection was also 
tested in 26 healthy adults. No serious problems occurred in any of the participants 
in these studies.  
 
During the 2022 monkeypox outbreak in the U.S., tecovirimat capsules have also 
been given to more than 230 people with poxvirus infection, including people with 
monkeypox, as of July 2022; side effects are being monitored but no serious 
problems with tecovirimat have been reported so far. Still, tecovirimat may cause 
some adverse events (side effects). There also may be other adverse events that we 
cannot predict. The most common adverse events in people who have taken 
tecovirimat were:  
• 
Headache  
• 
Nausea  
• 
Vomiting  
• 
Stomach pain  
 
As with any medication, there is a potential risk of an allergic reaction. An allergic 
reaction after receiving tecovirimat could include: 
• 
Rash 
• 
Difficulty breathing 
• 
Wheezing 
• 
Sudden drop in blood pressure causing dizziness or fainting 
• 
Swelling (around the mouth, throat, or eyes) 

 
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• 
Fast pulse 
• 
Sweating.  
 
Risks of Drug Interactions 
There are drug interactions with tecovirimat. Tecovirimat can lower or raise the 
concentrations of other medicines in your blood. When the blood concentrations of 
other medicines are lower, the other medicines may not work as well. When the blood 
concentrations of other medicines are raised, the other medicines may cause more 
side effects. Other medicines may also lower or raise the tecovirimat concentrations 
in the blood. To minimize the risk for drug interactions, it is important to review all of 
your child’s prescription and over-the- counter medicines and dietary and herbal 
supplements with study personnel. It is also important to notify study personnel 
before your child starts any new prescription or over-the-counter medicines and 
dietary and herbal supplements while taking the study drug.  
 
Risks of Skin Swabs  
These can be uncomfortable and occasionally there can be some bleeding.  
 
Questionnaires 
You or your child may be embarrassed by the questions about sex. 
 
Loss of Privacy - Photographs of Participant’s Face 
Your child may have photographs taken for this study of their face or areas of their skin 
that have distinctive markings such as tattoos. It is possible that these photographs may 
be recognizable and their identity may be known. All photographs taken during the study 
will be stored in your child’s electronic medical record or will be stored with a code 
instead of their name. 
 
Risks of Your Child Starting the Study Before Their Monkeypox Virus is Confirmed by a 
Lab 
There are other things that can cause lesions on your child’s skin, but we want your child 
to start the study as soon as possible, so we will let them begin study drug even if their 
skin lesions have not been tested by a lab and confirmed to be monkeypox. There is a 
chance that your child’s lab tests will show that they do not have monkeypox, so there is 
a risk that they will have taken study drug and participated in study tests when they do 
not have monkeypox.  
 
The study doctors at your child’s site will use their best judgement to make sure that this 
does not happen, but if it does happen your child will stop taking the study drug and the 
study staff at your study site will check on your child in 7 days to make sure that they do 
not have any side effects before they leave the study. 
 
Risks of Participating in the Study through Telemedicine 
Study providers are not able to fully examine your child through telemedicine. It is 
possible that their assessment is not complete or not as accurate as an in-person visit. 

 
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You are encouraged to see local providers in person if you or your child have concerns 
about their health. 
 
 
ARE THERE RISKS RELATED TO PREGNANCY AND BREASTFEEDING?  
 
Tecovirimat has not been studied in pregnant or nursing people. It is not known if 
giving tecovirimat to a pregnant person would hurt the unborn child. Tecovirimat 
has been tested on pregnant mice and rabbits. There were no serious problems in 
the unborn animals. Poxviruses during pregnancy can cause serious harm to the 
pregnant person and unborn baby.  
 
In animal studies, tecovirimat was present in animal milk. When a drug is present in 
animal milk it is likely to be present in human milk. Because of the potential for virus 
transmission through direct contact with the breastfed infant, breastfeeding is not 
recommended while the nursing individual has active lesions. A lactating person should 
consider pausing breastfeeding and consider pumping and discarding breast milk during 
study treatment. 
 
If your child can get pregnant but is not pregnant when they join the study and they are 
engaging in sexual activity that could lead to pregnancy, they must agree to use at least 
one effective method of contraception from the time they join the study until they are 
finished with the study. Effective methods of contraception are hormonal contraceptives 
(injected or in pills), male or female condoms, diaphragm or cervical cap with a 
spermicide, or an intrauterine device (an IUD). Abstinence (agreeing not to have sex) is 
also allowed as a way to prevent pregnancy. 
 
If at any point during the study you think your child may be pregnant, you should let the 
study staff at your site know. Your child is encouraged to obtain pregnancy testing if 
they believe they may be pregnant.  
 
If your child is pregnant or they become pregnant while on study, the study staff would 
like to obtain information from your child about the outcome of the pregnancy (even if it 
is after their participation in the study ends).  
 
 
ARE THERE BENEFITS TO TAKING PART IN THIS STUDY?  
 
We do not know for certain if your child will benefit from tecovirimat. Based on 
what we know about tecovirimat, the study drug may help to treat their infection 
and prevent it from getting worse, but we cannot make any guarantee. 
 
 
WHAT OTHER CHOICES DOES MY CHILD HAVE BESIDES THIS STUDY?  
 
There is no proven way to treat poxviruses, but research is ongoing. Your child may 
benefit from supportive therapy (such as IV fluids, or medicine to control fever or pain) 

 
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and antibiotics for any bacterial infections they may have. There may be other 
medications that your child’s study doctor may consider using to treat their infection. 
There may also be research studies looking at other new treatments for poxviruses.  
 
Please talk to your study doctor about these and other choices available to your child. 
Your study doctor will explain the risks and benefits of these choices.  
 
 
WHAT ABOUT CONFIDENTIALITY?  
 
We will do everything we can to protect your child’s privacy. In addition to the efforts of 
the study staff to help keep your child’s personal information private, we have gotten a 
Certificate of Confidentiality from the U.S. Federal Government. This certificate means 
that researchers cannot be forced to tell people who are not connected with this study, 
such as the court system, about your child’s participation. The researchers with this 
Certificate may not disclose or use information, documents, or biospecimens that may 
identify your child in any federal, state, or local civil, criminal, administrative, legislative, 
or other action, suit, or proceeding, or be used as evidence, for example, if there is a 
court subpoena, unless you have consented for this use. Information, documents, or 
biospecimens protected by this Certificate cannot be disclosed to anyone else who is not 
connected with the research except, if there is a federal, state, or local law that requires 
disclosure (see below); if you have consented to the disclosure, including for your 
child’s medical treatment; or if it is used for other scientific research, as allowed by 
federal regulations protecting research participants. 
 
The Certificate cannot be used to refuse a request for information from personnel of the 
United States federal or state government agency sponsoring the project that is needed 
for auditing or program evaluation by the agency which is funding this project or for 
information that must be disclosed in order to meet the requirements of the federal Food 
and Drug Administration (FDA). You should understand that a Certificate of 
Confidentiality does not prevent you from voluntarily releasing information about your 
child or your child’s involvement in this research. If you want your child’s research 
information released to an insurer, medical care provider, or any other person not 
connected with the research, you must provide consent to allow the researchers to 
release it. 
  
Having a Certificate of Confidentiality does not prevent you or your child from releasing 
information about your child and your child’s participation in the study. The Certificate of 
Confidentiality will not be used to prevent disclosure for any purpose you have 
consented to in this informed consent document. 
  
Even with the Certificate of Confidentiality, if the study staff learns of possible child 
abuse and/or neglect or a risk of harm to yourself or others, we will be required to tell the 
proper authorities. 
 
Your child’s records may be reviewed by the U.S. Food and Drug Administration (FDA), 
the AIDS Clinical Trials Group (ACTG), the U.S. Office for Human Research Protections 

 
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(OHRP), or other local, U.S., and international regulatory entities as part of their duties, 
Advarra Institutional Review Board (IRB) (a committee that protects the rights and safety 
of participants in research), National Institutes of Health (NIH), study staff, study 
monitors, drug companies supporting this study, and their designees.  
 
Also, any publication of this study will not use your child’s name or identify them 
personally. 
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as 
required by U.S. Law. This Web site will not include information that can identify you. At 
most, the Web site will include a summary of the results. You can search this Web site at 
any time.  
 
 
WHAT ARE THE COSTS TO MY CHILD?  
 
The study will pay for research-related tests and assessments. Taking part in this study 
may lead to added costs to your child and your insurance company. In some cases, it is 
possible that your insurance company will not pay for these costs because your child is 
taking part in a research study. If your child goes to a clinic other than their site clinic for 
STI testing, pregnancy testing, or other testing, the study will not pay for this testing.  
 
 
WILL MY CHILD RECEIVE ANY PAYMENT?  
 
«Compensation» 
 
You child will be paid up to a total of $xx.xx if they complete this study. You child will be 
paid for the visits they complete according to the following schedule: 
$xx.xx for Visits xxx.  
$xx.xx for Visits xxx.  
$xx.xx for Visits xxx.  
 
If your child does not complete the study, for any reason, they will be paid for each study 
visit they do complete.  
 
Your child will be paid ___________ [“following each completed visit”, “monthly”, 
“quarterly”, “at the end of their participation in the research study”, “following each 
completed visit or at the end of their participation in the research study, whichever you 
prefer”]. 
 
If you have any questions regarding your child’s compensation for participation, please 
contact the study staff.  
 
 

 
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WHAT HAPPENS IF MY CHILD IS INJURED?  
 
If your child is injured as a result of being in this study, they will be given immediate 
treatment for their injuries. There is no program for compensation through the NIH. The 
cost for this treatment will be charged to you or your insurance company. 
 
You will not be giving up any of your legal rights by signing this consent form.  
 
 
WHAT ARE MY CHILD’S RIGHTS AS A RESEARCH PARTICIPANT?  
 
Taking part in this study is completely voluntary. You or your child may choose not to 
take part in this study or leave this study at any time. You or your child’s decision will 
not have any impact on your or your child’s participation in other studies conducted by 
NIH and will not result in any penalty or loss of benefits to which you or your child are 
otherwise entitled.  
 
We will tell you about new information from this or other studies that may affect your 
child’s health, welfare, or willingness to stay in this study. If you want the results of the 
study, let the study staff know.  
 
 
WHOM TO CONTACT ABOUT THIS STUDY 
 
During the study, if your child experiences any medical problems, suffers a research-
related injury, or has questions, concerns or complaints about the study such as: 
• 
Whom to contact in the case of a research-related injury or illness; 
• 
Payment or compensation for being in the study, if any; 
• 
Their responsibilities as a research participant; 
• 
Eligibility to participate in the study; 
• 
The study doctor’s or study site’s decision to withdraw your child from participation; 
• 
Results of tests and/or procedures; 
 
Please contact the study doctor at the telephone number listed on the first page of this 
consent document.  
 
If you seek emergency care, or hospitalization is required, alert the treating physician 
that your child is participating in this research study.  
 
An institutional review board (IRB) is an independent committee established to help 
protect the rights of research participants. If you have any questions about your child’s 
rights as a research participant, contact: 
• 
By mail: 
Study Subject Adviser 
Advarra IRB 
6100 Merriweather Dr., Suite 600 

 
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Columbia, MD 21044 
• 
or call toll free:    877-992-4724 
• 
or by email:  adviser@advarra.com 
 
Please reference the following number when contacting the Study Subject Adviser: 
Pro00065749. 
 
 

 
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SIGNATURE PAGE  
 
If you have read this consent form (or had it explained to you), all your questions have 
been answered and you agree for your child to take part in this study, please sign your 
name below.  
 
 
 
 
 
 
 
 
 
 
 
Name of Child or Adolescent 
(print) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Name of Parent or Legal 
 
Parent or Legal Guardian 
  
Date 
Guardian 
 
 
 
Signature 
(print) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Name of Witness 
 
 
Witness Signature 
 
 
Date 
(if applicable, print) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Staff Conducting 
 
Study Staff Signature 
 
 
Date 
Consent Process Name (print) 
 
 
 

 
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AUTHORIZATION TO USE AND DISCLOSE PROTECTED HEALTH INFORMATION 
  
If you decide for your child to be in this study, the study doctor and study staff will use 
and share health data about your child to conduct the study. Health data may include: 
• 
Your child’s name. 
• 
Address. 
• 
Phone number. 
• 
Date of birth. 
• 
Medical history. 
• 
Information from your child’s study visits, including all test results.  
  
Health data may come from your child’s study records or from existing records kept by 
your child’s doctor or other health care workers.  
  
For this study, the study staff may share health data about you with authorized users. 
Authorized users may include: 
• 
Representatives of University of California, Los Angeles (UCLA) and National Institute 
of Allergy and Infectious Diseases (NIAID). 
• 
Representatives of ACTG. 
• 
Representatives of Advarra IRB (an Institutional Review Board that reviews this 
study). 
• 
The Food and Drug Administration (FDA) and other U.S. federal and state agencies. 
• 
Government agencies to whom certain diseases (like HIV, hepatitis, and STDs) must 
be reported. 
• 
Governmental agencies of other countries. 
• 
Outside individuals and companies, such as laboratories and data storage 
companies, that work with the researchers and sponsor and need to access your 
information to conduct this study. 
• 
Other research doctors and medical centers participating in this study, if applicable.  
• 
A data safety monitoring board which oversees this study, if applicable. 
  
Your child’s health data will be used to conduct and oversee the research, including for 
instance: 
• 
To see if the study drug works and is safe. 
• 
To compare the study drug to other drugs. 
• 
For other research activities related to the study drug. 
  
Once your child’s health data has been shared with authorized users, it may no longer be 
protected by federal privacy law and could possibly be used or disclosed in ways other 
than those listed here.  
  
Your permission to use and share health data about your child will end in 50 years 
unless you revoke it (take it back) sooner.  
  
You may revoke (take back) your permission to use and share health data about your 
child at any time by writing to the study doctor at the address listed on the first page of 

 
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this form. If you do this, your child will not be able to stay in this study. No new health 
data that identifies your child will be gathered after your written request is received. 
However, health data about your child that has already been gathered may still be used 
and given to others as described in this form.  
  
Your right to access your child’s health data in the study records will be suspended 
during the study to keep from changing the study results. When the study is over, you 
can access your child’s study health data. 
  
If you decide not to sign and date this form, your child will not be able to take part in the 
study. 
 
  
 
 

 
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STATEMENT OF AUTHORIZATION 
 
I have read this form and its contents were explained. My questions have been answered. 
I voluntarily agree to allow study staff to collect, use and share my child’s health data as 
specified in this form. I will receive a signed and dated copy of this form for my records. I 
am not giving up any of my or my child’s legal rights by signing and dating this form.  
  
 
 
 
 
 
 
 
 
Name of Child or Adolescent (print) 
 
 
 
 
 
 
 
 
 
 
 
 
 
Name of Parent or  
 
 
Parent or Legal Guardian 
  
Date 
Legal Guardian (print) 
 
Signature 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Name of Witness 
 
 
Witness Signature 
 
 
Date 
(if applicable, print) 
 
 
 

 
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ATTACHMENT B: CONSENT FOR USE OF SAMPLES IN OTHER STUDIES FOR 
PARENTS/LEGAL GUARDIANS OF CHILDREN 
 
Everything in the main study consent form you signed before still applies to your child’s 
participation in this study unless otherwise noted in this form. 
 
When samples are no longer needed for this study, the ACTG may want to use them in other 
studies and share them with other researchers. These samples are called “extra samples”. The 
ACTG will only allow your child’s extra samples to be used in other studies if you agree to this. If 
you have any questions, please ask.  
  
Identifiers will be removed from your child’s samples and from any private information that has 
been collected about your child. This means that no one looking at the labels or at other 
information will know that the samples or information came from your child.  
  
Extra samples are stored in a secure central place called a repository. Your child’s samples will 
be stored in the ACTG repository located in the United States.  
  
There is no limit on how long your child’s extra samples will be stored.  
  
When a researcher wants to use your child’s samples and information, their research plan must be 
approved by the ACTG. Also, the researcher’s institutional review board (IRB) or ethics committee (EC) will 
review their plan. IRBs/ECs protect the rights and well-being of people in research. If the research plan is 
approved, the ACTG will send your child’s samples to the researcher’s location. This means that 
researchers who are not part of the study team may use your child’s samples without asking you again for 
your consent.  
  
Your child will not be paid for their samples. Also, a researcher may make a new scientific 
discovery or product based on the use of your child’s samples. If this happens, there is no plan 
to share any money with your child.  
 
You may withdraw your consent for research on your child’s extra samples at any time and the 
specimens will be discarded.  
  
Please choose the response that matches what you want by putting your initials in the space 
provided. Please ask the study staff any questions that you have before you indicate your 
selection.  
  
Research without Human Genetic Testing 
If you agree, your child’s extra samples may be stored (with usual protection of their identity) 
and used for ACTG-approved research that does not include human genetic testing.  
  
____ (initials) I understand and I agree to this storage and possible use of my child’s samples 
  
OR  
____ (initials) I understand but I do not agree to this storage and possible use of my child’s samples  
  

 
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Research with Human Genetic Testing  
The ACTG has two studies that collect samples for genetic testing.  
 
If you live in the U.S., this study is called ACTG A5128, Plan for Obtaining Informed Consent to 
Use Stored Human Biological Materials for Currently Unspecified Analyses. 
 
If you live outside of the U.S., this study is called ACTG A5243, Plan for Obtaining Human 
Biological Samples at Non-U.S. Clinical Research Sites for Currently Unspecified Genetic 
Analyses. 
 
Your site might ask you if you would like for your child to participate in this study if it is being 
done where your child lives. If you would like your child to participate, you will sign and date a 
separate consent form. 
 
Your child’s extra samples will not be used for human genetic testing unless you sign and date 
a consent form for A5128 or A5243.  

 
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SIGNATURE PAGE  
  
If you have read this consent form (or had it explained to you), all your questions have been 
answered and you agree for your child to take part in this study, please sign your name below.  
  
  
 
 
 
 
 
 
Name of Child or Adolescent  
 
  
 
 
(print) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Name of Parent or Legal Guardian  
Parent or Legal Guardian Signature   
Date 
(print) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Name of Witness 
 
 
Witness Signature 
 
 
Date 
(if applicable, print) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Staff Conducting 
 
Study Staff Signature  
 
Date 
Consent Process Name (print) 
 
 
 
 
 

 
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APPENDIX VI: PARTICIPANT ASSENT FORM FOR STUDY PARTICIPATION FOR 
PARTICIPANTS AGED 7 TO AGE OF MAJORITY (AOM) WHO ARE ENROLLED/FOLLOWED 
IN PERSON 
 
Sponsor / Study Title: 
  
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 Human 
Monkeypox Virus Disease” 
 
Protocol Number: 
 
A5418 
 
Principal Investigator: 
(Study Doctor) 
 
«PiFullName» 
 
Telephone: 
 
«IcfPhoneNumber» 
 
Address: 
«PiLocations» 
 
 
INTRODUCTION 
 
You are being asked to take part in a research study. In order for you to take part, you must give 
your permission. Your parent/legal guardian must also give permission.  
 
This form gives information about the study. Please read it or have it read to you. Ask any 
questions you may have. After we talk with you about this, if you decide to take part in the study, 
you will write your decisions at the end of this form. You will be offered a copy to keep. 
 
 
ABOUT THE STUDY 
 
The study is testing a drug called, tecovirimat, which is being tested to see if it works to treat 
human monkeypox virus infection and if the study drug is safe in people. 
 
Participants in the study will take the tablets two or three times every day for two weeks and 
be checked by study nurses and study doctors to see if the tablets cause bad effects. 
Participants will have blood drawn to test for bad effects. Tests will also check the amount of 
study drug that can be found in the blood.  
 
 
YOUR RIGHTS  
 
It is up to you and your parent/legal guardian to decide if you will take part in this study. You can 
say yes or no. If you say yes now, you can change your mind later. Your decision will have no 
effect on your medical care. 
 

 
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You do not need to join this study to receive medical care but right now, there is no proven way 
to treat human monkeypox virus. There may be other treatments to help you feel better and you 
can receive that treatment outside the study. The study drug may be available outside this 
study. You may also qualify for other studies. Please ask any questions you may have about 
these options.  
 
 
WHAT HAPPENS IN THE STUDY? 
 
If you decide to take part in the study, we will first examine you (check your body), draw blood, 
and do some tests to see if you qualify to be in the study. You may also have to give a urine 
sample. 
 
If you are having sex, you will have a test for HIV. The study doctor may be required by law to 
report the result of this test to the local health authority. 
 
If you are living with HIV, you will have a test to see how much HIV virus is in your blood and 
how many immune cells you have in your blood (immune cells help fight infection). You will 
receive the results of these tests.  
 
While in the study, you will take the tablets being tested. We will remind you and your 
parent/legal guardian that you should take the tablets two or three times every day, for two 
weeks.  
 
You will come to this clinic for at least 6 visits.  
 
At these visits, we will ask you and your parent/legal guardian about your health, and the 
medicines you take. We will ask questions about the tablets being tested. We will examine you 
and draw blood for tests. We will collect swabs for monkeypox testing from your mouth, any 
lesions you have on your skin, and possibly your eyes (if you have infection in your eyes). 
 
If you are having sex, we will do tests at your first visit to see if you have any infections that 
people sometimes get from sex. You will receive the results of these tests. The study doctor 
may be required by law to report any positive test results to the local health authority. 
 
Besides coming in for these visits, we will also ask you to collect information at home. For 
example, you and your parent/legal guardian will be asked to fill out a study diary. 
 
We will tell you as much information as you want about the tablets being tested and what will 
happen when you come here for visits. Please ask any questions you may have. Please tell us if 
anything bothers you or scares you. We will do our best to explain the study and help you feel 
more comfortable.  
 
 
HOW LONG WILL I BE IN THIS STUDY? 
 
You will be in this study for about 2 months. 

 
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EXTRA BLOOD DRAWS 
 
You may have to have some extra blood tests done to measure the amount of study drug in 
your blood very closely. Whether you have to have these tests depends on how many kids have 
already joined the study who are about the same weight as you are. The study staff at your site 
will tell you if you have to have these tests.  
 
If you have to have these tests, we will ask that you have nothing to eat or drink except for water 
for 2-8 hours before your visit. You will arrive at the facility in the morning. You will have blood 
taken, eat a meal, and then take your study tablets. Additional blood samples will be taken 7 
more times that day. You will have to stay at the facility for up to 12 hours on the day of this 
visit. On the day of the visit, we will place a small plastic tube (like a “drip”) in your arm. The 
tube is attached to a plastic needle. The tube will stay in your arm until all the blood draws are 
done. We use the tube so we do not have to stick you with a needle each time blood is drawn. 
 
 
LEFTOVER BLOOD SAMPLES 
 
After your blood is tested for the study, some samples may be left over. We call these extra 
samples. We would like to keep these extra samples and use them for other research in the 
future. You and your parent/legal guardian can decide whether to allow your extra samples to 
be kept and used for future research. You are free to say yes or no, and to change your mind at 
any time. Your decision will have no effect on your being in the study.  
 
If you say no, all extra samples will be destroyed. 
 
If you say yes, there is no limit on how long extra samples will be kept or when they will be 
used.  
 
The results of research done with your extra samples will not be given to you or your 
parent/legal guardian. 
 
 
WHAT GOOD AND BAD EFFECTS COULD HAPPEN?  
 
By taking part in this study, you will be helping test a new drug that may benefit (have good 
effects for) people with monkeypox virus. You may also have good effects from the tablets being 
tested. For example, the tablets could work well for you and help you get healthy. However, we 
do not know this for sure.  
 
The study drugs may not work well for you. They could cause bad effects. For example, they 
could make you feel sick, by causing a headache, make you throw up or feel like you need to 
throw up, or have stomach pain. We will ask you to tell your parent/legal guardian any time you 
do not feel well. You and your parent/legal guardian should also tell us if you do not feel well. 
We will ask you to come here so we can check on you and try to make you feel better. 
 

 
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Having your blood drawn may cause fainting, pain, bleeding, bruising, swelling, or infection 
where the needle goes in your arm. You may feel nervous or embarrassed when answering 
questions for the study. 
 
Another possible risk is to your privacy. For example, if you agree, you may have photographs 
of your face taken for this study. It is possible that your face may be recognizable and your 
identity may be known. All photographs taken during the study will be stored with a code instead 
of your name. You do not have to agree to have photos taken to be in this study. Other 
people could find out that you are in the study or learn other information about you. We will 
make every effort to avoid this. For example, most of the records we keep here for the study will 
be labeled with a code number (not your name). We will share information about you, including 
information that you tell us, with your parent/legal guardian. We will not share your information 
with other people unless you or your parent/legal guardian ask us to.  
 
You may be embarrassed by some of the questions we ask you about your health and your 
sexual activity (if you have sex). You may be embarrassed or upset about sharing information 
with parents/legal guardians, especially information about sexual activity (if you have sex).  
 
Other people may review the records from your study visits, including people who work at your 
study clinic, people from the government agencies that are overseeing this study, and people 
who work for the company that make the study tablets that you will take. These records will not 
include your name. Your records will have a series of numbers that are used instead of your 
name.  
 
If we learn of new information while you are on the study that may make you change your mind 
about being in the study, we will tell you this information. 
 
 
GIRLS SHOULD KNOW 
  
The study drugs used in this study might hurt you or hurt a baby if you get pregnant. You will be 
asked questions to see if you can get pregnant. If you can get pregnant and you are having sex, 
you will have a pregnancy test. If you can get pregnant, you must use birth control while you are 
participating in this study.  
  
You should not get pregnant while you are in this study. If you are doing things that might get 
you pregnant, you have to take care to keep from getting pregnant to be in this study. The study 
doctor and your parents or legal guardian will explain what you need to do. If you think you 
might be pregnant, you must tell the study doctor or the study staff right away. 
 
 
WILL I GET PAID FOR BEING IN THIS STUDY? 
 
You will get paid a small amount for study visits and study tests. The study staff at your site can 
tell you more about how much you will get paid.  
 
 

 
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WHOM TO CONTACT ABOUT THIS STUDY? 
 
You and your parent/legal guardian can contact us at any time. Please talk to your parent/legal 
guardian and to us about any questions or problems you may have.  
 
For questions about this study or a research-related injury, contact the study doctor or other 
study staff at the telephone number on the first page of this assent document. 
 
An institutional review board (IRB) is an independent committee established to help protect the 
rights of research participants. If you have any questions about your rights as a research 
participant, contact: 
• 
By mail: 
Study Subject Adviser 
Advarra IRB 
6100 Merriweather Dr., Suite 600 
Columbia, MD 21044 
• 
or call toll free:    877-992-4724 
• 
or by email:  adviser@advarra.com 
 
Please reference the following number when contacting the Study Subject Adviser: Pro00065749. 
 
 
 

 
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SIGNATURES 
 
Before deciding whether to take part in this study, make sure you have read this form or had it 
read to you. Make sure all your questions have been answered. 
 
If you decide to join this study, please sign or make your mark below. 
 
 
____________________________ 
_________________________________________ 
Participant’s Name (print) 
Participant’s Signature and Date 
 
 
____________________________ 
_________________________________________ 
Study Staff Conducting 
Study Staff’s Signature and Date 
Consent Discussion (print 
 
 
 
 
 
If you have decided to join this study, please write your initials or make your mark below to show 
your choices for your leftover samples:  
 
_________ I allow my leftover samples to be kept and used for future research 
 
 
__________ I do not allow my leftover samples to be used for any future research.  
 
 

 
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APPENDIX VII: PARTICIPANT ASSENT FORM FOR STUDY PARTICIPATION FOR 
PARTICIPANTS AGED 7 TO AGE OF MAJORITY (AOM) WHO ARE 
ENROLLED/FOLLOWED REMOTELY 
 
Sponsor / Study Title: 
  
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 Human Monkeypox Virus Disease” 
 
Protocol Number: 
 
A5418 
 
Principal Investigator: 
(Study Doctor) 
 
«PiFullName» 
 
Telephone: 
 
«IcfPhoneNumber» 
 
Address: 
«PiLocations» 
 
 
INTRODUCTION 
 
You are being asked to take part in a research study. In order for you to take part, you 
must give your permission. Your parent/legal guardian must also give permission.  
 
This form gives information about the study. Please read it or have it read to you. Ask 
any questions you may have. After we talk with you about this, if you decide to take part 
in the study, you will write your decisions at the end of this form. You will be offered a 
copy to keep. 
 
 
ABOUT THE STUDY 
 
The study is testing a drug called, tecovirimat, which is being tested to see if it works to 
treat human monkeypox virus infection and if the study drug is safe in people. 
 
Participants in the study will take the tablets two or three times every day for two weeks 
and be checked by study nurses and study doctors to see if the tablets cause bad 
effects.  
 
 
YOUR RIGHTS  
 
It is up to you and your parent/legal guardian to decide if you will take part in this study. 
You can say yes or no. If you say yes now, you can change your mind later. Your 
decision will have no effect on your medical care. 
 

 
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You do not need to join this study to receive medical care but right now, there is no 
proven way to treat human monkeypox virus. There may be other treatments to help you 
feel better and you can receive that treatment outside the study. The study drug may be 
available outside this study. You may also qualify for other studies. Please ask any 
questions you may have about these options.  
 
 
WHAT HAPPENS IN THE STUDY? 
 
If you decide to take part in the study, we will first do an assessment to see if you qualify 
to be in the study.  
 
While in the study, you will take the tablets being tested. We will remind you and your 
parent/legal guardian that you should take the tablets two or three times every day, for 
two weeks.  
 
You will have at least 6 study visits. These visits will take place via telemedicine (a 
system where you and the study doctors can see and hear each other over video). 
 
At these visits, we will ask you and your parent/legal guardian about your health, and the 
medicines you take. We will ask questions about the tablets being tested. We will 
examine your skin.  
 
Besides these visits, we will also ask you to collect information at home. For example, 
you and your parent/legal guardian will be asked to fill out a study diary. You will also be 
asked to take swabs from the monkeypox sores that you have and mail them to the 
testing laboratory.  
 
We will tell you as much information as you want about the tablets being tested and what 
will happen when you come here for visits. Please ask any questions you may have. 
Please tell us if anything bothers you or scares you. We will do our best to explain the 
study and help you feel more comfortable.  
 
 
HOW LONG WILL I BE IN THIS STUDY? 
 
You will be in this study for about 2 months. 
 
 
WHAT GOOD AND BAD EFFECTS COULD HAPPEN?  
 
By taking part in this study, you will be helping test a new drug that may benefit (have 
good effects for) people with monkeypox virus. You may also have good effects from the 
tablets being tested. For example, the tablets could work well for you and help you get 
healthy. However, we do not know this for sure.  
 

 
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The study drugs may not work well for you. They could cause bad effects. For example, 
they could make you feel sick, by causing a headache, make you throw up or feel like 
you need to throw up, or have stomach pain. We will ask you to tell your parent/legal 
guardian any time you do not feel well. You and your parent/legal guardian should also 
tell us if you do not feel well. We will talk to you on the phone or by telemedicine so we 
can check on you and try to make you feel better. 
 
Another possible risk is to your privacy. For example, if you agree, you may have 
photographs of your face taken for this study. It is possible that your face may be 
recognizable and your identity may be known. All photographs taken during the study 
will be stored with a code instead of your name. You do not have to agree to have photos 
taken to be in this study. Other people could find out that you are in the study or learn 
other information about you. We will make every effort to avoid this. For example, most 
of the records we keep here for the study will be labeled with a code number (not your 
name). We will share information about you, including information that you tell us, with 
your parent/legal guardian. We will not share your information with other people unless 
you or your parent/legal guardian ask us to.  
 
You may be embarrassed by some of the questions we ask you about your health and 
your sexual activity (if you have sex). You may be embarrassed or upset about sharing 
information with parents/legal guardians, especially information about sexual activity (if 
you have sex).  
 
Other people may review the records from your study visits, including people who work 
at your study clinic, people from the government agencies that are overseeing this study, 
and people who work for the company that make the study tablets that you will take. 
These records will not include your name. Your records will have a series of numbers 
that are used instead of your name.  
 
If we learn of new information while you are on the study that may make you change your 
mind about being in the study, we will tell you this information. 
 
 
GIRLS SHOULD KNOW 
  
The study drugs used in this study might hurt you or hurt a baby if you get pregnant. You 
will be asked questions to see if you can get pregnant. If you can get pregnant, you must 
use birth control while you are participating in this study.  
  
You should not get pregnant while you are in this study. If you are doing things that 
might get you pregnant, you have to take care to keep from getting pregnant to be in this 
study. The study doctor and your parents or legal guardian will explain what you need to 
do. If you think you might be pregnant, you must tell the study doctor or the study staff 
right away. 
 
 

 
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WILL I GET PAID FOR BEING IN THIS STUDY? 
 
You will get paid a small amount for study visits and study tests. The study staff at your 
site can tell you more about how much you will get paid.  
 
 
WHOM TO CONTACT ABOUT THIS STUDY? 
 
You and your parent/legal guardian can contact us at any time. Please talk to your 
parent/legal guardian and to us about any questions or problems you may have.  
 
For questions about this study or a research-related injury, contact the study doctor or 
other study staff at the telephone number on the first page of this assent document. 
 
An institutional review board (IRB) is an independent committee established to help 
protect the rights of research participants. If you have any questions about your rights as 
a research participant, contact: 
• 
By mail: 
Study Subject Adviser 
Advarra IRB 
6100 Merriweather Dr., Suite 600 
Columbia, MD 21044 
• 
or call toll free:    877-992-4724 
• 
or by email:  adviser@advarra.com 
 
Please reference the following number when contacting the Study Subject Adviser: 
Pro00065749. 
 
 
 

 
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SIGNATURES 
 
Before deciding whether to take part in this study, make sure you have read this form or 
had it read to you. Make sure all your questions have been answered. 
 
If you decide to join this study, please sign or make your mark below. 
 
 
____________________________ 
_________________________________________ 
Participant’s Name (print) 
Participant’s Signature and Date 
 
 
____________________________ 
_________________________________________ 
Study Staff Conducting 
Study Staff’s Signature and Date 
Consent Discussion (print 
 
 
 
 
 
If you have decided to join this study, please write your initials or make your mark below 
to show your choices for your leftover samples:  
 
_________ I allow my leftover samples to be kept and used for future research 
 
 
__________ I do not allow my leftover samples to be used for any future research.