Conditions: Gastroenteritis Norovirus
Keywords: Efficacy Hematopoietic Stem Cell Nitazoxanide Norovirus Prospective, Randomized, Double-Blind Study Safety Solid Organ Transplant Recipients Treatment
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 31
Healthy volunteers: no

Brief summary:
This is a phase 2 multi-center, double-blind, placebo-controlled study of the efficacy and safety of nitazoxanide for the treatment of solid organ and hematopoietic stem cell transplant recipients with symptomatic diarrhea due to Norovirus. The study involves a total of 160 Hematopoietic Stem Cell or Solid Organ transplant recipients, equal to or greater than 12 years of age with diagnosis of Norovirus who will be selected and randomly assigned (1:1) to nitazoxanide or placebo group. The study duration is 60 months and subject participation duration is 6 months. Given the safety of prolonged therapy with nitazoxanide, lack of interactions with common post-transplant medications, putative antiviral activity and prolonged duration of viral shedding we are assessing 56 doses of therapy. The longitudinal monitoring phase will provide useful information on the course of host and viral responses in subjects with chronic Norovirus infection with and without treatment. Randomization will be stratified by age group (pediatric (12 through 17 years) vs. adult (greater than or equal to 18 years)), chronicity of Norovirus-associated symptoms (acute (less than 14 days) vs. chronic (greater than or equal to 14 days)) and transplant type (solid organ (SOT)) vs. hematopoietic stem cell transplant (HSCT)). Enrolled subjects will participate in 2 phases of the study: Treatment Phase, which will include dosing with the assigned study agent for 28 days. Longitudinal Monitoring Phase which will include telephone call on Days 35, 53, 113, 173. Primary objective is 1) to assess the clinical efficacy of nitazoxanide for the management of acute and chronic Norovirus in transplant recipients.

Detailed description:
This is a phase 2 multi-center, double-blind, placebo-controlled study of the efficacy and safety of nitazoxanide for the treatment of solid organ and hematopoietic stem cell transplant recipients with symptomatic diarrhea due to Norovirus. The study involves a total of 160 Hematopoietic Stem Cell or Solid Organ transplant recipients, equal to or greater than 12 years of age with diagnosis of Norovirus who will be selected and randomly assigned (1:1) into two treatment groups: nitazoxanide or placebo. The study duration is approximately 60 months and subject participation duration is approximately 6 months. Given the safety of prolonged therapy with nitazoxanide, lack of interactions with common post-transplant medications, putative antiviral activity and prolonged duration of viral shedding we are assessing 56 doses of therapy. The longitudinal monitoring phase will provide useful information on the course of host and viral responses in subjects with chronic Norovirus infection with and without treatment. Randomization will be stratified by age group (pediatric (12 through 17 years) vs. adult (greater than or equal to 18 years)), chronicity of Norovirus-associated symptoms (acute (less than 14 days) vs. chronic (greater than or equal to 14 days)) and transplant type (solid organ (SOT)) vs. hematopoietic stem cell transplant (HSCT)). Enrolled subjects will participate in 2 phases of the study: Treatment Phase, which will include dosing with the assigned study agent for 28 days. Longitudinal Monitoring Phase which will include telephone call on Days 35, 53, 113, 173. Primary objective is 1) to assess the clinical efficacy of nitazoxanide for the management of acute and chronic Norovirus in transplant recipients. Secondary Objectives are 1) to assess the virologic efficacy of nitazoxanide and 2) to assess the safety of nitazoxanide for the management of acute and chronic Norovirus in transplant recipients.

Arms:
arm 1: 500 mg (one tablet) nitazoxanide by mouth twice daily with food for 56 consecutive doses. N=80 arm 2: Placebo (one tablet) by mouth twice daily with food for 56 consecutive doses. N=80

Interventions: intervention 1: Nitazoxanide intervention 2: Placebo
Intervention descriptions: intervention 1: One 500 mg tablet twice daily with food for 56 consecutive doses intervention 2: One tablet twice daily with food for 56 consecutive doses

Protocol document:
Prot_000.pdf: 
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A Phase 2 Multi-Center, Prospective, Randomized, Double-Blind 
Study to Assess the Clinical and Antiviral Efficacy and Safety of 
Nitazoxanide for the Treatment of Norovirus in Hematopoietic Stem 
Cell and Solid Organ Transplant Recipients 
 
DMID Protocol Number: 16-0092 
DMID Funding Mechanism: Contract # HHSN272201600016C 
Pharmaceutical Support Provided by: Romark, L.C. 
Other Identifying Numbers: NIAID-DMID-NIH-AI-2014028 
IND Sponsor: National Institute of Allergy and Infectious Diseases, Division of Microbiology 
and Infectious Diseases 
Lead Principal Investigator: Michael G Ison, MD, MS  
DMID Clinical Protocol Manager: Gabriele Feolo, RN, MSN 
DMID Scientific Lead: Rodolfo M. Alarcón, PhD 
DMID Medical Officer: John Beigel, MD  
DMID Medical Monitor:  Jorge  Mejia-Galvis,  M.D.  [C] 
Version Number: 4.0 
21 January, 2020 
 


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STATEMENT OF COMPLIANCE 
The study trial will be carried out in accordance with Good Clinical Practice (GCP) and as 
required by the following: 
• 
United States Code of Federal Regulations (CFR) 45 CFR Part 46: Protection of Human 
Subjects 
• 
Food and Drug Administration (FDA) Regulations, as applicable: 21 CFR Part 50 
(Protection of Human Subjects), 21 CFR Part 54 (Financial Disclosure by Clinical 
Investigators), 21 CFR Part 56 (Institutional Review Boards), 21 CFR Part 11, and 21 
CFR Part 312 (Investigational New Drug Application), 21 CFR 812 (Investigational 
Device Exemptions) 
• 
International Conference on Harmonisation: Good Clinical Practice (ICH E6); 62 Federal 
Register 25691 (1997); and future revisions 
• 
Belmont Report: Ethical Principles and Guidelines for the Protection of Human Subjects 
of Research, Report of the National Commission for the Protection of Human Subjects of 
Biomedical and Behavioral Research 
• 
National Institutes of Health (NIH) Office of Extramural Research, Research Involving 
Human Subjects, as applicable 
• 
National Institute of Allergy and Infectious Diseases (NIAID) Clinical Terms of Award, 
as applicable 
• 
Applicable Federal, State, and Local Regulations and Guidance 
All key personnel (all individuals responsible for the design and conduct of this study) have 
completed Human Subjects Protection Training. 
 


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SIGNATURE PAGE 
The signature below provides the necessary assurance that this trial will be conducted according 
to all stipulations of the protocol, including all statements regarding confidentiality, and 
according to local legal and regulatory requirements and applicable US federal regulations and 
ICH E6 Good Clinical Practice (GCP) guidelines. 
 
I agree to conduct the study in compliance with GCP and applicable regulatory requirements. 
 
I agree to conduct the study in accordance with the current protocol and will not make changes to 
the protocol without obtaining the sponsor’s approval and IRB/IEC approval, except when 
necessary to protect the safety, rights, or welfare of subjects. 
 
Site Investigator Signature: 
 
Signed: 
 
Date: 
 
 
 
 
 
 


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TABLE OF CONTENTS 
Statement of Compliance ..................................................................................................................... 2 
Signature Page ...................................................................................................................................... 3 
Table of Contents .................................................................................................................................. 4 
LIST OF TABLES................................................................................................................................ 6 
LIST OF FIGURES .............................................................................................................................. 7 
List of Abbreviations ............................................................................................................................ 9 
Protocol Summary .............................................................................................................................. 11 
1 
Key Roles ................................................................................................................................... 18 
2 
Background Information and Scientific Rationale .................................................................. 25 
2.1 
Background Information .............................................................................................. 25 
2.2 
Rationale ........................................................................................................................ 37 
2.3 
Potential Risks and Benefits......................................................................................... 37 
2.3.1 Potential Risks .................................................................................................. 37 
2.3.2 Known Potential Benefits ................................................................................ 39 
3 
Objectives .................................................................................................................................. 40 
3.1 
Study Objectives ........................................................................................................... 40 
3.2 
Study Outcome Measures ............................................................................................. 40 
3.2.1 Primary Outcome Measures ............................................................................ 40 
3.2.2 Secondary Outcome Measures ........................................................................ 41 
3.2.3 Exploratory Outcome Measures ...................................................................... 41 
4 
Study Design.............................................................................................................................. 44 
5 
Study Enrollment and Withdrawal ........................................................................................... 45 
5.1 
Subject Inclusion Criteria ............................................................................................. 45 
5.2 
Subject Exclusion Criteria ............................................................................................ 46 
5.3 
Treatment Assignment Procedures .............................................................................. 46 
5.3.1 Randomization Procedures .............................................................................. 46 
5.3.2 Masking Procedures ......................................................................................... 47 
5.3.3 Reasons for Withdrawal and Discontinuation of Study Product 
Administration .................................................................................................. 48 
5.3.4 Handling of Withdrawals ................................................................................. 49 
5.3.5 Termination of Study ....................................................................................... 50 
6 
Study Intervention/Investigational Product ............................................................................. 51 
6.1 
Study Product Description ........................................................................................... 51 
6.1.1 Acquisition ........................................................................................................ 51 
6.1.2 Formulation, Packaging, and Labeling ........................................................... 51 
6.1.3 Product Storage and Stability .......................................................................... 52 


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6.2 
Dosage, Preparation and Administration of Study Intervention/Investigational 
Product ........................................................................................................................... 53 
         6.3       Modifiction of Study Intervention/Investigational Product for a Participant…...…53 
6.4 
Accountability Procedures for the Study Intervention/Investigational Product(s) ... 53 
6.5 
Assessment of Subject Compliance with Study Intervention/Investigational 
Product ........................................................................................................................... 54 
6.6 
Concomitant Medications/Treatments ......................................................................... 54 
7      Study Schedule……………………………………………...………………………………56 
7.1 
Screening/Baseline/Treatment Phase .......................................................................... 57 
7.2 
Follow-up ...................................................................................................................... 62 
7.3 
Final Study Visit ........................................................................................................... 63 
7.4 
Early Termination Visit ................................................................................................ 63 
7.5 
Unscheduled Visit ......................................................................................................... 63 
8 
Study Procedures/Evaluations .................................................................................................. 64 
8.1 
Clinical Evaluations ...................................................................................................... 64 
8.2 
Laboratory Evaluations ................................................................................................ 64 
8.2.1 Clinical Laboratory Evaluations ...................................................................... 64 
8.2.2 Special Assays or Procedures .......................................................................... 67 
8.2.3 Specimen Preparation, Handling, and Shipping ............................................. 70 
9 
Assessment of Safety ................................................................................................................ 73 
9.1 
Specification of Safety Parameters .............................................................................. 73 
9.2 
Methods and Timing for Assessing, Recording, and Analyzing Safety 
Parameters ..................................................................................................................... 73 
9.2.1 Adverse Events ................................................................................................. 73 
9.2.2 Serious Adverse Events ................................................................................... 75 
9.3 
Reporting Procedures ................................................................................................... 77 
9.3.1 Serious Adverse Events ................................................................................... 77 
9.3.2 Regulatory Reporting for Studies Conducted Under DMID-Sponsored 
IND .................................................................................................................... 78 
9.3.3 Reporting of Pregnancy ................................................................................... 78 
9.4 
Type and Duration of Follow-up of Subjects after Adverse Events .......................... 79 
9.5 
Halting Rules ................................................................................................................. 79 
9.6 
Safety Oversight (ISM plus SMC or DSMB) ............................................................. 80 
9.6.1 Independent Safety Monitor ............................................................................ 80 
9.6.2 Data and Safety Monitoring Board (DSMB) .................................................. 80 
10 
Clinical Monitoring ................................................................................................................... 82 
10.1 
Site Monitoring Plan ..................................................................................................... 82 
11 
Statistical Considerations .......................................................................................................... 83 


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11.1 
Study Hypotheses ......................................................................................................... 83 
11.2 
Sample Size Considerations ......................................................................................... 83 
11.3 
Planned Interim Analyses ............................................................................................. 84 
11.3.1 Safety Review ................................................................................................... 84 
11.3.2 Efficacy Review ............................................................................................... 84 
The DSMB will review available clinical and virologic efficacy data, however no 
formal hypothesis testing is planned. .......................................................................... 84 
11.4 
Final Analysis Plan ....................................................................................................... 84 
11.4.1 General Principles ............................................................................................ 84 
11.4.2 Analysis Populations ........................................................................................ 84 
                     11.4.3  Efficay Analysis……………………………………………………………85 
11.4.4 Safety Analyses ................................................................................................ 87 
11.4.5 Exploratory Analyses ....................................................................................... 87 
12 
Source Documents and Access to Source Data/Documents ................................................... 93 
13 
Quality Control and Quality Assurance ................................................................................... 94 
14 
Ethics/Protection of Human Subjects....................................................................................... 95 
14.1 
Ethical Standard ............................................................................................................ 95 
14.2 
Institutional Review Board........................................................................................... 95 
14.3 
Informed Consent Process ............................................................................................ 96 
14.3.1 Informed Consent/Assent Process (in Case of a Minor) ................................ 97 
14.4 
Exclusion of Women, Minorities, and Children (Special Populations) .................... 98 
14.5 
Subject Confidentiality ................................................................................................. 98 
14.6 
Study Discontinuation .................................................................................................. 99 
14.7 
Costs, Subject Compensation and Research Related Injuries There is no cost to 
subjects for taking part in this trial. ........................................................................... 100 
15 
Data Handling and Record Keeping ...................................................................................... 101 
15.1 
Data Management Responsibilities ........................................................................... 101 
15.2 
Data Capture Methods ................................................................................................ 101 
15.3 
Types of Data .............................................................................................................. 101 
15.4 
Timing/Reports ........................................................................................................... 102 
15.5 
Study Records Retention ............................................................................................ 102 
15.6 
Protocol Deviations .................................................................................................... 102 
16 
Publication Policy.................................................................................................................... 103 
17 
Literature References .............................................................................................................. 104 
18 
Appendix A: Schedule of Events ................................................................................................ 112 
         Appendix B: Laboratory Reference Ranges and Toxicity Grading…………………..………....…115 
         Appendix C: Patient Diary Component……………………...……………………..…………...…117 
LIST OF TABLES 


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Table 1 
Cause of Diarrhea in Hospitalized SOT Patients at a Single Center…………...………………..27 
 
Table 2 
Approved and Experimental Therapies with Norovirus Activity …………………...……….….29  
 
Table 3 
Plasma Pharmacokinetic Values Following a Single Oral Dose of Nitazoxanide……....……….30 
 
Table 4 
Activity of Nitazoxanide and Tizoxanide against Enteric Viruses in Cell Culture……..……….33 
 
Table 5 
Protocol PRO Completion Guide……………………………………………………………..….64 
 
Table 6 
Specimen Collection, Preparation, Processing and Storage…..………….…..…………….…....71 
 
 
 
 
 
 
 
 
 
 
 
 
LIST OF FIGURES 


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Figure 1 
Norovirus Capsid & Genome 
(3)………………………………..………………………………………………………….….25 
 
Figure 2 
HBGA Biosynthesis 
(4)…………………………………………………………………………………………..…..25 
 
Figure 3 
Nitazoxanide Metabolism………………………..……………….…...………….……….…...32 
 
 
 
 


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LIST OF ABBREVIATIONS 
AE 
Adverse Event/Adverse Experience 
AIDS 
Acquired Immune Deficiency Syndrome 
ALC 
Absolute Lymphocyte Count 
BID 
Twice Daily  
CBC 
Complete Blood Count 
CFR 
Code of Federal Regulations 
CKD 
Chronic Kidney Disease  
COR 
Contracting Officer’s Representative  
CRF 
Case Report Form 
DHHS 
Department of Health and Human Services 
DMID 
Division of Microbiology and Infectious Diseases, NIAID, NIH, DHHS 
DSMB 
Data and Safety Monitoring Board 
eCRF 
Electronic Case Report Form 
EIA 
Enzyme immunoassay 
FDA 
Food and Drug Administration 
FWA 
Federal Wide Assurance 
GCP 
Good Clinical Practice 
GVHD 
Graft Versus Host Disease  
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
Human Immunodeficiency Virus  
HSCT 
Hematopoietic Stem Cell Transplantation 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
ICMJE 
International Committee of Medical Journal Editors 
ICU 
Intensive Care Unit 
IND 
Investigational New Drug Application 
IRB 
Institutional Review Board 
JAMA 
Journal of the American Medical Association 
MOP 
Manual of Procedures 
N 
Number (typically refers to subjects) 
NEJM 
New England Journal of Medicine 
NIAID 
National Institute of Allergy and Infectious Diseases 
NIH 
National Institutes of Health 
NUCTC 
Northwestern University Comprehensive Transplant Center  
OCRA 
Office of Clinical Research Affairs, DMID, NIAID, NIH, DHHS 


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OHRP 
Office for Human Research Protections 
OHSR 
Office for Human Subjects Research 
ORA 
Office of Regulatory Affairs, DMID, NIAID, NIH, DHHS 
PHI 
Protected Health Information 
PI 
Principal Investigator 
PK 
Pharmacokinetics 
PRO 
Patient Reported Outcomes  
QA 
Quality Assurance 
QC 
Quality Control 
QOL 
Quality of Life 
RT-PCR 
Reverse Transcription Polymerase Chain Reaction 
SAE 
Serious Adverse Event/Serious Adverse Experience 
SDCC 
Statistical Data and Coordinating Center 
SOP 
Standard Operating Procedure 
SOT 
Solid Organ Transplant 
UGI 
Upper Gastro Intestinal  
UNOS 
United Network for Organ Sharing  
US 
United States 
WHO 
World Health Organization 
 


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PROTOCOL SUMMARY 
Title: 
A Phase 2 Multi-Center, Prospective, Randomized, Double-
Blind Study to Assess the Clinical and Antiviral Efficacy and 
Safety of Nitazoxanide for the Treatment of Norovirus in 
Hematopoietic Stem Cell and Solid Organ Transplant Recipients 
 
Phase: 
Phase 2 
Population: 
Sample Size: 160 male or female Hematopoietic Stem Cell or 
Solid Organ transplant recipients, equal to or greater than 12 
years of age with diagnosis of Norovirus. 
Number of Sites: 
12 
Study Duration: 
Approximately 60 months 
Subject Participation 
Duration: 
Approximately 6 months 
Description of Agent or 
Intervention: 
1. Nitazoxanide Arm: All subjects age ≥ 12 years:  500 mg (one 
tablet) Nitazoxanide by mouth twice daily with food for 56 
consecutive doses. 
2. Placebo Arm: All subjects age ≥ 12 years:  Placebo (one 
tablet) by mouth twice daily with food for 56 consecutive 
doses  
 
Objectives: 
 
Primary Objective:   
1. To assess the clinical efficacy of nitazoxanide for the 
management of acute and chronic Norovirus in transplant 
recipients. 
Secondary Objectives: 
1. To assess the virologic efficacy of nitazoxanide. 
2. To assess the safety of nitazoxanide for the management of 
acute and chronic Norovirus in transplant recipients. 
 
Exploratory Objectives: 
1. To assess initial clinical improvement in Norovirus Disease 
through 28 and 180 days.  


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2. To assess markers of virologic improvement of Norovirus 
Disease through 28 and180 days. 
3. To assess the contribution of immunologic response to 
Norovirus to the clinical course of disease in treated and 
untreated subjects. 
4. To define the pharmacokinetics and dose response 
relationships of nitazoxanide. 
5. To define the natural history of Norovirus in nitazoxanide 
treated and untreated subjects. 
 
Outcome Measures 
Primary Outcome: 
1. Time from randomization until initial clinical resolution of 
Norovirus symptoms for at least 48 hours through Day 180.  
Clinical resolution will be assessed from the daily diary by 
the subject and will be defined as cessation of vomiting and 
no stools classified by the Bristol Stool Chart as diarrhea 
(Type 6 or 7). 
Secondary Outcomes: 
Virologic Efficacy 
1. Time from the randomization to first negative viral load 
through 180 days. 
2. The change in viral titer between Day 1 and 180. 
Safety 
3. Incidence of unsolicited non-serious adverse events (see 
section 9 for details) through 60 days. 
4. Incidence of laboratory adverse events (WBC, Hemoglobin, 
Platelet count, Creatinine, Alkaline Phosphatase, ALT, AST, 
BUN and Bilirubin) through 60 days. 
5. Incidence of protocol-specified serious adverse events (see 
section 9 for details) through 60 days. 
6. Incidence of Hospitalization through 60 days.  
Exploratory Outcomes: 
Clinical Improvement: 
1. Time from randomization to initial clinical improvement in 
Norovirus disease through 28 and 180 days for at least 48 
hours, as defined by: 
a. 50% reduction in number of episodes of vomiting 
and, 
 


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b. Improvement in PO intake, as judged by the subjects 
and, 
c. 50% reduction in the number of episodes of diarrhea 
as classified by the subject by the Bristol Stool Chart 
as type 6 or 7 bowel movements, 
2. Time from randomization to initial cessation of vomiting 
through Day 180 (recurrent vomiting will be considered 
disease recurrence unless determined to be due to another 
etiology [i.e. GVHD]). 
3. Time from randomization to subject report of no loss of 
appetite that is maintained for 48 hours through Day180 
(measure will be first time that the subject reports that they 
have no “loss of appetite” on their daily diary).  
4. Time from randomization to initial cessation of diarrhea 
through Day 180 classified by the Bristol Stool Chart as type 
6 or 7 bowel movements (recurrent diarrhea will be 
considered disease recurrence unless determined to be due to 
another etiology [i.e. GVHD]). 
5. Time from randomization to 50% reduction in the amount of 
antimotility agents utilized by the subject through Day 180. 
6. Number of days of diarrhea through Day 28 and 180. 
7. Number of stools classified by the Bristol Stool Chart as type 
6 or 7 bowel movements through Day 28. 
8. Number of days of IV hydration or total parenteral nutrition 
(TPN) therapy through Day 28. 
9. Total number of days of hospitalization through Day 28 and 
180. 
10. Change in patient-reported quality of life as measured by 
EuroQOL-5 (global) and IBSQOL (diarrhea specific) [adult] 
or Euro QOL-5 Peds (global) and PedsQL GI Module 
PedsQL [children] from baseline to Day 180. 
11. Change in patient-reported physical function as measured by 
the NIH PROMIS Physical Function (Adult) Pediatric Global 
Health (Peds) from baseline to Day 180. 
12. Change in patient-reported emotional distress as measured by 
the NIH PROMIS Depression, Anxiety, Fatigue (Adult and 
Peds) from baseline to Day 180. 


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13. Change in patient-reported gastrointestinal symptoms as 
measured by the NIH PROMIS GI (Adult and Peds) 
symptoms (6 of 8 subscales) from baseline to Day 180. 
14. The effect of co-pathogens, as determined by the BioFire 
stool pathogen screen, on the primary outcome measure. 
15. Time from randomization until initial clinical resolution of 
Norovirus symptoms for at least 48 hours through Day 
180.  Clinical resolution will be assessed from the daily diary 
by the subject and will be defined as cessation of vomiting 
and no stools classified by the Bristol Stool Chart as diarrhea 
(Type 6 or 7) from the total population compared to the 
subgroup of subjects who do not report chromaturia 
(discoloration of urine) based on unsolicited self-reporting.   
16. Incidence of unsolicited non-serious adverse events (see 
section 9 for details) through 60 days, laboratory adverse 
events (WBC, Hemoglobin, Platelet count, Creatinine, 
Alkaline Phosphatase, ALT, AST, BUN and Bilirubin) 
through 60 days, protocol-specified serious adverse events 
(see section 9 for details) through 60 days, 
and Hospitalization through 60 days from the total 
population compared to the subgroup of subjects who do not 
report chromaturia (discoloration of urine) based on 
unsolicited self-reporting. 
 
Virologic Improvement: 
17. Time to ≥ 1 log reduction in stool Norovirus genome copies. 
18. Change in quantitative Norovirus load in the stool between 
Day 1 and Days 7, 14, 21, 28, 60, 120, and 180. 
19. Change in Norovirus sequence from Day 1 to Days 28 and 
60. 
20. The effect of co-pathogens, as determined by the BioFire 
stool pathogen screen, on the time from the randomization to 
first negative viral load through 180 days. 
21. Time from the randomization to first negative viral load 
through 180 days and the change in viral titer between Day 1 
and 180 from the total population compared to the subgroup 
of subjects who do not report chromaturia (discoloration of 
urine) based on unsolicited self-reporting. 
 


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Immunologic Response: 
22. Change in Norovirus-specific serum and stool IgA, IgM and 
IgG between Day 1 and Days 28 and 60 (stool only). 
23. Association between change in total lymphocyte count and T 
cell subsets at Day 1 and 180 and clinical resolution of 
Norovirus symptoms. 
24. Association between change in total lymphocyte count and T 
cell subsets at Day 1 and 180 and undetectable quantitative 
Norovirus PCR. 
25. Association between change in Norovirus-specific serum and 
stool IgA, IgM and IgG from Day 1 to Days 28 and 60 (stool 
only) and clinical resolution of symptoms. 
26. Association between change in Norovirus-specific serum and 
stool IgA, IgM and IgG from Day 1 to Days 28 and 60 (stool 
only) and undetectable quantitative Norovirus PCR. 
 
Pharmacokinetics and Dose Response: 
27. For subjects consenting to PK draws, concentrations of 
nitazoxanide metabolites (tizoxanide and tizoxanide 
glucuronide) 1 to 4 hours after the first dose on Day 7 and 10 
minutes before the second dose on Day 21. 
 
 
 
Natural History of Disease 
28. Time to Allograft rejection as per each center team.  
29. Time to allograft loss as reported to UNOS.  
30. Time to death. 
31. Time to withdrawal from the study because of intolerance or 
due to drug-related adverse events. 
32. Correlation of secretor status as defined by phenotype and 
genotype, separately, and clinical resolution of Norovirus as 
defined by the primary endpoint. 
 
Description of Study Design: 
 
A total of 160 subjects ≥ 12 years of age will be selected 
according to the inclusion and exclusion criteria.  Upon 
enrollment in the study, subjects will be randomized into two 
treatment groups:  active nitazoxanide and placebo.  
Randomization will be stratified by age group (pediatric (12-17 
 


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years) vs. adult ≥ 18 years), chronicity of Norovirus-associated 
symptoms (acute (<14 days) vs. chronic (≥14 days)) and 
transplant type (solid organ (SOT) vs. hematopoietic stem cell 
transplant (HSCT)).  Enrolled subjects will participate in 2 
phases of the study:  Treatment Phase, which will include dosing 
with the assigned study agent for 28 days and study visits on 
study Day 1, 7 ± 3 days, 14 ± 3 days, 21 ± 3 days, and 28 + 3 
days; Longitudinal Monitoring Phase which will include 
telephone call on Days 35 ± 3 days, 53 ± 7 days, 113 ± 7 days, 
173 ± 7 days.  study visits on study Day 60 ± 14 days, 120 ± 14 
days and 180 ± 14 days.  If symptoms recur after completion of 
the Treatment Phase, subjects can resume any therapy excluding 
nitazoxanide at the discretion of the principal investigator or 
his/her designee. Nitazoxanide can be used after Day 28 if the 
local PI attests that it is medically urgent to use the nitazoxanide 
because the patient is experiencing severe or life-threatening 
disease.  Although nitazoxanide can be used if it is felt critical to 
the subjects care, its use should be avoided until Day 180 
whenever felt to be safe to do so by the local PI. Additional stool 
specimens should be collected prior to initiation of therapy for 
testing in the central lab. 
 
Estimated Time to Complete 
Enrollment: 
60 months.  
 
 
 
 
 
 
 
 
 
 
 
Schematic of Study Design: 
 


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1 
KEY ROLES 
Individuals: 
 
Principal Investigator:   
 
 
 
 
 
DMID Clinical Project 
Manager: 
 
Michael G Ison, MD MS  
Professor, Divisions of Infectious Diseases and Organ 
Transplantation 
Northwestern University Feinberg School of Medicine 
Address: 676 N. St Clair Street, 19th Floor, 
Chicago, IL 60611 
Phone#: (312) 695-4186 
mgison@northwestern.edu 
 
 
Gabriele Feolo, RN, MSN 
EHDB/DMID/NIAID/NIH 
5601 Fishers Lane, 
Room: 8F56 
Bethesda, MD 20892- 9825 
(240) 292-4245 
gfeolo@niaid.nih.gov 
 
DMID Scientific Lead:   
 
 
 
 
 
 
 
DMID Medical Officer:  
 
 
 
 
 
 
 
DMID Medical Monitor:  
 
Rodolfo M. Alarcón, PhD 
EHDB/DMID/NIAID/NIH 
5601 Fishers Lane, 
Room #8F45 
Bethesda, MD 20895- 9825 
(240) 292-0871 
rodolfo.alarcon@nih.gov 
 
John Beigel, MD 
Associate Director for Clinical Research 
Division of Microbiology and Infectious Diseases 
National Institute of Allergy and Infectious Diseases (NIAID) 
Phone: (1) 301-451-9881 
 jbeigel@niaid.nih.gov 
 
 
 
Jorge  Mejia-Galvis,  M.D.  [C] 
OCRA/DMID/NIAID/NIH 
 


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5601 Fishers Lane, 7E56  
Rockville, MD 20892-9826 
Phone: 240-292-4713 
 Jorge.mejia-galvis@nih.gov 
 
 
 
 


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Institutions: 
PARTICIPATING SITES  
Cincinnati Children’s Hospital Medical Center 
Address: Cincinnati Children’s Hospital Medical Center 
3333 Burnet Avenue  
ML 7017 
Cincinnati, Ohio 45229-3039 
Site PI: Lara Danziger-Isakov, MD, MPH 
Phone#: 513-636-4578 
Email: Lara.Danziger-Isakov@cchmc.org 
 
Johns Hopkins University 
Address: School of Medicine/Division of Infectious Diseases  
The Johns Hopkins University  
1830 E. Monument St./Room 449  
Baltimore, MD 21205 
Site PI: Robin Avery, MD 
Phone#: 443-287-4694 
Email: ravery4@jhmi.edu 
 
University of Kansas 
Address: University of Kansas Medical Center Research   
Institute, Inc.  3901 Rainbow Blvd, MSN 1039, Kansas City, 
KS 66103-2937 
Site PI: Lisa Clough, MD 
Phone#:913-588-0857 
Email: clough@kumc.edu 
 
University of Michigan 
Address: University of Michigan 
Int Med-Infectious Diseases 
3119 TC, 1500 E Med Ctr Dr 
Ann Arbor, MI 48109-5378 
Site PI: Daniel Kaul, MD 
Phone#: 734-647-5899 
Email: kauld@umich.edu 
 
University of Nebraska 
Address: University of Nebraska Medical Center 
985400 Nebraska Medical Center, Omaha, NE 68198-5400 
Site PI: Diane Florescu, MD 
Phone#: 402-559-8650 
Email: dflorescu@unmc.edu 
 
University of Texas Southwestern Medical Center 


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Address: Division of Infectious Diseases 
5323 Harry Hines Blvd., Suite Y7.312C 
Dallas, TX 75390-9113 
Site PI: Pearlie Chong, MD  
Phone#: 214-648-6703 
Email: Pearlie.Chong@UTSouthwestern.edu 
 
University of Pittsburgh 
Address: Division of Infectious Diseases 
Scaife Hall, Suite 871 
3550 Terrace Street 
Pittsburgh, PA  15261-1816 
Site PI: Minh-Hong Nguyen, MD 
Phone#: 412-383-5193 
Email: mhn5@pitt.edu 
 
Children’s Hospital of Pittsburgh of UPMC 
Address: University of Pittsburgh, Pediatrics 
Children’s Hospital of Pittsburgh of UPMC 
4401 Penn Avenue, Faculty Pavilion 6135 
Pittsburgh PA 15224 
Site Co-PI: Michael Green MD, MPH 
Phone#:412-692-6111 
Email: Michael.green@chp.edu 
 
Address: 4401 Penn Avenue 
AOB Suite 2200 
Pittsburgh PA 15224 
Site Co PI: Marian G Michaels MD, MPH 
Phone #: 412-692-6768 
 
E-mail:  marian.michaels@chp.edu 
 
University of Washington 
Address: University of Washington 
1959 NE Pacific St. 
Box 356174 
Seattle, WA 98195 
Site PI:  Cynthia Fisher, MD, MPH 
Phone#: 206-598-9149 
Email: celaine@uw.edu 
 
Fred Hutchinson Cancer Research Center  
Address: Fred Hutchinson Cancer Research Center 


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1100 Fairview Ave, N, E4-100 
Seattle, WA 98109. 
Site PI: Steven Pergam, MD, MPH 
Phone#: (206) 667-7538 
Email: spergam@fredhutch.org 
 
 
COLLABORATORS  
Mount Sinai Hospital 
Address: Icahn School of Medicine at Mount Sinai 
CAM Building 
17 E. 102nd Street, 5th floor 
New York, NY 10029  
Collaborator: Laurie Keefer, PhD 
Phone#: 646-537-8921 
Email: laurie.keefer@mssm.edu 
 
Protocol Manager:  
Address: 676 N. St. Clair, 19-073 
Chicago, IL 60611 
Name: Susan Brietigam, CCRC, CAPM 
Phone#:312-694-0259 
Email: s-brietigam@northwestern.edu 
 
Statistician:  
Address: 680 N. Lake Shore Drive, Suite 1400 
Chicago, IL 60611 
Name: Lihui Zhao, PhD 
Phone#:312-503-7230 
Email: Lihui.zhao@northwestern.edu 
 
NU Institutional Review Board Contact Information:  
Arthur Rubloff Building, 7th Floor 
750 N. Lake Shore Dr. 
Chicago, IL 60611 
Phone: (312) 503-9338 
irb@northwestern.edu 
Safety and 
Pharmacovigilance 
Contractor  
 
DMID Pharmacovigilance Group 
Clinical Research Operations and Management Support 
(CROMS) 


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6500 Rock Spring Dr., Suite 650 
Bethesda, MD 20817 
SAE Hot Line: 1-800-537-9979 (US) 
SAE Fax: 800-275-7619 (US) 
SAE Email: PVG@dmidcroms.com 
 
Data Coordinating Center: 
 
The Emmes Company, LLC 
401 N. Washington Street, Suite 700 
Rockville, MD 20850 
Group E-mail: enterics@emmes.com 
 
Project Manager: Carey Rodeheffer Petrie, PhD  
301-251-1161 x10803 
cpetrie@emmes.com 
 
Protocol Statistician: Jill El-Khorazaty 
301-251-1161 x12873 
jelkhorazaty@emmes.com 
 
 
Laboratories  
Cincinnati Children’s Hospital Medical Center 
Address: Division of Infectious Diseases, S8.537 
Building S, Receiving Dock 1 
240 Albert Sabin Way 
Cincinnati, OH 45229 
Collaborator: Xi Jason Jian, PhD 
Phone#: 513-636-0119 
Email: jason.jiang@cchmc.org 
 
Cincinnati Children’s Hospital Medical Center 
Address: Diagnostic Infectious Diseases Testing Laboratory 
Department of Pathology and Laboratory Medicine 
3333 Burnet Avenue, B4.252, MLC 1010 
Cincinnati, OH 45229-3026 
Collaborator: Joel Mortensen, PhD 
Phone#: 513-636-5310 
Email: joel.mortensen@cchmc.org 
 


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Industry Representative 
Romark, L.C. 
Addresses: 3000 Bayport Drive, Suite 200 
Tampa, Florida 33607 
Industry Contact: Mathew Bardin, PharmD, BCPS 
Phone#: (813) 282-8544 
Email: Matthew.Bardin@romark.com 
 
 


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2 
BACKGROUND INFORMATION AND SCIENTIFIC 
RATIONALE 
2.1 
Background Information 
Norovirus 
Gastroenteritis is defined as a self-limiting diarrheal illness that is often accompanied by nausea, 
vomiting, fever, or abdominal pain.  In the United States, Norovirus is the single most common 
cause of acute gastroenteritis that leads to medical evaluation in adults, and the second most 
common cause of severe diarrhea in infants and young children.(3, 5) In the US, Norovirus is 
estimated to be responsible for 19–21 million episodes of gastroenteritis and 56,000–71,000 
hospitalizations annually.(1) Increasingly, Norovirus is recognized as a common cause of chronic 
gastroenteritis in immunocompromised patients. Prolonged diarrhea can lead to dehydration, 
allograft dysfunction, renal insufficiency and rarely death in these patients.(3, 6-11) 
Noroviruses are 
small, non-enveloped, 
single-stranded RNA 
viruses that are 
members of the 
Caliciviridae (Figure 
1). (3, 12)  Of the five 
genogroups (GI-GV), 
GI, GII and GIV are 
known to be human 
pathogens, although 
most are caused by GI 
and GII, which can be 
further classified into 
30 unique genotypes.  
GII.4 has been 
recognized as the 
most common cause 
of outbreaks of 
Norovirus infections 
globally. (13, 14) 
Norovirus is highly 
contagious as transmission is highly efficient with a median infectious dose of 18 viruses. There 
is generally high titers of virus within stool (105 to 1010 genome copies per gram of feces); (15, 16)  
Figure 1:Norovirus Capsid & Genome (3) 


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therefore contact with infected feces and vomit, fecally-contaminated food, water and surfaces 
are common sources of infection.(17, 18, 15, 16)Norovirus is also highly stable with retained 
infectivity under environmental conditions that would generally inactivate other viruses, 
including chlorine at concentrations used in drinking water.(19, 20) 
 
The Norovirus genome encodes 2 major structural proteins (VP1 and VP2) and 7 nonstructural 
proteins responsible for viral replication.  The viral VP1 protruding 2 (P2) domain binds 
saccharides of the human ABO, secretor (H), and Lewis families histo-blood group antigens to 
facilitate viral entry into the 
epithelial cells of the 
gastrointestinal tract.(4, 20, 21)  
Carbohydrate antigen 
expression on gastrointestinal 
epithelial cells are controlled 
by enzymes encoded by the 
ABO, FUT2 and FUT3 
alleles in humans.  Only 70-
80% of individuals have a 
functional copy of the FUT2 
(“secretor”) gene required for 
gut HBGA expression 
(Figure 2); these individuals 
are known as “secretors.” 
“Non-secretors” have 
inactivated FUT2 alleles 
typically due to homozygous G428A nonsense mutation or A385T missense mutation.  Non-
secretors appear to have reduced susceptibility or outright resistance to symptomatic infection. 
(22-25) Further, in vitro work suggests that A and B blood group blood type B patients have 
reduced susceptibility to infection.(26) However, it remains unclear if these proteins serve only as 
attachment ligands on host cells or are functional receptors that enable entry into the cells. 
   
While significant progress has been made in understanding host factors that modulate the risk of 
developing Norovirus disease, our understanding of the immune response to Noroviruses 
remains limited.(20) Adaptive immunity appears to play an incomplete role in the prevention and 
control of Norovirus infections.  There appears to be short and long-term immunity to infection 
based on data from challenge studies. Re-challenge with the same serotype within 6-14 weeks of 
initial infection generally prevents recurrent infections but not infection with heterotypic 
viruses.(27) Long-term immunity is more complex and re-challenge with the same virus 27-42 
Figure 2. HBGA Biosynthesis (4)
Figure 2: HBGA Biosynthesis (4) 


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months results in variable resistance that does not correlate with seroconversion.  In fact, data 
suggests that patients without pre-challenge antibodies are less likely to develop symptoms. 
Local mucosal IgA responses appear to be protective.  More recently, HBGA carbohydrate-
blocking antibodies that block Norovirus VLPs to H type 1 or H type 3 glycans appear to be 
protective.(20, 28)  Cell-mediated responses, including both T- and B-cell responses, are critical for 
clearance of Norovirus.  Following challenge with VLPs and Snow Mountain virus, there is a 
robust T-helper type 1 (Th-1) response with significant increases in interferon-α and IL-2, but 
not IL-4, IL-6, or IL-10.(29) Depletion of CD4+ cells results in reduced interferon production.(29) 
In a mouse model, CD4+ and CD8+ cells were required for clearance of murine Norovirus in the 
intestine.(30) Likewise, patients with defective T cell function more commonly have prolonged 
shedding and clearance of shedding in patients with chronic infection has been shown to be 
associated with the recovery of T cells.(31, 32)  
 
Cell-mediated responses, including both T- and B-cell and B-cell responses, are critical for 
clearance of Norovirus.  Following challenge with VLPs and Snow Mountain virus, there is a 
robust T-helper type 1 (Th-1) response with significant increases in interferon-, IL-2 but not IL-
4, IL-6, or IL-10.(29)  Depletion of CD4+ cells results in reduced interferon production.(29) Further, 
in a mouse model, CD4+ and CD8+ cells were required for clearance of murine Norovirus in the 
intestine.(30)  Likewise, patients with defective T cell function more commonly have prolonged 
shedding and clearance of shedding in patients with chronic infection has been shown to be 
associated with the recovery of T cells.(31, 32)  Norovirus appears to evolve rapidly with defects in 
cellular immunity (3.3% amino acid substitutions per year in chronic shedders) (3). 
 
Norovirus infections typically presents as an acute infection in immunocompetent hosts, with an 
incubation period of 10 to 51 hours. Symptoms include nausea, vomiting, watery non-bloody 
diarrhea, abdominal cramps and occasionally low-grade fever, muscle aches, chills and 
headache,(20) usually lasting from 24 to 60 hours. (33) While the acute phase of illness is typically 
short-lived, asymptomatic patients may continue to shed the virus for up to two weeks.(12, 20, 34) 
Unfortunately, approximately 570–800 deaths each year result from Norovirus infections in the 
US, with one third of fatal cases occurring in immunocompromised hosts.(35) 
Immunocompromised patients such as those with congenital immunodeficiencies, human 
immunodeficiency virus (HIV)-infected patients, solid organ transplant recipients, hematopoietic 
stem cell transplant patients and oncology patients undergoing chemotherapy can develop 
chronic Norovirus infections. (3, 36-41) Copious watery diarrhea with stool volume amounting to 
several liters per day comparable to volumes observed with cholera may last for 3–4 months or 
longer. (1, 37)  As a result, dehydration and elevated calcineurin inhibitor levels are common in 
patients at the time of initial diagnosis. 
 


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Chronic Norovirus infection is common in hematopoietic stem cell transplant recipients.(6, 11, 36, 
38, 42-45)  In one study, 18% of hematopoietic stem cell transplant patients developed Norovirus 
infection post-transplant, with prolonged shedding detected in most of these patients (median 3 
months, range 0.5 – 14 months).(38) Half had severe weight loss as the result of Norovirus 
gastroenteritis; one patient died of malnutrition attributed to Norovirus infection.  In another 
retrospective study in pediatric hematopoietic stem cell recipients, 16.3% of patients with 
diarrhea were proven to have Norovirus infections.  Norovirus developed at a median of 36.5 
days post-transplantation (range, 5-517 days) with prolonged shedding in most patients (median 
145, range 13- 263).(11) A more recent study demonstrated prolonged shedding of virus in sera 
(mean of 33.6 days) and in stool (mean of 61.6 days) in adult HSCT recipients with diarrhea.(44) 
 
Solid organ transplant recipients tend to have prolonged shedding of Norovirus as well.(7, 10, 36, 39, 
40, 46-48)  One of the earliest studies documented Norovirus in 17% of renal transplant patients 
who shed virus for 97-898 days.  This study was one of the first to sequence Noroviruses and 
demonstrated accumulation of mutations in several of the patients over time, resulting in amino 
acid changes predominantly in the P2 and P1-2 region.(40) Recently, our group conducted a 
retrospective study of solid organ transplant recipients admitted to the hospital with diarrhea.  In 
this study of 422 admissions involving 314 unique patients, Norovirus was the second most 
common documented cause of diarrhea after C. difficile (Table 1).(7)  Norovirus was more 
common among individuals who had community-acquired diarrhea.  
 
 
Recently, we expanded on our initial study to assess the epidemiology and outcomes of adult 
Table 1: Cause of Diarrhea in Hospitalized SOT Patients at a Single Center 
 
 
 


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solid organ transplant patients with Norovirus.(49) We retrospectively reviewed data from 67 SOT 
recipients with diarrhea who tested positive for Norovirus and 67 randomly selected SOT 
recipients with diarrhea who tested negative for Norovirus.  From this data, 35% of all patients 
evaluated for diarrhea had Norovirus, which was the most common infectious diagnosis among 
patients with diarrhea; C. difficile was the second most common diagnosis in 25% of patients.  
We found that nearly half of patients with Norovirus were diagnosed without the need for 
hospitalization.  Diarrheal duration was significantly protracted in Norovirus patients with an 
average of 241 days versus 75 days in the control (p=0.00065); 22.4% of Norovirus patients 
were still having diarrhea at the time of last evaluation suggesting that we are likely 
underestimating the duration of symptoms. There were 1 patient death and 3 graft failures related 
to the Norovirus illness within the first year after the onset of diarrhea and 30% of Norovirus 
patients had a ≥ 20% increase in creatinine within 1 year of the diagnosis.  Most (58%) of the 
Norovirus-infected patients required intravenous hydration on diagnosis and 81% had supra-
therapeutic tacrolimus levels at diagnosis.   
 
In another recent study of 116 pediatric solid organ and hematopoietic stem cell transplant 
recipients with diarrhea, 22% had documented Norovirus infection, making it the most 
commonly identified enteropathogen.(50) Over half of these patients had prolonged diarrhea with 
a median duration of 12.5 days (range 1-324 days) and 29% developed recurrent episode(s) of 
Norovirus-associated diarrhea. Patients with Norovirus were more likely to require ICU 
admission (27% vs. 0%, p = 0.02), had a greater rise in serum creatinine (median 0.3 vs. 
0.2 mg/dL, p = 0.01), and experienced greater weight loss (median 1.6 vs. 0.6 kg, p < 0.01). 
 
Diagnosis of Norovirus generally relies upon detection of Norovirus RNA or antigens in stool 
since cell culture is not available and direct visualization via electron microscopy is 
impractical.(34, 51)  Enzyme immunoassay (EIA) detection methods are also available 
commercially. Although simpler to perform, EIA assays have reduced sensitivity (58–93%) and 
specificity (85–100%) compared to RT-PCRs.(36, 51)  Qualitative or quantitative PCRs can be run 
on stool, vomitus, foods, and environmental specimens.(34) PCR methods generally use primers 
directed at highly conserved regions of ORFs 1, 2, and 3, including the POL region in ORF 1.(20, 
52) Sequencing the products of RT-PCRs allows tracking of individual strains, which may be 
useful in outbreaks.(14) Several multiplex panels that detect Norovirus, among other common 
gastrointestinal pathogens, have recently become widely available.(36) 
 
The current mainstay of therapy for Norovirus is supportive.(53, 54)  Reduction of 
immunosuppression is commonly practiced since diarrhea is a common adverse effect of many 
immunosuppressive drugs, including mycofenolate mofetil. It remains unclear, however, if 
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a few case reports that suggest that substitution of one of the immunosuppressive agents with one 
of the mTOR inhibitors may speed recovery, but the strength of this data is limited.(6, 47)  In these 
two cases, symptoms improved within days, and viral shedding was undetectable within weeks 
of changing to an mTOR inhibitor.  
Oral and intravenous 
immunoglobulins have 
been tried in 
immunosuppressed 
patients with variable 
success.  While there 
have been several case 
series that demonstrated 
improvement in 
diarrheal symptoms 
within 2–3 days of 
administration of oral 
immunoglobulins, a 
more recent cohort 
study failed to 
demonstrate 
improvement in time to 
resolution of diarrhea, 
length of hospital stay, 
or cost of 
hospitalization with the 
administration of oral 
immunoglobulins.(55-57) 
Likewise, breast milk 
has had variable results 
and is currently undergoing study as a potential treatment of Norovirus (ClinicalTrials.gov 
Identifier:  NCT02371538).  Systemic administration of immunoglobulin has provided 
conflicting evidence of clinical impact on Norovirus infection.(1, 3)  A novel monoclonal 
Norwalk-virus specific antibody has been developed and found to be effective in a chimpanzee 
model of infection, but efficacy in humans remains unproven.(58) A number of drugs that are 
currently approved, including nitazoxanide, ribavirin, suramin and human interferon-α have 
activity against Norovirus (Table 2). Several drugs including favipiravir in early phase of 
development show promise in the treatment of Norovirus (Table 2).(1, 3, 36) 
 
Table 2.  Approved and Experimental Therapies with 
Norovirus Activity (1) 
Table 2: Approved and Experimental Therapies with 
Norovirus Activity  


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Nitazoxanide (2-acetyloxy-N-(5-nitro-2-thiazolyl) benzamide Alinia®) is a thiazolide compound 
that is rapidly hydrolyzed to its active metabolite, tizoxanide, which has broad activity against 
bacteria, parasites and viruses.(59)  Nitazoxanide is approved by the United States Food and Drug 
Administration as an oral suspension (age ≥ 1 year) and a 500 mg tablet (age ≥ 12 years) for 
treating diarrhea caused by Giardia lamblia and Cryptosporidium parvum. The nitazoxanide 
table contains 500 mg of nitazoxanide and the following inactive ingredients: maize starch, 
pregelatinized corn starch, hydroxypropyl methylcellulose, sucrose, sodium starch glycolate, 
talc, magnesium stearate, soy lecithin, polyvinyl alcohol, xanthan gum, titanium dioxide, FD&C 
Yellow No. 10 Aluminum Lake, FD&C Yellow No. 6 Aluminum Lake, and FD&C Blue No. 2 
Aluminum Lake.  
 
Pharmacology of Nitazoxanide 
After oral administration, maximum plasma concentrations of the active metabolites tizoxanide 
and tizoxanide glucuronide are observed within 1-4 hours. The active metabolite elimination 
half-life is 7.3 hours.  The parent nitazoxanide is not detected in plasma.  Key pharmacokinetic 
parameters are summarized in Table 3.  From this data, it is clear that the oral suspension is not 
bioequivalent to the tablet formulation.  The relative bioavailability of the suspension compared 
to the tablet is 70%. 
 
Table 3: Plasma Pharmacokinetic Values Following a Single Oral Dose of Nitazoxanide  
1Mean (± SD). 2Mean (Range) 
1Mean (± SD). 2Mean (Range) 
 
 
Formulation Dose 
Age 
(Yrs) 
Tizoxanide 
Tizoxanide Glucuronide 
Cmax1 
(µg/mL) 
Tmax2 
(Hr) 
AUC1 
(μg•hr/mL) 
Cmax1 
(µg/mL) 
Tmax2 
(Hr) 
AUC1 
(μg•hr/m
L) 
Tablet 
500mg 
12-17 
9.1 (6.1) 
4.0 (1-4) 
39.5 (24.2) 
7.3 (1.9) 
4.0 (2-8) 
46.5 (18.2) 
500mg 
≥18 
10.6 (2.0) 
3.0 (2-4) 
41.9 (6.0) 
10.5 (1.4) 
4.5 (4-6) 
63.0 (12.3) 


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Administration of the tablet with food 
increased the AUCt of tizoxanide and 
tizoxanide glucuronide in plasma almost two-
fold and the Cmax by almost 50%.  Likewise, 
administration of the suspension with food 
increases 
the 
AUCt of 
tizoxanide 
and 
tizoxanide glucuronide by about 45-50% and 
the Cmax by ≤10%.  It is recommended to 
always take nitazoxanide with food to ensure 
maximal delivery of the active drug.  Repeat 
dosing of nitazoxanide every 12 hours for 7 
consecutive 
days 
failed 
to 
demonstrate 
significant accumulation of nitazoxanide metabolites tizoxanide or tizoxanide glucuronide 
detected in plasma. 
 
In plasma, the parent drug, nitazoxanide is generally not detected while 99% of tizoxanide is 
bound to proteins.  Following oral administration in humans, nitazoxanide is rapidly hydrolyzed 
to an active metabolite, tizoxanide (desacetyl-nitazoxanide). Tizoxanide then undergoes 
conjugation, primarily by glucuronidation.  In vitro metabolism studies have demonstrated that 
tizoxanide has no significant inhibitory effect on cytochrome P450 enzymes. (Alinia® 
(nitazoxanide) Prescribing Information. Romark, L.C., Tampa, FL. November 2013) 
 
Tizoxanide is excreted in the urine, bile and feces, and tizoxanide glucuronide is excreted in 
urine and bile. Approximately two-thirds of the oral dose of nitazoxanide is excreted in the feces 
and one- third in the urine.  The pharmacokinetics of nitazoxanide in pediatric patients less than 
one year of age and geriatric patients has not been studied.  Data in patients with impaired 
hepatic and renal function is limited. (60) The PK of nitazoxanide has been studied in patients 
given a single dose of nitazoxanide 600mg with mild renal impairment [eGFR 60-89 
mL/min/1.73 m2], moderate renal impairment [eGFR 30-59 mL/min/1.73 m2], severe renal 
impairment [eGFR 15-29 mL/min/1.73 m2] and end stage renal disease requiring dialysis (6 
subjects in each group). Terminal half-life and time to peak concentration for tizoxanide, the 
active metabolite, were similar between renal impaired patients and healthy subjects. There was 
a trend to increasing.  Cmax and AUCs for tizoxanide glucuronide, a non-active metabolite, 
increased with the degree of renal impairment.  There were no treatment emergent adverse 
events that were related to the study drug (Nitazoxanide Investigator’s Brochure, March 1, 
2018).  Similarly, there was a small phase I study of single dose nitazoxanide 600mg in patients 
with normal, mild (Child-Pugh Class A), moderate (Child-Pugh Class B) and severe hepatic 
Figure 3: Nitazoxanide Metabolism 


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impairment (Child-Pugh Class C) (6 subjects in each arm).  No clear relationships between 
tizoxanide and tizoxanide glucuronide PK parameters and hepatic function parameters (Child-
Pugh classification and the individual components serum albumin, serum bilirubin and INR) 
were apparent.  There were no treatment emergent adverse events (Nitazoxanide Investigator’s 
Brochure, March 1, 2018). 
 
Nitazoxanide has been extensively studied in multiple animal models to assess safety, 
pharmacokinetics and efficacy, as summarized in the attached IB.  To date, 4,751 patients have 
been exposed to nitazoxanide in clinical trials, and the product has been marketed for 
approximately nine years in the United States and sixteen years in Latin America with more than 
70 million people treated.  While nitazoxanide is specifically approved for twice daily dosing for 
3 days duration, there is extensive experience with more prolonged dosing, including dosing 
beyond 30 days (Alinia® (nitazoxanide) Prescribing Information. Romark, L.C., Tampa, FL. 
November 2013).  
 
Adverse reactions to nitazoxanide are related primarily to the gastrointestinal tract with mild and 
transient abdominal pain (6.6-7.8%), diarrhea (2.1-4.2%), headache (1.1-3.1%), nausea (3.0%) 
and vomiting (1.1%) being the most common adverse events reported. Mild and transient yellow 
discoloration of the urine and sclera have also been reported, particularly in patients receiving 
doses higher than 500 mg bid for extended durations.  Other rare adverse events occurring in less 
than 1% of patients include:  asthenia, fever, pain, allergic reaction, pelvic pain, back pain, chills, 
infection, malaise, flu syndrome, dizziness, somnolence, insomnia, tremor, hyperesthesia, 
dyspepsia, anorexia, flatulence, constipation, appetite increase, enlarged salivary glands, dry 
mouth, thirst, dysuria, amenorrhea, metrorrhagia, kidney pain, edema labia, increased creatinine, 
increased alanine aminotransferase (ALT), anemia, leukocytosis, rash, pruritus, sweating, ear 
ache, epistaxis, lung disease, pharyngitis, rhinitis, tachycardia, syncope, hypertension, myalgia, 
leg cramps, and spontaneous bone fracture. No drug-related serious adverse events have been 
reported during post-marketing experience with nitazoxanide.(61-70) 
 
While nitazoxanide has not shown signs of reproductive toxicity in animal studies, no adequate 
and well-controlled clinical studies have been conducted in pregnant or lactating females. It is 
not known whether nitazoxanide is excreted in breast milk.  The drug is classified as pregnancy 
category B by the US FDA.  No cases of overdose of nitazoxanide have been reported. Single 
doses of up to 4000 mg have been reasonably well tolerated in healthy volunteers. There is no 
specific antidote for nitazoxanide overdose, therefore, management of the patient should consist 
of symptomatic and supportive therapy.  
 
 


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Antiviral Activity of Nitazoxanide 
Nitazoxanide and its circulating metabolite, tizoxanide, suppress the replication of a broad range 
of DNA and RNA viruses in cell culture including Norovirus.  For viruses, the antiviral 
mechanism of nitazoxanide is believed to be due to targeting host-regulated processes involved 
in viral replication which leads to an inhibition of viral protein synthesis.(71-75) The relative 
activity of nitazoxanide and tizoxanide against enteric viruses is detailed in Table 4.  Of great 
interest, the IC50 and IC90 for tizoxanide in a Norovirus G1 replicon-assay system using an HG-
23 cell line were 0.5 and 1.2 µg/mL respectively.(75)  While the precise mechanism of action of 
nitazoxanide has not been fully defined for Norovirus, tizoxanide appears to inhibit the 
maturation of rotavirus viral protein 7 (VP7), a glycoprotein that forming the outer part of the 
virion and one of the six structural glycoproteins involved in rotavirus replication, in addition to 
altering viroplasm formation and interfering with viral morphogenesis.(74)  Nitazoxanide has also 
been shown to potentiate the production of type I interferons. The significance of this activity is 
not fully understood, but it could contribute to the antiviral activity of nitazoxanide by interfering 
with maturation of viral proteins or other mechanisms.(75) 
 
Table 4: Activity of Nitazoxanide and Tizoxanide against Enteric Viruses in Cell Culture 
Virus 
TIZ EC50  
TIZ CC50  
Simian rotavirus SA11 - G3P (72, 74) 
0.5 µg/ml 
>50  
Human rotavirus Wa - G1P (74) 
1.0 µg/ml 
>50 
Norovirus G1 (75) 
0.5 µg/ml 
14 
 
EC50 = drug concentration at which a 2-fold depression of viral DNA or RNA (relative to the 
average levels in untreated cultures) was observed.  CC50 = drug concentration at with a 2-fold 
depression of reduced MTT was observed relative to average levels in untreated cultures.  
 
Clinical Experience with Nitazoxanide in Treating Enteric Viruses 
The efficacy and safety of nitazoxanide suspension as a treatment for diarrhea caused by enteric 
viruses was first studied in Egypt.(72)  Children hospitalized with severe rotavirus gastroenteritis 
were randomized to either 7·5 mg/kg nitazoxanide as an oral suspension or placebo twice a day 
for 3 days.  Patients were monitored in the hospital for 7 days.  Of the 47 patients included in the 
efficacy analysis, 38 patients had rotavirus, 4 patients had adenovirus, 4 patients had rotavirus 
and adenovirus, and 1 patient had rotavirus and Norovirus at baseline.  The median time to 
resolution of illness was 31 h (IQR 22–73) for the nitazoxanide-treated group compared with 75 
h (51–124) for the placebo group (p=0·0137).  Two adverse events were reported in patients 
randomized to the placebo group, one was a case of bronchitis and the other was a case of mild 
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A second study evaluated the effect of nitazoxanide tablets for the treatment of viral 
gastroenteritis caused by Norovirus, rotavirus, or adenovirus in patients over the age of 12.(76) Of 
the 45 evaluable patients, 26 had rotavirus, 13 had Norovirus, 5 had adenovirus and 1 had both 
rotavirus and adenovirus detected.  Patients were randomly assigned to receive either 
nitazoxanide 500 mg twice daily or placebo twice daily for 3 days.  The results indicated the 
median time from first dose to resolution of symptoms was 1.5 days in the nitazoxanide treated 
patients and 2.5 days for the placebo group (P=0.0001). Time to symptom resolution was faster 
in nitazoxanide treated subjects who were infected with rotavirus (1.5 vs. 2.5 days, P=0.0052) 
and Norovirus (1.5 vs. 2.5 days, P=0.0295). The medication was well tolerated with no serious 
adverse events reported during this study. 
 
Given the severity of Norovirus in immunosuppressed patients, there has been significant interest 
in using nitazoxanide to improve outcomes.  One of the first published cases involved a 43-year-
old male with relapsed refractory acute myelogenous leukemia who had undergone 
hematopoietic stem cell transplantation and had biopsy-proven cutaneous and pulmonary graft-
versus-host disease.  Shortly after initiating ponatinib for management of his AML, he presented 
with Norovirus infection associated with 8 – 12 daily episodes of large volume, non-dysenteric 
watery diarrhea but without fever, chills, or any associated abdominal pain or tenesmus. He was 
significantly lymphopenic on admission.  He was also clinically unstable with tachycardia (115 
bpm) and hypotensive (88/55 mm Hg).  Stool studies were negative for all tested pathogens other 
than Norovirus.  He failed to respond to antimotility treatment and octreotide but, within 24 
hours of starting nitazoxanide 500mg twice daily, he had marked clinical improvement from 10 
to 2 bowel movements per day.  He had normal consistency and frequency of his bowel 
movements within 4 days of starting nitazoxanide.  Clinical resolution of acute gastroenteritis 
was achieved with a 7 day course of nitazoxanide but the patient continued to asymptomatically 
shed Norovirus in his stools for over 30 days.(77) 
 
Recently, one of the largest experiences of nitazoxanide for the treatment of Norovirus in 
immunosuppressed patients was presented at the 2015 BMT Tandem Meeting.(78, 79)  This 
retrospective study of 14 patients (3 receiving chemotherapy, 2 autologous HSCT and 9 
allogeneic HSCT) with Norovirus documented the impact of nitazoxanide was 100 mg PO BID 
for ages 1 to 4 years, 200 mg PO BID for age 4 to 11 years, and 500 mg PO BID for greater than 
11 years. 4 patients received 500 mg PO BID for 5-8 days (Mean duration 4.6 days, median 
duration 5 days. Incidence of adverse events are not yet published.  The patients, who were 1-21 
years old, included 3 who were pre-HSCT on chemo/immunotherapy and 8 patients who were 1 
day to 34 months after HSCT.  All of the HSCT patients were on immunosuppressive therapy 
and 5 had documented GVHD.  Therapy resulted in improvements in diarrhea, nausea, and 


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abdominal pain within 2-4 days (median 2 days).  Clearance of stool virus was variable. Two of 
3 patients treated prior to HSCT became negative on stool study within 5-14 days of treatment (1 
unknown duration). Among patients treated after HSCT 4 of 9 had persistent viral shedding, 2 
received drug until death (1 adenovirus, 1 congestive heart failure) both were treated greater than 
2 months, 3 with GVHD continue to shed virus after 6 months of treatment, and 4 have come off 
therapy and remain negative for Norovirus RNA. One HSCT patient with clinical resolution but 
persistent viral shedding stopped treatment, resulting in recurrence of clinical symptoms. This 
patient responded clinically to reinstitution of therapy within 2 days but continued to shed virus. 
UGI endoscopy/ colonoscopy were performed in 5 pts at the time of infection, all showed 
inflammation/edema but no GVHD was seen on histology.  
 
Clinical Experience with Nitazoxanide Used for Greater than 3 days 
There have been 3 studies (n=505) using nitazoxanide along or in combination with interferon 
for the treatment of hepatitis C for 3-10 months and one study of prolonged nitazoxanide for 
patients with AIDS and Cryptosporidiosis who were given 1-1528 days (median 62 days) of 
nitazoxanide.89-92 In the Cryptosporidiosis study, Fifty-six percent of patients reported a total of 
482 adverse events during the course of the study.92 Most adverse events (72%) were mild and 
deemed unrelated to the nitazoxanide. None of the deaths or other serious adverse events (life-
threatening or requiring hospitalization) was reported to be related to the use of nitazoxanide. 
Twenty-seven non-serious adverse events were considered possibly related to the use of the 
study drug. Twenty of these events were associated with the digestive tract (nausea, vomiting, 
diarrhea, abdominal pain and dyspepsia). Other events possibly related to treatment were allergic 
reaction (n = 2), rash (n = 1), yellowish discoloration of the sclera (n = 2), and discoloration of 
urine (n = 2). Each of these events was transient in nature resolving on treatment or upon the 
discontinuation of treatment. In the 3 HCV studies, were attributed to the peginterfron and/or the 
ribavirin without apparent enhancement of the incidence in those patients who received 
nitazoxanide.89-91 
 
Twenty-seven non-serious adverse events were considered possibly related to the use of the 
study drug. Twenty of these events were associated with the digestive tract (nausea, vomiting, 
diarrhea, abdominal pain and dyspepsia). Other events possibly related to treatment were allergic 
reaction (n = 2), rash (n = 1), yellowish discoloration of the sclera (n = 2), and discoloration of 
urine (n = 2). Each of these events was transient in nature resolving on treatment or upon the 
discontinuation of treatment. In the 3 HCV studies, were attributed to the peginterfron and/or the 
ribavirin without apparent enhancement of the incidence in those patients who received 
nitazoxanide.89-91 


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2.2 
Rationale 
Norovirus is a rare and emerging viral disease of medical importance in the 
immunocompromised subject. In vitro, nitazoxanide has been shown to be active against 
Norovirus.  Results from double-blind placebo-controlled studies demonstrate that nitazoxanide 
decreases the duration of illness in subjects with viral gastroenteritis.  Small observational 
studies suggest that nitazoxanide results in prompt improvement in clinical signs of Norovirus-
induced gastroenteritis.  Further, nitazoxanide enhanced local production of interferon which 
may contribute to more rapid clearance of virus.  Studies of nitazoxanide for the treatment of 
Norovirus has presented limited data on quantitative virology and its impact on viral load are less 
well defined.  Further, there are limited data on the impact of nitazoxanide on host and viral 
changes that may facilitate control and clearance of Norovirus.  
 
The present study is a phase 2 multi-center, prospective, randomized, double-blind study 
designed to assess the efficacy of nitazoxanide taken twice daily for 28 days compared to 
placebo for the treatment of Norovirus gastroenteritis in immunosuppressed transplant subjects.  
Given the safety of prolonged therapy with nitazoxanide (89-92), lack of interactions with common 
post-transplant medications, putative antiviral activity and prolonged duration of viral shedding 
we are assessing 28 days of therapy.  The longitudinal monitoring phase will provide useful 
information on the course of host and viral responses in subjects with chronic Norovirus 
infection with and without treatment. 
 
There are 2 arms of the study: 
 
Nitazoxanide Arm: All subjects age ≥ 12 years:  500 mg (one tablet) nitazoxanide by mouth 
twice daily with food for 28 consecutive days. 
 
Placebo Arm: All subjects age ≥ 12 years:  Placebo (one tablet) by mouth twice daily with food 
for 28 consecutive days. 
2.3 
Potential Risks and Benefits 
2.3.1 Potential Risks 
There are a number of potential risks associated with this study.  Risk is primarily derived from 
the study agent and the protocol-mandated procedures.   
 
Risks Associated with Nitazoxanide:  As outlined in the package insert for the nitazoxanide, the 
compound has been extensively studied and utilized clinically in a wide range of clinical settings 
including limited data in transplant recipients. The safety of nitazoxanide was evaluated in 2177 


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HIV-uninfected subjects 12 months of age and older who received nitazoxanide Tablets or 
nitazoxanide for Oral Suspension at the recommended dose for at least three days. In pooled 
controlled clinical trials involving 536 HIV-uninfected subjects treated with nitazoxanide Tablets 
or nitazoxanide for Oral Suspension, the most common adverse reactions were abdominal pain, 
headache, chromaturia and nausea (>2%). Safety data were analyzed separately for 280 HIV-
uninfected subjects’ ≥12 years of age receiving nitazoxanide at the recommended dose for at 
least three days in 5 placebo-controlled clinical trials and for 256 HIV-uninfected subjects 1 
through 11 years of age in 7 controlled clinical trials. There were no differences between the 
adverse reactions reported for nitazoxanide -treated subjects based upon age. 
 
The following adverse reactions have been identified during post approval use of nitazoxanide. 
Because these reactions are reported voluntarily from a population of uncertain size, it is not 
always possible to reliably estimate their frequency or establish a causal relationship to drug 
exposure. The following is a list of adverse reactions spontaneously reported with nitazoxanide  
Tablets which were not included in clinical trial listings: 
 
Gastrointestinal disorders: diarrhea, gastroesophageal reflux disease.  
Nervous System disorders: dizziness. 
Respiratory, thoracic and mediastinal disorders: dyspnea.  
Skin and subcutaneous tissue disorders: rash, urticaria. 
 
Risks Associated with Protocol-Mandated Procedures: 
Blood Samples: 
Drawing blood from a vein may cause local pain, bruising, occasional 
light-headedness, fainting, and very rarely, infection at the site of the 
blood draw.  
Buccal Swabs: 
Buccal swabs may cause discomfort, irritation, or a gagging sensation.  
Stool Collection: 
Providing a stool specimen might make the subject feel embarrassed. 
Urine Test: 
Female who could become pregnant, providing urine for a pregnancy test 
might feel embarrassed.  
Questionnaires: 
Completion of a questionnaire and the questions might make the subject 
feel uncomfortable or upset.  
Others: 
Pregnancy: There are no data with this drug in pregnant women to inform a drug-associated risk. 
No teratogenicity or fetotoxicity was observed in animal reproduction studies with 
administration of nitazoxanide to pregnant rats and rabbits during organogenesis at exposures 30 
and 2 times, respectively, the exposure at the maximum recommended human dose of 500 mg 
twice daily based on body surface area (BSA).  
In the U.S. general population, the estimated background risk of major birth defects and 
miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.  
 


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Breach of Confidentiality: Instances like lost or stolen laptops storing participant information, 
lost or stolen thumb drives, paperwork with subject PHI left unsecured may result in breach in 
confidentiality. 
 
Unknown risks: Nitazoxanide and protocol mandated procedures may have risks previously 
unknown.  
2.3.2 Known Potential Benefits 
Given the limited clinical experience with nitazoxanide, there is no guarantee that subjects will 
receive direct benefit from participating in this study.  It is possible that nitazoxanide will reduce 
the duration of symptoms secondary to Norovirus infection and may also reduce the duration of 
Norovirus shedding.  There have been no prospective studies of Norovirus in the transplant 
setting and this study will allow a better assessment of the natural history of Norovirus in this 
setting.  Lastly, collection of various immune response markers will allow assessment of the 
relative role of the host immune response and antiviral therapy to recovery from Norovirus 
infection in transplant recipients.  All subjects will get the local standard of care provided to 
patients with Norovirus (i.e. antimotility agents and hydration). 


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3 
OBJECTIVES 
3.1 
Study Objectives 
A. Primary Objective:   
1. To assess the clinical efficacy of nitazoxanide for the management of acute and 
chronic Norovirus in transplant recipients. 
 
B. Secondary Objectives 
1. To assess virologic efficacy of nitazoxanide 
2. To assess the safety of nitazoxanide for the management of acute and chronic 
Norovirus in transplant recipients. 
C. Exploratory Objectives 
1. To assess initial clinical improvement in Norovirus Disease through 28 and 180 days.  
2. To assess markers of virologic improvement Norovirus Disease through 28 and 180 
days. 
3. To assess the contribution of immunologic response to Norovirus to the clinical 
course of disease in treated and untreated subjects. 
4. To define the pharmacokinetics and dose response relationships of nitazoxanide. 
5. To define the natural history of Norovirus in nitazoxanide treated and untreated 
subjects. 
3.2 
Study Outcome Measures 
No studies have been conducted to establish the optimal endpoint for assessing novel drugs for 
the treatment of Norovirus in immunosuppressed subjects.  Further, there are no published FDA 
guidance documents to inform optimal endpoint selection for this indication. (1)  Available 
literature and expert opinion was consulted to define proposed endpoints for this study. 
3.2.1 Primary Outcome Measures 
1. The time from randomization until initial clinical resolution of Norovirus symptoms 
for at least 48 hours through 180 days.   
 
Clinical resolution will be assessed from the daily diary by the subject and will be 
defined as: 
a. Cessation of vomiting and, 
b. No stools classified by the Bristol Stool Chart as diarrhea (Type 6 or 7) 
 


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3.2.2 Secondary Outcome Measures 
Virologic Efficacy 
1. Time from randomization to first negative viral load through 180 days. 
2. The change in viral titer between Day 1 and 180. 
Safety 
3. Incidence of unsolicited non-serious adverse events (see section 9 for details) through 
60 days.  
4. Incidence of laboratory adverse events (WBC, Hemoglobin, Platelet Count, 
Creatinine, Alkaline Phosphatase, ALT, AST, BUN and Bilirubin) through 60 days. 
5. Incidence of protocol-specified serious adverse events (see section 9 for details) 
through 60 days.  
6. Incidence of Hospitalization through 60 days. 
 
3.2.3 Exploratory Outcome Measures 
Clinical Improvement; 
1. Time from randomization to initial clinical improvement in Norovirus disease 
through 28 and 180 days for at least 48 hours, as defined by: 
a. 50% reduction in number of episodes of vomiting and, 
b. Improvement in PO intake, as judged by the subjects and, 
c. 50% reduction in the number of episodes of diarrhea as classified by the 
subject by the Bristol Stool Chart as type 6 or 7 bowel movements. 
2. Time from randomization to initial cessation of vomiting through Day 180 (recurrent 
vomiting will be considered disease recurrence unless determined to be due to another 
etiology [i.e. GVHD]). 
3. Time from randomization to subject report of no loss of appetite that is maintained for 
48 hours through Day 180 (measure will be first time that the subject reports that they 
have no “loss of appetite” on their daily diary).  
4. Time from first dose to initial cessation of diarrhea through Day 180 classified by the 
Bristol Stool Chart as type 6 or 7 bowel movements (recurrent diarrhea will be 
considered disease recurrence unless determined to be due to another etiology [i.e. 
GVHD]). 
5. Time from randomization to 50% reduction in the amount of antimotility agents 
utilized by the subject through Day 180 
6. Number of days of diarrhea through Days 28 and 180. 
7. Number of stools classified by the Bristol Stool Chart as type 6 or 7 bowel 
movements through Day 28. 
8. Number of days of IV hydration or total parenteral nutrition (TPN) therapy through 
Day 28. 


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9. Total number of days of hospitalization through Days 28 and 180. 
10. Change in patient-reported quality of life as measured by EuroQOL-5 (global) and 
IBSQOL (diarrhea specific) [adult] or EuroQOL-5 Peds (global) and PedsQL GI 
Module [children] from baseline to Day 180. 
11. Change in patient-reported physical function as measured by NIH PROMIS Physical 
Function (Adult) Pediatric Global Health (Peds) from baseline to Day 180. 
12. Change in patient-reported emotional distress as measured by the NIH PROMIS 
Depression, Anxiety, Fatigue (Adult and Peds) from baseline to Day 180. 
13. Change in patient-reported gastrointestinal symptoms as measured by the NIH 
PROMIS GI (Adult and Peds) symptoms (6 of 8 subscales) from baseline to Day 180. 
14. The effect of co-pathogens, as determined by the BioFire stool pathogen screen, on 
the primary outcome measure. 
15. Time from randomization until initial clinical resolution of Norovirus symptoms for 
at least 48 hours through Day 180.  Clinical resolution will be assessed from the daily 
diary by the subject and will be defined as cessation of vomiting and no stools 
classified by the Bristol Stool Chart as diarrhea (Type 6 or 7) from the total 
population compared to the subgroup of subjects who do not report chromaturia 
(discoloration of urine) based on unsolicited self-reporting.   
16. Incidence of unsolicited non-serious adverse events (see section 9 for details) through 
60 days, laboratory adverse events (WBC, Hemoglobin, Platelet count, Creatinine, 
Alkaline Phosphatase, ALT, AST, BUN and Bilirubin) through 60 days, protocol-
specified serious adverse events (see section 9 for details) through 60 days, 
and Hospitalization through 60 days from the total population compared to the 
subgroup of subjects who do not report chromaturia (discoloration of urine) based on 
unsolicited self-reporting. 
 
 
Virologic Improvement: 
17. Time to ≥ 1 log reduction in stool Norovirus genome copies. 
18. Change in quantitative Norovirus load in the stool between Day 1 and Day 7, 14, 21, 
28, 60, 120, and 180. 
19. Change in Norovirus sequence from Day 1 to Days 28 and 60. 
20. The effect of co-pathogens, as determined by the BioFire stool pathogen screen, on 
the time from the randomization to first negative viral load through 180 days. 
21. Time from the randomization to first negative viral load through 180 days and the 
change in viral titer between Day 1 and 180 from the total population compared to the 
subgroup of subjects who do not report chromaturia (discoloration of urine) based on 
unsolicited self-reporting. 
 


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Immunologic Response: 
22. Change in Norovirus-specific serum and stool IgA, IgM and IgG between Day 1 and 
Day 28 and 60 (stool only). 
23. Association between change in total lymphocyte count and T cell subsets at Day 1 
and 180 and clinical resolution of Norovirus symptoms. 
24. Association between change in total lymphocyte count and T cell subsets at Day 1 
and 180 and undetectable quantitative norovirus PCR. 
25. Association between change in Norovirus-specific serum and stool IgA, IgM and IgG 
from Day 1 to Days 28 and 60 (stool only) and clinical resolution of Norovirus 
symptoms. 
26. Association between change in Norovirus-specific serum and stool IgA, IgM and IgG 
from Day 1 to Days 28 and 60 (stool only) and undetectable quantitative Norovirus 
PCR. 
 
Pharmacokinetics and Dose Response: 
27. For subjects consenting to PK draws, concentrations of nitazoxanide metabolites 
(tizoxanide and tizoxanide glucuronide) 1 to 4 hours after the first dose on Day 7 and 
10 minutes before the second dose on Day 21.  
Natural History of Disease: 
28. Time to allograft rejection as per each center team 
29. Time to allograft loss as reported to UNOS.  
30. Time to death.   
31. Time to withdrawal from the study because of intolerance or drug related adverse 
events. 
32. Correlation of secretor status as defined by phenotype and genotype, separately, and 
clinical resolution of Norovirus as defined by the primary endpoint. 
 
 
 
 


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4 
STUDY DESIGN 
The study will be a phase 2 multi-center double-blind placebo-controlled study of the efficacy 
and safety of nitazoxanide for the treatment of solid organ and hematopoietic stem cell transplant 
recipients with symptomatic diarrhea due to Norovirus. The study will involve approximately 
160 subjects randomly assigned (1:1) to nitazoxanide or placebo. The study duration is 60 
months and subject participation duration is 6 months. Given the safety of prolonged therapy 
with nitazoxanide, lack of interactions with common post-transplant medications, putative 
antiviral activity and prolonged duration of viral shedding we are assessing 56 doses of therapy.  
The longitudinal monitoring phase will provide useful information on the course of host and viral 
responses in subjects with chronic Norovirus infection with and without treatment. 
  
The primary endpoint 
 is to determine the clinical efficacy of nitazoxanide that will be assessed as the time from 
randomization until clinical resolution of Norovirus symptoms for at least 48 hours, assessed 
through 180 days. Secondary endpoints include virologic efficacy of nitazoxanide that will be 
assessed as the time from randomization to first negative viral load through 180 days and by 
comparing the change in viral titer between Day 1 and 180; safety of nitazoxanide that will 
assessed by the frequency of adverse events and serious adverse events. 
 
There are 2 arms of the study: 
 
Nitazoxanide Arm: All subjects age ≥ 12 years:  500 mg (one tablet) nitazoxanide by mouth 
twice daily with food for 56 consecutive doses. 
 
Placebo Arm: All subjects age ≥ 12 years:  Placebo (one tablet) by mouth twice daily with food 
for 56 consecutive doses. 
 


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5 
STUDY ENROLLMENT AND WITHDRAWAL 
Approximately 160 males and females ≥ 12 years of age inclusive, who meet all eligibility 
criteria will be enrolled.  All candidates at all centers that are eligible to be included in the 
studies will be offered the opportunity to participate in the trial. Study subjects are seen in patient 
or clinic setting and have either community onset or hospital acquired disease.  
5.1 
Subject Inclusion Criteria 
Subjects should meet all of the following inclusion criteria 
1. Male or female age ≥ 12 years. 
2. Recipient of a solid organ or hematopoietic stem cell transplant. 
3. Positive test result for Norovirus within 14 days of enrollment that is obtained as part of 
routine clinical care using a Norovirus testing available to the site. 
4. Active GI symptoms (diarrhea or vomiting) that, in the opinion of the PI, are secondary 
to Norovirus.#  
5. Willing and able to provide written informed consent and assent before initiation of any 
study procedures, consistent with local IRB policy. 
6. Subjects must be of non-childbearing potential or if of childbearing potential, must be 
using an effective method of birth control or must be abstinent.  
• Non-childbearing potential is defined as surgically sterile or postmenopausal for > 
one year. 
• Effective methods of birth control include the use of hormonal or barrier birth control 
such as implants, injectable contraceptives, combined oral contraceptives, intrauterine 
devices [IUDs] or condoms with spermicidal agents during study period.  Female 
subjects must be using an effective method of birth control or practice abstinence and 
must agree to continue such precautions during the study and for 30 days after the 
Day 28 study visit. 
• A woman is eligible if she is monogamous with a vasectomized male. This subject is 
considered low risk and not required to use contraception.  
7. Agrees to complete all screening requirements, study visits and procedures. 
 
 
 
 
 
# Patients must have active diarrhea, which is defined as at least 3 days of Bristol 6 or 7 stools in the past 2 
weeks prior to enrollment per patient report. 


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5.2 
Subject Exclusion Criteria 
Subjects meeting any of the exclusion criteria at baseline will be excluded from study 
participation  
1. Other identified infectious causes of diarrhea at screening*.  
2. Any condition that would, in opinion of the Site Investigator, place the subject at an 
unacceptable risk of injury or render the subject unable to meet the requirements of the 
protocol.  
3. Subjects receiving oral or intravenous immunoglobulin therapy concurrently or in the 14 
days prior to enrollment.  
4. Nitazoxanide use for any illness in the previous 30 days prior to randomization. 
5. Have received experimental products within 30 days prior to the study entry or plan to 
receive experimental products at any time during the study 
6. Known sensitivity to nitazoxanide or any of the excipients comprising the nitazoxanide 
tablets. 
7. Subjects unable to swallow oral medications. 
8. Subjects with ostomy. 
9. Women who are pregnant or lactating or have a positive urine pregnancy test at 
screening/enrollment/Day 1. 
 
Co-enrollment in other studies is allowed if none of the above exclusion criteria are met.  
*Alternative diagnosis requiring treatment would be considered a co-infection; if the testing is 
positive for a pathogen that the PI does not feel is causing the symptoms, they may be included 
but the PI or his/her designee must document that the positive test is not clinically significant, 
does not require treatment and is not causing the symptoms making the patient eligible for 
enrollment. 
 
5.3 
Treatment Assignment Procedures 
5.3.1 Randomization Procedures 
Enrollment of subjects will be done online using the enrollment module of AdvantageEDCSM. 
Approximately 160 subjects will be randomized into two treatment groups:  active nitazoxanide 
and placebo with equal allocation (1 to 1 randomization) after providing consent and 
confirmation of eligibility based on the study inclusion and exclusion criteria.  
 


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The study will use a stratified, permuted block randomization scheme. Permuted block 
randomization is used to avoid the potential for serious imbalance in the number of participants 
assigned to each group, an imbalance that can occur in the simple randomization procedures.  
 
Stratification will be by:  
 
• Duration of Symptoms:  onset of Norovirus-associated symptoms (diarrhea, 
nausea and/or abnormal appetite) < 14 days vs. ≥ 14 days 
• Transplant Type:  solid organ vs. hematopoietic stem cell transplant 
• Age Range:  pediatric (12-17 years) vs. adult ≥ 18 years 
 
The randomization list will be computer-generated by statisticians at the SDCC using a stratified, 
permuted block randomization scheme and is included in the enrollment module for the trial. 
AdvantageEDCSM will assign each subject to a treatment group after the demographic, duration 
of symptoms, transplant type, and eligibility data have been entered into the system.  
Each site will have a supply of two 60cc identical blinded bottles pre-labeled with randomization 
numbers, each containing 30 tablets, sufficient to treat a subject with 56 doses.  The two identical 
containers will be packaged in the same plastic bag. Once a subject is assigned a randomization 
number, the corresponding bottles will be distributed to the subject. 
5.3.2 Masking Procedures 
All subjects will take either nitazoxanide or matching placebo twice daily for 56 doses.  The 
placebo will be manufactured by Romark, L.C., Ltd. to match the appearance (color, size, with 
“CTM” imprints) of the active compound and will be dispensed in identical bottles.  Bottles will 
be labeled in such a way that it will not be obvious to the care team or the subject which arm 
they have been randomized to.  Bottles will be delivered to the site pre-filled containing either 
nitazoxanide or placebo and will have a unique number.  At the time of randomization, the 
unique number will be assigned to the individual subject.  No member of the study team will be 
aware of the arm that the subject has been assigned to unless the site PI specifically requests 
unblinding (see section 5.3.4).   
 
Refer to the MOP for unblinding procedures, including emergency unblinding procedures 
(Section 5.2 of MOP). 


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5.3.3 Reasons for Withdrawal and Discontinuation of Study Product 
Administration 
Subjects may voluntarily withdraw their consent for study participation at any time without 
penalty or loss of benefits to which they are otherwise entitled.   
 
An investigator may also withdraw a subject from receiving the study product for any reason. 
Follow-up safety evaluations will be conducted, if the subject agrees.  If a subject withdraws or 
is withdrawn prior to completion of the study, the reason for this decision must be recorded in 
the case report forms (CRFs).  
 
The reasons, might include, but are not limited to the following: 
• 
Subject no longer meets eligibility criteria 
• 
Subject withdraws consent 
• 
Subject not able to comply with study procedures 
• 
Subject becomes noncompliant 
• 
Evidence of toxicity including study drug-related AE/SAE, laboratory abnormality, 
intercurrent illness, or other medical condition or situation occurs that continued 
participation in the study would not be in the best interest of the subject.   
• 
Medical disease or condition, or new clinical finding(s) for which continued 
participation, in the opinion of the investigator might compromise the safety of the 
subject, interfere with the subject's successful completion of this study, or interfere with 
the evaluation of responses 
• 
Subject lost to follow-up 
• 
Decision by the Investigator that termination is in the subject’s best medical interest. 
• 
Decision by the sponsor to stop or cancel the study 
• 
Decision by local regulatory authorities (IRB/IEC) to stop or cancel the study 
• 
Determined by a physician’s discretion to require additional therapy not indicated in the 
protocol to ensure subject’s health and well-being (or treatment failure, if applicable) 
 
The investigator should be explicit regarding study follow-up (e.g. safety follow-up) that might 
be carried out despite the fact the subject will not receive further study product.  If the subject 
consents, every attempt will be made to follow all AEs through resolution.  The procedures that 
collect safety data for the purposes of research must be inclusive in the original informed consent 
or the investigator may seek subsequent informed consent using an IRB/IEC-approved consent 
form with the revised procedures. 
 
The investigator will inform the subject that already collected data will be retained and analyzed 
even if the subject withdraws from this study.  


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5.3.4 Handling of Withdrawals 
Subjects who withdraw or are withdrawn from participation in the study at any time. Subjects 
may also withdraw voluntarily from receiving the study intervention for any reason. An 
investigator may also withdraw a subject from receiving further intervention 
 
Subjects who withdraw, or are withdrawn from the efficacy endpoint analysis, or are lost to 
follow-up after signing the informed consent form, randomization, and receipt of study product 
will not be replaced. Subjects who withdraw consent after signing the informed consent form and 
randomization but before receipt of study product may be replaced.  
 
 
If a subject withdraws from the study after receiving any amount of study drug the subject will 
be asked to continue scheduled study procedures including safety and efficacy evaluations, if 
possible, and be given appropriate care under medical supervision if symptoms of any AE related 
to participation in the study are continuing. The participant will be followed until the AE is 
resolved or until the subject’s condition becomes stable.  
Subjects who request to withdraw their consent after study treatment from further participation in 
the study will be reminded of the importance of continuing the study for safety evaluations and 
will be encouraged to complete the Early Termination Visit if they choose not to complete the 
remaining study visits. The Early Termination Visit procedures are listed in Section 7.4. Subjects 
who choose to decline continuation in study participation will no longer be contacted for follow-
up.  
 
If a subject is withdrawn at any time due to an AE, the event will be followed until it is resolved 
or in the opinion of the Investigator is determined medically stable with the consent from the 
subject. The site PI may request unblinding of the study drug assignment if they feel that such 
information is essential for the management of an AE or SAE.  If the PI feels that unblinding is 
essential for management of the AE or SAE, they will request unblinding by contacting the 
DMID Medical Monitor.  Clinical failure is not an acceptable reason to request unblinding.   
Refer to the MOP and the DMID policy “Unblinding Individual Participants in DMID Clinical 
Research,” the current policy is available at https://www.niaid.nih.gov/research/dmid-data-
management.  
 
In the case of subjects who fail to appear for a follow-up safety assessment, extensive effort (i.e., 
three documented contact attempts via phone calls, e-mails, etc., made on separate occasions and 
followed by a certified letter) will be made to locate or recall them, or at least to determine their 
health status.  Although the subject is not obliged to give reasons for withdrawing early, the 


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investigator should make a reasonable effort to ascertain the reasons while fully respecting the 
subject’s rights. These efforts will be documented in the subject’s records. 
5.3.5 Termination of Study  
The study will be terminated if the DSMB determines that the study should be terminated based 
on safety concerns.  If the study is terminated, the DSMB will be permitted to allow the 
longitudinal monitoring phase of the study to proceed.  DMID and/or the IND holder may 
terminate the study at their sole discretion. Although the sponsor had every intention of 
completing this trial, it reserves the right to terminate this trial at any time for clinical or 
administrative reasons. Reasons for termination include, but not limited to, study closure due to 
DSMB review and recommendation and at the discretion of DMID. 
 
If the study is prematurely terminated by the sponsor, any regulatory authority, or the 
investigator for any reason, the investigator will promptly inform the study subjects and assure 
appropriate therapy or follow-up for the subjects, as necessary. The investigator will provide a 
detailed written explanation of the termination to the IRB/IEC. 
 
 
5.3.6 Recruitment and Retention 
Study subjects are seen either inpatient or clinic setting, and the Transplant Infectious Disease 
team is notified and consulted on all patients diagnosed with Norovirus. All candidates at all 
centers that are eligible to be included in the study will be offered the opportunity to participate 
in the trial. 
The transplant patient population have a proven track record of a high compliance and retention 
rate in research related activities. The study subject clinical appointments will be adjusted to 
coincide with their research visit windows to ensure convenience.  In addition, the subjects will 
be compensated for their research study visit. 


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6 
STUDY INTERVENTION/INVESTIGATIONAL PRODUCT 
6.1 
Study Product Description 
Nitazoxanide is a synthetic antiprotozoal agent for oral administration. It is designated 
chemically as 2-acetyloxy-N- (5-nitro-2-thiazolyl) benzamide. The molecular formula is 
C12H9N3O5S and the molecular weight is 307.3.  The placebo will look identical to nitazoxanide, 
and will have the same inactive ingredients (described in section 6.1.2). 
6.1.1 Acquisition 
Romark, L.C. will provide any necessary nitazoxanide 500mg tablets and matching placebo at no 
cost. Upon request from DMID, the study products (nitazoxanide and placebo) will be shipped to 
the following address:  
DMID Clinical Materials Services (CMS)  
Fisher BioServices 
20439 Seneca Meadows Parkway 
Germantown, MD 20876 
Phone: 240-477-1350 
Fax: 240-477-1360 
Email: DMID.CMS@ThermoFisher.com 
Study products, nitazoxanide 500mg tablets and matching placebo will be shipped from DMID 
CMS to investigational site upon request and approval by DMID. 
6.1.2 Formulation, Packaging, and Labeling 
 
Nitazoxanide Tablets 
Nitazoxanide will be supplied as a 500 mg round, yellow, film-coated tablet with “CTM” 
imprint, manufactured by Romark, L.C. Per the package insert, inactive ingredients include: 
maize starch, pregelatinized corn starch, hydroxypropyl methylcellulose, sucrose, sodium starch 
glycollate, talc, magnesium stearate, soy lecithin, polyvinyl alcohol, xanthan gum, titanium 
dioxide, FD&C Yellow No. 10 Aluminum Lake, FD&C Yellow No. 6 Aluminum Lake, and 
FD&C Blue No. 2 Aluminum Lake.  
 
Placebo Tablets 
Placebo will be supplied as a matching tablet of the active drug which will also be a round, 
yellow, film-coated tablet with “CTM” imprint.  Ingredients include: lactose monohydrate, 
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Yellow No. 10 Aluminum Lake, FD&C Yellow No. 6 Aluminum Lake, and FD&C Blue No. 2 
Aluminum Lake. In order to maintain the blind, the placebo will be formulated for the same 
appearance as the active study drug. 
 
Package and Labeling 
All study product will be packaged in two 60cc identical containers each containing 30 tablets. 
Each container will also be labeled in compliance with applicable regulatory requirements, 
including the FDA-required cautionary statement “Caution: - New drug -Limited by Federal 
Law to Investigational Use.”   
 
6.1.3 Product Storage and Stability 
Nitazoxanide and Placebo for Nitazoxanide tablets must be stored at 25°C (77°F); excursions are 
permitted to 15-30°C (59-86°F). [See USP Controlled Room Temperature]. 
The temperature of the storage unit must be manually recorded daily (excluding non-business 
days and holidays, as applicable) and continuously monitored and recorded during the course of 
this trial per the participating site standard operating procedures (SOPs), and documentation will 
be maintained. If the temperature fluctuates outside of the required range, the affected study 
product(s) must be quarantined at the correct storage temperature and labeled as ‘Do Not Use’ 
(until further notice). The participating site’s research pharmacist must alert the site principal 
investigator and study coordinator, if the temperature fluctuates outside of the required range. In 
the event the temperature fluctuates outside of the required range, including accidental deep-
freezing or disruption of the cold chain, the affected study product(s) must not be administered. 
The site principal investigator or responsible person should immediately contact the DMID 
Product Support Team at DMIDProductSupportTeam@niaid.nih.gov for further instructions 
before any additional study productare administered. Based on the information collected, DMID 
and/or the manufacturer will determine whether the affected study product(s) can be used. If it 
cannot be used, the site will receive specific instructions on how to return the affected study 
product(s) to the DMID CMS or destroy it on site.  
For subjects in the hospital, the participating sites will maintain a temperature log to record 
temperature once per day in the room where the study products are stored for the period that the 
patient is in the hospital. 
 


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6.2 
Dosage, Preparation and Administration of Study 
Intervention/Investigational Product 
Nitazoxanide (administered orally as one 500 mg tablet) or placebo (administered orally as a 
matching tablet) twice daily with food for 56 doses. If the patient is NPO, product can be taken 
with water.  
 
Subjects in the hospital will be provided the study drug consistent with the site SOP while 
ambulatory subjects will be provided two bottles, each containing 30 tablets. 
 
A Site Research Pharmacist may be delegated the responsibility of study product dispensation. 
The Research Pharmacist must be a licensed, registered pharmacist and is the preferred 
healthcare practitioner to be delegated to perform this activity. If a Research Pharmacist is not 
available, a physician, nurse practitioner, physician assistant, registered nurse, or other 
authorized healthcare practitioner who is a member of the clinical study staff may be delegated 
to dispense the study product. These personnel must be licensed, trained, and qualified to prepare 
investigational study product and must be authorized to dispense the study product under state 
and local rules and regulations.  
 
6.3 
Modification of Study Intervention/Investigational Product for a 
Participant 
There will be no modification of the dose of nitazoxanide during the 56 dose treatment phase.  
Subject’s discontinuation of study treatment will be determined by the study site physician.  
 
6.4 
Accountability Procedures for the Study Intervention/Investigational 
Product(s) 
Study product will be stored and shipped from the DMID contract repository, Fisher 
BioServices, to the Clinical Sites. Once received, study product will be stored in and dispensed 
by the Investigational Pharmacy.  
Used/opened product will be counted and disposed in accordance with site’s SOPs with two staff 
members (two research pharmacists or a research pharmacist and/or a study team member) 
present co-signing and verifying the count (see MOP for additional detail).  In addition, this 
verification form will be added to the protocol file so that DMID monitors can verify when at the 
sites for a routine IMV. In addition, used/opened product can also be retained until monitored 
and released for disposition, as applicable. 
The United States Food and Drug Administration (FDA) requires accounting for the disposition 
of all investigational products. The Investigator is responsible for ensuring that a current record 


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of product disposition is maintained, and product is dispensed only at an official study site by 
authorized personnel as required by applicable regulations and guidelines. Records of product 
disposition, as required by federal law, consist of the date received, date administered, quantity 
administered, and the subject number to whom the drug was administered.  
The Investigational Pharmacist will be responsible for maintaining accurate records of the 
shipment and dispensing of the investigational product. The pharmacy records must be available 
for inspection by the DMID monitoring contractors, and is subject to inspection by a regulatory 
agency (e.g., FDA) at any time. An assigned Study Monitor will review the pharmacy records. 
 
Unused investigational product will be stored at 25°C (77°F); excursions permitted to 15-30°C 
(59-86°F) [See USP Controlled Room Temperature] in the Investigational Pharmacy until 
monitored and released for disposition as applicable. At study completion or termination, all 
unused investigational product will be disposed in accordance with the MOP following complete 
drug accountability and monitoring. Final disposition of the unused study product will be 
determined by DMID and communicated to the participating sites by the DMID Clinical Project 
Manager. 
6.5 
Assessment of Subject Compliance with Study 
Intervention/Investigational Product  
Subjects will be requested to bring study drug with them to all visits during the Treatment Phase.  
Remaining pill count will be done by the site staff during each visit to assess compliance.  If 
subjects forget to bring in their study drug or they lose their container, subject interview and 
study diary will be used to confirm medication adherence.  
6.6 
Concomitant Medications/Treatments 
Subjects may receive any therapy that is deemed appropriate to treat the signs and symptoms of 
Norovirus after randomization at the discretion of their treating provider except for nitazoxanide 
and oral immunoglobulin. This can include: 
 
• 
Intravenous immunoglobulin 
• 
Changes in immunosuppression 
• 
Anti-motility agents 
 
Any treatment utilized should be included on the concomitant medications at the time of 
enrollment. Any concomitant medication pre- or post-randomization that is being used to treat 
the signs or symptoms of Norovirus should be marked as such on the Case Report Form for the 
entire duration of the study.  Likewise, any change to immunosuppressive therapy would have a 


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note in the Case Report Form noting if the change was made because of elevated drug levels, for 
treatment of Norovirus or for other purposes. Concomitant medications will be collected through 
visit 12 (Day 180 after initial dose of study treatment) or early termination, whichever occurs 
first. If the Investigator learns that the subject has taken a prohibited medication (see 
inclusion/exclusion criteria) prior to the last dose, the Investigator will contact the DMID 
Medical Officer and CPM for instructions regarding the subject’s continuation in the study. 
 
Medications that might interfere with the evaluation of the investigational product should not be 
used unless absolutely necessary. 


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7 
STUDY SCHEDULE 
The study will need to enroll 160 subjects who meet inclusion and exclusion criteria and agree to 
participate in the study (Section 5.1, 5.2-Subject Inclusion Criteria, Subject Exclusion Criteria).  
Upon enrollment in the study, subjects will be randomized into two treatment groups:  active 
nitazoxanide and placebo: 
 
a. Nitazoxanide Arm:  All subjects age ≥ 12 years:  500 mg (one tablet) nitazoxanide by 
mouth twice daily with food for 56 consecutive doses. 
b. Placebo Arm:  All subjects age ≥ 12 years:  Placebo (one tablet) by mouth twice daily 
with food for 56 consecutive doses. 
Randomization will be stratified by age group (adult vs. pediatric), chronicity of Norovirus-
associated symptoms (acute vs. chronic) and transplant type (HSCT vs. SOT) as follows: 
 
• Duration of Symptoms:  onset of Norovirus-associated symptoms (diarrhea, nausea    
and/or abnormal appetite) < 14 days vs. ≥ 14 days 
• Transplant Type:  solid organ vs. hematopoietic stem cell transplant 
• Age Range:  pediatric (12-17 years) vs. adult ≥ 18 years 
Both investigators and subjects will be blinded to study treatments.  Subjects will take study 
product preferably with food for 56 consecutive doses. If the study subject has an episode of 
emesis or spits out the study medication within one hour of administration, the event will be 
documented in the subject’s record and then the full dose will be re-administered one time only 
per scheduled dose. All subjects must have therapy discontinued after taking 56 doses.   
If a subject misses a dose, they will be instructed to skip that dose and resume taking their next 
dose as scheduled and to record the missed dose on their Subject Diary. 
If symptoms recur after discontinuing therapy, subjects can resume any therapy at the discretion 
of the principal investigator or his/her designee with the exception of nitazoxanide.  
Nitazoxanide can be used after Day 28 if the local PI attests that it is medically urgent to use the 
nitazoxanide because the patient is experiencing severe or life-threatening disease.  Although 
nitazoxanide can be used if it is felt critical to the subjects care, its use should be avoided until 
Day 180 whenever felt to be safe to do so by the local PI.  Any use of nitazoxanide beyond Day 
28 will be documented on the concomitant medication form and prescribed from commercial 


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stock and not provided by the study.  Additional stool specimens should be collected prior to 
initiation of therapy for testing in the central lab when feasible. 
The study will have 2 phases: 
1. Treatment Phase (Study Day 1-28) 
2. Longitudinal Monitoring Phase (Study Day 29-180) 
7.1 
Screening/Baseline/Treatment Phase  
Any subject ≥ 12 years of age, recipient of a solid organ or hematopoietic stem cell transplant 
with a positive test for Norovirus within 7 days as part of routine clinical care will be approached 
to participate in the study.  Once consent is obtained, then laboratory testing and medical history 
will be reviewed to determine eligibility unless local IRB waiver allows to review data prior to 
consent. Assessment required for eligibility may not be measured more than twice. 
a. Screening/Enrollment/Baseline  
• Consent/Assent will be reconfirmed with eligible subjects, consistent with local 
IRB policy for consent and assent of subjects. 
• Subject and their chart will be reviewed to collect a medical history, concurrent 
medications. 
• Urine pregnancy test will be obtained from women of childbearing potential. 
Results must be known and negative prior to dosing. 
• WBC, TLC (Total Lymphocyte Count) Hb, Platelets (Derived from Complete 
Blood Count -within 3 days of enrollment). 
• Creatinine, Alk Phos, AST, ALT, BUN, Bilirubin (Derived from Complete 
Metabolic Panel-within 3 days of enrollment). 
• T Cell Subsets will be drawn unless CBC shows an ALC <100.   
• Samples to be sent to the central laboratory are collected and processed: 
▪ Buccal swab and saliva samples for secretor assay. 
▪ Stool for quantitative Norovirus RT-PCR and sequencing. 
▪ Stool for other pathogen testing. 
▪ Stool for Norovirus-specific IgA, IgG, and IgM studies. 
• Serum for quantitative Norovirus-specific IgA, IgG, and IgM and total IgG. 
• Randomization. 
• Vital signs will be obtained (pulse, temperature, BP, respiration, height and 
weight). 
• Weekly Recall Packet will be administered.  
• Detailed Subject Reported Outcome and Severity Score Assessment. 
• Physical examination will be performed. 


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• Plastic bag with two 30-count bottles of study product will be dispensed to the 
subject. The first dose of study product (nitazoxanide or placebo) will be given by 
the study team.   
 
The study product (nitazoxanide or placebo) will be taken by the subject twice daily for 28 days. 
 
Subjects will be given a paper diary (to inquire about symptoms and severity along with overall 
well-being) that will be completed daily, at the time of study product dosing.  The time of study 
product dosing will also be recorded. This will be completed on a daily basis through day 28.  
The pack of paper diary along with instructions that is given at enrollment will cover the entire 
study period.  
 
The stool sample must have been produced within 24 hours of the visit and if it exceeds 24 hours 
it must be disposed. Subject would be encouraged to provide another sample within the visit 
window and if not, a rectal swab may be used for virus detection.  
 
b. Study Day 7 ± 3 days 
• Collection and review of completed diary pages. 
• WBC, TLC, Hb, Platelets (Derived from Complete Blood Count).  
• Creatinine, Alk Phos, AST, ALT, BUN, Bilirubin (Derived from Complete 
Metabolic Panel).   
• Pill count to assess adherence. 
• Samples of stool (collected at home or at clinic) to be sent to the central 
laboratory are collected and processed: 
▪ Stool for quantitative Norovirus RT-PCR and sequencing. 
▪ Stool for other pathogen testing; stool will be stored for later testing 
and this assay will not be performed for formed stool after Day 1.   
▪ 
Nitazoxanide PK drawn 1-4 hours after the subject takes his/her dose, for subjects 
consenting to this optional assessment.  The time of the blood draw and the time 
of the previous dose will be recorded. 
▪ Vital signs (temperature, BP, respiration, weight and pulse) will be obtained. 
▪  Weekly Recall Packet will be administered (Table 5). 
▪ Collect concurrent medications. 
▪ Inquiry about hospitalization since last assessment. 
▪ Assess for adverse events.  
 
c. Study Day 14 ± 3 days:  Virtual Visit 
• 
Team to call subject 


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• 
Review of completed diary pages. 
• 
Subject to collect stool sample and store in freezer until day 28 study visit  
• 
Weekly Recall Packet will be administered (Table 5). 
• 
Collect concurrent medications. 
• 
Inquiry about hospitalization since last assessment. 
• 
Assess for adverse events. 
 
d. Study Day 21 ± 3 days- Virtual Visit except for patients who agree to optional PK study 
• Team to call subject not enrolled in the PK Sub Study (those patients will have in 
person visit) 
• Review of completed diary pages. 
• Subject to collect stool sample and store in freezer until day 28 study visit. 
• For patients in the PK Sub Study: 
▪ Samples of stool to be sent to the central laboratory are collected and 
processed: 
o Stool for quantitative Norovirus RT-PCR and sequencing. 
o Stool for other pathogen testing; stool will stored for later testing 
and this assay will not be performed for formed stool after Day 1. 
▪ Nitazoxanide PK drawn 10 minutes before the subject takes his/her dose, 
for subjects consenting to this optional assessment.  The time of the blood 
draw and the time of the previous dose will be recorded. 
• Weekly Recall Packet will be administered (Table 5) 
• Collect concurrent medications. 
• Assess for adverse events. 
• Inquiry about hospitalization since last assessment. 
 
e. Study Day 28 + 3 days 
All subjects should have dosing of medication stopped after 56 doses and residual medication 
returned.  If this occurs after the day 28 visit, the patient should be informed of the date and time 
of the last dose and return the residual medications and bottles on Study Day 60. 
• 
Collection and review of completed diary pages. 
• 
WBC, TLC, Hb, Platelets (Derived from Complete Blood Count). 
• Creatinine, Alk Phos, AST, ALT, BUN, Bilirubin (Derived from Complete 
Metabolic Panel).   
• 
Samples of stool (collected at home or at clinic) to be sent to the central 
laboratory are collected and processed: 
▪ 
Stool for quantitative Norovirus RT-PCR and sequencing. 


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▪ 
Stool for other pathogen testing; stool will stored for later testing and 
this assay will not be performed for formed stool after Day 1. 
▪ 
Stool Norovirus-specific IgA, IgG, and IgM studies. 
• Serum for quantitative Norovirus-specific IgA, IgG, and IgM and total IgG. 
• Vital signs will be obtained (temperature, BP, pulse, respiration and weight). 
• Weekly Recall Packet will be administered (Table 5). 
• Detailed PROs packet will be collected (Table 5). 
• Collect concurrent medications. 
• Assess for adverse events. 
• Physical examination will be performed. 
• Inquiry about hospitalization since last assessment. 
• Pill count to assess adherence and left-over pills will be collected by study 
coordinator.  
 
Instructions will be given to subjects for the Longitudinal Monitoring Phase diary (Diary 29-180 
days) at the Day 28 visit.   
 
If symptoms recur after discontinuing therapy, subjects can resume any therapy at the discretion 
of the principal investigator or his/her designee.  Additional stool specimens should be collected 
prior to initiation of therapy for testing in the central lab, including stool for quantitative 
Norovirus PCR, sequencing and other pathogen testing when feasible. 
 
e. Study Day 35 ± 3 days: Telephone Call for an update to health status and reminder 
for appointment 
• Collect concurrent medications. 
• Assess for adverse events.  
• Inquiry about hospitalization since last assessment. 
• Weekly Recall packet will be administered by the coordinator on the phone. 
 
f. Day 53 ± 7 days-Telephone Call for an update to health status and reminder for 
appointment 
• 
Weekly Recall packet will be administered by the coordinator on the phone. 
• 
Appointment reminder for the next scheduled visit. 
 
g. Study Day 60 ± 14 days: Option to do as a virtual visit or in person visit.  Must be in 
person if medication not collected on day 28 visit. 


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• A pill count will be conducted if the patient did not complete dosing at the Day 28  
visit. 
• Review of completed diary pages. 
• Subject to collect stool sample and store in freezer until day 120 or 180 study 
visit. 
▪ Samples of stool to be sent to the central laboratory are collected and 
processed (if in person visit): 
▪ Stool for quantitative Norovirus RT-PCR and sequencing. 
▪ Stool for other pathogen testing; stool will stored for later testing and 
this assay will not be performed for formed stool after Day 1. 
▪ Stool Norovirus-specific IgA, IgG, and IgM studies. 
• Daily Diary and Detailed PROs packet will be collected (Table 5)  
• Weekly Recall Packet will be administered (Table 5) 
• Collect concurrent medications. 
• Inquiry about hospitalization since last assessment. 
• Assess for adverse events. 
h. Study Day 113 ± 7 days-Telephone call for update to health status and reminder for 
appointment 
• Weekly Recall packet will be administered by the coordinator on the phone. 
• 
Appointment reminder for the next scheduled visit. 
 
i. Study Day 120 ± 14 days: Option to do as a virtual visit or in person visit 
• Review of completed diary pages. 
• Subject to collect stool sample and store in freezer until day 180 study visit. 
• Samples of stool  to be sent to the central laboratory are collected and processed(if 
in person visit): 
▪ Stool for quantitative Norovirus RT-PCR and sequencing. 
▪ Stool for other pathogen testing; stool will stored for later testing and 
this assay will not be performed for formed stool after Day 1. 
▪ Stool Norovirus-specific IgA, IgG, and IgM studies. 
• Daily Diary and Detailed PROs packet will be collected (see Table 5). 
• Weekly Recall Packet will be administered (Table 5) 
• Collect concurrent medications. 
• Inquiry about hospitalizations since last assessment. 


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j. Study Day 173 ± 7 days-Telephone call for update to health status and reminder for 
appointment 
• Weekly Recall Packet will be administered by the coordinator on the phone. 
• 
Appointment reminder for the next scheduled visit. 
k. Study Day 180 ± 14 days 
• Collection and review of completed diary pages. 
• WBC, TLC (Total Lymphocyte Count) Hb, Platelets (Derived from Complete 
Blood Count).  
• Creatinine, Alk Phos, AST, ALT, BUN, Bilirubin (Derived from Complete 
Metabolic Panel. 
• T Cell Subsets will be drawn unless CBC shows an ALC <100.   
• Samples of stool (collected at home or at clinic) to be sent to the central
 
laboratory are collected and processed: 
▪ Stool for quantitative Norovirus RT-PCR and sequencing 
▪ Stool for other pathogen testing; stool will stored for later testing and 
this assay will not be performed for formed stool after Day 1. 
▪ Stool Norovirus-specific IgA, IgG, and IgM studies 
• Serum for quantitative Norovirus-specific IgA, IgG, and IgM and total IgG. 
• Vital signs (temperature, BP, pulse, respiration and weight) will be obtained. 
• Daily Diary and Detailed PROs packet will be collected (see Table 5). 
• Weekly Recall Packet will be administered (Table 5) 
• Collect concurrent medications. 
• Inquiry about hospitalizations since last assessment. 
7.2 
Follow-up  
All subjects will be followed weekly while on study medication (visits on study Day 1, 7, 14, 21 
and 28) and will be called 1 week after stopping medication to assess their clinical status and to 
assess for any adverse events.  Subject will have laboratory assessments (WBC with total 
lymphocyte count), Hb, Platelets-derived from complete blood count and Creatinine, Alk Phos, 
AST, ALT, BUN, Bilirubin-derived from comprehensive metabolic panel) on study Day 1, 7, 28 
and 180.  Subjects will also be seen on study Day 60, 120 and 180 as part of the longitudinal 
monitoring phase of the study.  If subjects develop recurrent diarrheal symptoms between visits, 
they should alert the study team, provide a sample of stool for central assessment and assessment 
locally.  Likewise, if they develop adverse events between visits, they should alert the study 
team.  More frequent evaluation can be done at the clinician’s discretion. (Please refer to 
Appendix A and Section 7 for details of study evaluations at each visit) 


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7.3 
Final Study Visit 
The final study visit will take place on study Day 180 ± 14 days or if the subject withdraws from 
the study at an earlier time point.  For any ongoing adverse event or serious adverse event, the 
subject should be followed until resolution of the event. (Please refer to Appendix A and Section 
7 for details of study evaluations at final visit) 
7.4 
Early Termination Visit 
If a subject is terminated from the study, they will be asked to return to the site as soon as 
possible after termination but no greater than 7 days after the decision to terminate them from the 
study.  At this visit, the subject should return all unused study medication, their diary, and all 
procedures planned for Day 180 should be completed on this day.  If termination is due to an 
adverse event or serious adverse event, the subject should be followed until resolution of the 
event with the consent from the subject. (Please refer to Appendix A for details of study 
evaluations at each visit) 
7.5 
Unscheduled Visit  
If subjects develop recurrent diarrheal symptoms between visits, they should alert the study 
team, provide a sample of stool for central assessment and assessment locally.  If the patient 
comes to the study site for an unscheduled visit, the patient should have vital signs, assessment 
for adverse events and review the patient diary and weekly PRO packet; laboratory assessments 
will only be collected if standard of care labs are ordered by the study team.  Likewise, if they 
develop adverse events between visits, they should alert the study team.  More frequent 
evaluation can be done at the clinician’s discretion. (Please refer to Appendix A for details of 
study evaluations at each visit) 


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8 
STUDY PROCEDURES/EVALUATIONS 
8.1 
Clinical Evaluations 
1. Medical History 
2. Physical Exam 
3. Vital Signs including weight 
4. Review of Concurrent Meds 
5. Assessment for adverse events 
6. Daily and Recall Diary (See Appendix C) 
7. Weekly Patient Reported Outcomes Tool (See Appendix C) 
 
To minimize missing diary data, we have added a recall diary protocol, administered by the 
coordinator at the appointment reminder call, which can be used to offset any missing daily diary 
data. In a subset of participants enrolled in Irritable Bowel Syndrome Outcome Study, IBSOS, 
prospective daily diary was aggregated across 7 days and served as the “gold standard” by which 
to compare end-of-period self-reported recall of symptoms over the past 7 days.94  The 
participant groups’ mean level of symptom severity based on weekly recall were within one 
point of each other for the core symptoms in this trial: diarrhea frequency and consistency 
[Bristol Stool Scale], urgency, and abdominal pain.  If at all, participants were likely to over-
estimate their symptoms on recall which would potentially favor our placebo condition.  Because 
this prospective study, included participants who were already monitoring daily symptoms as 
part of a clinical trial, we recommend our participants continue to monitor daily during 
assessment periods in case the act of daily monitoring itself influences recall at one week.  We 
will consider 80% compliance across the monitoring period acceptable [missing no more than 
1.5/7 days per week over the 8 weeks].   While we will not exclude patients, who are below this 
compliance for any monitoring period, we will conduct a sensitivity analysis comparing those 
with few missing values to those with greater than 2 missing values per week. 
 
A schematic of diary and PRO data collection is listed on the next page.   
 
8.2 
Laboratory Evaluations 
8.2.1 Clinical Laboratory Evaluations 
1. Complete Blood Count with Differential: This assay will be done in the individual site’s 
laboratory using standard methodology.  Normal ranges for the key components of the 
complete blood count (white blood cell count, neutrophil count, lymphocyte count, 
eosinophil count, monocyte, hemoglobin, hematocrit, mean corpuscular volume, and platelet 
count) will be obtained for each site. Assessment of these lab values will be conducted as 


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per described in Section 9.1 The Complete Blood Count will be collected as this generally 
considered standard of care by transplant centers, but only white blood cell count, 
hemoglobin and platelet count will be utilized for safety outcomes. 
Comprehensive Metabolic Panel:  This assay will be done in the individual site’s laboratory 
using standard methodology.  Normal ranges for the comprehensive metabolic panel 
(sodium, potassium, bicarbonate, chloride, blood urea nitrogen, creatinine, glucose, calcium, 
albumin, total protein, alkaline phosphatase, alanine amino-transferase, aspartate amino-
transferase, and bilirubin) will be obtained for each site.  Assessment of these lab values will 
be conducted as per described in Section 9.1.  The Comprehensive Metabolic Panel will be 
collected as this is generally considered standard of care by transplant centers but only 
sodium, potassium, creatinine, alkaline phosphatase, alanine amino-transferase, aspartate 
amino-transferase, and bilirubin will be utilized for safety outcomes.  
2. Urine Pregnancy Test:  This assay will be done in the individual site’s laboratory using 
standard methodology and must utilize an FDA-approved, cleared, or licensed test system. 
3. T-Cell Subsets:  This assay will be done in the individual site’s laboratory using standard 
methodology to provide absolute number and % of CD3+, CD4+ and CD8+ cells. 
4. Stool for Pathogen Screen:  This assay will be performed in the Diagnostic Infectious 
Diseases Testing Laboratory (Cincinnati Children’s Hospital Medical Center (CCHMC, 
Cincinnati, OH) which will be provided a 1-gram aliquot of stool from the Jiang Laboratory.  
Day 1 stool specimen and non-formed stool samples from subsequent visits will be screened 
for additional pathogens (Bacteria- Campylobacter (jejuni, coli and upsaliensis), 
Clostridium difficile (Toxin A/B), Plesiomonas shigelloides, Salmonella species, Yersinia 
enterocolitica, Vibrio species (parahaemolyticus, vulnificus and cholerae), Diarrheagenic 
E.coli/Shigella including, Enteroaggregative E. coli (EAEC), Enteropathogenic E. coli 
(EPEC), Enterotoxigenic E. coli (ETEC), Shiga-like toxin-producing E. coli (STEC), 
Shigella/Enteroinvasive E. coli (EIEC); Parasites- Cryptosporidium, Cyclospora 
cayetanensis, Entamoeba histolytica, Giardia lamblia; Viruses - Adenovirus F40/41, 
Astrovirus, Norovirus GI/GII, Rotavirus A, Sapovirus (I, II, IV and V)) using the  FDA-
cleared FilmArray system from BioFire Diagnostics (bioMerieux, Marcy l’Etoile, France).  
After collection in the stool hat, the subjects can wipe down and disinfect the outside of the 
container and place it in a bag for transport then refrigerate until they come to their visit 
with the research staff. The sample must have been produced within 24 hours of the visit 
and if it exceeds 24 hours it must be disposed. Subject would be encouraged to provide 
another sample within the visit window and if not, a rectal swab may be used for virus 
detection. 


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Table 5:  Protocol PRO Completion Guide 
Phase 
Treatment 
Post-treatment monitoring 
Unsche
duled 
Visit 
Early 
Termin
ation 
Visit 
Assessment 
Time Point 
Screen 
Enroll 
Day 1 
Day 7 
(±3 d) 
Day 
14₩ 
(±3 d) 
Day 
21₩ 
(±3d) 
Day 28 
(+3 d) 
Day 
35 (± 
3d) 
*Day 
53 
(±7d) 
₩Day 
60 
 (±14 d) 
*Day 
113 
 ±7d 
₩Day 
120 
 (±14 d) 
*Day 
173 
 ±7d 
Day 180 
(±14 d) 
Daily Diary 
  
Days  
1-7 
Days    
8-14 
Days    
15-21 
Days    
22-28 
 
 
Days      
29-60 
 
Days  
61-120 
 
Days 
121-180 
 X 
Last 
week 
before 
term 
Weekly Recall/ 
Phone Packet 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
Detailed PROs 
Packet 
X 
  
  
  
X 
  
 
X 
 
X 
 
X 
  
X 
  
Daily Diary: To be completed by subject daily.  Diary 1-28 days; Diary 29-180 days  See MOP for details. 
Weekly Recall Packet:  To be completed by study staff.  See MOP for details. 
Detailed PROs Packet:  To be completed by study staff.  This will include PROMIS and QOL Questionnaires. See MOP for details. 
*Phone call-Appointment reminder and Weekly Recall Packet to be completed 
₩Can be Virtual Visits 


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8.2.2 Special Assays or Procedures 
1. Stool for Norovirus Assays:  These assays will be performed in the Jiang Laboratory 
(CCHMC, Cincinnati, OH).  Bulk stool samples are collected from subjects and aliquoted 
on site into cryovials. Aliquots are frozen at <-70°C before shipment to the Jiang Lab.  One-
gram bulk stool aliquots are necessary for the following assays. 
a. Norovirus Quantitative RT-PCR (qRT-PCR):  Stool suspensions (10% w/v) will be 
prepared in sterile water. Viral RNA will be purified from the clarified extracts using the 
QiaAmp Viral Mini kit (Qiagen) according to the manufacturer’s instructions. The viral 
RNA will be eluted in a final volume of 60ul. Each sample will be tested in triplicate 
using the TaqMan Fast Virus 1-Step Master Mix (Applied Biosystems). GI NoVs are 
amplified with forward primer – QNIF4 5’CGC TGG ATG CGN TTC CAT, reverse 
primer – NV1LCR 5’CCT TAG ACG CCA TCA TTT AC, and probe – NV1LCpr 
5’VIC-TGG ACA GGA GAY CGC RAT CT-MGBNFQ, while GII NoVs are amplified 
with forward primer – QNIF2d 5’ATG TTC AGR TGG ATG AGR TTC TCW GA, 
reverse primer – Cog2R 5’TCG ACG CCA TCT TCA TTC ACA, and probe – RING2 
5’6-FAM-TGG GAG GGC GAT CGC AAT CT-MGBNFQ. Real-time RT-PCR will be 
performed using the 7500 Fast Real-time PCR System (Applied Biosystems). All samples 
will be compared among each other, as well as against known GI and GII positive 
controls for relative Ct values. 
Stool  samples  will  be  processed  for  extraction  of  norovirus  RNAs.  RT-PCR  will  
be  performed  via  a  standard  procedure  using  primers  targeting  the  RNA-dependent  
RNA  polymerase  gene  of  norovirus  genome.  This  will  result  in  a  319-nucleotide  
fragment  as  PCR  products.  PCRs  will  contain  40  cycles  of  amplifications;  a  
positive  and  negative  control  will  be  included  to  make  sure  PCR  being  working.  
As  explained  above,  stool  sampling  will  be  performed according  to  an  SOP;  there  
is  no  approaches  at  the  laboratory  level  to  account  for  sampling  error.  The  PCR  
product  of  norovirus  genome  fragment  will  be  sequenced  at  CCHMC’s  DNA  
Sequencing  Core  Facility  equipped  with  state-of-the-art  capillary  DNA  analyzers  
(Sanger  Sequencing). 
b. Norovirus Genotyping:  Once NoV-positive samples have been identified by qRT-PCR, 
routine RT-PCR and sequencing can be employed to identify genotype. This 
amplification uses a set of primers (p289H,I/p290H,I,J,K) designed to detect all NoV 
genotypes. PCR products are run on an agarose gel and visible bands at the correct size 
are cut from the gel, purified, and sequenced. Sequences are compared to published NoV 
sequences with known genotypes downloaded from GenBank to determine genotype. 
c. Norovirus Phylogenetic Analysis:  After sequencing RT-PCR products from subjects 
over the course of the study to determine genotype, as described above, sequences from 
the same subject over time will be compared to identify mutations. Various analyses can 
be performed to assess sequences changes over time. 


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2. Stool for Norovirus-Specific Immunoglobulin Studies:  These assays will be performed in 
the Jiang Laboratory (CCHMC, Cincinnati, OH).  Bulk stool samples are collected from 
subjects and aliquoted on site into cryovials. Aliquots are frozen at <-70°C before shipment 
to the Jiang Lab.  One-gram bulk stool aliquots are necessary for the following assays.  For 
stool Norovirus-specific IgA, IgM and IgG studies, a 96-well microtiter plates are coated 
with rabbit antibody specific to Noroviruses overnight at 4°C. Following a wash the plates 
are blocked with 5% nonfat dry milk. For Norovirus-specific Igs, purified Norovirus P-
particles (PP) are then added. After incubation 1 hour at 37°C, dilutions of subject 10% 
stool suspensions are added and the plates are incubated at 37°C for 1 hour. Horseradish 
peroxidase conjugated goat anti-human Ig antiserum is then added to each plate. After 
incubation the wells are washed and TMB substrate solution is added to each well followed 
by incubation at room temperature. The reaction is stopped by the addition of 1M 
Phosphoric Acid.  Plates are read using an EIA spectra reader (at a wavelength of 450 nm 
according to manufacturer’s instructions). All assays will include positive and negative 
control stool. 
3. Stool Pathogen Screen: The Stool Pathogen Screen will utilize the BioFire FilmArray 
Gastrointestinal Panel to screen for a range of pathogens (Campylobacter (C. jejuni/C. 
coli/C. upsaliensis),Clostridium difficile (C. difficile) toxin A/B, Plesiomonas 
shigelloides, Salmonella, Vibrio (V. parahaemolyticus/V. vulnificus/ V. cholerae), including 
specific identification of Vibrio cholerae, Yersinia enterocolitica, Enteroaggregative 
Escherichia coli (EAEC), Enteropathogenic Escherichia coli (EPEC), Enterotoxigenic 
Escherichia coli (ETEC) lt/st, Shiga-like toxin-producing Escherichia coli (STEC) stx1/stx2 
(including specific identification of the E. coli O157serogroup within STEC), Shigella/ 
Enteroinvasive Escherichia coli (EIEC), Cryptosporidium, Cyclospora 
cayetanensis, Entamoeba histolytica, Giardia lamblia (also known as G. intestinalis and G. 
duodenalis), Adenovirus F 40/41, Astrovirus, Norovirus GI/GII, Rotavirus A, Sapovirus 
(Genogroups I, II, IV, and V)). The samples are placed in Cary-Blair. Test is performed 
according to manufacturer’s instructions. Once completed, the results are reviewed for 
internal controls and possible pathogen detection. The internal controls must be positive for 
the run to pass. If controls fail, the samples is retested with a new pouch. Any unusual 
pathogens detected will be brought to the attention of the Director and study PI.  
4. Serum for Immunoglobulin Assays:  These assays will be performed in the Jiang Laboratory 
(CCHMC, Cincinnati, OH).  For these assays, at least 4, 1 mL serum aliquots are required.  
Whole blood is collected in 10 mL SST tubes and serum is processed and aliquoted into 
cryovials at the sites and frozen at <-70°C before shipment to the Jiang Lab. 
a. Quantitative Total IgG Level:  Total IgG levels are also measured using a similar EIA 
method. Instead of coating Norovirus-specific antibodies to the microtiter plates, anti-IgG 
antibodies are used for the initial coating before addition of subject serum samples. 
Similar to above, horseradish peroxidase conjugated anti-human Ig antiserum is added to 
each plate before TMB substrate and phosphoric acid addition and measurement. Known 


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standard concentrations of total IgG can be included for quantitative assessment of 
subject samples compared to the standards. 
b. Norovirus-Specific Serum IgA, IgM and IgG:  96-well microtiter plates are coated with 
rabbit antibody specific to Noroviruses overnight at 4°C. Following a wash the plates are 
blocked with 5% nonfat dry milk. For Norovirus-specific Igs, purified Norovirus P-
particles (PP) are then added. After incubation 1 hour at 37°C, subject serum samples are 
added and the plates are incubated at 37°C for 1 hour. Horseradish peroxidase conjugated 
goat anti-human Ig antiserum is then added to each plate. After incubation the wells are 
washed and TMB substrate solution is added to each well followed by incubation at room 
temperature. The reaction is stopped by the addition of 1M Phosphoric Acid.  Plates are 
read using an EIA spectra reader (at a wavelength of 450 nm according to manufacturer’s 
instructions). All assays will include positive and negative control serum. 
 For the NoV-specific ELISAs, they will be performed for subjects after the sample           
genotyping has been completed. Since we are interested in the antibody responses in each 
subject, the antigens in the ELISAs will match their genotypes. The ELISA SOPs (see 
MOP) gives the example of our NoV GII.4 P-domain protein as the antigen that we make 
in-house but also states that other genotypes may be used as long as the protein 
concentration has already been determined for the antigen. 
5. Buccal Swab/Saliva for Secretor Status Phenotype and Genotype:  These assays will be 
performed in the Jiang Laboratory (CCHMC, Cincinnati, OH).  5-10 mL of saliva will be 
collected in a sterile cup and aliquot into 5 1mL tubes which can then be frozen at <-70°C C 
before being shipped to the Jiang Lab.  Buccal swab will be collected by rubbing the oral 
swab on the cheeks and gums.  This should provide enough buccal cells for the analysis. 
Swabs are stored in 1 mL distilled water in the swab container and can be sealed then frozen 
at <-70°C before shipment to the Jiang Lab. 
Both phenotypic and genotypic evaluation will be performed to compare results of the two 
methods. In the case of discordant results, for this trial, the results from the phenotypic 
method will be used to classify secretor status. 
a. Secretor Status Phenotyping:  The secretor status of individual subjects will be 
determined based on the detection of histo-blood group antigens (HBGAs) for the 
secretor antigens (Leb, Ley, H types) vs. the non-secretor antigens (Lea and Lex) in their 
saliva. In this assay, boiled human saliva samples are diluted and used to coat wells of a 
96-well EIA plate in duplicate. The HBGAs present in a sample are determined by testing 
with a panel of monoclonal antibodies specific to each individual HBGA. A set of saliva 
samples with known HBGA profiles are used as positive and negative controls, including 
at least one positive and one negative control sample for each assay. An OD result >0.2 
obtained after application of HRP-conjugated anti-mouse antibody of the correct isotope 
determines if a sample is positive for a particular HBGA. 
b. Secretor Status Genotyping: A FUT2 genotyping method using sequence specific 
primers-PCR (SSP-PCR) is based on single nucleotide polymorphisms (SNPs) of the 
FUT2 gene. Primers covering three major mutations are synthesized [wild-type 385A (5’-


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AGGAGGAATACCGCCACAT), mutated 385T (5’-GAGGAGGAATACCGCCACT), 
wild-type 428G (5’-GCTACCCCTGCTCCTGG), mutated 428A (5’-
CGGCTACCCCTGCTCCTA), wild-type 571C (5’-TAGGGGTCCATGTTCGCC), and 
mutated 571T (5’-GTAGGGGTCCATGTTCGCT)].  An antisense primer (5’-
GGCTGCCTCTGGCTTAAAG) is paired with FUT2 wild-type and mutated sense 
primers. DNA is extracted from buccal cells in saliva samples. DNA amplification is 
carried out using the following program: 95°C for 2 min, 10 cycles of 95°C for 20 sec, 
66°C for 1 min, and 70°C for 1 min; then 20 cycles of 95°C for 20 sec, 62°C for 1 min, 
and 72°C for 1 min; and a final extension at 72°C for 5 min. The human growth hormone 
gene is used as PCR internal control. 
6. Nitazoxanide Blood Levels for Pharmacokinetic Assessments:  First 20% of the subjects 
who consent (20% convenience sample) will be asked to provide PK samples. After 20% 
sample requirements have been met, NU team will notify sites as to no longer ask subject to 
participate in providing this sample. 
All samples are de-identified with only study assigned numbers. This assay will be 
conducted by SGS Biopharma SA, Wavre, Belgium who is the only company that assesses 
nitazoxanide blood levels.  Whole blood sample will be centrifuged (At 1500g during 10 
minutes at 4°C) within maximum 30 min after blood collection. Blood collection has to be 
performed in Li Hep polyproprylene collection tube. 2 aliquots of around 400µL of plasma 
will be sufficient for tizoxanide determination. A maximum of 486 days has been validated 
for the long term storage of plasma samples below -20°C. Therefore, it’s recommended to 
ship samples to the bioanalytical laboratory after maximum 400 days of storage to perform 
the analyses of tizoxanide and its glucuronide.  These will be shipped first to the Jiang lab 
and then onto SGS for testing per Romark, L.C. approved protocol.  
 
8.2.3 Specimen Preparation, Handling, and Shipping 
 
Specific collection and handling of assays will be as below (Table 6). Local laboratories should 
analyze specimens on the day of specimen collection.  
 
Specific instructions will be provided to subjects about specimen handling at home and 
transportation to the study site (outlined in the MOP). The sites may call the subjects the night 
before the in-person visit to remind the subjects to bring in the samples with them.  
 
 
  


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Table 6: Specimen Collection, Preparation, Processing and Storage 
Sample Collection 
Schedule for 
Assays  
Objective 
Study Day 
Collection 
Tube 
Processed  
Assayed* 
Processing / 
tubes 
needed 
Use as 
Storage 
Blood for Serum 
Ig studies 
(NoV-specific IgA, IgG, 
and IgM and total IgG) 
Exploratory 
1, 28 
10mL Gold 
tube 
Sites 
Jiang Lab 
1mL aliquots in 
2mL vials 
2 x 1mL 
required 
Frozen 
Samples will be shipped to 
Jiang Lab. 
Future Use 
180 
10mL Gold 
tube 
Sites 
Jiang Lab 
1mL aliquots in 
2mL vials 
2 x 1mL 
required 
Frozen 
Samples will be shipped to 
Jiang Lab 
Saliva 
Saliva for Secretor Status 
Phenotype and Genotype Exploratory 
1 
Sterile Cup 
Sites 
Jiang Lab 
1mL aliquots in 
2mL vials 
5 x 1mL 
required 
Frozen 
All samples will be 
shipped to Jiang Lab. 
Buccal Swab  for 
Secretor Status 
Phenotype and Genotype 
Exploratory 
1 
1 swab in 
1mL distilled 
water 
No processing 
Jiang Lab 
1 swab in 1mL 
distilled water 
Frozen 
All samples will be 
shipped to Jiang Lab. 
Stool 
NoV Viral Load by qRT-
PCR 
Secondary 
1, 7, 14, 21, 28, 
60, 120, 180, and 
with recurrent 
diarrhea 
1g aliquots 
Sites 
Jiang Lab 
1g aliquots 
2 x 1g required  
Frozen 
Samples will be shipped to 
Jiang Lab. 
Ig studies 
(NoV-specific IgA, IgG, 
and IgM 
Exploratory 
1, 28, 60 
1g aliquots 
Sites 
Jiang Lab 
1g aliquots 
2 x 1g required 
Frozen 
Samples will be shipped to 
Jiang Lab. 
Future Use 
14, 120, 180 
1g aliquots 
Sites 
Jiang Lab 
1g aliquots 
2 x 1g required 
Frozen 
Shipped to Jiang Lab 
NoV RT-PCR and 
Sequencing 
Exploratory 
1, 28, 60 
1g aliquots 
Sites 
Jiang Lab 
1g aliquots 
1 x 1g required 
Frozen 
Samples will be shipped to 
Jiang Lab. 
Future Use 
7, 14, 21, 120, 
180, and with 
recurrent diarrhea 
1g aliquots 
Sites 
Jiang Lab 
1g aliquots 
1 x 1g required 
Frozen 
Samples will be shipped to 
Jiang Lab 
Pathogen Screen 
(BioFire) 
Exploratory 
1, 180 (all 
subjects) also 7, 
14, 21, 28, 60, 
120, and with 
recurrent diarrhea 
if unformed stool 
on study day 
1g aliquots 
Sites 
Mortensen Lab 
1g aliquots 
1 x 1g required 
Frozen 
Samples will be shipped to 
Jiang Lab-will provide stool 
aliquots to Mortensen Lab 
(3333 Burnet Ave, ML 1010, 
Cincinnati, OH 45229) as 
requested when ready to 
perform assay. 
Backup Specimen 
Exploratory 
and Future 
Use 
1, 7, 14, 21, 28, 
60, 120, 180, and 
with recurrent 
diarrhea 
1g aliquots 
Sites 
Jiang Lab 
1g aliquots 
3 x 1g required 
Frozen 
Samples will be shipped to 
Jiang Lab 


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Initial sample collection tubes, except for the buccal swab, will be labeled with the study 
number, subject ID number, and date obtained. The buccal swab initial collection tube and all 
processed sample aliquots to be tested in the central laboratory will be barcoded. 
 
The central laboratory for this study will be Dr. Xi Jason Jiang’s laboratory at Cincinnati 
Children’s Hospital Medical Center. Northwestern will provide the sites with key required study 
consumables (e.g. blood and stool collection tubes), shipping containers and FedEx pre-paid 
shipping labels for all specimens being tested in Dr. Jiang’s laboratory  
Jiang Lab 
Attn: Ming Tan, PhD 
Division of Infectious Diseases, S8.537 
Building S, Receiving Dock 1 
240 Albert Sabin Way 
Cincinnati, OH 45229 
 
 
In addition, blood collected for the PK testing performed will be stored and sent to SGS 
Biopharma SA, Wavre, Belgium for testing; samples for PK testing will be sent to SGS 
Biopharma once per year. 
 
Frozen samples will be batched and shipments to the central laboratory will occur at minimum 
every other month after communication with Dr. Jiang’s study coordinator. All residual 
specimens will remain in the Jiang Laboratory until the end of the study. At this time unused 
sample aliquots will be returned to the NUCTC laboratory for banking. Detailed instructions for 
sample preparation, handling, storage and shipment are included in the protocol-specific Manual 
of Procedures. 
 


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9 
ASSESSMENT OF SAFETY 
9.1 
Specification of Safety Parameters 
For HSCT, the rate of survival and hospitalization is greatly dependent upon the underlying 
malignancy, the type of stem cell transplantation and the stage of disease at the time of 
transplantation.  As such, a single mortality rate is challenging to report.  The 1 year survival of 
autologous HSCT for multiple myeloma is 87.1% (95% CI 84.8-89.1%); 1 year survival for 
acute myeloid leukemia is 75.4% (95%CI 70.2-79.8%), 72.5% (95%CI 70.6-74.2%), and 64.8% 
(95%CI 63.1-66.3%) for autologous, allogeneic (HLA-identical), and allogeneic (matched 
unrelated), respectively.93 
 
 
For SOT, the rate of survival and hospitalization is greatly dependent on the specific organ, the 
indication for transplantation and the type of organ transplanted (living vs. deceased donor).  For 
patients treated at Northwestern, the 1 year survival rate is 98.3% for kidney transplant, 87.2% 
for liver transplant and 95.7% for pancreas transplant.  Admission data is typically measured at 
30 days for transplant and greatly falls off after 30 days.  At Northwestern, the rate of 30-day 
hospitalization is 28% and 13% for deceased and living donor kidney transplantation and 31% 
and 54% for deceased and living donor kidney transplantation. 
 
The safety of nitazoxanide will be assessed by the frequency of protocol specified unsolicited 
clinical adverse events, laboratory adverse events and serious adverse events. We observe the 
following safety parameters: Laboratory values, clinical assessments and subject complaints as 
collected on the subject diary.  
 
The safety follow-up period for nitazoxanide will be through day 60 and will include telephone 
based assessment on Day 35 and laboratory testing performed on Day 60. Any abnormal labs on 
Day 60 will be followed based at the discretion of the study site physician until value returns to 
the normal range or baseline level for the subject. 
9.2 
Methods and Timing for Assessing, Recording, and Analyzing Safety 
Parameters 
9.2.1 Adverse Events 
 
ICH E6 defines an AE as any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product regardless of its causal relationship 
to the study treatment.  FDA defines an AE as any untoward medical occurrence associated with 
the use of a drug in humans, whether or not considered drug related. 
 


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An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of medicinal (investigational) 
product.  The occurrence of an AE may come to the attention of study personnel during study 
visits and interviews of a study recipient presenting for medical care, or upon review by a study 
monitor 
 
Unsolicited clinical AEs are those non serious AEs that are not being collected as clinical 
outcome measures. For this study, unsolicited clinical AEs to be captured on the appropriate case 
report form, will be only those clinical AEs that meet either of the following criteria through 60 
days: 
• Result in modification in the administration of the study drug (nitazoxanide or 
placebo). 
• Result in discontinuation of the study drug (nitazoxanide or placebo). 
 
The following solicited safety laboratory parameters will be assessed on Day 7, 28 and 60: 
WBC, Hemoglobin, Platelet count, Creatinine, Alkaline Phosphatase, ALT, AST, BUN and 
Bilirubin. Additional laboratory parameters performed as part of the CBC and complete 
metabolic panel results need to be recorded in the source document with the evaluation of the site 
physician. Those additional laboratory value will need to be reported as AE only if clinically 
significant and not attributable to Norovirus infection or underlying SOT/HSCT medical 
conditions.   
 
Abnormal values observed in the clinical laboratory assessment that are conducted by the clinical 
team outside the study visits, will be reported as AE only if the site physician assess that the 
laboratory value is clinically significant and not attributable to Norovirus infection or underlying 
SOT/HSCT medical conditions. The evaluation should be recorded in the source documents. 
 
Laboratory AEs will be reported as defined in section 9.2.3. 
 
Information to be collected for these unsolicited clinical AEs and laboratory AEs includes event 
description, time of onset, clinician’s assessment of severity, relationship to study product 
(assessed only by those with the training and authority to make a diagnosis- a licensed study 
physician listed on the Form FDA 1572 as the site principal investigator or sub-investigator), and 
time of resolution/stabilization of the event.  These events occurring while on study must be 
documented appropriately regardless of relationship will be followed to adequate resolution. 
 
Any medical condition that is present at the time that the subject is screened should be 
considered as baseline and not reported as an AE.  However, if it deteriorates at any time during 
the study, it should be recorded as an AE as defined above. 
 


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Severity of Event:  Unsolicited clinical AEs (as defined above) and all protocol specified SAEs 
will be assigned the severity level of Grade 3.  Laboratory AEs will be assessed by the clinician 
using a protocol defined grading system (Appendix B).   
 
Relationship to Study Products:  The clinician’s assessment of an AE's relationship to test 
article (study drug) is part of the documentation process, but it is not a factor in determining what 
is or is not reported in the study.  If there is any doubt as to whether a clinical observation is an 
AE, the event should be reported.  AEs must have their relationship to study product assessed 
using the terms:  related or not related.  In a clinical trial, the study product must always be 
suspect.  To help assess, the following guidelines are used. 
 
• Related – There is a reasonable possibility that the study product caused the adverse event. 
Reasonable possibility means that there is evidence to suggest a causal relationship between 
the study product and the adverse event. 
• Not Related – There is not a reasonable possibility that the administration of the study 
product caused the event. 
9.2.2 Serious Adverse Events 
 
Hospitalizations are being collected as an outcome measure for the secondary objective and 
therefore for this study will not be reported as SAEs. 
 
An adverse event or suspected adverse reaction is considered “serious” if, in the view of either 
the site principal investigator or sponsor, it results in any of the following outcomes through Day 
60: 
• Death, 
• A life-threatening adverse event*, 
• A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions, or 
• A congenital anomaly or birth defect, 
• Important medical events that may not result in death, be life threatening, or require 
hospitalization, may be considered serious when, based upon appropriate medical 
judgment, they may jeopardize the patient or subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition.  Examples of such 
medical events include allergic bronchospasm requiring intensive treatment in an 
emergency room or at home, blood dyscrasias or convulsions that do not result in 
inpatient hospitalization, or the development of drug dependency or drug abuse. 
 
 


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* Life-threatening adverse event. An adverse event is considered “life-threatening” if, in the 
view of either the investigator or sponsor, its occurrence places the patient or subject at 
immediate risk of death.  It does not include an adverse event that, had it occurred in a more 
severe form, might have caused death.  
 
Unexpected: An adverse reaction, the nature or severity of which is not consistent with the 
applicable product information (e.g. IB for an unapproved investigational medicinal product). 
SAEs will be: 
• Assessed by a licensed study physician listed on the Form FDA 1572 as the site principal 
investigator or sub-investigator. 
• Recorded on the appropriate SAE form and CRF. 
• Followed through resolution or stabilization by a study physician licensed to make 
medical diagnoses and listed on the Form FDA 1572 as the site principal investigator or 
sub-investigator. 
• Reviewed and evaluated by the DSMB (periodic review), DMID, and the IRB. 
 
9.2.3 Procedures to be followed in the Event of Abnormal Laboratory Test Values or 
Abnormal Clinical Findings 
 
The site principal investigator or appropriate sub-investigator is responsible for recording all 
AE/SAEs that are observed or reported during this trial, regardless of the relationship to study 
product. AE/SAEs, abnormal laboratory test values, or abnormal clinical findings will be 
collected, assessed, documented, reported, and followed appropriately. 
 
The criteria for an abnormal laboratory test finding being classified as an AE are any of the 
following and will be documented on the AE form: 
• Test result is associated with a sign or symptom, and/or 
• Test result requires additional diagnostic testing, and/or 
• Test result requires a medical or surgical intervention, and/or 
• Test result leads to a change in study dosing outside of the protocol defined dosing or 
discontinuation from the study treatment, and/or 
• Test result requires significant additional treatment, i.e. addition of new medication, 
significant increase in dose of current medication 
 
Baseline clinical labs performed on Day 1 (screening/enrollment visit) might fall outside of the 
normal range. Laboratory values in all subsequent visits for subjects in which baseline clinical 
labs results fall outside the normal range will be considered adverse events only if there is a 
worsening in the grading of the event (e.g., value that on screening falls within grade 1, and 
subsequently on grade 2 will be considered AE; value that on both screening and on subsequent 
testing fall within grade 2 will not be considered AE). 


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For those clinical testing that performed on Day 1 and falls within grade 3, for all subsequent 
testing that also falls within grade 3, the clinician will need to assess and document this 
assessment on the source documents whether there is a clinically significant worsening of the 
value. Only those laboratory value that judged to have a clinically significant worsening and not 
attributable to Norovirus infection or underlying SOT/HSCT medical conditions will be reported 
as AEs. 
 
The protocol defined grading system is used to determine the cut off point for reporting. As such, 
laboratory results that are abnormal according to the local laboratory reference range but not 
considered a Grade 1 abnormality, will not be considered laboratory AEs. Those events will be 
followed-up clinically at the discretion of the study site physician. 
9.3 
Reporting Procedures 
9.3.1 Serious Adverse Events 
Any AE that meets a protocol-specified serious criterion (see section 9.2.2) through Day 60 must 
be submitted immediately (within 24 hours of site awareness) on an SAE form to the DMID 
Pharmacovigilance Group, at the following address:  
 
DMID Pharmacovigilance Group 
Clinical Research Operations and Management Support (CROMS) 
6500 Rock Spring Dr. Suite 650 
Bethesda, MD 20817, USA 
SAE Hot Line: 1-800-537-9979 (US) or 1-301-897-1709 (outside US) 
SAE FAX Phone Number: 1-800-275-7619 (US) or 1-301-897-1710 (outside US) 
SAE Email Address: PVG@dmidcroms.com 
 SAEs will be followed until satisfactory resolution or until the PI or Co-Investigator deems the 
event to be chronic or the subject to be stable 
In addition to the SAE form, selected SAE data fields must also be entered into 
AdvantageEDCSM. Please see the protocol-specific MOP for details regarding this procedure. 
Other supporting documentation of the event may be requested by the DMID Pharmacovigilance 
Group and should be provided as soon as possible.  
The site will send a copy of the SAE report(s) to the ISM (as deemed necessary) when they are 
provided to the DMID Pharmacovigilance Group.  The DMID Medical Monitor and DMID 
Clinical Project Manager will be notified of the SAE by the DMID Pharmacovigilance Group.  
The DMID Medical Monitor will review and assess the SAE for regulatory reporting and 
potential impact on study subject safety and protocol conduct. 


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At any time after completion of the study, if the site principal investigator or appropriate sub-
investigator becomes aware of an SAE that is suspected to be related to study product, the site 
principal investigator or appropriate sub-investigator will report the event to the DMID 
Pharmacovigilance Group. 
SAEs will be reported to the IRB in accordance with IRB policy. 
Note: Hospitalizations are being collected as an outcome measure for the secondary 
objective and therefore for this study will not be reported as SAEs. 
9.3.2 Regulatory Reporting for Studies Conducted Under 
DMID-Sponsored IND 
Following notification from the site principal investigator or appropriate sub-investigator, 
DMID, the Investigational New Drug (IND) sponsor, will report any suspected adverse reaction 
that is both serious and unexpected. DMID will report an adverse event as a suspected adverse 
reaction only if there is evidence to suggest a causal relationship between the drug and the 
adverse event. DMID will notify FDA and all participating site principal investigators (i.e., all 
principal investigators to whom the sponsor is providing drug under its IND(s) or under any 
principal investigator’s IND(s) in an IND safety report of potential serious risks from clinical 
trials or any other source, as soon as possible, but in no case later than 15 calendar days after the 
sponsor determines that the information qualifies for reporting as specified in 21 CFR Part 
312.32. DMID will also notify FDA of any unexpected fatal or life-threatening suspected 
adverse reaction as soon as possible, but in no case later than 7 calendar days after the sponsor’s 
initial receipt of the information. Relevant follow up information to an IND safety report will be 
submitted as soon as the information is available. Upon request from FDA, DMID will submit to 
FDA any additional data or information that the agency deems necessary, as soon as possible, 
but in no case later than 15 calendar days after receiving the request. 
All serious events designated as “not related” to study product(s), will be reported to the FDA at 
least annually in a summary format. 
9.3.3 Reporting of Pregnancy 
Pregnancies occurring in study subjects will be reported via AdvantageEDCSM on the Report 
form. No further study drug will be administered to pregnant subjects, but with the subject’s 
permission all protocol-required samples will be obtained, and the subject will continue to be 
followed for safety for the duration of this trial. Efforts will be made to follow all pregnancies 
reported during the course of this trial to pregnancy outcome pending the subject’s permission. 


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9.4 
Type and Duration of Follow-up of Subjects after Adverse Events 
Potentially study drug-related AEs and SAEs will be followed from the time of the first study 
procedure through resolution even if this extends beyond the study-reporting period. Resolution 
of an AE is defined as the return to pretreatment status or stabilization of the condition with the 
expectation that it will remain chronic. Follow-up procedures, evaluations, and outcomes will be 
recorded on the appropriate data collection form. 
 
9.5 
Halting Rules 
Further enrollment will be halted for DSMB review/recommendation if any of the following are 
reported through Day 60: 
• Two or more subjects experience a study product-related SAE. 
• ≥4 subjects experience the same severe (Grade 3) study product-related unsolicited AE 
until 80 subjects enrolled or ≥5% or more subjects experience the same severe (Grade 3) 
study product-related unsolicited AE after 80 subjects have been enrolled. 
• ≥4 subjects experience the same severe (Grade 3) study product-related safety laboratory 
AE until 80 subjects enrolled or ≥5% or more subjects experience the same severe (Grade 
3) study product-related safety laboratory AE after 80 subjects have been enrolled. 
Further enrollment will be halted for DSMB review/recommendation if the ratio of each clinical 
adverse outcome incidence rate per subject between the study arms is two or higher through Day 
180: 
• Death:  Minimum of 4 or more subjects experience death in all study arms. 
• Hospitalization:  Minimum of 10 or more subjects experience hospitalization in all study 
arms. 
• Graft rejection:  Minimum of 5 or more subjects experience graft rejection in all study 
arms. 
• Graft loss:  Minimum of 5 or more subjects experience graft loss in all study arms 
• Renal insufficiency, defined as a 20% or greater increase in serum creatinine relative to 
screening/enrollment/baseline value:  Minimum of 10 or more subjects experience renal 
insufficiency in all study arms. 
 
DMID retains the authority to suspend additional enrollment and study interventions/ 
administration of study product during the entire study, as applicable. 
 
 


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9.6 
Safety Oversight (ISM plus SMC or DSMB) 
9.6.1 Independent Safety Monitor 
For this clinical trial, an ISM is not required.  However, at each participating site, upon 
DMID Medical Monitor request, the principal investigator (PI) will identify a physician with 
relevant expertise, to act as a Secondary Medical Assessor (SMA). The SMA will examine a 
subject and/or medical records and provide a medical assessment (or second medical opinion) to 
the DMID of the safety event in question. The PI will send to the DMID MM, a summary of the 
event and include the PI and SMA assessments.   
 
Note: In the case that DMID has requested this type of evaluation multiple times, DMID may 
request the site(s) identify a SMA to assist DMID with safety oversight.   
9.6.2 Data and Safety Monitoring Board (DSMB) 
Safety oversight will be conducted by a DSMB that is an independent group of experts that 
monitors subject safety and advises DMID.  The DSMB members will be separate and 
independent of study personnel participating in this trial and should not have scientific, financial 
or other conflict of interest related to this trial.  The DSMB will consist of members with 
appropriate expertise to contribute to the interpretation of the data from this trial. 
 
The DSMB will operate under the rules of a DMID-approved charter that will be written at the 
organizational meeting of the DSMB. Procedures for DSMB reviews/meetings will be defined in 
the charter. Reports may include enrollment and demographic information, medical history, 
concomitant medications, physical assessments, clinical laboratory values, dosing compliance, 
and solicited and unsolicited AE/SAEs.  The DSMB will review SAEs on a regular basis and ad 
hoc during this trial. The DMID Medical Monitor and the ISM (as deemed necessary) will be 
responsible for reviewing SAEs in real time.  
 
 The DSMB will review and discuss study data: 
 
• At the following enrollment milestones with the relevant percentage of patients 
completing Day 60 of the study: 25% (N=40), 50% (N=80), 75% (N=120);the DSMB 
will review available safety data through Day 60 and Norovirus infection clinical adverse 
outcome through Day 180 and available clinical and virologic efficacy data and study 
product nitazoxanide retreatment data.   
• Final review meeting: 6 to 8 months after clinical database lock to review the cumulative 
unblinded safety and efficacy data for the study.  The data will be provided in a standard 
summary format.  The DSMB may be asked to provide recommendations in response to 
questions posed by DMID. 
• Ad hoc review: may be in response to a safety issue such as a halting rule being met. 


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(Enrollment will be monitored to ensure there is a DSMB review each year of the study during 
active enrollment.  In the case one of the enrollment milestones has not be met and a review has 
not occurred within the previous 12 months, DMID may request the DSMB review the study for 
safety.) 
  
The DSMB may also be convened for an ad hoc meeting. An Ad hoc meeting is an unplanned 
meeting that is called for a specific purpose such as when a study halting rule is met.  The 
meeting can be requested by any party with the responsibility of overseeing the trial (such as the 
PI, DSMB, DMID, industry collaborator).  In the case of an ad hoc meeting, the DSMB may 
request special reports on an as-needed basis.  
 
If the study is discontinued, subjects will not receive study product and, follow-up visits for 
safety would continue. 
 
Additional data may be requested by the DSMB, and interim statistical reports may be generated 
as deemed necessary and appropriate by DMID. The DSMB may receive data in aggregate and 
presented by treatment arm. The DSMB may also be provided with expected and observed rates 
of the expected AEs in an unblinded fashion, and may request the treatment assignment be 
unblinded for an individual subject if required for safety assessment. The DSMB will review 
grouped and unblinded data in the closed session only. As an outcome of each review/meeting, 
the DSMB will make a recommendation as to the advisability of proceeding with study 
investigational product (as applicable), and to continue, modify, or terminate this trial. 
 


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10 
CLINICAL MONITORING 
10.1 Site Monitoring Plan 
Site monitoring is conducted to ensure that the human subject protections, study and laboratory 
procedures, study intervention administration, and data collection processes are of high quality 
and meet sponsor, ICH/GCP guidelines and applicable regulations, and that this trial is 
conducted in accordance with the protocol, protocol-specific MOP and applicable sponsor 
standard operating procedures.  DMID, the sponsoring agency, or its designee will conduct site-
monitoring visits as detailed in the clinical monitoring plan. 
Site visits will be made at standard intervals as defined by DMID and may be made more 
frequently as directed by DMID.  Monitoring visits will include, but are not limited to, review of 
regulatory files, accountability records, CRFs, source data (paper and electronic), audit trails, 
ICFs, medical and laboratory reports, and protocol and GCP compliance.  Site monitors will 
have access to the study site, study personnel, and all study documentation according to the 
DMID-approved site monitoring plan.  Study monitors will meet with site principal investigators 
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11 
STATISTICAL CONSIDERATIONS 
11.1 Study Hypotheses 
A formal hypothesis test is planned to compare nitazoxanide to placebo with respect to the 
primary efficacy outcome measure. The time from randomization until clinical resolution of 
Norovirus for at least 48 hours through 180 days will be compared between the two study arms. 
 
The null hypothesis is that there is no difference in time until clinical resolution between study 
arms, with a two-sided alternative. The test for primary efficacy hypothesis will be conducted 
using a Log-Rank test at the 5% two-sided level of significance. 
11.2 Sample Size Considerations 
Sample size calculations assume a 50% reduction in the median duration of diarrhea for the 
nitazoxanide-treated group compared to those receiving placebo. The median diarrhea duration 
for the placebo group is assumed to be 135 days, while the median diarrhea duration for the 
treatment group is assumed to be 67.5 days. Given these assumptions, a sample size of 64 
subjects in each arm (128 total) is required to achieve 90% power using the Log-Rank test. 
Accounting for a 20% attrition rate, final sample size will be 80 in each arm (160 total).  
 
Though discouraged, the protocol allows for subjects in either study group to receive additional 
nitazoxanide after 28 days.  Under the assumptions of treatment efficacy, additional treatment 
received by placebo subjects would reduce the median duration of symptoms for the placebo 
group to be closer to that of the nitazoxanide-treated group. It is assumed that subjects who 
would have the worst study outcomes (longest time to clinical resolution of diarrhea) will be the 
most likely to receive additional treatment.  Subjects receiving additional treatment will be 
imputed as having the worst outcome (time to resolution censored at 180 days). Accounting for 
this imputation method, the power attained for the primary comparison was computed via 
simulation (R version 3.0.3).  Estimated power is displayed in the following table, varying the 
proportion of subjects in each study group who receive additional treatment 
 
Proportion Receiving Additional Treatment in the Placebo Group 
0% 
5% 
10% 
15% 
20% 
25% 
30% 
Proportion 
re-treated in 
the 
nitazoxanide 
Group 
0% 
91.3% 
91.6% 
91.7% 
91.6% 
91.8% 
92.0% 
92.3% 
5% 
91.4% 
91.5% 
91.6% 
91.2% 
91.2% 
91.8% 
92.5% 
10% 
- 
91.5% 
92.0% 
91.2% 
91.8% 
91.2% 
92.2% 
15% 
- 
- 
90.7% 
90.7% 
91.0% 
91.6% 
91.8% 
20% 
- 
- 
- 
87.3% 
87.1% 
87.0% 
87.7% 
25% 
- 
- 
- 
- 
74.0% 
73.9% 
75.2% 
30% 
- 
- 
- 
- 
- 
40.0% 
40.9% 
 


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For example, if 15% of placebo subjects receive nitazoxanide, and 5-10% of subjects in the 
nitazoxanide-treated group receive additional treatment, the power is estimated to be 91.2%.  
Note that implausible scenarios (where substantially more nitazoxanide subjects receive 
additional treatment than do placebo subjects) have been omitted from the table. 
11.3 Planned Interim Analyses 
11.3.1 Safety Review 
As described in Section 9.6, the DSMB will meet and review safety data at regular enrollment 
milestones. The study will be monitored to determine if any of the safety halting rules described 
in Section 9.5 is met. The halting rules do not utilize any statistical criteria and no formal 
hypothesis testing is planned to occur for the safety reviews.  
 
11.3.2 Efficacy Review 
The DSMB will review available clinical and virologic efficacy data, however no formal hypothesis 
testing is planned. 
 
11.4 Final Analysis Plan 
11.4.1 
General Principles 
The SDCC will perform all analyses after final data lock. Tabulations will be used extensively to 
summarize the data. Summary statistics displayed for continuous data will include measures of 
central tendency such as the mean or median, and measures of dispersion such as the standard 
deviation or inter-quartile range. Summary statistics for discrete data will include absolute and 
relative frequencies and confidence intervals where appropriate. 
 
In presenting statistical inferences, the statistical claim (i.e. null and alternative hypotheses) will 
be clearly stated, the method used for hypothesis testing will be described and appropriately 
referenced, and the assumptions underlying the methods will be validated. 
 
More details of the analyses to be performed will be included in a separate Statistical Analysis 
Plan.   
 
11.4.2 
Analysis Populations 
The safety population (grouped by actual treatment received) will include all subjects who are 
randomized, have received at least one dose of study treatment and have at least one safety 
assessment.  


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The modified intent-to-treat (mITT) population includes all randomized subjects who received at 
least one dose of assigned study drug. Analyses are performed according to randomized 
treatment assignment, not the treatment received. 
The per-protocol (PP) population will include all subjects who met all inclusion/exclusion 
criteria, complied with the assigned study product, complied with the daily diary, and were 
followed up until resolution of symptoms, or completed 180 days without resolution of 
symptoms.  
A subject is considered to be compliant with the assigned study product if he/she takes at least 
75% of the scheduled doses through 28 days, and does not receive additional nitazoxanide before 
their primary outcome is observed.  
A subject is considered to be compliant with the daily diary if he/she is missing no more than 
1.5/7 days per week over the 8 weeks.  
11.4.3 Efficacy Analyses 
11.4.3.1 
Analysis of Primary Outcome Measure 
The primary efficacy outcome measure is the time from randomization to initial clinical 
resolution of Norovirus for at least 48 hours, assessed through 180 days, in each study arm.  
Clinical resolution will be assessed from the daily diary by the subject and will be defined as: 
a. Cessation of vomiting and 
b. No stools classified by the Bristol Stool Chart as diarrhea (Type 6 or 7)  
 
The primary efficacy outcome measure will be assessed in the mITT population. Subjects who 
receive additional treatment with nitazoxanide other than their assigned study product will be 
considered censored at 180 days. To assess the effect of the choice of analysis population and 
additional treatment, the analysis will be repeated as a secondary analysis in the PP population. 
Sensitivity analyses may be performed to further assess the effect of additional treatment. The 
details of any sensitivity analyses will be detailed in the Statistical Analysis Plan.  
 
The null hypothesis that the time to first clinical resolution of Norovirus is the same in both 
treatment arms will be tested using a stratified Log-Rank test to take into account the 
stratification at randomization. Estimates for median time to resolution and corresponding 95% 
confidence intervals will be reported for each treatment arm. 
We will consider 80% compliance across the monitoring period acceptable [missing no more 
than 1.5/7 days per week over an 8 week period]. While we will not exclude patients, who are 
below this compliance for any monitoring period, we will conduct a sensitivity analysis 
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With respect to missing data for the primary endpoint, the primary analysis will be handled as 
follows: 
• Data that are missing after a subject has reached clinical resolution will not affect the 
primary time to event analysis and therefore will be ignored 
• Subjects who drop out, are lost to follow-up, withdraw consent, or otherwise stop 
completing daily diary entries before clinical resolution will be censored on the day of their 
last completed diary 
• Subjects with a gap in outcome data prior to clinical resolution will be handled depending 
on their last completed diary entry and their next completed diary entry: 
▪ If the last completed diary entry and the next completed diary entry have the same 
outcome (i.e., they are still symptomatic on both days or they have no symptoms 
on both days), then the gap will be imputed with the same outcome 
▪ If this imputation results in the subject being defined as having clinical resolution 
during this gap, their time to resolution will be the median of the interval 
• If the last completed diary entry and the next completed diary entry have different 
outcomes (i.e., the last one is symptomatic and the next one is asymptomatic, or vice 
versa), then the gap will be imputed with a symptomatic outcome (no resolution) 
 
The above method will be considered primary and additional methods such as worst case 
scenario or best case scenario may be explored as supportive analyses to assess robustness of 
results. 
 
11.4.3.2 
Analysis of Secondary Efficacy Outcome Measures 
All secondary efficacy outcome measures will be assessed in the mITT and PP populations 
separately.  
 
The secondary efficacy outcome measures are as follows: 
1. The time from the randomization to first negative viral load through 180 days.  
2. The change in viral titer between Day 1 and Day 180. 
 
Secondary outcome measure 1 will be assessed  through Kaplan-Meier curves along with results 
from a Log-Rank test to compare the time from randomization to first negative viral load 
between the nitazoxanide treated group and the placebo group. 


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Secondary outcome measure 2 will be assessed using analysis of covariance (ANCOVA) 
adjusting for baseline viral titer.  
11.4.3.3 
 Sensitivity Analysis of Primary and Secondary Efficacy Outcome Measures 
As a sensitivity analysis, all primary and secondary efficacy analyses will be conducted among 
the subgroup of subjects who do not report chromaturia (discoloration of urine) based on 
unsolicited self-reporting, in order to help determine if knowledge of this side effect may have 
impacted these outcomes. 
11.4.4 Safety Analyses 
Unsolicited AEs will be coded by MedDRA for preferred term and system organ class. The 
proportion of subjects and exact 95% confidence intervals of AEs in aggregate, as well as by 
MedDRA categories, will be computed. The number of SAEs will be reported by a detailed 
listing showing the type, MedDRA coding, relevant dates (treatment dosing dates and AE onset 
and resolution dates), severity, relatedness, and outcome for each event.  
 
11.4.4.1 Analysis of Secondary Safety Outcome Measures 
Safety outcome measures will be analyzed in the safety analysis population. 
 
The safety outcome measures are as follows: 
1. Incidence of unsolicited non-serious adverse events through 60 days. 
2. Incidence of laboratory adverse events (WBC, Hemoglobin, Platelet count, Creatinine, 
Alkaline Phosphatase, ALT, AST, BUN, and Bilirubin) through 60 days. 
3. Incidence of protocol-specified serious adverse events (see section 9.2.3 for details) 
through 60 days.  
4. Incidence of hospitalization through 60 days. 
 
For all safety outcome measures above, the proportion of subjects with events will be presented 
by treatment arm and overall. Point estimates for proportions and difference in proportions along 
with the corresponding 95% confidence intervals will be reported. A Barnard’s exact test at the 
5% two-sided level of significance level will be used for the comparisons of proportions between 
treatment arms.  
11.4.5 
Exploratory Analyses 
The exploratory outcome measures are as follows: 
Clinical Improvement; 
1. Time from randomization to initial clinical improvement in Norovirus disease 
through 28 and 180 days for at least 48 hours, as defined by: 


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a. 50% reduction in number of episodes of vomiting and, 
b. Improvement in PO intake, as judged by the subjects and, 
c. 50% reduction in the number of episodes of diarrhea as classified by the 
subject by the Bristol Stool Chart as type 6 or 7 bowel movements and, 
2. Time from randomization to initial cessation of vomiting through Day 180 
(recurrent vomiting will be considered disease recurrence unless determined to be 
due to another etiology [i.e. GVHD]). 
3. Time from randomization to subject report of no loss of appetite that is 
maintained for 48 hours through Day 180 (measure will be first time that the 
subject reports that they have no “loss of appetite” on their daily diary).  
4. Time from randomization to initial cessation of diarrhea through Day 180 
classified by the Bristol Stool Chart as type 6 or 7 bowel movements (recurrent 
diarrhea will be considered disease recurrence unless determined to be due to 
another etiology [i.e. GVHD]). 
5. Time from randomization to 50% reduction in the amount of antimotility agents 
utilized by the subject through Day 180. 
6. Number of days of diarrhea through Days 28 and 180. 
7. Number of stools classified by the Bristol Stool Chart as type 6 or 7 bowel 
movements through Day 28. 
8. Number of days of IV hydration or total parenteral nutrition (TPN) therapy 
through Day 28. 
9. Total number of days of hospitalization through Days 28 and 180. 
10. Change in patient-reported quality of life as measured by EuroQOL-5 (global) 
and IBSQOL (diarrhea specific) [adult] or Euro QOL-5 Peds (global) and PedsQL 
GI Module [children] from baseline to Day 180. 
11. Change in patient-reported physical function as measured by the NIH PROMIS 
Physical Function (Adult) Pediatric Global Health (Peds) from baseline to Day 
180. 
12. Change in patient-reported emotional distress as measured by the NIH PROMIS 
Depression, Anxiety, Fatigue (Adult and Peds) from baseline to Day 180. 
13. Change in patient-reported gastrointestinal symptoms as measured by the NIH 
PROMIS GI (Adult and Peds) symptoms (6 of 8 subscales) from baseline to Day 
180. 
14. The effect of co-pathogens, as determined by the BioFire stool pathogen screen, 
on the primary outcome measure 
15. Time from randomization until initial clinical resolution of Norovirus symptoms 
for at least 48 hours through Day 180.  Clinical resolution will be assessed from 
the daily diary by the subject and will be defined as cessation of vomiting and no 
stools classified by the Bristol Stool Chart as diarrhea (Type 6 or 7) from the 


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total population compared to the subgroup of subjects who do not report 
chromaturia (discoloration of urine) based on unsolicited self-reporting.   
16. Incidence of unsolicited non-serious adverse events (see section 9 for details) 
through 60 days, laboratory adverse events (WBC, Hemoglobin, Platelet count, 
Creatinine, Alkaline Phosphatase, ALT, AST, BUN and Bilirubin) through 60 
days, protocol-specified serious adverse events (see section 9 for details) through 
60 days, and Hospitalization through 60 days from the total population compared 
to the subgroup of subjects who do not report chromaturia (discoloration of 
urine) based on unsolicited self-reporting. 
 
 
Virologic Improvement: 
17. Time to ≥ 1 log reduction in stool Norovirus genome copies. 
18. Change in quantitative Norovirus load in the stool between Day 1 and Day 7, 14, 
21, 28, 60, 120, and 180. 
19. Change in Norovirus sequence from Day 1 to Days 28 and 60. 
20. The effect of co-pathogens, as determined by the BioFire stool pathogen screen, 
on the time from the randomization to first negative viral load through 180 days 
21. Time from the randomization to first negative viral load through 180 days and the 
change in viral titer between Day 1 and 180 from the total population compared 
to the subgroup of subjects who do not report chromaturia (discoloration of urine) 
based on unsolicited self-reporting. 
 
Immunologic Response: 
22. Change in Norovirus-specific serum and stool IgA, IgM and IgG between Day 1 
and Day 28 and 60 (stool only). 
23. Association between change in total lymphocyte count and T cell subsets at Day 1 
and 180 and clinical resolution of symptoms. 
24. Association between change in total lymphocyte count and T cell subsets at Day 1 
and 180 and undetectable quantitative Norovirus PCR. 
25. Association between change in Norovirus-specific serum and stool IgA, IgM and 
IgG at from Day 1 to Days 28 and 60 (stool only) and clinical resolution of 
symptoms. 
26. Association between change in Norovirus-specific serum and stool IgA, IgM and 
IgG from Day 1 and Days 28 and 60 (stool only) and undetectable quantitative 
Norovirus PCR. 
 
Pharmacokinetics and Dose Response: 


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27. For subjects consenting to PK draws, concentrations of nitazoxanide metabolites   
(tizoxanide and tizoxanide glucuronide) 1 to 4 hours after the first dose on Day 7 and 
10 minutes before the second dose on Day 21. 
 
Natural History of Disease: 
28. Time to allograft rejection as per each center team. 
29. Time to graft loss as reported to UNOS.  
30. Time to death.   
31. Time to withdrawal from the study because of intolerance or drug related adverse 
events. 
32. Correlation of secretor status as defined by phenotype and genotype, separately 
and clinical resolution of Norovirus as defined by the primary endpoint. 
 
 
Clinical Improvement: 
For exploratory outcomes 1 through 5, Kaplan-Meier curves will be produced along with results 
from a Log-Rank test to compare the time from randomization to clinical improvement in 
Norovirus disease between the nitazoxanide treated group and the placebo group. The Cox 
proportional hazards model will be used to estimate the corresponding hazard ratio and 95% 
confidence interval. If baseline demographic variables are shown to be unbalanced among the 
treatment groups, those variables will be adjusted in the Cox model. 
 
For exploratory outcomes 6-8, if the number of days of diarrhea follows an approximately 
normal distribution, then the average number of days will be estimated and compared between 
the two groups. If the number of days of diarrhea does not follow a normal distribution, a 
Poisson distribution or non-parametric analysis such as the Wilcoxon test will be considered.  
 
For exploratory outcomes 9, if number of days of hospitalization follows an approximately 
normal distribution, then the average number of days will be estimated and compared between 
groups using a two-sample t-test. If the number of days of hospitalization does not follow a 
normal distribution, a Poisson distribution or a non-parametric analysis such as the Wilcoxon test 
will be considered.  
 
For exploratory outcomes 10-13, subjects will complete Detailed PRO and Symptom Severity 
questionnaires at each visit to track changes over time in each of the psychosocial and QOL 
constructs.  An ANCOVA model will be fit using the two groups as the between-subjects factor, 
time as the within-subjects factor and baseline scores as a covariate. In addition, groups will be 
compared on unadjusted change over time using a mixed-design analysis of variance (ANOVA) 
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there are statistically significant pairwise contrasts between the groups on unadjusted change 
between baseline and subsequent time points, and on adjusted change (controlling for baseline).  
 
For exploratory outcome 14, a Cox proportional hazards model will be utilized to determine the 
effect of the presence or absence of co-pathogens at any time point on the time to clinical 
resolution of Norovirus symptoms for at least 48 hours through Day 180. A binary covariate 
representing the presence or absence of co-pathogens will be included in the model. As an 
alternative, if it is determined that subjects’ co-pathogen status changes often throughout the 
study, the effect may be considered as a time-varying covariate.  
 
For exloratoy outcome 15,16-please see section 11.4.3.3 
 
Virologic Improvement:  
For exploratory outcomes 17-19, analysis of Norovirus sequencing data, mutations will be 
compared between the nitazoxanide and placebo treatment groups. Non-
synonymous/synonymous (dN/dS) mutation analysis will be performed for each subject to 
determine whether selection is occurring within the polymerase, as well as Viral Epidemiology 
Signature Pattern Analysis (VESPA) and Random Effects Likelihood and Fixed Effects 
Likelihood (REL and FEL) methods to perform site-specific analyses and to identify trends 
within the nitazoxanide treatment group and differences between the treatment and placebo 
groups. 
 
For exploratory outcome 20, a Cox proportional hazards model will be utilized to determine the 
effect of the presence or absence of co-pathogens at any time point on the time to first negative 
viral load through 180 days. A binary covariate representing the presence or absence or co-
pathogens will be included in the model. As an alternative, if it is determined that subjects’ co-
pathogen status changes often throughout the study, the effect may be considered as a time-
varying covariate. 
 
For exploratory outcome 21, please see section 11.4.3.3 
 
Immunologic Response: 
For stool immunoglobulin testing, Day 1 will assess baseline values, Day 28 will assess end of 
treatment levels and Day 60 will give a single post-treatment level.  The proportion of subjects 
with ≥4-fold rise in Norovirus-specific Ig titers from Day 1 will be assessed at each follow-up 
time point comparing the nitazoxanide treatment group to the placebo group. 
 
Serum Immunoglobulin Testing (Serum total Ig and Norovirus-specific levels):  Day 1 will 
assess baseline values, Day 28 will assess end of treatment levels.  The proportion of subjects 
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the nitazoxanide treatment group to the placebo group. In addition, the ratios of Norovirus-
specific IgG to total IgG will also be compared between the nitazoxanide and placebo groups.   
 
For exploratory outcome 22, an ANCOVA model will first be used to compare the treatment and 
placebo groups with respect to difference in changes of Norovirus-specific serum and stool IgA, 
IgM and IgG between Day 1 and Day 28 and between Day 1 and Day 60 (for stool only). A 
mixed effects model will then be used to compare the treatment and placebo groups with respect 
to difference in the changes of Norovirus-specific serum and stool IgA, IgM and IgG, which will 
use the longitudinal data observed at all three time points. 
 
For exploratory outcomes 23-26, a Fisher’s Z-transformation will be applied to the Pearson 
correlations between change in total lymphocyte count and T cell subsets at Day 1 and 180 and 
clinical resolution of symptoms in both the treatment and placebo groups, which will then be 
compared using a Z-test.  
 
Pharmacokinetics and Dose Response:  
For exploratory outcome 27, plasma concentrations of nitazoxanide metabolites in subjects 
consenting for PK blood draws at two time points will be described and summarized. Descriptive 
statistics (e.g. n, mean, standard deviation, % CV, median, and range) will be calculated for each 
sampling time.  
 
Cox proportional hazard regression models will be used to examine the dose response 
relationship of Day 7 and Day 21 nitazoxanide metabolite concentrations on time from 
randomization until initial clinical resolution of Norovirus symptoms for at least 48 hours 
through Day 180. Additional analyses of PK endpoints may be described in the SAP. 
 
 
Natural History of Disease: 
Exploratory outcomes 28-31 are all time-to-event outcomes. They will be analyzed similarly as 
exploratory outcome 1. 
 
Exploratory outcome 32 will be assessed similarly to exploratory outcome 14. 
 
 
 
 
 


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12 
SOURCE DOCUMENTS AND ACCESS TO SOURCE 
DATA/DOCUMENTS 
Each participating site will maintain appropriate medical and research records in compliance 
with ICH E6, Section 4.9 and regulatory and institutional requirements for the protection of 
confidentiality of subjects. Each site will permit authorized representatives of the DMID, its 
designees, and appropriate regulatory agencies to examine (and when required by applicable law, 
to copy) clinical records for the purposes of quality assurance reviews, audits, and evaluation of 
the study safety and progress. These representatives will be permitted access to all source data 
and source documents, which include, but are not limited to, hospital records, clinical and office 
charts, laboratory notes, memoranda, subjects’ memory aid or evaluation checklists, pharmacy 
dispensing records, recorded data from automated instruments, copies or transcriptions certified 
after verification as being accurate and complete, microfiches, photographic negatives, microfilm 
or magnetic media, x-rays, and subject files and records kept at the pharmacy, at the laboratories, 
and medico-technical departments involved in the clinical trial.  
 
 


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13 
QUALITY CONTROL AND QUALITY ASSURANCE 
Following a written DMID-accepted protocol-specific quality management plan, each 
investigational site is responsible for conducting routine quality control (QC) and quality 
assurance (QA) activities to internally monitor study progress and protocol compliance.  Each 
site Principal Investigator will provide direct access to all protocol-related source data/source 
documents, and reports for the purpose of monitoring and auditing by the sponsor, and inspection 
by local and regulatory authorities. Each site Principal Investigator will ensure all study 
personnel are appropriately trained and current documentations are maintained on site.  
 
DMID-designated clinical monitors will verify the clinical trial data are generated, documented 
(recorded), and reported in compliance with the protocol, Good Clinical Practice standards, and 
the applicable regulatory requirements.  Clinical monitoring reports will be submitted to DMID. 
 
The Statistical and Data Coordinating Center (SDCC) will implement quality control procedures 
beginning with the data entry system; database quality control checks will be implemented. Any 
missing data or data anomalies will be communicated to the site(s) for clarification and 
resolution. 


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14 
ETHICS/PROTECTION OF HUMAN SUBJECTS 
14.1 Ethical Standard 
The site principal investigator (PI) will ensure that this trial is conducted in full conformity with 
principles of the Belmont Report:  Ethical Principles and Guidelines for the Protection of Human 
Subjects of Research (National Commission for the Protection of Human Subjects of Biomedical 
and Behavioral Research [April 18, 1979]) and codified in 45 CFR 46, 21 CFR 50 and 21 CFR 
56, as applicable.  The PI will also ensure conformity with ICH E6 Good Clinical Practice, and 
applicable federal regulations, guidance, and guidelines for Good Clinical Practice and Clinical 
Trials with humans. 
 
14.2 Institutional Review Board 
Each site principal investigator will obtain IRB approval for this protocol to be conducted at 
his/her research site(s), and send supporting documentation to the DMID before initiating 
recruitment of subjects.  The investigator will submit applicable information to the IRB/IEC on 
which it relies for the review, to conduct the review in accordance with 45 CFR 46, ICH E6 
GCP, and as applicable, 21 CFR 56 (Institutional Review Boards) and 21 CFR 50 (Protection of 
Human Subjects), other federal, state, and local regulations. The IRB/IEC must be registered 
with OHRP [OHRP-only or OHRP/FDA] as applicable to the research.  DMID must receive the 
documentation that verifies IRB/IEC-approval for this protocol, associated informed consent 
documents, and upon request any recruitment material and handouts or surveys intended for the 
subjects, prior to the recruitment and enrollment of subjects.     
Any amendments to the protocol or consent materials will be approved by the IRB/IEC before 
they are implemented.  IRB/IEC review and approval will occur at least annually throughout the 
enrollment and follow-up of subjects, and may cease if annual review is no longer required by 
applicable regulations.  The investigator will notify the IRB/IEC of deviations from the protocol 
and reportable SAEs, as applicable to the IRB/IEC policy. 
Each institution engaged in this research will hold a current Federalwide Assurance (FWA) 
issued by the Office of Human Research Protection (OHRP) for federally funded research. 
 
 
 
 


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14.3 Informed Consent Process 
 
Informed consent is a process that is initiated prior to an individual agreeing to participate in a 
trial and continuing throughout the individual’s trial participation.  Before any study procedures 
are performed, informed consent will be obtained and documented.  Subjects will receive a 
concise and focused presentation of key information about the clinical trial, verbally and with a 
written consent form. The explanation will be organized, and presented in lay terminology and 
language that facilitates understanding why one might or might not want to participate. 
An investigator or designee will describe the protocol to potential subjects face-to-face. The key 
information about the purpose of the study, the procedures and experimental aspects of the study, 
risks and discomforts, any expected benefits to the subject, and alternative treatment will be 
presented first to the subject.   
Subjects will also receive an explanation that the trial involves research, and a detailed summary 
of the proposed study procedures and study interventions/products.  This will include aspects of 
the trial that are experimental, the probability for random assignment to treatment groups, any 
expected benefits, all possible risks (including a statement that the particular treatment or 
procedure may involve risks to the subject or to the embryo or fetus, if the subject is or may 
become pregnant, that are currently unforeseeable), the expected duration of the subject’s 
participation in the trial, alternative procedures that may be available and the important potential 
benefits and risks of these available alternative procedures.  
Subjects will be informed that they will be notified in a timely manner if information becomes 
available that may be relevant to their willingness to continue participation in the trial. Subjects 
will receive an explanation as to whether any compensation and any medical treatments are 
available if injury occurs, and, if so, what they consist of, or where further information may be 
obtained. Subjects will be informed of the anticipated financial expenses, if any, to the subject 
for participating in the trial, as well as any anticipated prorated payments, if any, to the subject 
for participating in the trial. They will be informed of whom to contact (e.g., the investigator) for 
answers to any questions relating to the research project.  
Information will also include the foreseeable circumstances and/or reasons under which the 
subject’s participation in the trial may be terminated. The subjects will be informed that 
participation is voluntary and that they are free to withdraw from the study for any reason at any 
time without penalty or loss of benefits to which the subject is otherwise entitled.   
The extent of the confidentiality of the subjects’ records will be defined, and subjects will be 
informed that applicable data protection legislation will be followed. Subjects will be informed 
that the monitor(s), auditors(s), IRB, NIAID, and regulatory authority(ies) will be granted direct 
access to the subject’s original medical records for verification of clinical trial procedures and/or 
data without violating the confidentiality of the subject, to the extent permitted by the applicable 


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laws and regulations, and that, by signing a written informed consent form, the subject is 
authorizing such access.  
 
Subjects will be informed that records identifying the subject will be kept confidential, and, to 
the extent permitted by the applicable laws and/or regulations, will not be made publicly 
available and, if the results of the trial are published, the subject’s identity will remain 
confidential. Subjects will be informed whether private information collected from this research 
and/or specimens will be used for additional research, even if identifiers are removed.   
Subjects will be allowed sufficient time to consider participation in this research trial, and have 
the opportunity to discuss this trial with their family, friends or legally authorized representative, 
or think about it prior to agreeing to participate. 
Informed consent forms will be IRB-approved, and subjects will be asked to read and review the 
consent form. Subjects must sign the informed consent form prior to starting any study 
procedures being done specifically for this trial. 
 
Once signed, a copy of the informed consent form will be given to the subject(s) for their 
records.  The subject(s) may withdraw consent at any time throughout the course of the trial.  
The rights and welfare of the subject(s) will be protected by emphasizing to them that the quality 
of their medical care will not be adversely affected if they decline to participate in this study. 
Study personnel may employ recruitment efforts prior to obtaining study consent if a patient-
specific screening consent is on record or if the IRB has agreed that chart review is allowed 
without a fully executed screening consent.  In cases where there is not a patient-specific 
screening consent on record, site Clinical staff may pre-screen via chart review and refer 
potential subjects to the Research staff.  Research staff would obtain written consent per the 
standard informed consent process before conducting protocol-specific screening activities. 
New information will be communicated by the site principal investigator to subjects who consent 
to participate in this trial in accordance with IRB requirements.  The informed consent document 
will be updated, and subjects will be re-consented per IRB requirements, if necessary.  Subjects 
will be given a copy of all informed consent forms that they sign. 
14.3.1 Informed Consent/Assent Process (in Case of a Minor) 
Investigators will follow IRB/IEC requirements for enrollment of minors in this study.  Minors 
will be informed about the study to the extent understandable to the minor.  Investigators or 
designee will conduct the consent process with the parent(s)/legal guardian, who will be given an 
IRB/IEC-approved permission form, which may be referred to as a consent form, to read, review, 
and sign prior to any study procedures. The parent(s)/legal guardian will be provided meaningful 
study information including a statement that this study involves research, the child may not 
benefit from the trial, and the study involves risk. The required elements will be clearly 
presented, including the purpose of the study, the experimental procedures, the potential risks 


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and discomforts, known adverse effects, possible benefits of the study for the subject, alternative 
therapies that may be beneficial, use and disclosure of private information, and other elements 
that are part of obtaining proper consent. The subject’s parent(s)/legal guardian will be allowed 
sufficient time to discuss questions with the investigator.   
The investigator or designee will describe in simplified terms the details of the study 
intervention/product, study procedures, risks and discomforts, benefits, and other consent 
elements, as appropriate. A separate IRB/IEC-approved assent form will be used for the minor, 
who may read and sign the form, or have it read to him/her prior to participation in study 
procedures.  Assent may be obtained verbally or waived when approved by the IRB/IEC as 
appropriate to age.  If a child declines to participate in the trial when assent is required by the 
IRB/IEC, the subject will not be enrolled even though the parents have provided permission.  
To ensure that consent is an ongoing process throughout the subject’s participation in the study, 
the investigator and staff will review information as needed with the subject and the 
parent(s)/legal guardian and confirm that assent and permission are continuing.  The permission 
and assent documents will be updated when new information is acquired that may impact the 
decision to continue in the study, and the subject’s assent and the parent(s)/legal guardian’s 
permission will be obtained, as applicable.   
14.4 Exclusion of Women, Minorities, and Children (Special Populations) 
This trial will be inclusive of all subjects who are ≥ 12 years of age and thus will follow all 
guidelines detailed in Subpart D – Additional Protections for Children Involved as Subjects in 
Research (45 CFR Part 46.401-409) who meet the Subject Inclusion/Exclusion Criteria, 
regardless of religion, gender, or ethnic background.   
 
14.5 Subject Confidentiality 
Subject confidentiality is strictly held in trust by the participating investigators, their staff, and 
the sponsor(s) and their agents. This confidentiality includes documentation, investigation data, 
subject’s clinical information, and all other information generated during participation in the 
study. No information concerning the study or the data generated from the study will be released 
to any unauthorized third party without prior written approval of the DMID and the subject. 
Subject confidentiality will be maintained when study results are published or discussed in 
conferences.  The study monitor or other authorized representatives of the sponsor or 
governmental regulatory agencies may inspect all documents and records required to be 
maintained by the investigator, including but not limited to, medical records (office, clinic, or 
hospital) and pharmacy records for the subjects in this study. The clinical study site will permit 
access to such records. 
All records will be kept locked and all computer entry and networking programs will be carried 
out with coded numbers only and with password protected systems. All non-clinical specimens, 


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evaluation forms, reports, and other records that leave the site will be identified only by a coded 
number. 
 
The study monitor, representatives from the NIH/DMID, representatives from Northwestern 
University and their affiliates, applicable regulatory authorities, such as the FDA and the IRB, 
representatives of Romark, L.C., or other authorized representatives of the sponsor may inspect 
all documents and records required to be maintained by the investigator, including but not 
limited to, medical records (office, clinic, or hospital) and pharmacy records for the subjects in 
this study.  The clinical study sites will permit access to such records. 
 
To protect privacy, we have received a Certificate of Confidentiality.  With this Certificate, the 
researchers cannot be forced to release information that may identify the research subject, even 
by a court subpoena, in any federal, state, or local civil, criminal, administrative, legislative, or 
other proceedings.  The researchers will use the Certificate to resist any demands for information 
that would identify the subject, except as explained below. 
The Certificate cannot be used to resist a demand for information from personnel of the United 
States Government that is used for auditing or evaluation of federally funded projects, like this 
study, or for information that must be released in order to meet the requirements of the Federal 
Food and Drug Administration (FDA). 
A Certificate of Confidentiality does not prevent the subject from voluntarily releasing 
information about themselves or their involvement in this research.  If any person or agency 
obtains a written consent to receive research information, then the researchers may not use the 
Certificate to withhold that information.   
The Certificate of Confidentiality does not prevent the researchers from reporting without the 
subject’s consent, information that would identify the subject as a participant in the research 
project regarding matters that must be legally reported including: child and elder abuse, sexual 
abuse, or wanting to harm themselves or others.   
14.6 Study Discontinuation 
If the study is prematurely terminated by the sponsor, any regulatory authority, or the 
investigator for any reason, the investigator will promptly inform the study subjects and assure 
appropriate therapy or follow-up for the subjects, as necessary. The investigator will provide a 
detailed written explanation of the termination to the IRB/IEC. If any subject’s private 
information will continue to be collected for this study, the IRB/IEC must approve a consent 
form with the study procedures, any risks and discomforts, and applicable elements, and the 
investigator or designee will re-consent the subjects as approved by the IRB/IEC. 
 
In the event that the study is discontinued, subjects who were randomized to study drug can 
continue the use of the medication at the discretion of their clinician.  


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14.7 Costs, Subject Compensation and Research Related Injuries There is no 
cost to subjects for taking part in this trial. 
Subjects may be compensated for their participation in this trial.  Compensation will be in 
accordance with the local IRB’s policies and procedures, and subject to IRB approval (no more 
than $25/visit). 
If it is determined by the participating site and the site principal investigator that an injury 
occurred to a subject as a result of the tests or treatments that are done for this trial, then referrals 
to appropriate health care facilities will be provided to the subject.  Study personnel will try to 
reduce, control, and treat any complications from this trial.  Immediate medical treatment may be 
provided by the participating site, such as giving emergency medications to stop allergic 
reactions to the study drug.  No financial compensation will be provided to the subject by the 
participating site for any injury suffered due to participation in this trial 
 
14.8 Future Use of Stored Specimens  
For the duration of the study, the specimens will be stored at the Central Lab. Upon completion 
of the study, buccal cells and saliva samples will be destroyed and no further host genetic testing 
will be performed. Stool and viruses will be stored at NUCTC laboratory facilities indefinitely. 
IRB will review future studies, and protections of confidentiality for any future studies with the 
stored specimens, e.g., each sample will be encoded (labeled) only with a barcode and a unique 
tracking number to protect the subject’s confidentiality.  
 
Subjects may be given the option to decide if they want their samples to be used for future 
research or have their samples destroyed at the end of the trial.  The subject’s decision can be 
changed at any time by notifying the study doctor’s in writing, and the unused identifiable 
samples will be destroyed.  However, if the subject originally consents to future use and 
subsequently changes his/her decision, any data obtained prior to the withdrawal of consent may 
still be used for research. 
 
All sites will follow guidelines of local IRB offices in regard to the need to obtain re-consent 
from minors for future use once they reach the age of consent.  Samples may be shared with 
investigators at the other participating sites or investigators at other institutions. Samples will not 
be sold or used directly for production of commercial product.  
 
 


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15 
DATA HANDLING AND RECORD KEEPING 
The investigator is responsible to ensure the accuracy, completeness, legibility, and timeliness of 
the data reported.  All source documents should be completed in a neat, legible manner to ensure 
accurate interpretation of data.  Black or blue permanent ink is required to ensure clarity of 
reproduced copies.  When making changes or corrections, cross out the original entry with a 
single line, and initial and date the change.  DO NOT ERASE, OVERWRITE, OR USE 
CORRECTION FLUID OR TAPE ON THE ORIGINAL. 
Copies of the electronic CRF (eCRF) will be provided for use as source data collection forms 
and maintained for recording data for each subject enrolled in the study.  Data reported in the 
eCRF derived from source data collection forms should be consistent or the discrepancies should 
be explained. 
DMID and/or its designee will provide guidance to the site principal investigators and other 
study personnel on making corrections to the data collection forms and eCRF. 
15.1 Data Management Responsibilities 
Data collection is the responsibility of the study personnel at the participating clinical study site 
under the supervision of the site principal investigator.  During the study, the site principal 
investigator must maintain complete and accurate documentation for the study. 
The data coordinating center for this study will be responsible for data management, quality 
review, analysis, and reporting of the study data. 
 
Emmes will serve as the Statistical and Data Coordinating Center for this study and will be 
responsible for data management, quality review, analysis, and reporting of the study data. 
15.2 Data Capture Methods 
Clinical data (including AEs, concomitant medications data) and clinical laboratory data will be 
entered into a 21 CFR Part 11-compliant Internet Data Entry System (IDES) provided by the 
SDCC.  The data system includes password protection and internal quality checks, such as 
automatic range checks, to identify data that appear inconsistent, incomplete, or inaccurate.  
Clinical data will be entered directly from the source documents. 
15.3 Types of Data 
Data for this study will include safety, laboratory (immunologic and virologic), and patient 
reported outcome measures-patient diary (safety, adverse events). 
 


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15.4 Timing/Reports 
 
A final clinical study report will be prepared following availability of all safety, PK, and efficacy 
data.  See Section 9.6.2 for additional reporting requirements. 
15.5 Study Records Retention 
Study documents will be retained for a minimum of 2 years after the last approval of a marketing 
application in an ICH region and until there are no pending or contemplated marketing 
applications in an ICH region or at least 2 years have elapsed since the formal discontinuation of 
clinical development of the investigational product. Consents with future use provisions will be 
retained until all samples are used or destroyed.  All study documents will be retained for a 
longer period, however, if required by local regulations. No records will be destroyed without the 
written consent of the sponsor. It is the responsibility of the sponsor to inform the investigator 
when these documents no longer need to be retained.   
15.6 Protocol Deviations 
A protocol deviation is any noncompliance with the clinical study protocol, Good Clinical 
Practice (GCP), or Manual of Procedures requirements.  The noncompliance may be either on 
the part of the subject, the investigator, or the study site staff.  As a result of deviations, 
corrective actions are to be developed by the site and implemented promptly.  
 
 
These practices are consistent with ICH E6: 
 
4.5 
Compliance with Protocol, sections 4.5.1, 4.5.2, and 4.5.3 
5.1 
Quality Assurance and Quality Control, section 5.1.1 
5.20 
Noncompliance, sections 5.20.1, and 5.20.2. 
 
It is the responsibility of the site to use continuous vigilance to identify and report deviations 
within 5 working days of identification of the protocol deviation, or within 5 working days of the 
scheduled protocol-required activity.  All deviations must be promptly reported to DMID, via 
The SDDC’s AdvantageEDCSM.  
 
All deviations from the protocol must be addressed in study subject source documents.  A 
completed copy of the DMID Protocol Deviation Form must be maintained in the regulatory file, 
as well as in the subject’s source document.  Protocol deviations must be sent to the local IRB 
per their guidelines.  The site PI/study staff is responsible for knowing and adhering to their IRB 
requirements. 


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16 
PUBLICATION POLICY 
All investigators funded by the NIH must submit or have submitted for them to the National 
Library of Medicine’s PubMed Central (http://www.ncbi.nlm.nih.gov/pmc/) an electronic 
version of their final, peer-reviewed manuscripts upon acceptance for publication, to be made 
publicly available no later than 12 months after the official date of publication.  The NIH Public 
Access Policy ensures the public has access to the published results of NIH funded research.  It 
requires investigators to submit final peer-reviewed journal manuscripts that arise from NIH 
funds to the digital archive PubMed Central upon acceptance for publication.  Further, the policy 
stipulates that these papers must be accessible to the public on PubMed Central no later than 12 
months after publication. 
Refer to: 
• 
NIH Public Access Policy, http://publicaccess.nih.gov/ 
• 
NIH Office of Extramural Research (OER) Grants and Funding, 
http://grants.nih.gov/grants/oer.htm 
As of January 2018, all clinical trials supported by the NIH must be registered on 
ClinicalTrials.gov, no later than 21 days after the enrollment of the first subject. Results of all 
clinical trials supported by the NIH, generally, need to be submitted no later than 12 months 
following the primary completion date. A delay of up to 2 years is available for trials that meet 
certain criteria and have applied for certification of delayed posting. 
As part of the result posting a copy of this protocol (and its amendments) and a copy of the 
Statistical Analysis Plan will be posted on ClincialTrials.gov. 
For this trial the responsible party is [DMID] which will register the trial and post results.   
The responsible party [DMID] to request certification of delayed posting. 
Refer to: 
• 
Public Law 110-85, Section 801, Clinical Trial Databases 
• 
42CFR11 
• 
NIH NOT-OD-16-149 
 


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agent nitazoxanide induces phosphorylation of eukaryotic initiation factor 2alpha via protein 
kinase activated by double-stranded RNA activation. Gastroenterology. 2009;137(5):1827-
35. doi: 10.1053/j.gastro.2009.07.056. PubMed PMID: 19664635. 
72. Rossignol JF, Abu-Zekry M, Hussein A, Santoro MG. Effect of nitazoxanide for treatment of 
severe rotavirus diarrhoea: randomised double-blind placebo-controlled trial. Lancet. 
2006;368(9530):124-9. doi: 10.1016/S0140-6736(06)68852-1. PubMed PMID: 16829296. 
73. Rossignol JF, Elfert A, El-Gohary Y, Keeffe EB. Improved virologic response in chronic 
hepatitis C genotype 4 treated with nitazoxanide, peginterferon, and ribavirin. 
Gastroenterology. 2009;136(3):856-62. doi: 10.1053/j.gastro.2008.11.037. PubMed PMID: 
19135998. 
74. La Frazia S, Ciucci A, Arnoldi F, Coira M, Gianferretti P, Angelini M, et al. Thiazolides, a 
new class of antiviral agents effective against rotavirus infection, target viral morphogenesis, 
inhibiting viroplasm formation. J Virol. 2013;87(20):11096-106. doi: 10.1128/JVI.01213-13. 
PubMed PMID: 23926336; PubMed Central PMCID: PMC3807293. 
75. Rossignol JF. Nitazoxanide: a first-in-class broad-spectrum antiviral agent. Antiviral Res. 
2014;110:94-103. doi: 10.1016/j.antiviral.2014.07.014. PubMed PMID: 25108173. 


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110 
76. Rossignol JF, El-Gohary YM. Nitazoxanide in the treatment of viral gastroenteritis: a 
randomized double-blind placebo-controlled clinical trial. Aliment Pharmacol Ther. 
2006;24(10):1423-30. doi: 10.1111/j.1365-2036.2006.03128.x. PubMed PMID: 17081163. 
77. Siddiq DM, Koo HL, Adachi JA, Viola GM. Norovirus gastroenteritis successfully treated 
with nitazoxanide. J Infect. 2011;63(5):394-7. doi: 10.1016/j.jinf.2011.08.002. PubMed 
PMID: 21839773; PubMed Central PMCID: PMC3368802. 
78. Morris J, Brown W, Morris CL. Nitazoxanide Is Effective Therapy For Norovirus 
Gastroenteritis After Chemotherapy and Hematopoietic Stem Cell Transplantation (HSCT).  
55th American Soceity of Hematology Annual Meeting; December 9, 2013; New Orleans, 
Louisiana2013. p. Abstract 4581. 
79. Morris J, Morris C. Nitazoxanide Is Effective Therapy for Norovirus Gastroenteritis after 
Chemotherapy and Hematopoietic Stem Cell Transplantation (HSCT).  2015 BMT Tandem 
Meetings; San Diego, California2015. p. Abstract 358. 
80. Freedman SB, Eltorky M, Gorelick M, Pediatric Emergency Research Canada Gastroenteritis 
Study G. Evaluation of a gastroenteritis severity score for use in outpatient settings. 
Pediatrics. 2010;125(6):e1278-85. doi: 10.1542/peds.2009-3270. PubMed PMID: 20439605. 
81. Ruuska T, Vesikari T. Rotavirus disease in Finnish children: use of numerical scores for 
clinical severity of diarrhoeal episodes. Scand J Infect Dis. 1990;22(3):259-67. doi: 
10.3109/00365549009027046. PubMed PMID: 2371542. 
82. Schnadower D, Tarr PI, Gorelick MH, O'Connell K, Roskind CG, Powell EC, et al. 
Validation of the modified Vesikari score in children with gastroenteritis in 5 US emergency 
departments. J Pediatr Gastroenterol Nutr. 2013;57(4):514-9. doi: 
10.1097/MPG.0b013e31829ae5a3. PubMed PMID: 23676445; PubMed Central PMCID: 
PMC3788842. 
83. EuroQol G. EuroQol--a new facility for the measurement of health-related quality of life. 
Health Policy. 1990;16(3):199-208. PubMed PMID: 10109801. 
84. Weinstein MC, Siegel JE, Gold MR, Kamlet MS, Russell LB. Recommendations of the Panel 
on Cost-effectiveness in Health and Medicine. JAMA. 1996;276(15):1253-8. PubMed PMID: 
8849754. 
85. Patrick DL, Drossman DA, Frederick IO, DiCesare J, Puder KL. Quality of life in persons 
with irritable bowel syndrome: development and validation of a new measure. Dig Dis Sci. 
1998;43(2):400-11. PubMed PMID: 9512138. 
86. Varni JW, Franciosi JP, Shulman RJ, Saeed S, Nurko S, Neigut DA, et al. PedsQL 
Gastrointestinal Symptoms Scales and Gastrointestinal Worry Scales in Pediatric Patients 
with Inflammatory Bowel Disease in Comparison with Healthy Controls. Inflamm Bowel 
Dis. 2015;21(5):1115-24. doi: 10.1097/MIB.0000000000000351. PubMed PMID: 25793327. 
87. Varni JW, Seid M, Kurtin PS. PedsQL 4.0: reliability and validity of the Pediatric Quality of 
Life Inventory version 4.0 generic core scales in healthy and patient populations. Med Care. 
2001;39(8):800-12. PubMed PMID: 11468499. 
88. Kahan BC, Morris TP. Improper analysis of trials randomised using stratified blocks or 
minimisation. Stat Med. 2012;31(4):328-40. doi: 10.1002/sim.4431. PubMed PMID: 
22139891. 


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89. Rossignol JF, Elfert A, El-Gohary Y, Keeffe EB. Improved virologic response in chronic 
hepatitis C genotype 4 treated with nitazoxanide, peginterferon, and ribavirin. 
Gastroenterology. 2009 Mar;136(3):856-62. doi: 10.1053/j.gastro.2008.11.037. Epub 2008 
Nov 19. 
90. Rossignol JF, Elfert A, Keeffe EB. Treatment of chronic hepatitis C using a 4-week lead-in 
with nitazoxanide before peginterferon plus nitazoxanide. J Clin Gastroenterol. 2010 
Aug;44(7):504-9. doi: 10.1097/MCG.0b013e3181bf9b15. 
91. Rossignol JF, Kabil SM, El-Gohary Y, Elfert A, Keeffe EB. Clinical trial: randomized, 
double-blind, placebo-controlled study of nitazoxanide monotherapy for the treatment of 
patients with chronic hepatitis C genotype 4. Aliment Pharmacol Ther. 2008 Sep 
1;28(5):574-80. doi: 10.1111/j.1365-2036.2008.03781.x. Epub 2008 Jun 26. 
92. Rossignol JF. Nitazoxanide in the treatment of acquired immune deficiency syndrome-
related cryptosporidiosis: results of the United States compassionate use program in 365 
patients. Aliment Pharmacol Ther. 2006 Sep 1;24(5):887-94. 
93. Center for International Blood and Marrow Transplant, a contractor for the C.W. Bill Young 
Cell Transplantation Program operated through the U. S. Department of Health and Human 
Services, Health Resources and Services Administration, Healthcare Systems Bureau. U.S. 
Patient Survival Report, 2008-2012. Data accessed: October 16, 2016. 
94. Lackner, J. M., Jaccard J., Keefer L, Firth R, Carosella AM, Sitrin M, Brenner D for the 
IBSOS Research Group. The accuracy of patient-reported measures for GI symptoms: a 
comparison of real time and retrospective reports. Neurogastroenterol Motil.  2014 Dec; 
26(12): 1802-1811. PMID:  2542458 
95. Lee LY, Ladner DP, Ison MG.  Norovirus infection in solid organ transplant recipients:  A 
single-center retrospective study.  Transplant Infect Dis.  2016;18:932-938. 
96. Kaufman DB, Leventhal JR, Axelrod D, Gallon LG, Parker MA, Stuart FP.  Alemtuzumab 
induction and prednisone-free maintenance immunotherapy in kidney transplantation:  
Comparison with basiliximab induction – long-term results.  Am J Transplant. 2005; 5: 2539-
2548. 
 
 
 
 
 
 
 
 
 


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APPENDIX A: Schedule of Events 
Phase 
Treatment Phase 
Longitudinal Monitoring Phase  
 
Procedure 
Screen
/Enroll
/Day 
1 
Day 7 
(±3 d) 
Day 
14₩ 
(±3 d) 
Day 
21₩ 
(±3d) 
Day 28 
(+3 d) 
Day 
35 
(±3 
d) 
Day 
53 
( ± 
7d) 
Day 
60₩ 
(±14 
d) 
Day 
113 
 (± 
7d) 
Day 
120₩ 
(±14 d) 
Da
y 
173 
( ± 
7d) 
Day 
180 
(±14 d) 
Unsche
duled 
Visit 
Early 
Termination 
visit 
Visit 
01 
02 
03 
04 
05 
06 
07 
08 
09 
10 
11 
12 
 
 
Consent1 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine Pregnancy2 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood Draw 
22.5 
mL₱ 
8.5 
mL3 
 
 
18.5 
mL3 
 
 
 
 
 
 
22.5 
mL3 
 
22.5 mL3 
Pill Count  
 
X 
 
 
X 
 
 
X10 
 
 
 
 
 
 
Vital Signs*  
X 
X 
 
 
X 
 
 
X 
 
 
 
X 
X 
X 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Exam 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
Inquiry about 
hospitalization 
since last 
Assessment 
 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Collect Stool 
X8¶ 
X7¶ 
X7¶ 
X7¶ 
X87¶ 
 
 
X87¶ 
 
X7¶ 
 
X7¶ 
X7¶ 
X7¶ 
Buccal 
Swab/Saliva 
Collection 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Nitazoxanide PK4 
 
4.5 mL 
 
4.5 mL 
 
 
 
 
 
 
 
 
 
 


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Nitazoxanide or 
placebo5 
X 
X  
X  
X  
X  
 
 
 
 
 
 
 
 
 
Return residual 
medication 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
Review 
concomitant 
medications 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
Assess for 
adverse events 
 
X 
X 
X 
X 
X 
 
X 
 
 
 
 
X 
X 
Administer 
Detailed PROs 
Packet 
X 
 
 
 
X 
 
 
X 
 
X 
 
X 
 
X 
Administer 
Weekly Packet 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Collect or Review 
Daily Diary6 
 
X 
X 
X 
X 
 
 
X 
 
X 
 
X 
X 
X 
Phone Call  
 
 
Xⱥ 
Xⱥ 
 
X 
X 
Xⱥ 
X 
Xⱥ 
X 
 
 
 
1Consent/Assent must be obtained from eligible subjects, consistent with local IRB policy for consent and assent of subjects and must be obtained prior to any study procedures being performed  
2 Urine pregnancy test will be obtained from women of childbearing potential, results of test must be known and negative prior to dosing. 
3Values obtained within 7 days of the study visit, if obtained for clinical indication, can be utilized during the treatment phase and within 14 days of the study visit for the longitudinal monitoring phase. Blood collection 
includes CBC, Complete Metibolic Panel, & T Cell Subsets (T cell subset will be drawn unless CBC shows an ALC<100). Serum for Ig studies on Days 28 & 180. 
4 The PK specimen on Day 7 will be collected 1-4 hours after the subject takes the study dose and on Day 21 will be a pre-dose trough and will be drawn only in subjects consenting to this optional assessment. 
5 Nitazoxanide or placebo kit will be provided to the subject. Study drug (Nitazoxanide or placebo) given BID for 28 days. 
6 Diary recorded once a day during the treatment phase and once a day during the longitudinal monitoring phase.  Copies of completed pages are collected at each study visit. One pack give an enrollment and additional 
copies provided at Day 28. 
7 Stool for pathogen screen will not be performed for formed stool except on Day 1 and 180.  An aliquot will be retained for later testing if indicated.  Norovirus testing includes quantitative viral load at all time points. 
8 Sequencing at selected time points. 
10Day 60 pill count only needs to be conducted if the dosing was not completed and medications returned during Study Day 28. 
₩ Can covert to virtual visit  


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§ If diarrhea recurs after stopping therapy, would have subject provide a stool specimen for pathogen screen and Norovirus PCR; therapy is at the discretion of the site.  
¥ The sample must have been produced within 24 hours of the visit and if it exceeds 24 hours it must be disposed.  After collection in the stool hat, the subjects can wipe down and disinfect the outside of the container and 
place it in a bag for   transport then refrigerate until they come to their visit with the research staff. Subjects would be encouraged to provide another sample within the visit window and if not, rectal swab may be used for 
all assays related to stool collection.  
*Vital Signs include weight, Blood Pressure, Respiration, Pulse, Temperature and Height. Height is only measured at Screening/Enrollment/Baseline visit.  
#Derived from Complete Blood Count.  
€Derived from Complete Metabolic Panel. 
¶Specimen also stored for future use. 
₱Must be within 3 days of enrollment. Blood collection includes CBC, Complete Metibolic Panel, T Cell Subsets, and Serum for Ig studies. 
ⱥIf Virtual Visit 
Ʊ If part of PK substudy 
  
 
 
 


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Appendix B: Laboratory Reference Ranges and Toxicity Grading 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1 Depending upon the lab used, references ranges, eligibility ranges and grading may be split out by sex and/or age. 
2 Reference range of individual study site laboratory 
3 High, Low, Not Graded 
ULN – upper limit of normal; LLN – lower limit of normal 
Blood, Serum, or Plasma Chemistries1 
Reference 
Range2 
LO/
HI/
N3 
Mild  
(Grade 1) 
Moderate 
(Grade 2) 
Severe  
(Grade 3) 
Creatinine (mg/dL) 
 
HI 
>ULN - 1.5 x 
ULN 
>1.5 – 3.0 x 
ULN 
>3.0 x ULN 
Blood Urea Nitrogen (BUN, mg/dL) 
 
HI 
>ULN - 26 
27 - 31 
>31 
Alkaline phosphatase (U/L) 
 
HI 
>ULN – 2.5 x 
ULN 
>2.5 – 5.0 x 
ULN 
>5.0 x ULN 
AST (U/L) 
 
HI 
>ULN – 3.0 x 
ULN 
>3.0 – 5.0 x 
ULN 
>5.0 x ULN 
ALT (U/L) 
 
HI 
>ULN – 3.0 x 
ULN 
>3.0 – 5.0 x 
ULN 
>5.0 x ULN 
Bilirubin, serum total (mg/dL)  
 
HI 
>ULN – 1.5 x 
ULN 
>1.5 – 3.0 x 
ULN 
>3.0 x ULN  


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Hematology 
Reference 
Range4 
LO/H
I/N5 
Mild  
(Grade 1)6 
Moderate 
(Grade 2) 
Severe  
(Grade 3) 
Hemoglobin  (g/dL) 
 
LO 
<LLN – 10.0 
<10.0 – 8.0 
<8.0  
 
 
White Blood Cell Count (WBC, K/CUMM ) 
 
HI 
>ULN - 15.00 
15.00 - 20.00 
>20.00 
 
LO 
<LLN – 3.0 
<3.0 – 2.0 
<2.0 
Platelets (K/CUMM) 
 
LO 
<LLN - 75 
<75 - 50 
<50 
 
Other Laboratory Parameters 
 
LO 
/HI 
Test result is 
associated with a 
mild sign or 
symptom. 
Test result 
requires 
minimal, local 
or non-invasive 
intervention. 
Test result requires an 
invasive medical or 
surgical intervention, or 
change in study dosing 
outside of the protocol 
defined dosing or 
discontinuation from the 
study treatment, or 
addition of new 
medication.   
 
4 Reference range of individual study site laboratory 
5 High, Low, Not Graded 
ULN – upper limit of normal; LLN – lower limit of normal 
 
 
 


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Appendix C: Patient Diary Components 
 
Symptom Diary 
Bristol Stool Scale 
Lewis SJ, Heaton KW (1997). "Stool form scale as a useful guide to 
intestinal transit time". Scand. J. Gastroenterol. 32 (9): 920–4. 
doi:10.3109/00365529709011203. PMID 9299672. 
 
Scale is free and in public domain, no permission required 
Positive and Negative 
Affect Scale (weekly 
diary only) 
Public domain, http://www.parqol.com/page.cfm?id=87  
Watson, D., Clark, L. A., & Tellegen, A. (1988). Development and 
validation of brief measures of positive and negative affect: The 
PANAS scales. Journal of Psychology, 54(6), 1063-1070. 
Other individual 
questions about 
diarrhea, nausea and 
abdominal pain 
Additional items in daily/weekly symptom diary were either validated 
in Dr Keefer’s NIH Trial or were arrived at with expert consensus 
with study investigators 
 
No copyright, Dr Keefer is a Co-investigator on this trial 
Detailed Patient Reported Outcome and Severity Score Assessment 
PROMIS Short 
Forms-- Adults 
 
 
 
PROMIS measures in English and Spanish are publicly available 
without license, fee, or royalty. 
 
http://www.healthmeasures.net/explore-measurement-systems/promis;  
 
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2829758/ 
 
Depression 
Anxiety 
Fatigue 
Sleep Disturbance 
GI symptoms 
Physical function 
Fecal incontinence 
PROMIS Short-
Forms-- Pediatrics 
Depression 
Anxiety 
Fatigue 
EuroQOL-5D 
Validated general QOL measure, permission obtained and study 
registered with company http://www.euroqol.org/ 
IBS-Quality of Life 
Scale 
Validated GI specific QOL measure, Permission requested/study 
registered with ePROVIDE    


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https://eprovide.mapi-trust.org/instruments/irritable-bowel-syndrome-
quality-of-life 
 
PedsQL4 
Validated general QOL measure for pediatrics, Permission 
requested/study registered with PEDSQL 
http://www.pedsql.org/pedsql13.html 
 
 

SAP_001.pdf: 
 
CLINICAL RESEARCH IN INFECTIOUS DISEASES 
 
 
 
STATISTICAL ANALYSIS PLAN 
for 
DMID Protocol: 16-0092 
Study Title: 
A Phase 2 Multi-Center, Prospective, Randomized, 
Double-Blind Study to Assess the Clinical and 
Antiviral Efficacy and Safety of Nitazoxanide for the 
Treatment of Norovirus in Hematopoietic Stem Cell 
and Solid Organ Transplant Recipients 
 
NCT03395405 
 
Draft Version 2.0 
 
DATE: August 01, 2022 
 
THIS COMMUNICATION IS PRIVILEGED AND CONFIDENTIAL  
 
 


Statistical Analysis Plan - DMID Protocol: 16-0092  
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STUDY TITLE 
Protocol Number Code: 
DMID Protocol: 16-0092 
Development Phase: 
Phase 2 
Products: 
56 doses of 500mg Nitazoxanide 
Form/Route: 
Oral 
Indication Studied: 
Norovirus 
Sponsor: 
Division of Microbiology and Infectious Diseases 
National Institute of Allergy and Infectious Diseases 
National Institutes of Health 
Clinical Trial Initiation Date: 
15 October 2018 
Clinical Trial Completion Date: 
24 August 2021 
Date of the Analysis Plan: 
01 August 2022 
Version Number: 
2.0 
This study was performed in compliance with Good Clinical Practice. 
Information contained in this publication is the property of Division of Microbiology and Infectious Diseases and is confidential. This 
information may not be disclosed to third parties without written authorization from Division of Microbiology and Infectious Diseases. This 
report may not be reproduced, stored in a retrieval system or transmitted in any form or by any means - electronic, mechanical, recording or 
otherwise - without the prior authorization from Division of Microbiology and Infectious Diseases. This document must be returned to Division 
of Microbiology and Infectious Diseases upon request. 
 


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TABLE OF CONTENTS 
STUDY TITLE ................................................................................................................................2 
TABLE OF CONTENTS .................................................................................................................3 
LIST OF ABBREVIATIONS ..........................................................................................................6 
1. 
PREFACE .....................................................................................................................8 
2. 
INTRODUCTION ........................................................................................................9 
2.1. 
Purpose of the Analyses ..............................................................................................10 
3. 
STUDY OBJECTIVES AND ENDPOINTS ..............................................................11 
3.1. 
Study Objectives .........................................................................................................11 
3.1.1. 
Primary Objective: ......................................................................................................11 
3.1.2. 
Secondary Objectives: ................................................................................................11 
3.1.3. 
Exploratory Objectives: ..............................................................................................11 
3.2. 
Endpoints ....................................................................................................................11 
3.2.1. 
Primary Outcome Measure .........................................................................................11 
3.2.2. 
Secondary Efficacy Outcome Measures .....................................................................11 
3.2.3. 
Secondary Safety Outcome Measures ........................................................................11 
3.2.4. 
Exploratory Outcome Measures .................................................................................12 
3.3. 
Study Definitions and Derived Variables ...................................................................14 
4. 
INVESTIGATIONAL PLAN .....................................................................................24 
4.1. 
Overall Study Design and Plan ...................................................................................24 
4.2. 
Discussion of Study Design, Including the Choice of Control Groups ......................24 
4.3. 
Selection of Study Population ....................................................................................24 
4.4. 
Treatments ..................................................................................................................25 
4.4.1. 
Treatments Administered ............................................................................................25 
4.4.2. 
Identity of Investigational Product(s) .........................................................................26 
4.4.3. 
Method of Assigning Subjects to Treatment Groups (Randomization) .....................26 
4.4.4. 
Selection of Doses in the Study ..................................................................................27 
4.4.5. 
Selection and Timing of Dose for Each Subject .........................................................27 
4.4.6. 
Blinding ......................................................................................................................27 
4.4.7. 
Prior and Concomitant Therapy ..................................................................................28 
4.4.8. 
Treatment Compliance ................................................................................................28 


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4.5. 
Efficacy, Immunogenicity, Safety, and Other Variables ............................................28 
4.5.1. 
Efficacy Variables ......................................................................................................29 
4.5.2. 
Immunogenicity Variables ..........................................................................................31 
4.5.3. 
Safety Variables ..........................................................................................................31 
4.5.4. 
Other Variables ...........................................................................................................33 
5. 
SAMPLE SIZE CONSIDERATIONS .......................................................................34 
6. 
GENERAL STATISTICAL CONSIDERATIONS ....................................................35 
6.1. 
General Principles .......................................................................................................35 
6.2. 
Timing of Analyses .....................................................................................................35 
6.3. 
Analysis Populations ..................................................................................................35 
6.3.1. 
Modified Intention-to-Treat (mITT) Population ........................................................35 
6.3.2. 
Per Protocol (PP) Population ......................................................................................35 
6.3.3. 
Safety Population ........................................................................................................35 
6.3.4. 
Immunogenicity Population ........................................................................................36 
6.4. 
Covariates and Subgroups ..........................................................................................36 
6.5. 
Missing Data ...............................................................................................................36 
6.6. 
Interim Analyses and Data Monitoring ......................................................................37 
6.7. 
Multicenter Studies .....................................................................................................37 
6.8. 
Multiple Comparisons/Multiplicity ............................................................................37 
7. 
STUDY SUBJECTS ...................................................................................................38 
7.1. 
Disposition of Subjects ...............................................................................................38 
7.2. 
Protocol Deviations ....................................................................................................38 
8. 
EFFICACY EVALUATION ......................................................................................39 
8.1. 
Primary Efficacy Analysis ..........................................................................................39 
8.1.1. 
Supplemental and Sensitivity Analyses ......................................................................39 
8.2. 
Secondary Efficacy Analyses .....................................................................................40 
8.3. 
Exploratory Efficacy Analyses ...................................................................................41 
9. 
SAFETY EVALUATION ..........................................................................................44 
9.1. 
Demographic and Other Baseline Characteristics ......................................................44 
9.1.1. 
Prior and Concurrent Medical Conditions ..................................................................44 
9.1.2. 
Prior and Concomitant Medications ...........................................................................44 


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9.2. 
Measurements of Treatment Compliance ...................................................................44 
9.3. 
Adverse Events ...........................................................................................................45 
9.3.1. 
Unsolicited Adverse Events ........................................................................................45 
9.4. 
Deaths, Serious Adverse Events and other Significant Adverse Events ....................45 
9.5. 
Pregnancies .................................................................................................................46 
9.6. 
Clinical Laboratory Evaluations .................................................................................46 
9.7. 
Vital Signs and Physical Evaluations .........................................................................46 
9.8. 
Concomitant Medications ...........................................................................................46 
9.9. 
Other Safety Measures ................................................................................................47 
10. 
IMMUNOGENICITY ................................................................................................48 
11. 
OTHER ANALYSES .................................................................................................50 
12. 
REPORTING CONVENTIONS ................................................................................51 
13. 
TECHNICAL DETAILS ............................................................................................52 
14. 
SUMMARY OF CHANGES IN THE CONDUCT OF THE STUDY OR 
PLANNED ANALYSES ............................................................................................53 
14.1. 
Changes in the Conduct of the Study .........................................................................53 
14.1.1. 
Protocol Amendments ................................................................................................53 
14.1.2. 
Study Product Administration ....................................................................................53 
14.1.3. 
Daily Diary Completion Time ....................................................................................54 
14.2. 
Changes in Planned Analyses .....................................................................................54 
15. 
REFERENCES ...........................................................................................................55 
16. 
LISTING OF TABLES, FIGURES, AND LISTINGS ..............................................58 
APPENDICES ...............................................................................................................................59 
APPENDIX 1. TABLE MOCK-UPS..........................................................................................60 
APPENDIX 2. FIGURE MOCK-UPS ......................................................................................132 
APPENDIX 3. LISTINGS MOCK-UPS ...................................................................................146 
 


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LIST OF ABBREVIATIONS 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
ANCOVA 
Analysis of Covariance 
ANOVA 
Analysis of Variance 
AST 
Aspartate Aminotransferase 
BP 
Blood Pressure  
BUN 
Blood Urea Nitrogen 
C 
Celsius 
CI 
Confidence Interval 
CRF 
Case Report Form 
DMID 
Division of Microbiology and Infectious Diseases 
DSMB 
Data and Safety Monitoring Board 
EDC 
Electronic Data Capture 
ELISA 
Enzyme-linked Immunosorbent Assay 
ER 
Emergency Room 
F 
Fahrenheit 
GGT 
Gamma Glutamyl Transferase 
GI 
Gastrointestinal 
GMT 
Geometric Mean Titer 
GMFR 
Geometric Mean Fold Rise 
GVHD 
Graft vs Host Disease 
IBSQOL 
Irritable Bowel Syndrome Quality of Life Measure 
ICH 
International Conference on Harmonisation 
IRB 
Institutional Review Board 
ITT 
Intention to Treat 
L 
Liter 
LLN 
Lower Limit of Normal 
LLOQ 
Lower Limit of Quantification 
mcg 
Microgram 
MedDRA 
Medical Dictionary for Regulatory Activities  


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mEq 
Milliequivalent 
mg 
Milligram 
mITT 
Modified Intention to Treat 
mL 
Milliliter 
MAR 
Missing at Random 
MCAR 
Missing Completely at Random 
MNAR 
Missing Not at Random 
N 
Number (typically refers to subjects) 
NIH 
National Institutes of Health 
PI 
Principal Investigator 
PP 
Per Protocol 
PRO 
Patient-Reported Outcomes 
PROMIS 
Patient-Reported Outcomes Measurement Information System 
PT 
Preferred Term 
RBC 
Red Blood Cell 
RCD 
Reverse Cumulative Distribution  
SAE 
Serious Adverse Event 
SD 
Standard Deviation 
SDCC 
Statistical and Data Coordinating Center 
SMC 
Safety Monitoring Committee 
SOC  
System Organ Class 
SOP 
Standard Operating Procedures 
TPN 
Total Parenteral Nutrition 
U 
Units 
ULN 
Upper Limit of Normal 
UNOS 
United Network for Organ Sharing 
WBC 
White Blood Cell 
WHO 
World Health Organization 
 


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1. 
PREFACE 
The Statistical Analysis Plan (SAP) for “A Phase 2 Multi-Center, Prospective, Randomized, Double-Blind 
Study to Assess the Clinical and Antiviral Efficacy and Safety of Nitazoxanide for the Treatment of Norovirus 
in Hematopoietic Stem Cell and Solid Organ Transplant Recipients” (DMID Protocol 16-0092) describes and 
expands upon the statistical information presented in the protocol. 
This document describes the analyses planned and provides reasons and justifications for these analyses. 
Planned analyses for pharmacokinetics (PK) and microbiome endpoints will not be included and will instead 
be provided in addendums to this SAP. It also includes sample tables, listings, and figures planned for the 
final analyses. Regarding the final analyses and Clinical Study Report (CSR), this SAP follows the 
International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals 
for Human Use (ICH) Guidelines, as indicated in Topic E3 (Structure and Content of Clinical Study Reports), 
and more generally is consistent with Topic E8 (General Considerations for Clinical Trials) and Topic E9 
(Statistical Principles for Clinical Trials). The structure and content of the SAP provides sufficient detail to 
meet the requirements identified by the FDA and ICH, while all work planned and reported for this SAP will 
follow internationally accepted guidelines published by the American Statistical Association and the Royal 
Statistical Society for statistical practice. 
This document contains four sections: (1) a review of the study design, (2) general statistical considerations, 
(3) comprehensive statistical analysis methods for efficacy and safety outcomes, and (4) a list of proposed 
tables and figures. Within the table, figure, and listing mock-ups (Appendices 1, 2, and 3), references to CSR 
sections are included. Any deviation from this SAP will be described and justified in protocol amendments 
and/or in the CSR, as appropriate. The reader of this SAP is encouraged to also review the study protocol for 
details on conduct of the study and the operational aspects of clinical assessments. 


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2. 
INTRODUCTION 
Gastroenteritis is defined as a self-limiting diarrheal illness that is often accompanied by nausea, vomiting, 
fever, or abdominal pain. In the United States, Norovirus is the single most common cause of acute 
gastroenteritis that leads to medical evaluation in adults, and the second most common cause of severe 
diarrhea in infants and young children [1, 2]. In the US, Norovirus is estimated to be responsible for 19 – 21 
million episodes of gastroenteritis and 56,000 – 71,000 hospitalizations annually. [3] Increasingly, Norovirus 
is recognized as a common cause of chronic gastroenteritis in immunocompromised patients. Prolonged 
diarrhea can lead to dehydration, allograft dysfunction, renal insufficiency and rarely death in these patients 
[1, 4-9].  
Noroviruses are small, non-enveloped, single-stranded RNA viruses that are members of the Caliciviridae. (1, 
10] Of the five genogroups (GI – GV), GI, GII, and GIV are known to be human pathogens, although most 
are caused by GI and GII, which can be further classified into 30 unique genotypes. GII.4 has been recognized 
as the most common cause of outbreaks of Norovirus infections globally. [11, 12] 
Norovirus is highly contagious as transmission is highly efficient with a median infectious dose of 18 viruses. 
There are generally high titers of virus within stool (105 to 1010 genome copies per gram of feces); [13, 14] 
therefore contact with infected feces and vomit, fecally-contaminated food, water and surfaces are common 
sources of infection. Norovirus is also highly stable with retained infectivity under environmental conditions 
that would generally inactivate other viruses, included chlorine at concentrations used in drinking water. [15, 
16]. 
Norovirus infections typically present as an acute infection in immunocompetent hosts, with an incubation 
period of 10 to 51 hours. Symptoms include nausea, vomiting, water non-bloody diarrhea, abdominal cramps 
and occasionally low-grade fever, muscle aches, chills and headache, [16] usually lasting from 20 to 60 hours. 
[17] While the acute phase of illness is typically short-lived, asymptomatic patients may continue to shed the 
virus for up to two weeks. [10, 16, 18] Unfortunately, approximately 570 – 800 deaths each year results from 
Norovirus infections in the US, with one third of fatal cases occurring in immunocompromised hosts. [19] 
Immunocompromised patients such as those with congenital immunodeficiencies, human immunodeficiency 
virus (HIV)-infected patients, solid organ transplant recipients, hematopoietic stem cell transplant patients and 
oncology patients undergoing chemotherapy can develop chronic Norovirus infections. [1, 20-25] Copious 
watery diarrhea with stool volume amounting to several liters per day comparable to volumes observed with 
cholera may last for 3 – 4 months or longer. [3, 21] As a result, dehydration and elevated calcineurin inhibitor 
levels are common in patients at the time of initial diagnosis. 
In vitro, nitazoxanide has been shown to be active against Norovirus. Results from double-blind placebo-
controlled studies demonstrate that nitazoxanide decreases the duration of illness in subjects with viral 
gastroenteritis. Small observational studies suggest that nitazoxanide results in prompt improvement in 
clinical signs of Norovirus-induced gastroenteritis. Further, nitazoxanide enhanced local production of 
interferon which may contribute to more rapid clearance of virus. Studies of nitazoxanide for the treatment of 
Norovirus has presented limited data on quantitative virology and its impact on viral load are less well 
defined. Further, there are limited data on the impact of nitazoxanide on host and viral changes that may 
facilitate control and clearance of Norovirus. 
The present study is a phase 2 multi-center, prospective, randomized, double-blind study designed to assess 
the efficacy of nitazoxanide taken twice daily for 28 days compared to placebo for the treatment of Norovirus 
gastroenteritis in immunosuppressed transplant subjects. Given the safety of prolonged therapy with 
nitazoxanide [26-29], lack of interactions with common post-transplant medications, putative antiviral activity 
and prolonged duration of viral shedding we are assessing 28 days of therapy. The longitudinal monitoring 


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phase will provide useful information on the course of host and viral responses in subjects with chronic 
Norovirus infection with and without treatment. 
2.1. 
Purpose of the Analyses 
These analyses will assess the efficacy and safety of nitazoxanide in comparison with placebo for the 
management of acute and chronic Norovirus in transplant recipients and will be included in the clinical study 
report. 


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3. 
STUDY OBJECTIVES AND ENDPOINTS 
3.1. 
Study Objectives 
3.1.1. 
Primary Objective: 
• To assess the clinical efficacy of nitazoxanide for the management of acute and chronic Norovirus in 
transplant recipients. 
3.1.2. 
Secondary Objectives: 
• To assess the virologic efficacy of nitazoxanide. 
• To assess the safety of nitazoxanide for the management of acute and chronic Norovirus in transplant 
recipients. 
3.1.3. 
Exploratory Objectives: 
• To assess initial clinical improvement in Norovirus Disease through 28 and 180 days. 
• To assess markers of virologic improvement in Norovirus Disease through 28 and 180 days. 
• To assess the contribution of immunologic response to Norovirus to the clinical course of disease in 
treated and untreated subjects. 
• To define the pharmacokinetics and dose response relationships of nitazoxanide. 
• To define the natural history of Norovirus in nitazoxanide treated and untreated subjects. 
3.2. 
Endpoints 
3.2.1. 
Primary Outcome Measure 
• The time from randomization until initial clinical resolution of Norovirus symptoms for at least 48 
hours through 180 days. 
Clinical resolution will be assessed from the daily diary by the subject and will be defined as: 
o Cessation of vomiting and, 
o No stools classified by the Bristol Stool Chart as diarrhea (Type 6 or 7) 
3.2.2. 
Secondary Efficacy Outcome Measures 
• Time from randomization to first negative viral load through 180 days. 
• The change in viral titer between Day 1 and 180. 
3.2.3. 
Secondary Safety Outcome Measures 
• Incidence of unsolicited non-serious adverse events through 60 days. 
• Incidence of laboratory adverse events (White Blood Cell Count (WBC), Hemoglobin, Platelet Count, 
Creatinine, Alkaline Phosphatase, Alanine Aminotransferase (ALT), Aspartate Aminotransferase 
(AST), Blood Urea Nitrogen (BUN), and Bilirubin) through 60 days. 
• Incidence of protocol-specified serious adverse events through 60 days. 


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• Incidence of hospitalization through 60 days. 
3.2.4. 
Exploratory Outcome Measures 
• Time from randomization to initial clinical improvement in Norovirus disease through 28 and 180 
days for at least 48 hours, as defined by: 
o 50% reduction in number of episodes of vomiting and, 
o Improvement in PO intake, as judged by the subjects and, 
o 50% reduction in the number of episodes of diarrhea as classified by the subject by the Bristol 
Stool Chart as type 6 or 7 bowel movements. 
• Time from randomization to initial cessation of vomiting through Day 180 (recurrent vomiting will be 
considered disease recurrence unless determined to be due to another etiology [i.e. GVHD]). 
• Time from randomization to subject report of no loss of appetite that is maintained for 48 hours 
through Day 180 (measure will be first time that the subject reports that they have no “loss of appetite” 
on their daily diary). 
• Time from first dose to initial cessation of diarrhea through Day 180 classified by the Bristol Stool 
Chart as type 6 or 7 bowel movements (recurrent diarrhea will be considered disease recurrence unless 
determined to be due to another etiology [i.e. GVHD]). 
• Time from randomization to 50% reduction in the amount of antimotility agents utilized by the subject 
through Day 180. 
• Number of days of diarrhea through Days 28 and 180. 
• Number of stools classified by the Bristol Stool Chart as type 6 or 7 bowel movements through Day 
28. 
• Number of days of IV hydration or total parenteral nutrition (TPN) therapy through Day 28. 
• Total number of days of hospitalization through Days 28 and 180. 
• Change in patient-reported quality of life as measured by EuroQOL-5 (global) and IBSQOL (diarrhea 
specific) [adult] or EuroQOL-5 Peds (global) and PedsQL GI Module [children] from baseline to Day 
180. 
• Change in patient-reported physical function as measured by NIH PROMIS Physical Function (Adult) 
Pediatric Global Health (Peds) from baseline to Day 180. 
• Change in patient-reported emotional distress as measured by the NIH PROMIS Depression, Anxiety, 
Fatigue (Adult and Peds) from baseline to Day 180. 
• Change in patient-reported gastrointestinal symptoms as measured by the NIH PROMIS GI (Adult and 
Peds) symptoms (6 of 8 subscales) from baseline to Day 180. 
• The effect of co-pathogens, as determined by the BioFire stool pathogen screen, on the primary 
outcome measure. 
• Time from randomization until initial clinical resolution of Norovirus symptoms for at least 48 hours 
through Day 180. Clinical resolution will be assessed from the daily diary by the subject and will be 
defined as cessation of vomiting and no stools classified by the Bristol Stool Chart as diarrhea (Type 6 


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or 7) from the total population compared to the subgroup of subjects who do not report chromaturia 
(discoloration of urine) based on unsolicited self-reporting. 
• Incidence of unsolicited non-serious adverse events through 60 days, laboratory adverse events (WBC, 
Hemoglobin, Platelet Count, Creatinine, Alkaline Phosphatase, ALT, AST, BUN, and Bilirubin) 
through 60 days, protocol-specified serious adverse events through 60 days, and hospitalization 
through 60 days from the total population compared to the subgroup of subjects who do not report 
chromaturia (discoloration of urine) based on unsolicited self-reporting 
• Time to ≥ 1 log reduction in stool Norovirus genome copies. 
• Change in quantitative Norovirus load in the stool between Day 1 and Day 7, 14, 21, 28, 60, 120, and 
180. 
• Change in Norovirus sequence from Day 1 to Days 28 and 60. 
• The effect of co-pathogens, as determined by the BioFire stool pathogen screen, on the time from 
randomization to first negative viral load through 180 days. 
• Time from randomization to first negative viral load through 180 days and the change in viral titer 
between Day 1 and 180 from the total population compared to the subgroup of subjects who do not 
report chromaturia (discoloration of urine) based on unsolicited self-reporting. 
• Change in Norovirus-specific serum and stool IgA, IgM and IgG between Day 1 and Days 28 and 60. 
• Association between change in total lymphocyte count and T cell subsets at Day 1 and 180 and 
clinical resolution of Norovirus symptoms. 
• Association between change in total lymphocyte count and T cell subsets at Day 1 and 180 and 
undetectable quantitative norovirus PCR. 
• Association between change in Norovirus-specific serum and stool IgA, IgM and IgG from Day 1 to 
Days 28 and 60 and clinical resolution of Norovirus symptoms. 
• Association between change in Norovirus-specific serum and stool IgA, IgM and IgG from Day 1 to 
Days 28 and 60 and undetectable quantitative Norovirus PCR. 
• For subjects consenting to PK draws, concentrations of nitazoxanide metabolites (tizoxanide and 
tizoxanide glucuronide) 1 to 4 hours after the first dose on Day 7 and 10 minutes before the second 
dose on Day 21. 
• Time to allograft rejection as per each center team. 
• Time to allograft loss as reported to United Network for Organ Sharing (UNOS). 
• Time to death. 
• Time to withdrawal from the study because of intolerance or drug related adverse events. 
• Correlation of secretor status as defined by phenotype and genotype, separately, and clinical resolution 
of Norovirus as defined by the primary endpoint. 


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3.3. 
Study Definitions and Derived Variables  
Diarrhea: 
Diarrhea will be defined as Type 6 or 7 on the Bristol Stool chart.  
Baseline Value: 
The baseline value will be defined as the last value obtained prior to the first dose of study product unless 
otherwise noted. 
Additional Nitazoxanide: 
Any nitazoxanide reported as a concomitant medication will be considered additional nitazoxanide. 
Initial Clinical Resolution of Norovirus Symptoms: 
Clinical resolution of Norovirus symptoms will be assessed from the daily diary by the subject and will be 
defined as: 
• Cessation of vomiting and, 
• No stools classified by the Bristol Stool Chart as diarrhea (Type 6 or 7). 
Subjects will need to have at least two consecutive daily diary entries where they reported no vomiting, no 
Bristol Stool Type 6, and no Bristol Stool Type 7 to meet the criteria for initial clinical resolution. There are 
several variables in the daily diary that indicate whether the subject had diarrhea or vomiting for that day.  
Daily Diary Diarrhea Questions: 
• Phase 1 (Treatment Phase): 
o Number of Bristol Type 6 stools? (Quantitative) 
o Were there too many Bristol Type 6 stools to count? (Qualitative) 
o Number of Bristol Type 7 stools? (Quantitative) 
o Were there too many Bristol Type 7 stools to count? (Qualitative) 
• Phase 2 (Longitudinal Phase): 
o Did you have diarrhea today? (By diarrhea, we mean at least ONE bowel movement that could be 
described as Type 6 or 7.) (Qualitative) 
Daily Diary Vomiting Questions: 
• Phase 1 (Treatment Phase): 
o Did you have to take another dose because you threw up the first dose within 1 hour? (Qualitative) 
o How many times did you vomit today? (Quantitative) 
• Phase 2 (Longitudinal Phase): 
o Did you vomit today? (Qualitative) 
For a day to count towards clinical resolution during the treatment phase, the following responses must be 
recorded in the daily diary entry: 
• Both quantitative diarrhea questions must be 0 


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• Both qualitative diarrhea questions must be missing (i.e. not “yes”) 
• The quantitative vomiting questions must be 0 
• The qualitative vomiting question must be “no” 
For a day to count towards clinical resolution during the longitudinal phase, the following responses must be 
recorded in the daily diary entry: 
• The qualitative diarrhea question must be “no” 
• The quantitative vomiting question must be 0 
If a daily diary entry is missing, refer to the imputation rules in Section 6.5. 
Viral Load: 
As Norovirus surveillance laboratories have observed that Norovirus type GII is predominant compared to 
Norovirus type GI and dual infection by both GI and GII viruses is rare, all specimens are tested for Norovirus 
GII viral load first (Dr. Ming Tan, Dr. Xi Jason Jiang, person communication). Only specimens that are 
negative for Norovirus GII viral load will be tested for Norovirus GI viral load. Subjects will only be analyzed 
for the viral load test type (Norovirus GII or Norovirus GI) that they tested positive for at baseline (Visit 01). 
If a subject initially tested positive for GI and later tested positive for Norovirus GII before they tested 
negative for Norovirus GI, the subject will be considered positive for Norovirus GI until they test negative for 
Norovirus GII and Norovirus GI. Subjects that did not test positive for either Norovirus GII or Norovirus GI 
at baseline will be excluded from the analyses. The first day of undetectable quantitative Norovirus PCR is the 
first day the subject had either a negative result or a result less than the lower limit of quantitation (LLOQ) for 
the viral load test type (Norovirus GII or Norovirus GI) that they initially tested positive for at baseline. Viral 
load will be quantified as the geometric mean of the replicates. Negative results will be imputed as ½ the 
LLOQ and results greater than the upper limit of quantification (ULOQ) will be imputed as the ULOQ. 
Initial Clinical Improvement in Norovirus Disease: 
Initial clinical improvement in Norovirus disease through 28 and 180 days for at least 48 hours, is defined by: 
a. 50% reduction in number of episodes of vomiting and, 
b. Improvement in PO intake, as judged by the subjects and, 
c. 50% reduction in the number of episodes of diarrhea as classified by the subject by the Bristol Stool 
Chart as type 6 or 7 bowel movements.  
The baseline values for number of episodes of vomiting and diarrhea will be the numbers provided on the first 
non-missing daily diary entry for the vomiting and diarrhea questions, respectively. Subjects must answer 
“yes” to the daily diary question “Did you eat your usual diet today?” to meet the improvement in PO intake 
criteria. 
Detailed Patient-Reported Outcome (PRO) Measures: 
Study personnel will administer detailed PRO questionnaires to subjects at Visit 01 (Day 1), Visit 05 (Day 
28), Visit 08 (Day 60), Visit 10 (Day 120), and Visit 12 (Day 180).  
Quality of Life. 
Adult subjects will complete two questionnaires for quality of life: NNITS PRO EuroQOL-5 and NNITS PRO 
IBSQOL [30]. There were no pediatric subjects enrolled in the study. The IBSQOL contains 34 items, each 
with a five-point response scale. The score for each subject/visit will be: 


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𝑆𝑐𝑜𝑟𝑒𝐼𝐵𝑆𝑄𝑂𝐿= 𝑇ℎ𝑒 𝑠𝑢𝑚 𝑜𝑓 𝑡ℎ𝑒 𝑖𝑡𝑒𝑚𝑠−𝑙𝑜𝑤𝑒𝑠𝑡 𝑝𝑜𝑠𝑠𝑖𝑏𝑙𝑒 𝑠𝑐𝑜𝑟𝑒 
𝑝𝑜𝑠𝑠𝑖𝑏𝑙𝑒 𝑟𝑎𝑤 𝑠𝑐𝑜𝑟𝑒 𝑟𝑎𝑛𝑔𝑒
 × 100 
If items are missing, confirm that at least 17 (50%) have been answered before calculating the score. If less 
than 17 questions have been answered, the score will be left as missing. 
The scoring guide for the EuroQOL-5 questionnaire [31] states that a single index value is not currently 
possible. Instead, the levels will be dichotomized into ‘no problems’ (i.e. level 1) and ‘problems’ (i.e. levels 2 
and 3). 
 
Patient-Reported Physical Function: 
Adult subjects will complete the NNITS PRO PROMIS [32] Physical Function questionnaire. The raw score 
will be the sum of the items from the questionnaire. The score for each subject/visit will then use the 
following table to convert the raw score into a t-score: 
 


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If items are missing, confirm that at least 4 (50%) have been answered before calculating the score. If less 
than 4 questions have been answered, the score will be left as missing. If less than 4 items are missing, the 
pro-rated raw score will be: 
𝑅𝑎𝑤 𝑠𝑐𝑜𝑟𝑒= 
𝑅𝑎𝑤 𝑠𝑢𝑚 × 8
𝑁𝑢𝑚𝑏𝑒𝑟 𝑜𝑓 𝑖𝑡𝑒𝑚𝑠 𝑡ℎ𝑎𝑡 𝑤𝑒𝑟𝑒 𝑎𝑐𝑡𝑢𝑎𝑙𝑙𝑦 𝑎𝑛𝑠𝑤𝑒𝑟𝑒𝑑 
If the result is a fraction, round up to the nearest whole number. 
Patient-Reported Emotional Distress: 
Adult subjects will complete the NNITS PROMIS Emotional Questionnaire. Patient-reported emotional 
distress will be reported in three separate categories: depression, anxiety, and fatigue.  
The raw score for depression will be the sum of questions #1-4. The depression score for each subject/visit 
will then use the following table to convert the raw score into a t-score: 
 
All questions must be answered to receive a depression score. 


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The raw score for anxiety will be the sum of questions #5-8. The anxiety score for each subject/visit will then 
use the following table to convert the raw score into a t-score: 
 
All questions must be answered to receive an anxiety score. 
The raw score for fatigue will be the sum of questions #9-12. The fatigue score for each subject/visit will then 
use the following table to convert the raw score into a t-score: 
 
All questions must be answered to receive a fatigue score. 


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Patient-Reported Gastrointestinal Symptoms: 
Adult subjects will complete the NNITS PROMIS GI Questionnaire. For question 17, each belly pain area 
marked “yes” will indicate 1 point (e.g. if a subject answers “yes” for belly pain area 1, belly pain area 6, and 
belly pain area 8, their score for question 17 would be 3). The GI Questionnaire contains questions from four 
domains: diarrhea (questions 1 – 3 and 8 – 10), nausea (questions 4 – 7), fecal incontinence (questions 11 – 
14), and belly pain (questions 15 – 20) and therefore cannot be summarized into a single score. Instead each 
domain will be reported separately. The raw scores for each domain will be the sum of the items from the 
questionnaire that are in the domain. The score for each subject/visit will then use the following tables to 
convert the raw scores into  t-scores: 
Diarrhea: 
 
 


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Nausea: 
 
Fecal Incontinence: 
 


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Belly Pain: 
 
If items are missing, confirm that at least 50% have been answered before calculating the score. If less than 
50% of the questions have been answered, the score will be left as missing. If less than 50% of the items are 
missing, the pro-rated raw score will be: 
𝑅𝑎𝑤 𝑠𝑐𝑜𝑟𝑒= 𝑅𝑎𝑤 𝑠𝑢𝑚 × 𝑇𝑜𝑡𝑎𝑙 𝑛𝑢𝑚𝑏𝑒𝑟 𝑜𝑓 𝑞𝑢𝑒𝑠𝑡𝑖𝑜𝑛𝑠 𝑖𝑛 𝑑𝑜𝑚𝑎𝑖𝑛
𝑁𝑢𝑚𝑏𝑒𝑟 𝑜𝑓 𝑖𝑡𝑒𝑚𝑠 𝑡ℎ𝑎𝑡 𝑤𝑒𝑟𝑒 𝑎𝑐𝑡𝑢𝑎𝑙𝑙𝑦 𝑎𝑛𝑠𝑤𝑒𝑟𝑒𝑑 
If the result is a fraction, round up to the nearest whole number. Note that only three of the four nausea 
questions from the GI questionnaire were included, therefore in order to meet the 50% criteria at least 2 of the 
3 questions must be answered.  
Positive and Negative Affect Scale (PANAS): 
Adult subjects will complete the NNITS PROMIS PANAS Questionnaire. Patient-reported positive and 
negative affect scores will be reported in two separate categories: positive affect score and negative affect 
score.  
The score for positive affect will be the sum of questions #1, 3, 5, 9, 10, 12, 14, 16, 17, and 19. The score for 
negative affect will be the sum of questions #2, 4, 6, 7, 8, 11, 13, 15, 18, and 20. 


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Reduction in Amount of Antimotility Agents: 
The amount of antimotility agents for a given day will be defined as the response to the “# of antidiarrheals 
today” question in the Phase 1 (Treatment Phase) Daily Symptom Diary. Missing responses will be left as 
missing. 50% reduction in the amount of antimotility agents will be defined as the first study day in which the 
subject’s response was less than or equal to 50% of their response given on Day 1. 
Number of Days of Diarrhea: 
The number of days of diarrhea will be based on the Daily Diary Diarrhea Questions (see above). For a day to 
count towards the number of days of diarrhea, one of the following must occur: a quantitative diarrhea 
question must be greater than 0 or a qualitative question must be marked “yes”. Missing responses will be left 
as missing. 
Number of Type 6 or 7 Stools: 
The number of Type 6 or 7 stools through Day 28 will be defined as the sum of the responses to the 
quantitative Daily Diary Diarrhea Questions during the Treatment Phase (see above). Missing responses will 
be left as missing. 
Number of Days of IV Hydration or Total Parenteral Nutrition (TPN) Therapy: 
The number of days of IV hydration or TPN therapy will be defined as the number of days with a concomitant 
medication with any indication related to IV hydration or TPN therapy. A blinded review of the concomitant 
medication data will be performed by the Medical Monitor to identify medications that should be included in 
the analysis. Days prior to Day 1 will not be included in the calculation of the number of days. Medications 
that are ongoing after Day 28 will be censored at 28 days. 
Co-pathogen Status: 
Co-pathogen status will be determined by the BioFire stool pathogen screen on Days 1 and 180. Co-pathogen 
status will be determined on Days 7, 14, 21, 28, 60, 120, and with recurrent diarrhea if unformed stool is 
present on study day. Analyses will only include whether pathogens were detected or not and will not 
differentiate by co-pathogen type. The listing will include which co-pathogens were detected at each 
subject/visit (Listing 18). 
Secretor Status: 
Saliva is collected at screening to determine H type 1 secretor status (phenotyping), while a buccal swab is 
collected to perform FUT2 genotyping. Phenotype and genotype results will either be “secretor” or “non-
secretor” for each subject. 
Norovirus-Specific Immunoglobulins (Ig): 
Results below the lower limit of detection (LLOD) will be imputed as ½ the LLOD. Results above the upper 
limit of detection (ULOD) will be imputed as the ULOD. 
Responders: 
A subject is classified as a responder if he or she has a four-fold or greater increase in Norovirus-specific Ig 
titers compared to baseline (Day 1). 
Study Day: 
Study day will be reported as the number of days from randomization with the day of randomization reported 
as study day 1. 


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Days Post-Randomization: 
Days post-randomization will be reported as the number of days since randomization; if an event began on the 
day of randomization, the days post-randomization is reported as 0. 
Duration: 
Duration will be reported as the difference between the start and end dates, inclusive of the day the event 
started. 
 


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4. 
INVESTIGATIONAL PLAN 
4.1. 
Overall Study Design and Plan 
A total of 160 subjects ≥ 12 years of age will be selected according to the inclusion and exclusion criteria.  
Upon enrollment in the study, subjects will be randomized into two treatment groups:  active nitazoxanide and 
placebo. The nitazoxanide arm will be given one 500mg tablet of nitazoxanide by mouth twice daily with 
food for 56 consecutive doses. The placebo arm will be given one placebo tablet by mouth twice daily with 
food for 56 consecutive doses. Randomization will be stratified by age group (pediatric (12-17 years) vs. adult 
(≥ 18 years)), chronicity of Norovirus-associated symptoms (acute (<14 days) vs. chronic (≥14 days)) and 
transplant type (solid organ (SOT) vs. hematopoietic stem cell transplant (HSCT)).  Enrolled subjects will 
participate in 2 phases of the study:  Treatment Phase, which will include dosing with the assigned study 
agent for 28 days and study visits on study Day 1, 7 ± 3 days, 14 ± 3 days, 21 ± 3 days, and 28 + 3 days; 
Longitudinal Monitoring Phase which will include telephone call on Days 35 ± 3 days, 53 ± 7 days, 113 ± 7 
days, and 173 ± 7 days, and study visits on study Day 60 ± 14 days, 120 ± 14 days and 180 ± 14 days.  If 
symptoms recur after completion of the Treatment Phase, subjects can resume any therapy excluding 
nitazoxanide at the discretion of the principal investigator or his/her designee. Nitazoxanide can be used after 
Day 28 if the local PI attests that it is medically urgent to use the nitazoxanide because the patient is 
experiencing severe or life-threatening disease.  Although nitazoxanide can be used if it is felt critical to the 
subject’s care, its use should be avoided until Day 180 whenever felt to be safe to do so by the local PI. 
Additional stool specimens should be collected prior to initiation of therapy for testing in the central lab. 
Figure 1 presents the schematic of the study design. 
4.2. 
Discussion of Study Design, Including the Choice of Control Groups 
Subjects are randomized at a ratio of 1:1 to receive one 500mg tablet of nitazoxanide or one placebo tablet by 
mouth twice daily with food for 28 days (56 consecutive doses). 
4.3. 
Selection of Study Population 
All candidates at all centers who meet all eligibility requirements will be offered the opportunity to participate 
in the trial. Study subjects are seen in patient or clinic setting and have either community onset or hospital 
acquired disease. 
Inclusion Criteria 
Subjects should meet all of the following inclusion criteria: 
1. Male or female age ≥ 12 years. 
2. Recipient of a solid organ or hematopoietic stem cell transplant. 
3. Positive test result for Norovirus within 14 days of enrollment that is obtained as part of routine 
clinical care using a Norovirus testing available to the site. 
4. Active GI symptoms (diarrhea or vomiting) that, in the opinion of the PI, are secondary to Norovirus.#  
# Patients must have active diarrhea, which is defined as at least 3 days of Bristol 6 or 7 stools in the past 2 weeks prior to 
enrollment per patient report. 
5. Willing and able to provide written informed consent and assent before initiation of any study 
procedures, consistent with local IRB policy. 


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6. Subjects must be of non-childbearing potential or if of childbearing potential, must be using an 
effective method of birth control or must be abstinent.  
• Non-childbearing potential is defined as surgically sterile or postmenopausal for > one year. 
• Effective methods of birth control include the use of hormonal or barrier birth control such as 
implants, injectable contraceptives, combined oral contraceptives, intrauterine devices [IUDs] or 
condoms with spermicidal agents during study period.  Female subjects must be using an effective 
method of birth control or practice abstinence and must agree to continue such precautions during 
the study and for 30 days after the Day 28 study visit. 
• A woman is eligible if she is monogamous with a vasectomized male. This subject is considered 
low risk and not required to use contraception.  
7. Agrees to complete all screening requirements, study visits and procedures. 
Exclusion Criteria: 
Subjects meeting any of the following exclusion criteria at baseline will be excluded from study participation: 
1. Other identified infectious causes of diarrhea at screening*. 
*Alternative diagnosis requiring treatment would be considered a co-infection; if the testing is positive for a pathogen that 
the PI does not feel is causing the symptoms, they may be included but the PI or his/her designee must document that the 
positive test is not clinically significant, does not require treatment and is not causing the symptoms making the patient 
eligible for enrollment  
2. Any condition that would, in opinion of the Site Investigator, place the subject at an unacceptable risk 
of injury or render the subject unable to meet the requirements of the protocol.  
3. Subjects receiving oral or intravenous immunoglobulin therapy concurrently or in the 14 days prior to 
enrollment.  
4. Nitazoxanide use for any illness in the previous 30 days prior to randomization. 
5. Have received experimental products within 30 days prior to the study entry or plan to receive 
experimental products at any time during the study 
6. Known sensitivity to nitazoxanide or any of the excipients comprising the nitazoxanide tablets. 
7. Subjects unable to swallow oral medications. 
8. Subjects with ostomy. 
9. Women who are pregnant or lactating or have a positive urine pregnancy test at 
screening/enrollment/Day 1. 
Co-enrollment in other studies is allowed if none of the above exclusion criteria are met.  
4.4. 
Treatments 
4.4.1. 
Treatments Administered  
Subjects will be randomized to receive either one 500 mg tablet of nitazoxanide twice daily with food for 56 
consecutive doses, or placebo. Nitazoxanide is a synthetic antiprotozoal agent for oral administration. The 
placebo will look identical to nitazoxanide and will have the same inactive ingredients. 


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4.4.2. 
Identity of Investigational Product(s) 
Nitazoxanide Tablets: 
Nitazoxanide will be supplied as a 500 mg round, yellow, film-coated tablet with “CTM” imprint, 
manufactured by Romark, L.C. Per the package insert, inactive ingredients include: maize starch, 
pregelatinized corn starch, hydroxypropyl methylcellulose, sucrose, sodium starch glycollate, talc, magnesium 
stearate, soy lecithin, polyvinyl alcohol, xanthan gum, titanium dioxide, FD&C Yellow No. 10 Aluminum 
Lake, FD&C Yellow No. 6 Aluminum Lake, and FD&C Blue No. 2 Aluminum Lake. 
Placebo Tablets: 
Placebo will be supplied as a matching tablet of the active drug which will also be a round, yellow, film-
coated tablet with “CTM” imprint.  Ingredients include: lactose monohydrate, magnesium stearate, talc, soy 
lecithin, polyvinyl alcohol, xanthan gum, titanium dioxide, FD&C Yellow No. 10 Aluminum Lake, FD&C 
Yellow No. 6 Aluminum Lake, and FD&C Blue No. 2 Aluminum Lake. In order to maintain the blind, the 
placebo will be formulated for the same appearance as the active study drug. 
All study product will be packaged in two 60cc identical containers each containing 30 tablets. Each container 
will also be labeled in compliance with applicable regulatory requirements, including the FDA-required 
cautionary statement “Caution: - New drug -Limited by Federal Law to Investigational Use.”   
Upon request from DMID, the study products will be shipped from the manufacturer to the DMID Clinical 
Materials Services (CMS). Study products will be shipped from the DMID CMS to investigational site upon 
request and approval from DMID. 
4.4.3. 
Method of Assigning Subjects to Treatment Groups (Randomization) 
Enrollment of subjects will be done online using the enrollment module of Advantage eClinical. Eligible 
subjects will be randomized and assigned in a 1:1 ratio to active nitazoxanide or placebo. The study will use a 
stratified, permuted block randomization scheme. Permuted block randomization is used to avoid the potential 
for serious imbalance in the number of subjects assigned to each group, an imbalance that can occur in the 
simple randomization procedures. 
Stratification will be by: 
• Duration of symptoms: onset of Norovirus-associated symptoms (diarrhea, nausea and/or abnormal 
appetite) < 14 days vs. ≥ 14 days 
• Transplant Type: solid organ vs hematopoietic stem cell transplant 
• Age Range: pediatric (12-17 years) vs. adult ≥ 18 years 
The randomization list will be computer-generated by statisticians at the Statistical and Data Coordinating 
Center (SDCC) using a stratified, permuted block randomization scheme and is included in the enrollment 
module for the trial. Advantage eClinical will assign each subject to a treatment group after the demographic, 
duration of symptoms, transplant type, and eligibility data have been entered into the system. 
Each site will have a supply of two 60cc identical blinded bottles pre-labeled with randomization numbers, 
each containing 30 tablets, sufficient to treat a subject with 56 doses. The two identical containers will be 
packaged in the same plastic bag. Once a subject is assigned a randomization number, the corresponding 
bottles will be distributed to the subject. 


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4.4.4. 
Selection of Doses in the Study 
Subjects will receive either one 500 mg tablet of nitazoxanide twice daily with food for 56 consecutive doses, 
or placebo. In vitro, nitazoxanide has been shown to be active against Norovirus. Results from double-blind 
placebo-controlled studies demonstrate that nitazoxanide decreases the duration of illness in subjects with 
viral gastroenteritis. Small observational studies suggest that nitazoxanide results in prompt improvement in 
clinical signs of Norovirus-induced gastroenteritis. Further, nitazoxanide enhanced local production of 
interferon which may contribute to more rapid clearance of virus.  
Given the safety of prolonged therapy with nitazoxanide [26-29], lack of interactions with common post-
transplant medications, putative antiviral activity and prolonged duration of viral shedding we are assessing 
28 days of therapy.    
4.4.5. 
Selection and Timing of Dose for Each Subject 
Nitazoxanide (administered orally as one 500 mg tablet) or placebo (administered orally as a matching tablet) 
twice daily with food for 56 doses. If the patient is NPO, product can be taken with water. 
Subjects in the hospital will be provided the study drug consistent with the site SOP while ambulatory 
subjects will be provided two bottles, each containing 30 tablets. 
If the subject has an episode of emesis or spits out the study medication within one hour of administration, the 
event will be documented in the Subject Diary and then the full dose will be re-administered. Replacement 
medication can only be taken one time per scheduled dose. 
Within a 24-hour period, the first and second dose should not be taken less than 8 hours apart. 
If a subject misses a dose, they will be instructed to skip that dose and resume taking their next dose as 
scheduled and to record the missed dose on their Subject Diary.  
4.4.6. 
Blinding 
Study product will be distributed by a site research pharmacist or other authorized healthcare provider at the 
site via a pre-labeled kit containing two labeled bottles. All study assessments will be performed by blinded 
study personnel. All other staff, as well as all subjects, will be blinded to treatment assignment. Samples 
provided to the lab for virologic, immunogenic, and pharmacokinetic analyses will be blinded to Subject ID 
and visit number in addition to treatment assignment. 
The Principal Investigator should be available to review and evaluate any notable reactions. In the case of a 
medical emergency, the PI or Secondary Medical Assessor (SMA) may deem it medically necessary to 
unblind the subject's treatment assignment. If the PI or SMA believes that unblinding would benefit the 
medical care of the subject and time permits, DMID will be consulted prior to unblinding, and concurrence 
will be obtained. 
The PI, or SMA will contact the study PI, and DMID Medical Monitor (or designees) to confirm that the 
unblinded treatment assignment is required for the safety of the subject and treatment of their symptoms. The 
Northwestern University Principal Investigator and DMID Medical Monitor will obtain approval from the 
Director of the Office of Clinical Research Affairs. After DMID has approved the unblinding, the Medical 
Monitor will relate the request to Emmes. 
Emmes will provide the treatment assignment to an independent medical doctor or appropriate designee 
identified by the study PI, who is NOT the principal investigator or blinded staff at the clinical site. The 
treatment assignment will be distributed a secure, restricted access posting on the Emmes website (or 


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verbally, if it is an emergency). The person receiving the information should not be involved in any subject 
assessments to maintain the blind, and it cannot be shared with other staff or DMID. 
4.4.7. 
Prior and Concomitant Therapy  
Subjects may receive any therapy that is deemed appropriate to treat the signs and symptoms of Norovirus 
after randomization at the discretion of their treating provider except for nitazoxanide and oral 
immunoglobulin. This can include: 
• Intravenous immunoglobulin 
• Changes in immunosuppression 
• Anti-motility agents 
Any treatment utilized should be included on the concomitant medications at the time of enrollment. Any 
concomitant medication pre- or post-randomizations that is being used to treat the signs or symptoms of 
Norovirus should be marked as such on the Case Report Form for the entire duration of the study. Likewise, 
any change to immunosuppressive therapy would have a note in the Case Report Form noting if the change 
was made because of elevated drug levels, for treatment of Norovirus or other purposes. Concomitant 
medications will be collected through visit 12 (Day 180 after initial dose of study treatment) or early 
termination, whichever occurs first. If the Investigator learns that the subject has taken a prohibited 
medication (see inclusion/exclusion criteria) prior to the last dose, the Investigator will contact the DMID 
Medical Officer and CPM for instructions regarding the subject’s continuation in the study. 
Medications that might interfere with the evaluation of the investigational product should not be used unless 
absolutely necessary. 
If symptoms recur after discontinuing therapy, subjects can resume any therapy at the discretion of the 
principal investigator or his/her designee with the exception of nitazoxanide. Nitazoxanide can be used after 
Day 28 if the local PI attests that it is medically urgent to use the nitazoxanide because the patient is 
experiencing severe or life-threatening disease. Although nitazoxanide can be used if it is felt critical to the 
subjects care, its use should be avoided until Day 180 whenever felt to be safe to do so by the local PI. Any 
use of nitazoxanide beyond Day 28 will be documented on the concomitant medication form and prescribed 
from commercial stock and not provided by the study. 
4.4.8. 
Treatment Compliance 
Each subject will receive 2 bottles of nitazoxanide or placebo each containing 30 tablets, to be taken twice a 
day for 56 consecutive doses. If study subject has an episode of emesis or spits out the study medication 
within one hour of administration, the event will be documented in the subject’s record and then the full dose 
will be re-administered one time only per scheduled dose. Subjects will be requested to bring study drug with 
them to all visits during the Treatment Phase. Remaining pill count will be done by the site staff during each 
visit to assess compliance. If subjects forget to bring in their study drug or they lose their container, subject 
interview and study diary will be used to confirm medication adherence. 
4.5. 
Efficacy, Immunogenicity, Safety, and Other Variables 
Stool and blood samples will be collected at different visits as per the schedule of events (Table 1). 


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4.5.1. 
Efficacy Variables 
The primary efficacy variables to be assessed are the cessation of vomiting and no stools classified by the 
Bristol Stool Chart as diarrhea (Type 6 or 7) and are based on outcomes reported in the Subject Daily Diary. 
The subject diaries were prepared by Northwestern University. They will be reviewed and collected at every 
visit, including unscheduled or early termination visits. The Subject Daily Symptom Dairies will be 
completed by the subject daily, in real-time, from Day 1 through Day 180. All diaries should be completed at 
the same time every day, when possible. Subjects will complete the NNITS Daily Symptom Diary [Day 1 – 
28] from the time of study treatment dispensation until visit 05. At visit 05 (Study Day 28), subjects will 
complete the NNITS Daily Symptom Diary – Post Treatment [Day 29 – 180]. 
The exploratory efficacy variables for the following outcome measures are also based on subject daily diaries: 
•  Time from randomization to initial clinical improvement in Norovirus disease through 28 and 180 
days for at least 48 hours. 
• Time from randomization to initial cessation of vomiting through Day 180 (recurrent vomiting will be 
considered disease recurrence unless determined to be due to another etiology [i.e. GVHD]). 
• Time from randomization to subject report of no loss of appetite that is maintained for 48 hours 
through Day 180 (measure will be first time that the subject reports that they have no “loss of appetite” 
on their daily diary).  
• Time from randomization to initial cessation of diarrhea through Day 180 classified by the Bristol 
Stool Chart as type 6 or 7 bowel movements (recurrent diarrhea will be considered disease recurrence 
unless determined to be due to another etiology [i.e. GVHD]). 
• Time from randomization to 50% reduction in the amount of antimotility agents utilized by the subject 
through Day 180. 
• Number of days of diarrhea through Days 28 and 180. 
• Number of stools classified by the Bristol Stool Chart as type 6 or 7 bowel movements through Day 
28. 
• Number of days of IV hydration or total parenteral nutrition (TPN) therapy through Day 28. 
The secondary efficacy variable to be assessed is viral load and is based on stool for Norovirus assays. 
Norovirus viral load assays will be performed in the Jiang Laboratory (CCHMC, Cincinnati, OH) and will be 
measured using Quantitative RT-PCR (qRT-PCR) at Study Days 1, 7, 14, 21, 28, 60, 120, 180, and with 
recurrent diarrhea.  
The exploratory efficacy variables for the following outcome measures are based on patient reported outcome 
(PRO) questionnaires: 
• Change in patient-reported quality of life as measured by EuroQOL-5 (global) and IBSQOL (diarrhea 
specific) [adult] or EuroQOL-5 Peds (global) and PedsQL GI Module [children] from baseline to Day 
180. 
• Change in patient-reported physical function as measured by NIH PROMIS Physical Function (Adult) 
Pediatric Global Health (Peds) from baseline to Day 180. 
• Change in patient-reported emotional distress as measured by the NIH PROMIS Depression, Anxiety, 
Fatigue (Adult and Peds) from baseline to Day 180. 


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• Change in patient-reported gastrointestinal symptoms as measured by the NIH PROMIS GI (Adult and 
Peds) symptoms (6 of 8 subscales) from baseline to Day 180. 
The PRO questionnaires were prepared by Northwestern University. Study personnel administer detailed PRO 
questionnaires to subjects at Visit 01 (Day 1), Visit 05 (Day 28), Visit 08 (Day 60), Visit 10 (Day 120), and 
Visit 12 (Day 180). Adult subjects will complete the following six questionnaires: 
• NNITS Patient Reported Outcome Measures – IBSQOL Questionnaire (labeled Norovirus QOL) 
• NNITS Patient Reported Outcome Measures – EuroQOL Questionnaire 
• NNITS Patient Reported Outcome Measures – PROMIS Emotional Questionnaire 
• NNITS Patient Reported Outcome Measures – PROMIS GI Questionnaire (labeled Gastrointestinal 
Symptom Scale) 
• NNITS Patient Reported Outcome Measures – PANAS Questionnaire 
• NNITS Patient Reported Outcome Measures – PROMIS Physical Function Questionnaire 
Pediatric subjects will complete the following six questionnaires: 
• NNITS Patient Reported Outcome Measures – PedsQL GI Questionnaire (labeled PedsQL 3.0 
Gastrointestinal Symptoms Scale) 
• NNITS Patient Reported Outcome Measures – EuroQOL Questionnaire 
• NNITS Patient Reported Outcome Measures – PROMIS Emotional Pediatric Questionnaire 
• NNITS Patient Reported Outcome Measures – PROMIS GI Questionnaire (labeled Gastrointestinal 
Symptom Scale; labeled “Adult”) 
• NNITS Patient Reported Outcome Measures – PANAS-C Questionnaire 
• NNITS Patient Reported Outcome Measures – PROMIS Global Health Questionnaire 
Additional exploratory efficacy variables include chromaturia and co-pathogens. Chromaturia (discoloration 
of urine) will be based on unsolicited self-reporting. Co-pathogen status in stool will be determined utilizing 
the BioFire FilmArray Gastrointestinal Panel to screen for a range of pathogens (Campylobacter (C. jejuni/C. 
coli/C. upsaliensis),Clostridium difficile (C. difficile) toxin A/B, Plesiomonas shigelloides, Salmonella, Vibrio 
(V. parahaemolyticus/V. vulnificus/ V. cholerae), including specific identification of Vibrio cholerae, Yersinia 
enterocolitica, Enteroaggregative Escherichia coli (EAEC), Enteropathogenic Escherichia coli 
(EPEC), Enterotoxigenic Escherichia coli (ETEC) lt/st, Shiga-like toxin-producing Escherichia coli (STEC) 
stx1/stx2 (including specific identification of the E. coli O157serogroup within STEC), Shigella/ 
Enteroinvasive Escherichia coli (EIEC), Cryptosporidium, Cyclospora cayetanensis, Entamoeba 
histolytica, Giardia lamblia (also known as G. intestinalis and G. duodenalis), Adenovirus F 
40/41, Astrovirus, Norovirus GI/GII, Rotavirus A, Sapovirus (Genogroups I, II, IV, and V)). Pathogen 
screening will occur on Days 1 and 180 for all subjects along with Days 7, 14, 21, 28, 60, 120, and with 
recurrent diarrhea if unformed stool on study day.  


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4.5.2. 
Immunogenicity Variables 
Exploratory immunogenicity variables will be measured in the Jiang Laboratory (CCHMC, Cincinnati, OH) 
by the following assays: 
• Norovirus-specific stool IgA, IgM, and IgG results 
• Quantitative Total IgG Level results 
• Norovirus-specific serum IgA, IgM, and IgG results  
All immunogenicity variables are measured using an EIA spectra reader on Days 1, 28, and 60 and will 
include positive and negative controls. The Norovirus-specific ELISAs will be performed for subjects after 
the sample genotyping has been completed and the antigens in the ELISAs will match their genotype. 
Total lymphocyte count and t cell subsets will be measured at Day 1. T cell subset will not be drawn if the 
CBC shows an ALC<100. 
4.5.3. 
Safety Variables 
The safety of nitazoxanide will be assessed by the frequency of protocol specified unsolicited clinical adverse 
events, laboratory adverse events and serious adverse events.  
Unsolicited Adverse Events (AEs): 
Unsolicited clinical Adverse Events are those non serious AEs that are not being collected as clinical outcome 
measures. For this study, unsolicited clinical AEs to be captured on the appropriate case report form, will be 
only those clinical AEs that meet either of the following criteria through 60 days: 
• Result in modification in the administration of the study drug (nitazoxanide or placebo). 
• Result in discontinuation of the study drug (nitazoxanide or placebo). 
Any medical condition that is present at the time that the subject is screened should be considered as baseline 
and not reported as an AE.  However, if it deteriorates at any time during the study, it should be recorded as 
an AE as defined above. 
Unsolicited clinical AEs will be assigned the severity level of Grade 3.   
The clinician’s assessment of an AE's relationship to test article (study drug) is part of the documentation 
process, but it is not a factor in determining what is or is not reported in the study.  If there is any doubt as to 
whether a clinical observation is an AE, the event should be reported.  AEs must have their relationship to 
study product assessed using the terms:  related or not related.  In a clinical trial, the study product must 
always be suspect.  To help assess, the following guidelines are used. 
• Related – There is a reasonable possibility that the study product caused the adverse event. Reasonable 
possibility means that there is evidence to suggest a causal relationship between the study product and 
the adverse event. 
• Not Related – There is not a reasonable possibility that the administration of the study product caused 
the event. 


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Safety Laboratory Parameters: 
The following solicited safety laboratory parameters will be assessed on Day 7, 28 and 60: WBC, 
Hemoglobin, Platelet count, Creatinine, Alkaline Phosphatase, ALT, AST, BUN and Bilirubin. Additional 
laboratory parameters performed as part of the CBC and complete metabolic panel results need to be recorded 
in the source document with the evaluation of the site physician. Those additional laboratory values will need 
to be reported as AEs only if clinically significant and not attributable to Norovirus infection or underlying 
SOT/HSCT medical conditions.   
Abnormal values observed in the clinical laboratory assessment that are conducted by the clinical team 
outside the study visits, will be reported as AEs only if the site physician assesses that the laboratory value is 
clinically significant and not attributable to Norovirus infection or underlying SOT/HSCT medical conditions. 
The criteria for an abnormal laboratory test finding being classified as an AE are any of the following and will 
be documented on the AE form: 
• Test result is associated with a sign or symptom, and/or 
• Test result requires additional diagnostic testing, and/or 
• Test result requires a medical or surgical intervention, and/or 
• Test result leads to a change in study dosing outside of the protocol defined dosing or discontinuation 
from the study treatment, and/or 
• Test result requires significant additional treatment, i.e. addition of new medication, significant 
increase in dose of current medication 
Baseline clinical labs performed on Day 1 (screening/enrollment visit) might fall outside of the normal range. 
Laboratory values in all subsequent visits for subjects in which baseline clinical labs results fall outside the 
normal range will be considered adverse events only if there is a worsening in the grading of the event (e.g., 
value that on screening falls within grade 1, and subsequently on grade 2 will be considered AE; value that on 
both screening and on subsequent testing fall within grade 2 will not be considered AE). 
For those clinical labs performed on Day 1 that fall within grade 3, for all subsequent testing that also falls 
within grade 3, the clinician will need to assess and document this assessment on the source documents 
whether there is a clinically significant worsening of the value. Only those laboratory values judged to have a 
clinically significant worsening and not attributable to Norovirus infection or underlying SOT/HSCT medical 
conditions will be reported as AEs. 
The protocol defined grading system is used to determine the cut off point for reporting. As such, laboratory 
results that are abnormal according to the local laboratory reference range but not considered a Grade 1 
abnormality, will not be considered laboratory AEs. Those events will be followed-up clinically at the 
discretion of the study site physician. 
Laboratory AEs will be assessed by the clinician using a protocol defined grading system (Table 5).   


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Serious Adverse Events (SAEs): 
An adverse event or suspected adverse reaction is considered “serious” if, in the view of either the site 
principal investigator or sponsor, it results in any of the following outcomes through Day 60: 
• Death, 
• A life-threatening adverse event*, 
• A persistent or significant incapacity or substantial disruption of the ability to conduct normal life 
functions, or 
• A congenital anomaly or birth defect, 
• Important medical events that may not result in death, be life threatening, or require hospitalization, 
may be considered serious when, based upon appropriate medical judgment, they may jeopardize the 
patient or subject and may require medical or surgical intervention to prevent one of the outcomes 
listed in this definition.  Examples of such medical events include allergic bronchospasm requiring 
intensive treatment in an emergency room or at home, blood dyscrasias or convulsions that do not 
result in inpatient hospitalization, or the development of drug dependency or drug abuse. 
* Life-threatening adverse event. An adverse event is considered “life-threatening” if, in the view of either the 
investigator or sponsor, its occurrence places the patient or subject at immediate risk of death.  It does not 
include an adverse event that, had it occurred in a more severe form, might have caused death. 
Note that hospitalizations are being collected as an outcome measure for the secondary objective and 
therefore will not be reported as SAEs.  
All protocol specified SAEs will be assigned the severity level of Grade 3.   
4.5.4. 
Other Variables 
Additional variables to be assessed include graft rejection or graft loss. These will not be entered as 
unsolicited adverse events but instead entered on the Graft Rejection or Loss eCRF.  
Time to death variable will be assessed using the date of death located on the Death eCRF. 
Time to withdrawal from the study because of intolerance or drug related adverse events will be assessed 
using the date treatment discontinued on the Study Status eCRF for all subjects that terminated early. Reasons 
for early termination will undergo a review, blinded to outcome value, to determine if the withdrawal was due 
to intolerance or a drug related adverse event. 
Saliva is collected on Day 1 to determine H type 1 secretor status (phenotyping) and a buccal swab is also 
collected to perform FUT2 genotyping. Secretor status will be measured in the Jiang Laboratory (CCHMC, 
Cincinnati, OH). Both phenotypic and genotypic evaluation will be performed to compare results of the two 
methods. Detection of secretor antigens (Leb, Ley, H types) and non-secretor antigens (Lea and Lex) will be 
performed using monoclonal antibodies by ELISA. In the case of discordant results, the results from the 
phenotypic method will be used to classify secretor status.  


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5. 
SAMPLE SIZE CONSIDERATIONS 
Sample size calculations assume a 50% reduction in the median duration of diarrhea for the nitazoxanide-
treated group compared to those receiving placebo. The median diarrhea duration for the placebo group is 
assumed to be 135 days, while the median diarrhea duration for the treatment group is assumed to be 67.5 
days. Given these assumptions, a sample size of 64 subjects in each arm (128 total) is required to achieve 90% 
power using the Log-Rank test. Accounting for a 20% attrition rate, final sample size will be 80 in each arm 
(160 total). 
Though discouraged, the protocol allows for subjects in either study group to receive additional nitazoxanide 
after 28 days. Under the assumptions of treatment efficacy, additional treatment received by placebo subjects 
would reduce the median duration of symptoms for the placebo group to be closer to that of the nitazoxanide-
treated group. It is assumed that subjects who would have the worst study outcomes (longest time to clinical 
resolution of diarrhea) will be the most likely to receive additional treatment. Subjects receiving additional 
treatment will be imputed as having the worst outcome (time to resolution censored at 180 days). Accounting 
for this imputation method, the power attained for the primary comparison was computed via simulation (R 
version 3.0.3). Estimated power is displayed in Table 2, varying the proportion of subjects in each study 
group who receive additional treatment. 
For example, if 15% of placebo subjects receive nitazoxanide, and 5-10% of subjects in the nitazoxanide-
treated group receive additional treatment, the power is estimated to be 91.2%. Note that implausible 
scenarios (where substantially more nitazoxanide subjects receive additional treatment than do placebo 
subjects) have been omitted from the table. 


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6. 
GENERAL STATISTICAL CONSIDERATIONS 
6.1. 
General Principles 
All continuous variables will be summarized using the following descriptive statistics: n (non-missing sample 
size), mean, standard deviation, median, minimum, and maximum. The frequency and percentages (based on 
the non-missing sample size) of observed levels will be reported for all categorical measures. In general, all 
data will be listed, sorted by site, treatment, and subject, and when appropriate, by visit number within 
subject. All summary tables will be structured with a column (or row) for each treatment group in the order 
from left to right (or top to bottom): Nitazoxanide 500 mg, Placebo. Where necessary, summary tables will be 
stratified with Nitazoxanide 500 mg presented in one table and Placebo presented in the table immediately 
following. Tables will be annotated with the total population size relevant to that table/treatment, including 
any missing observations. 
6.2. 
Timing of Analyses 
The study was stopped early due to low enrollment and other unforeseen challenges, and thus the primary 
CSR will be generated once the last subject last visit has occurred, data monitoring and cleaning is complete, 
and the database is locked. PK and microbiome endpoints will not be included and will instead be provided in 
addendums to the CSR. 
6.3. 
Analysis Populations 
A tabular listing of all subjects excluded from the analysis populations will be provided in the CSR (Listing 
5). 
6.3.1. 
Modified Intention-to-Treat (mITT) Population 
The mITT population includes all randomized subjects who received at least one dose of assigned study drug. 
Analyses are performed according to randomized treatment assignment, not the treatment received. This 
analysis set will be used for all efficacy analyses and will be considered the primary analysis for the primary 
efficacy outcome measure. 
6.3.2. 
Per Protocol (PP) Population 
The PP population will include all subjects who met all inclusion/exclusion criteria, complied with the 
assigned study product, complied with the daily diary, and were followed up until resolution of symptoms, or 
completed 180 days without resolution of symptoms.  
A subject is considered to be compliant with the assigned study product if he/she takes at least 75% of the 
scheduled doses through 28 days and does not receive additional nitazoxanide (defined as in Section 3.3) 
before their primary outcome is observed. A subject is compliant with the daily diary if he/she is missing no 
more than 1.5/7 days per week over the first 8 weeks (Day 1 through Day 60). 
This analysis set will be used for all efficacy analyses and will be considered secondary to analyses conducted 
in the mITT population. 
6.3.3. 
Safety Population 
The safety population (grouped by actual treatment received) will include all subjects who are randomized, 
have received at least one dose of study treatment. This analysis set will be used for all safety analyses. 


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6.3.4. 
Immunogenicity Population 
The immunogenicity population will include all randomized subjects who received at least one dose of 
assigned study drug and have at least one stool and/or serum immunoglobulin test result. This analysis set will 
be used for all immunogenicity analyses. 
6.4. 
Covariates and Subgroups 
As described in Section 4.4.3, the randomization of treatment assignments and the primary analysis will be 
performed as stratified by duration of symptoms, transplant type, and age range. 
The protocol also defines formal subgroup analyses as exploratory outcome measures; however, the study was 
not powered to perform these subgroup analyses. Subgroup sensitivity analyses for the primary and secondary 
outcome measures will evaluate the treatment effect across the following subgroups: 
• Additional nitazoxanide: Subjects that took additional nitazoxanide (defined as in Section 3.3) will be 
excluded from the analyses 
• Chromaturia: Subjects with unsolicited self-reported chromaturia (discoloration of urine) will be 
excluded from the analyses. 
Listing 22 and Listing 11 provide listings of subjects that reported chromaturia or took additional 
nitazoxanide, respectively. 
6.5. 
Missing Data 
All attempts were made to collect all data per protocol. Imputations will only be performed for missing daily 
diary data as it relates to the primary endpoint. Missing daily diary data for the primary endpoint will be 
handled as follows: 
• Data that are missing after a subject has reached clinical resolution will not affect the primary time to 
event analysis and therefore will be ignored 
• Subjects who drop out, are lost to follow-up, withdraw consent, or otherwise stop completing daily 
diary entries before clinical resolution will be censored on the day of their last completed diary 
• Subjects with a gap in outcome data prior to clinical resolution will be handled depending on their last 
completed diary entry and their next completed diary entry: 
o If the last completed diary entry and the next completed diary entry have the same outcome (i.e., 
they are still symptomatic on both days or they have no symptoms on both days), then the gap will 
be imputed with the same outcome 
o If this imputation results in the subject being defined as having clinical resolution during this gap, 
their time to resolution will be the median of the interval 
o If the last completed diary entry and the next completed diary entry have different outcomes (i.e., 
the last one is symptomatic and the next one is asymptomatic, or vice versa), then the gap will be 
imputed with the symptomatic outcome (no resolution). 
Table 3 provides summary statistics (n, mean, median, standard deviation, minimum, and maximum) of the 
number of imputed diary days per subject given the above imputation rules and the number of overall missing 
diary days per subject. The above method will be considered the primary imputation method for the primary 
endpoint. In addition, a sensitivity analysis on the primary endpoint will be conducted using worst case 
scenario for subjects who drop out, are lost to follow-up, withdraw consent, or otherwise stop completing 


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daily diary entries before clinical resolution. These subjects will be censored at 180 days (i.e., assuming 
resolution of symptoms occurred after Day 180). Listing 9 provides subject-level details for the number of 
diaries missed by week. 
6.6. 
Interim Analyses and Data Monitoring 
The Data and Safety Monitoring Board (DSMB) planned to review and discuss study data when 25% (N=40), 
50% (N=80), and 75% (N=120) of patients completed Day 60 of the study. All planned DSMB reviews were 
to include descriptive summaries and were not intended to serve as formal interim analyses. Blinded and 
unblinded reports on safety data through Day 60, Norovirus infection clinical adverse outcome through Day 
180 along with available clinical and virologic efficacy data and study product nitazoxanide retreatment data 
were expected to be reviewed at each study milestone. 
At the time of this SAP, the study was stopped after 31 subjects enrolled due to enrollment challenges. Even 
though the study never reached the first milestone (N=40 subjects), the DSMB completed an unplanned 
electronic review of the Open and Closed Safety and Summary Reports on 02 November 2020. 
The halting rules did not utilize any statistical criteria and no formal hypothesis testing occurred for the safety 
or efficacy review; therefore, no adjustment for multiple testing will be performed. 
A final review meeting will be conducted 6 to 8 months after clinical database lock to review the cumulative 
unblinded safety and efficacy data for the study.  
6.7. 
Multicenter Studies 
Data will be pooled across all clinical sites. Center effects are not anticipated because the sites are using 
standardized procedures for product administration and assessment of safety and efficacy endpoints.   
6.8. 
Multiple Comparisons/Multiplicity 
There is only one primary endpoint. No adjustments for multiple testing are planned. 


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7. 
STUDY SUBJECTS 
7.1. 
Disposition of Subjects 
Table 9 will present a summary of the reasons that subjects were screened but not enrolled. 
The composition of analysis populations, including reasons for subject exclusion, by treatment arm, is 
presented in Table 7. 
The disposition of subjects in the study will be tabulated by treatment group (Table 6). 
A flowchart showing the disposition of study subjects, adapted from the CONSORT Statement, will be 
included (Figure 2). This figure will present the number of subjects screened, enrolled, lost to follow-up, and 
analyzed, by treatment group. 
A listing of subjects who terminated from study follow-up or discontinued treatment and the reason will be 
included in Listing 2. 
7.2. 
Protocol Deviations 
A summary of subject-specific protocol deviations will be presented by deviation category, type, and 
treatment group for all subjects (Table 4). All subject-specific protocol deviations and non-subject specific 
protocol deviations will be included in Appendix 3 as data listings (Listing 3 and Listing 4, respectively). 
 


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8. 
EFFICACY EVALUATION 
All primary and secondary efficacy analyses will be conducted in the mITT and PP populations.  Data will be 
summarized by treatment group with a column for each treatment in the order (Nitazoxanide, Placebo) and 
will be annotated with the total population size relevant to that table/treatment. Subgroups with less than five 
subjects per treatment group will be excluded from efficacy tables and figures. All efficacy variables will be 
listed by site, treatment group and subject, and when appropriate, by visit number within subject (Listing 12, 
Listing 13, Listing 14, Listing 15, Listing 16, Listing 17, Listing 18, Listing 19, and Listing 22).   
8.1. 
Primary Efficacy Analysis 
The primary efficacy outcome measure is the time from randomization to initial clinical resolution of 
Norovirus for at least 48 hours, assessed through 180 days, in each study arm. Clinical resolution will be 
assessed from the daily diary by the subject and will be defined as in Section 3.3. 
The protocol calls for a formal hypothesis test to compare nitazoxanide to placebo. The null hypothesis is that 
there is no difference in time until clinical resolution between study arms, with a two-sided alternative. A 
stratified Log-Rank test at the 5% two-sided level of significance was planned to test the hypothesis, however, 
due to early closure of the study, the number of subjects is too small to use a Log-Rank test. Instead, a 
stratified Cox proportional hazards model will be used to compare treatment to control through Day 180 with 
respect to time to clinical resolution. Stratification is based on acute versus chronic symptoms at baseline. No 
pediatric subjects were enrolled in the study and only one hematopoietic stem cell transplant subject was 
enrolled in the study; therefore, the transplant type and age range stratums will not be included in the final 
analysis.   
The primary analysis will be performed in the mITT analysis population. Missing diary data will be imputed 
using the methods described in Section 6.5. The treatment hazard ratio estimate, 95% confidence interval and 
p-value from the likelihood ratio test will be presented (Table 16). The median time to clinical resolution and 
95% confidence interval will be summarized by treatment arm and duration of symptoms. In addition, 
stratum-specific estimates of the treatment hazard ratio within each duration of symptoms strata will be 
presented. Kaplan-Meier curves for each treatment arm will be displayed in Figure 3. Figure 6 will present 
Kaplan-Meier curves for each treatment arm and duration of symptoms strata.  
8.1.1. 
Supplemental and Sensitivity Analyses 
The primary analysis will be repeated in the Per Protocol analysis population, where subjects who were not 
compliant with the diary and/or treatment will be excluded from the analysis. The tabular and graphical 
summaries described in the previous section will be replicated for this Per Protocol analysis (Table 16, Figure 
4, and Figure 7). 
Sensitivity analyses will be performed using the stratified Cox proportional hazards model on both the mITT 
population and PP population using the worst-case scenario imputation method for subjects who drop out, are 
lost to follow-up, withdraw consent, or otherwise stop completing daily diary entries before clinical resolution 
(Table 17). These subjects will be censored at 180 days. Kaplan-Meier curves for each treatment arm will be 
presented (Figure 5). Kaplan-Meier curves for each treatment arm and duration of symptoms strata will be 
displayed in Figure 8. 
The primary analysis will be repeated on the mITT population using the subgroups defined in Section 6.4 
(Table 18). A sensitivity analysis will be performed using the stratified Cox proportional hazards model on 
the mITT population with stratification based on subjects with less than 2 missing diaries per week versus 


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those with 2 or more missing diaries per week (Table 19). Kaplan-Meier curves for each treatment arm and 
diary compliance strata will be presented in Figure 9. 
8.2. 
Secondary Efficacy Analyses 
The secondary efficacy outcome measures are as follows: 
• The time from randomization to first negative viral load through 180 days. 
• The change in viral titer between Day 1 and Day 180. 
The protocol calls for a Log-Rank test to compare time from randomization to first negative viral load through 
180 days between the nitazoxanide treated group and the placebo group; however, due to early closure of the 
study, the number of subjects is too small to use a Log-Rank test. Number and percentage of subjects with 
positive viral load and geometric mean viral titer in positive subjects with 95% confidence intervals will be 
presented by test type, treatment group and study day in the mITT Population (Table 20). A stratified Cox 
proportional hazards model will be used to compare treatment to control through Day 180 with respect to time 
to first negative viral load. Stratification will be based on acute versus chronic symptoms at baseline. GII and 
GI test types will be analyzed independently. 
The analysis will be conducted in both the mITT population and the PP population. The treatment hazard ratio 
estimate, 95% confidence interval and p-value from the likelihood ratio test will be presented for each test 
type (Table 21 and Table 22). The median time to clinical resolution and 95% confidence interval will be 
summarized by treatment arm and duration of symptoms for each test type. In addition, stratum-specific 
estimates of the treatment hazard ratio within each duration of symptoms strata will be presented for each test 
type. Kaplan-Meier curves for each treatment arm will be displayed in Figure 10, Figure 11, Figure 12 and 
Figure 13, for each test type in the mITT and PP populations. Figure 14 and Figure 15 will present Kaplan-
Meier curves for each treatment arm and duration of symptoms strata for Norovirus GII and Norovirus GI test 
types, respectively, in the mITT population.  
The analysis will be repeated on the mITT population using the subgroups defined in Section 6.4 for each test 
type (Table 23 and Table 24). 
The change in viral titer between Day 1 and Day 180 will be assessed using analysis of covariance 
(ANCOVA) adjusting for baseline viral titer. The analysis will be conducted in both the mITT population and 
the PP population for both Norovirus GII and Norovirus GI test types. Table 25 and Table 26 will present the 
observed means and standard deviations of the change in viral titer between Day 1 and Day 180 for each 
treatment group and duration of symptoms strata for Norovirus GII and Norovirus GI test types, respectively. 
Levene’s test and normality checks will be carried out to check if the assumptions of ANCOVA are met. If 
assumptions of ANCOVA have been met, the adjusted mean, standard error, and 95% confidence intervals 
will also be presented for each treatment group and duration of symptoms strata. The p-value for the test of 
between treatment differences will also be presented. If the assumptions of ANCOVA are not met, 
transformations of the change in viral titer variable may be utilized to correct any skewness in residuals or 
heterogeneity of the variances. If a transformation of the dependent variable is used, a footnote in the table 
will denote which transformation was used in the analyses. If the assumptions of ANCOVA cannot be met 
through transformation of the dependent variable, only the observed mean, standard deviation and 95% 
confidence intervals of the unadjusted change in viral titer between Day 1 and Day 180 will be reported. A 
forest plot will display the adjusted means and 95% confidence intervals of the change in viral titer between 
Day 1 and Day 180 for each treatment group and duration of symptoms strata for each test type (Figure 16, 
Figure 17, Figure 18 and Figure 19). 


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The ANCOVA analysis will be repeated on the mITT population using the subgroups defined in Section 6.4 
for each test type (Table 27 and Table 28). 
8.3. 
Exploratory Efficacy Analyses 
The protocol calls for a Log-Rank test at the 5% two-sided level of significance for the following exploratory 
outcome measures: 
• Time from randomization to initial clinical improvement in Norovirus disease through 28 and 180 
days for at least 48 hours. 
• Time from randomization to initial cessation of vomiting through Day 180 (recurrent vomiting will be 
considered disease recurrence unless determined to be due to another etiology [i.e. GVHD]). 
• Time from randomization to subject report of no loss of appetite that is maintained for 48 hours 
through Day 180 (measure will be first time that the subject reports that they have no “loss of appetite” 
on their daily diary).  
• Time from randomization to initial cessation of diarrhea through Day 180 classified by the Bristol 
Stool Chart as type 6 or 7 bowel movements (recurrent diarrhea will be considered disease recurrence 
unless determined to be due to another etiology [i.e. GVHD]). 
• Time from randomization to 50% reduction in the amount of antimotility agents utilized by the subject 
through Day 180. 
However, due to early closure of the study, the number of subjects is too small to use a Log-Rank test. 
Instead, a stratified Cox proportional hazards model will be used to compare treatment to control through Day 
28 and/or Day 180. Stratification is based on acute versus chronic symptoms at baseline. No pediatric subjects 
were enrolled in the study and only one hematopoietic stem cell transplant subject was enrolled in the study; 
therefore, the transplant type and age range stratums will not be included in the final analysis.   
The analysis will be performed in the mITT analysis population. The treatment hazard ratio estimate, 95% 
confidence interval and p-value from the likelihood ratio test will be presented for each event (Table 29). The 
median time to event and 95% confidence interval will be summarized by treatment arm and duration of 
symptoms. In addition, stratum-specific estimates of the treatment hazard ratio within each duration of 
symptoms strata will be presented. Kaplan-Meier curves for each treatment arm will be displayed in Figure 
20, Figure 21, Figure 22, Figure 23, and Figure 24. 
The protocol calls for two-sample t-tests to be used for the below outcome measures. However, due to early 
closure of the study, the number of subjects is too small to meet the normality assumptions of the t-test; 
therefore Wilcoxon-Mann-Whitney exact rank sum tests will be used to compare treatment to placebo through 
Day 28 and/or Day 180 in the mITT analysis population (Table 30) for the following outcome measures 
(defined in Section 3.3):  
• Number of days of diarrhea through Days 28 and 180. 
• Number of stools classified by the Bristol Stool Chart as type 6 or 7 bowel movements through Day 
28. 
• Number of days of IV hydration or total parenteral nutrition (TPN) therapy through Day 28. 


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The following patient-reported outcome measures will be assessed using ANCOVA adjusting for the baseline 
patient-reported measure: 
• Change in patient-reported quality of life as measured by EuroQOL-5 (global) and IBSQOL (diarrhea 
specific) [adult] or Euro QOL-5 Peds (global) and PedsQL GI Module [children] from baseline to Day 
180. 
• Change in patient-reported physical function as measured by the NIH PROMIS Physical Function 
(Adult) Pediatric Global Health (Peds) from baseline to Day 180. 
• Change in patient-reported emotional distress as measured by the NIH PROMIS Depression, Anxiety, 
Fatigue (Adult and Peds) from baseline to Day 180. 
• Change in patient-reported gastrointestinal symptoms as measured by the NIH PROMIS GI (Adult and 
Peds) symptoms (6 of 8 subscales) from baseline to Day 180. 
The analysis will be conducted in the mITT population. Table 31 and Table 32 will present the frequency of 
reported problems the EuroQOL-5 quality of life by dimension and study day for the nitazoxanide and 
placebo groups, respectively. Table 33 will present the observed means and standard deviations of the change 
in each patient-reported measure between baseline and Day 180 for each treatment group. Levene’s test and 
normality checks will be carried out to check if the assumptions of ANCOVA are met. If assumptions of 
ANCOVA have been met, the adjusted mean, standard error, and 95% confidence intervals for each treatment 
group. The p-value for the test of between-treatment differences will also be presented. If the assumptions of 
ANCOVA are not met, transformations of the change in patient-reported measure variable may be utilized to 
correct any skewness in residuals or heterogeneity of the variances. If a transformation of the dependent 
variable is used, a footnote in the table will denote which transformation was used in the analyses for each 
patient-reported measure. If the assumptions of ANCOVA cannot be met through transformation of the 
dependent variable, only the observed mean, standard deviation and 95% confidence intervals of the 
unadjusted change in patient-reported measure and study day will be reported. The protocol also calls for 
pairwise contrasts between groups on the unadjusted change between baseline and subsequent timepoints and 
on adjusted change (controlling for baseline) using a mixed-design analysis of variance (ANOVA) model with 
all times, including baseline, as a repeated measures factor. However, due to early closure of the study, the 
number of subjects is too small to provide adequate power for any multiple comparison tests. Instead, Table 
33 will present the observed means and standard deviations of the change in each patient-reported measure 
between baseline and Days 28, 60, and 120 for each treatment group. Since a single index is not currently 
possible for the EuroQOL-5 questionnaire, these results will not be included in Table 33. If ANCOVA 
assumptions are met, the adjusted mean, standard error, and 95% confidence intervals for each treatment 
group and study day will also be presented. 
The effect of co-pathogens, as determined by the BioFire stool pathogen screen, on the primary outcome 
measure is presented in Table 34, where the presence or absence of co-pathogens will be represented as a 
binary covariate in the Cox proportional hazards model. If it is determined that subjects’ co-pathogen status 
changes often throughout the study, the effect of co-pathogens will be a time-varying covariate instead of a 
binary covariate. 
Time from randomization until clinical resolution of Norovirus symptoms for at least 48 hours through Day 
180. Clinical resolution will be assessed from the daily diary by the subject and will be defined as cessation of 
vomiting and no stools classified by the Bristol Stool Chart as diarrhea (Type 6 or 7) from the total population 
compared to the subgroup of subjects who do not report chromaturia (discoloration of urine) based on 
unsolicited self-reporting is presented in Table 18. 


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The effect of co-pathogens, as determined by the BioFire stool pathogen screen, on the time from 
randomization to first negative viral load through 180 days is presented in Table 35 and Table 36 for 
Norovirus GII and Norovirus GI test types, respectively, where the presence or absence of co-pathogens will 
be represented as a binary covariate in the Cox proportional hazards model. If it is determined that subjects’ 
co-pathogen status changes often throughout the study, the effect of co-pathogens will be a time-varying 
covariate instead of a binary covariate. 
Time from the randomization to first negative viral load through 180 days and the change in viral titer 
between Day 1 and 180 from the total population compared to the subgroup of subjects who do not report 
chromaturia (discoloration of urine) based on unsolicited self-reporting will be presented in Table 23 and 
Table 24 for Norovirus GII and Norovirus GI test types, respectively . 
Analyses of the following exploratory outcome measures are not covered in this SAP: 
• Time to > 1 log reduction in stool Norovirus genome copies 
• Change in quantitative Norovirus load in the stool between Day 1 and Day 7, 14, 21, 28, 60, 120, and 
180. 
• Change in Norovirus sequence from Day 1 to Days 28 and 60. 


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9. 
SAFETY EVALUATION 
All summaries and analysis of safety data will be presented for the Safety Analysis Population. Safety 
summaries will be presented overall and by treatment group. 
Listings will be sorted by treatment group, subject ID, parameter (if applicable), and visit. 
Continuous variables will be summarized using the following descriptive statistics: n (non-missing sample 
size), mean, standard deviation, median, maximum and minimum. All categorical measures will be 
summarized by the frequency and percentages (based on the non-missing sample size) of observed levels. 
9.1. 
Demographic and Other Baseline Characteristics 
Summaries of age, sex, ethnicity, race, duration of symptoms, transplant type, and categorical age range will 
be presented by treatment group, overall and by site (Table 11, Table 12, Table 13, and Table 14). Ethnicity is 
categorized as Hispanic or Latino, or not Hispanic and not Latino. In accordance with NIH reporting policy, 
subjects may self-designate as belonging to more than one race or may refuse to identify a race, the latter 
reflected in the CRF as “No” to each racial option. 
Individual subject listings (Appendix 3) will be presented for all demographics (Listing 6); pre-existing 
medical conditions (Listing 7); vital signs and oral temperature (Listing 27); and concomitant medications 
(Listing 32). 
9.1.1. 
Prior and Concurrent Medical Conditions 
All current illnesses and past pre-existing medical conditions will be MedDRA® coded using MedDRA 
dictionary version 24.0 or higher.  
Summaries of subjects’ pre-existing medical conditions will be presented by treatment group (Table 15). 
Individual subject listings will be presented for all medical conditions (Listing 7). 
9.1.2. 
Prior and Concomitant Medications  
Summaries of medications that were started prior to dosing and continuing at the time of dosing, as well as 
any medications collected through visit 12 (Day 180) or early termination, whichever occurs first, will be 
presented by WHO Drug Levels 1 and 2 and treatment group (Table 115). 
Individual subject listings will be presented for all concomitant medications (Listing 32). 
9.2. 
Measurements of Treatment Compliance 
The number of subjects who received any treatment and the number of subjects who received all scheduled 
treatments through Days 7, 14, 21, and 28 is presented by treatment group in Table 6. The number of subjects 
that received any additional nitazoxanide and additional nitazoxanide after Day 28 will also be included in the 
table. A subject is considered compliant with the assigned study product if they take at least 75% of the 
scheduled doses through 28 days and do not receive additional nitazoxanide before the primary outcome is 
observed. Table 10 provides the number of subjects compliant with study product, the mean cumulative 
number of pills taken and the mean percentage of pills taken for each treatment group at Days 7, 14, 21, and 
28. A listing of treatment compliance by subject is presented in Listing 8. 


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9.3. 
Adverse Events 
When calculating the incidence of adverse events (i.e., on a per subject basis), each subject will only be 
counted once and any repetitions of adverse events within a subject will be ignored; the denominator will be 
the total number of subjects in the Safety Population. All adverse events reported will be included in the 
summaries and analyses. 
An overall summary of adverse events is presented in Table 49. Table 50 presents subject-level rates and 
differences between treatment groups for the following safety outcome measures: 
• Incidence of unsolicited non-serious adverse events through 60 days (Day 60) 
• Incidence of laboratory adverse events (WBC, Hemoglobin, Platelet count, Creatinine, Alkaline 
Phosphatase, ALT, AST, BUN, and Bilirubin) through 60 days (Day 60) 
• Incidence of protocol-specified serious adverse events through 60 days (Day 60) 
• Incidence of hospitalization through 60 days (Day 60) 
Table 51 repeats these subject-level rates and differences between treatment groups for the subjects that do 
not report chromaturia. 
9.3.1. 
Unsolicited Adverse Events 
The proportion of subjects reporting at least one unsolicited adverse event will be summarized by MedDRA 
System Organ Class (SOC) and Preferred Term. Denominators for percentages are the number of subjects in 
the safety population. 
Adverse events by subject will be presented in Listing 21. 
The following summaries for unsolicited adverse events will be presented by MedDRA System Organ Class, 
Preferred Term, and treatment group: 
• Summary of adverse events occurring in 5% of subjects (Table 52); 
• Subject incidence and total frequency of adverse events over time by study phase with 95% CI 
(Treatment Phase, Longitudinal Phase) (Table 53, Table 54, and Table 55) 
• Summary of severity and relationship to study product (Table 56, Table 57 , and Table 58 ); 
• Summary of incidence and total frequency of related adverse events during the treatment phase (Days 
1 – 28) (Table 59) 
• Subject listing of serious adverse events (Table 60 ); 
• Subject listing of non-serious adverse events of moderate or greater severity (Table 61 ); 
• Bar chart of related adverse events by MedDRA SOC and severity (Figure 25); 
• Bar chart of incidence of related adverse events by MedDRA SOC and maximum severity (Figure 26); 
9.4. 
Deaths, Serious Adverse Events and other Significant Adverse Events 
A subject listing of deaths and serious adverse events (Table 60 ) will be presented including Subject ID, 
Adverse Event Description, Adverse Event Onset Day and Duration, Reason Reported as an SAE, Severity, 
Relationship to Treatment, Alternate Etiology if not Related, and Outcome. A subject level listing of deaths 
including cause of death will be included in Listing 30. 


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9.5. 
Pregnancies 
For any subjects in the Safety population who became pregnant during the study, every attempt was made to 
follow these subjects to completion of pregnancy to document the outcome, including information regarding 
any complications with pregnancy and/or delivery. A listing of pregnancies and outcomes will be presented 
(Listing 33, Listing 34, Listing 35, Listing 36, and Listing 37). 
9.6. 
Clinical Laboratory Evaluations 
Safety laboratory parameters are defined in Section 4.5.3. Chemistry parameters include creatinine, alkaline 
phosphatase, AST, ALT, BUN, and total bilirubin. Hematology parameters include WBC, hemoglobin, and 
platelets. In addition, T-Cell subsets were also collected and include CD3 (CD3+), CD3/lymphocytes (CD3 + 
%), CD3 (CD3+), CD4/lymphocytes (CD4 + %), CD8 (CD8+), and CD8/lymphocytes (CD8 + %) and other 
hematology parameters (neutrophil, lymphocyte, eosinophil, monocyte, hematocrit, and mean corpuscular 
volume) were collected. The distribution of laboratory results by time point, treatment group, and maximum 
severity will be presented in Table 64, Table 65, Table 66, Table 67, Table 68, Table 69, and Table 70 for 
chemistry parameters and in Table 84, Table 85, Table 86, and Table 87 for hematology parameters. The 
distribution of abnormal laboratory results related to study treatment by time point, treatment group, and 
maximum severity will be presented in Table 71, Table 72, Table 73, Table 74, Table 75, Table 76, and Table 
77 for chemistry parameters and in Table 88, Table 89, Table 90, and Table 91 for hematology parameters. 
Descriptive statistics including mean, standard deviation, median, minimum, and maximum values by time 
point, for each laboratory parameter, will be summarized in Table 78, Table 79, Table 80, Table 81, Table 82, 
and Table 83 for chemistry parameters and Table 92, Table 93, and Table 94 for hematology parameters. 
Additionally, descriptive statistics will be summarized in Table 95, Table 96, Table 97, Table 98, Table 99, 
Table 100, Table 101, Table 102, Table 103, Table 104, Table 105, and Table 106 for the T-Cell subset 
parameters and other hematology data that were not evaluated for abnormality. 
Listing of abnormal laboratory results for chemistry and hematology parameters will be presented in Table 62 
and Table 63, respectively. Listing 24 and Listing 25 will provide a complete listing of individual clinical 
laboratory results with applicable reference ranges. A complete listing of individual T-Cell subset results will 
be provided in Listing 26. 
9.7. 
Vital Signs and Physical Evaluations 
Vital sign measurements included weight, systolic blood pressure, diastolic blood pressure, respiration, pulse, 
and oral temperature. Vital signs were assessed at Day 1, Day 7, Day 14, Day 21, Day 28, Day 60, Day 120, 
and Day 180. Height was also measured at Day 1. Vital signs will be tabulated by visit and treatment group 
(Table 109, Table 110, Table 111, Table 112, Table 113, and Table 114). All vital signs will be listed by 
subject and time point in Listing 27.  
Physical Examinations were performed at Day 1 and Day 28. The change in physical examination data from 
Day 1 will be summarized for each visit by treatment group for subjects in the Safety population (Listing 31).  
9.8. 
Concomitant Medications 
Concomitant medications will be coded to the Anatomical Therapeutic Classification (ATC) using the WHO 
Drug Dictionary. The use of prior and concomitant medications taken during the study will be recorded on the 
CRFs. A by-subject listing of concomitant medication use will be presented (Listing 32). The use of 
concomitant medications during the study will be summarized by ATC1, ATC2 code and treatment group for 
the Safety Population (Table 115). 


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9.9. 
Other Safety Measures 
Hospitalizations were collected as an outcome measure for the secondary objective and therefore were not 
reported as serious adverse events. Table 50 presents subject-level rates and differences between treatment 
groups for the incidence of hospitalization through 60 days. The protocol calls for the average number of days 
of hospitalization to be estimated and compared between treatment groups using a two-sample t-test. 
However, due to early closure of the study, the number of subjects is too small to meet the normality 
assumptions of the t-test; therefore Wilcoxon-Mann-Whitney exact rank sum tests will be used to compare the 
number of days of hospitalization between treatment and placebo through Day 28 and Day 180 in the Safety 
Population (Table 107). A listing of all hospitalizations is presented in Listing 28. 
 


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10. 
IMMUNOGENICITY 
Summary statistics including the number of subjects with a valid result, geometric mean titer and 95% CI, 
median, minimum, and maximum will be provided by study day and treatment group for Norovirus-specific 
serum and stool IgA, IgM, and IgG in Table 37. In addition, geometric mean fold-rise and proportion of 
responders (defined as four-fold or greater increase from baseline) with 95% confidence intervals will be 
displayed in Table 38 Confidence intervals for the proportion of responders will be Wilson score two-sided 
95% CIs. Table 37 and Table 38 will also provide summaries for Total Serum IgG and the ratio of Norovirus-
specific IgG to Total IgG for each study day and treatment group.  
The change in Norovirus-specific serum and stool IgA, IgM, and IgG between Day 1 and Day 28 and Day 1 
and Day 60 will be assessed using analysis of covariance (ANCOVA) adjusting for baseline assay value. The 
analysis will be conducted in the mITT population. Table 39 will present the observed means and standard 
deviations of the change in Norovirus-specific serum and stool IgA, IgM, and IgG between Day 1 and Day 28 
and Day 1 and Day 60 for each treatment group. Levene’s test and normality checks will be carried out to 
check if the assumptions of ANCOVA are met. If assumptions of ANCOVA have been met, the adjusted 
mean, standard error, and 95% confidence intervals will also be presented for each treatment group. The p-
value for the test of between treatment differences will also be presented. If the assumptions of ANCOVA are 
not met, transformations of the change in assay variable may be utilized to correct any skewness in residuals 
or heterogeneity of the variances. If a transformation of the dependent variable is used, a footnote in the table 
will denote which transformation was used in the analyses. If the assumptions of ANCOVA cannot be met 
through transformation of the dependent variable, only the observed mean, standard deviation and 95% 
confidence intervals of the unadjusted change in Norovirus-specific serum and stool IgA, IgM, and IgG 
between Day 1 and Day 28 and between Day 1 and Day 60 will be reported.  
A mixed effects model will be used to compare the change in each Norovirus-specific serum and stool IgA, 
IgM, and IgG between nitazoxanide and placebo for each assay. Norovirus-specific serum and stool IgA, 
IgM, and IgG measured on study days 1, 28 and 60 will be included in the mixed effects model. Below the 
mixed effects model for Norovirus-specific serum IgA is described. Analyses for each assay type will be 
performed in a similar manner. 
The mean Norovirus-specific serum IgA with 95% confidence intervals will be displayed graphically for each 
time point for each treatment group. If a linear relationship between Norovirus-specific serum IgA and time is 
observed for both groups, then a model that makes use of this simplifying assumption will be used.  Letting Y 
denote Norovirus-specific serum IgA, t denote the time point (study day), and i be a subject index, and letting 
treatment=1 for those in the nitazoxanide group and treatment=0 for those in the placebo group, we will 
model serum IgA as: 
𝑌𝑖𝑡= 𝛽0 + 𝛽1𝑡+ 𝜇𝑖+ 𝛼𝑖𝑡+ 𝛽2𝑡𝑟𝑒𝑎𝑡𝑚𝑒𝑛𝑡+ 𝛽3𝑡𝑟𝑒𝑎𝑡𝑚𝑒𝑛𝑡∙𝑡+ 𝜖𝑖𝑡, 
If the relationship is nonlinear, then a transformation (e.g. log transformation) may be applied, or we will fit 
the following model, which relaxes the linearity assumption.  Let 1[t=k] denote an indicator variable taking the 
value one when t=k and zero otherwise. Let ui denote the random intercept for subject i and let αi denote the 
random slope for subject i, and assume these random effects are normally distributed with mean zero.  Then 
without assuming linearity, the serum IgA for subject i at time t can be modeled as:  
𝑌𝑖𝑡= 𝛽0 + 𝜇𝑖+ 𝛼𝑖𝑡+ 𝛽1 ∙𝑡𝑟𝑒𝑎𝑡𝑚𝑒𝑛𝑡+ 𝛽2 1[t=28] + 𝛽3 1[t=28] ∙𝑡𝑟𝑒𝑎𝑡𝑚𝑒𝑛𝑡+ 𝛽41[t=60]
+ 𝛽5 1[t=60] ∙𝑡𝑟𝑒𝑎𝑡𝑚𝑒𝑛𝑡+ 𝜖𝑖𝑡, 


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The error terms, 𝜖𝑖𝑡,  are assumed to be independent and normally distributed with constant variance and mean 
zero. If residual plots indicate that variance is not constant and/or the errors are not normally distributed, 
transformations (e.g., the log transformation of the response) will be considered.  Choice of covariance 
structures for the random effects (e.g., compound symmetric and autoregressive), will be explored. 
In this model, the expected serum IgA for the placebo group on Day 1 is 𝛽0, and on Day 28 (t=28) is 𝛽0 + 𝛽2.  
Therefore, the expected change from time Day 1 to Day 28 is 𝛽2 for the placebo group. The expected serum 
IgA for the nitazoxanide group on Day 1 is 𝛽0 + 𝛽1, and on Day 28, it is 𝛽0 + 𝛽1 + 𝛽2 + 𝛽3.  Therefore, the 
expected change for the nitazoxanide group from Day 1 to Day 28 is 𝛽2 + 𝛽3. Thus, the difference in rate of 
change in Norovirus-specific serum IgA from Day 1 to Day 28 between nitazoxanide and placebo groups is, 
on average, 𝛽3.  The interpretation for parameter 𝛽5 is similar. 
The analyses will be performed on the Immunogenicity population. Table 40 will present the coefficient 
estimates for the mixed effects model for the Norovirus-specific serum IgA assay. Table 41, Table 42, Table 
43, Table 44, and Table 45 will present the coefficient estimates for the mixed effects models for the 
remaining assay types.  
The relationship between change in total lymphocyte count between Day 1 and 180 and the day of initial 
clinical resolution of symptoms will be evaluated using Pearson correlations. A Fisher’s Z-transformation will 
be applied to the Pearson correlations in both the nitazoxanide and placebo groups. These will then be 
compared using a Z-test and the p-value will be reported along with the Pearson correlations and 95% 
confidence intervals in Table 46. The following relationships will also be evaluated in Table 46: 
• Change in T cell subsets between Day 1 and 180 and the day of initial clinical resolution of symptoms. 
• Change in total lymphocyte count between Day 1 and 180 and the first day of undetectable 
quantitative Norovirus PCR (see viral load in Section 3.3). 
• Change in T cell subsets between Day 1 and 180 and the first day of undetectable quantitative 
Norovirus PCR (see viral load in Section 3.3). 
Similarly, Table 47 will evaluate the following relationships: 
• Change in Norovirus-specific serum and stool IgA, IgM, and IgG from Day 1 to Day 28 and the day of 
initial clinical resolution of symptoms. 
• Change in Norovirus-specific serum and stool IgA, IgM, and IgG from Day 1 to Day 60 and the day of 
initial clinical resolution of symptoms. 
• Change in Norovirus-specific serum and stool IgA, IgM, and IgG from Day 1 to Day 28 and the first 
day of undetectable quantitative Norovirus PCR (see viral load in Section 3.3). 
• Change in Norovirus-specific serum and stool IgA, IgM, and IgG from Day 1 to Day 60 and the first 
day of undetectable quantitative Norovirus PCR (see viral load in Section 3.3). 
All immunogenicity variables will be listed by treatment group, subject, and visit in Listing 20 and Listing 21 
.Total lymphocyte counts, and T-Cell subsets will be listed in Listing 23 and Listing 24, respectively. 


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11. 
OTHER ANALYSES 
The protocol calls for a Log-Rank test at the 5% two-sided level of significance for the following outcome 
measures: 
• Time to allograft rejection as per each center team. 
• Time to graft loss as reported to UNOS. 
• Time to death. 
• Time to withdrawal from the study because of intolerance or drug related adverse events. 
However, due to early closure of the study, the number of subjects is too small to use a Log-Rank test. 
Instead, a stratified Cox proportional hazards model will be used to compare treatment to control through Day 
180. Stratification is based on acute versus chronic symptoms at baseline. No pediatric subjects were enrolled 
in the study and only one hematopoietic stem cell transplant subject was enrolled in the study; therefore, the 
transplant type and age range stratums will not be included in the final analysis.   
The analysis will be performed in the mITT analysis population. The treatment hazard ratio estimate, 95% 
confidence interval and p-value from the likelihood ratio test will be presented for each event (Table 108). 
The median time to event and 95% confidence interval will be summarized by treatment arm and duration of 
symptoms. In addition, stratum-specific estimates of the treatment hazard ratio within each duration of 
symptoms strata will be presented. Kaplan-Meier curves for each treatment arm will be displayed in Figure 
27, Figure 28, Figure 29, and Figure 30. A listing of graft loss and rejection is presented in Listing 29 and a 
listing of deaths is presented in Listing 30. 
The primary analysis will be repeated on the mITT population using secretor status as defined by phenotype 
and genotype, separately (Table 48). Individual secretor status data is presented in Listing 19. 


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12. 
REPORTING CONVENTIONS 
P-values >0.001 and <0.999 will be reported to 3 decimal places; p-values less than 0.001 will be reported as 
“<0.001”. The mean, standard deviation, and other statistics will be reported to 1 decimal place greater than 
the original data. The minimum and maximum will use the same number of decimal places as the original 
data. Proportions will be presented as 2 decimal places; values greater than zero but <0.01 will be presented as 
“<0.01”. Percentages will be reported to the nearest whole number; values greater than zero but <1% will be 
presented as “<1”; values greater than 99% but less than 100% will be reported as “>99”. Estimated 
parameters, not on the same scale as raw observations (e.g. regression coefficients) will be reported to 3 
significant figures. 


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13. 
TECHNICAL DETAILS 
SAS version 9.4 or above will be used to generate all tables, figures and listings or R version 4.1.1 or higher. 


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14. 
SUMMARY OF CHANGES IN THE CONDUCT OF THE STUDY OR 
PLANNED ANALYSES 
14.1. 
Changes in the Conduct of the Study 
14.1.1. 
Protocol Amendments 
The first subject enrolled on protocol version 2.0. Subjects were also enrolled on protocol version 3.0. 
Substantive changes between these protocol versions are summarized below. 
• Day 28 Visit will not reflect completion of treatment phase as subject will have to take the final dose 
after the visit. Treatment phase description was updated to reflect number of doses. 
• The following stool related exploratory outcome measures and urine sensitivity outcome measures 
were added: 
o The effect of co-pathogens, as determined by the BioFire stool pathogen screen, on the primary 
outcome measure. 
o Time from randomization until initial clinical resolution of Norovirus symptoms for at least 48 
hours through Day 180.  Clinical resolution will be assessed from the daily diary by the subject 
and will be defined as cessation of vomiting and no stools classified by the Bristol Stool Chart as 
diarrhea (Type 6 or 7) from the total population compared to the subgroup of subjects who do not 
report chromaturia (discoloration of urine) based on unsolicited self-reporting. 
o Incidence of unsolicited non-serious adverse events (see section 9 for details) through 60 
days, laboratory adverse events (WBC, Hemoglobin, Platelet count, Creatinine, Alkaline 
Phosphatase, ALT, AST, BUN and Bilirubin) through 60 days, protocol-specified serious adverse 
events (see section 9 for details) through 60 days, and Hospitalization through 60 days from the 
total population compared to the subgroup of subjects who do not report chromaturia 
(discoloration of urine) based on unsolicited self-reporting. 
o Time from the randomization to first negative viral load through 180 days and the change in viral 
titer between Day 1 and 180 from the total population compared to the subgroup of subjects who 
do not report chromaturia (discoloration of urine) based on unsolicited self-reporting.  
• Addition of a + 3-day window for the Study Day 35 call. 
14.1.2. 
Study Product Administration 
One site (University of Nebraska) received multiple kits representing one study product and no kits of the 
other study product when it ordered study product from the DMID Clinical Materials Services contractor. Due 
to this imbalance, the online randomization module in Advantage eClinical would have prevented 
randomization if it was attempted. To resolve the issue, the site was instructed to order additional kits, 
although they described their inventory as sufficient. The site was informed a second time that the number of 
kits they had on-site were insufficient and they would not be able to randomize unless they ordered more kits. 
The site subsequently agreed to order additional kits. This communication was considered by the SDCC to 
meet the definition of an accidental partial unblinding as it could be inferred that all the kits on-hand were 
identical. To address the issue, the MOP was updated to instruct sites to always order a minimum number of 
kits in addition to always maintaining a number of kits on-site. No changes to planned analyses were made in 
response to this situation. 


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14.1.3. 
Daily Diary Completion Time 
Subjects were instructed to complete their daily diary at the same time each day. During manual review of the 
data, it was discovered that subjects had entry dates with morning diary times and/or diary times that were 
<12 hours from their previous entry’s diary time. Given the inconsistencies in the timing of the daily diary 
entries, it is difficult to know if subjects were recording information for the previous study day or the prior 24 
hours. For diary entries that are <12 hours apart, it is likely that information has been duplicated. The analyses 
assume that the data reflected in each diary is for the date of diary completion; however, this is a limitation 
that was not able to be resolved during the study. The number of diaries completed in pre-specified windows 
(12pm – 6am, 6pm – 12am, 12am – 6am, and number completed less than 12 hours after previous diary 
completed) is provided in Listing 10. 
14.2. 
Changes in Planned Analyses 
It was originally planned that the study would enroll 160 subjects allowing for larger sample statistical 
methods to be used; however, due to early closure of the study only 31 subjects enrolled. Therefore, it is 
anticipated that many of these tests will no longer be valid. Many of the analyses from the protocol have been 
updated to employ small sample techniques and will be primarily descriptive.  


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15. 
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30. Patrick DL. 22 March 2007. Information Sheet on the Irritable Bowel Syndrome-Quality of Life 
Measure (IBS-QOL). University of Washington, accessed on 20 December 2021. 
<http://depts.washington.edu/seaqol/docs/IBS-QOL_Info.pdf >. 
31. EuroQol Research Foundation. EQ-5D-3L User Guide, 2018. Available from: 
https://euroqol.org/publications/user-guides. 
32. HealthMeasures. PROMIS Scoring Manuals. Available from: 
https://www.healthmeasures.net/index.php?option=com_content&view=article&id=180&Itemid=994 


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16. 
LISTING OF TABLES, FIGURES, AND LISTINGS  
Table, figure, and listing shells are presented in Appendices 1, 2, and 3. 
 


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APPENDICES 


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APPENDIX 1. TABLE MOCK-UPS 
LIST OF TABLES 
Table 1: 
Schedule of Study Procedures ....................................................................................67 
Table 2: 
Sample Size/Probability Estimates .............................................................................69 
Table 3: 
Missing Diary Days by Treatment Group ..................................................................70 
Table 4: 
Distribution of Protocol Deviations by Category, Type, and Treatment 
Group ..........................................................................................................................71 
Table 5: 
Laboratory Adverse Event Grading Scale ..................................................................72 
Table 6: 
Subject Disposition by Treatment Group ...................................................................73 
Table 7: 
Analysis Populations by Treatment Group .................................................................74 
Table 8: 
Dates of First Treatment by Site and Treatment Group .............................................75 
Table 9: 
Ineligibility Summary of Screen Failures ...................................................................76 
Table 10: Treatment Compliance by Study Day and Treatment Group, Safety 
Population ...................................................................................................................77 
Table 11: Summary of Categorical Demographic and Baseline Characteristics by 
Treatment Group .........................................................................................................78 
Table 12: Summary of Categorical Demographic and Baseline Characteristics by Site ............78 
Table 13: Summary of Continuous Demographic and Baseline Characteristics by 
Treatment Group .........................................................................................................79 
Table 14: Summary of Continuous Demographic and Baseline Characteristics by Site ............79 
Table 15: Summary of Subjects with Pre-Existing Medical Conditions by MedDRA 
System Organ Class and Treatment Group ................................................................80 
Table 16: Time to Initial Clinical Resolution by Treatment Group and Duration of 
Symptoms ...................................................................................................................81 
Table 17: Time to Initial Clinical Resolution by Treatment Group and Duration of 
Symptoms:  Worst Case Scenario Sensitivity Analysis .............................................81 
Table 18: Time to Initial Clinical Resolution by Treatment Group and Duration of 
Symptoms:  Subgroup Sensitivity Analysis – mITT Population ................................82 
Table 19: Time to Initial Clinical Resolution by Treatment Group and Diary 
Compliance – mITT Population .................................................................................83 
Table 20: Summary of Virologic Improvement by Test Type, Treatment Group, and 
Study Day – mITT Population ....................................................................................84 
Table 21: Time to First Negative Viral Load by Treatment Group and Duration of 
Symptoms – Norovirus GII ........................................................................................85 
Table 22: Time to First Negative Viral Load by Treatment Group and Duration of 
Symptoms – Norovirus GI ..........................................................................................85 


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Table 23: Time to First Negative Viral Load by Treatment Group and Duration of 
Symptoms:  Subgroup Sensitivity Analysis – Norovirus GII, mITT 
Population ...................................................................................................................86 
Table 24: Time to First Negative Viral Load by Treatment Group and Duration of 
Symptoms:  Subgroup Sensitivity Analysis – Norovirus GI, mITT 
Population ...................................................................................................................86 
Table 25: Change in Viral Titer between Day 1 and Day 180 by Treatment Group and 
Duration of Symptoms – Norovirus GII .....................................................................87 
Table 26: Change in Viral Titer between Day 1 and Day 180 by Treatment Group and 
Duration of Symptoms – Norovirus GI ......................................................................87 
Table 27: Change in Viral Titer between Day 1 and Day 180 by Treatment Group and 
Duration of Symptoms: Subgroup Sensitivity Analysis – Norovirus GII, 
mITT Population .........................................................................................................88 
Table 28: Change in Viral Titer between Day 1 and Day 180 by Treatment Group and 
Duration of Symptoms: Subgroup Sensitivity Analysis – Norovirus GI, 
mITT Population .........................................................................................................88 
Table 29: Exploratory Time to Event by Treatment Group and Duration of Symptoms 
– mITT Population ......................................................................................................89 
Table 30: Exploratory Summary Statistics of Clinical Improvement Measures by 
Treatment Group – mITT Population .........................................................................90 
Table 31: Patient-Reported Quality of Life by EuroQOL-5 Dimension and Study Day 
– Nitazoxanide 500 mg, mITT Population .................................................................91 
Table 32: Patient-Reported Quality of Life by EuroQOL-5 Dimension and Study Day 
– Placebo, mITT Population .......................................................................................91 
Table 33: Change in Patient-Reported Measures from Baseline to Day 28, 60, 120, and 
180 by Treatment Group – mITT Population .............................................................92 
Table 34: Time to Initial Clinical Resolution by Treatment Group and Co-Pathogen – 
mITT Population .........................................................................................................93 
Table 35: Time to First Negative Viral Load by Treatment Group and Co-Pathogen – 
Norovirus GII, mITT Population ................................................................................94 
Table 36: Time to First Negative Viral Load by Treatment Group and Co-Pathogens – 
Norovirus GI, mITT Population .................................................................................94 
Table 37: Summary Statistics of Norovirus-Specific Serum and Stool IgA, IgM, and 
IgG Results by Study Day and Treatment Group – Immunogenicity 
Population ...................................................................................................................95 
Table 38: Norovirus-Specific Serum and Stool IgA, IgM, and IgG Results by Study 
Day and Treatment Group – Immunogenicity Population .........................................96 
Table 39: Change in Norovirus-Specific Immunoglobulin Assays between Day 1 and 
Study Day 28 and 60 by Treatment Group – Immunogenicity Population ................97 


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Table 40: Mixed Effects Model Coefficient Estimates – Norovirus-Specific Serum 
IgA, Immunogenicity Population ...............................................................................98 
Table 41: Mixed Effects Model Coefficient Estimates – Norovirus-Specific Stool IgA, 
Immunogenicity Population ........................................................................................98 
Table 42: Mixed Effects Model Coefficient Estimates – Norovirus-Specific Serum 
IgG, Immunogenicity Population ...............................................................................98 
Table 43: Mixed Effects Model Coefficient Estimates – Norovirus-Specific Stool IgG, 
Immunogenicity Population ........................................................................................98 
Table 44: Mixed Effects Model Coefficient Estimates – Norovirus-Specific Serum 
IgM, Immunogenicity Population ...............................................................................98 
Table 45: Mixed Effects Model Coefficient Estimates – Norovirus-Specific Stool IgM, 
Immunogenicity Population ........................................................................................98 
Table 46: Correlation of Change in T-Cell Subset from Day 1 to Day 180 vs Clinical 
Resolution of Symptoms and Negative PCR by Treatment Group – 
Immunogenicity Population ........................................................................................99 
Table 47: Correlation of Change in Norovirus-Specific Immunoglobulin Assays vs 
Clinical Resolution of Symptoms and Negative PCR by Study Day and 
Treatment Group – Immunogenicity Population ......................................................100 
Table 48: Time to Initial Clinical Resolution by Test, Treatment Group and Secretor 
Status – mITT Population .........................................................................................101 
Table 49: Overall Summary of Adverse Events .......................................................................102 
Table 50: Subject-Level Rates of Adverse Events through Day 60 and Differences 
between Treatment Groups – Safety Population ......................................................103 
Table 51: Subject-Level Rates of Adverse Events through Day 60 and Differences 
between Treatment Groups: Chromaturia Sensitivity Analysis – Safety 
Population .................................................................................................................104 
Table 52: Adverse Events Occurring in 5% of Subjects in Any Treatment Group by 
MedDRA Preferred Term, System Organ Class, and Treatment Group – 
Safety Population ......................................................................................................105 
Table 53: Summary of Unsolicited Adverse Events by MedDRA System Organ Class, 
Preferred Term, and Study Phase – Nitazoxanide 500 mg, Safety Population ........106 
Table 54: Summary of Unsolicited Adverse Events by MedDRA System Organ Class, 
Preferred Term, and Study Phase – Placebo, Safety Population ..............................106 
Table 55: Summary of Unsolicited Adverse Events by MedDRA System Organ Class, 
Preferred Term, and Study Phase – All Subjects, Safety Population .......................106 
Table 56: Unsolicited Adverse Events by MedDRA System Organ Class and Preferred 
Term, Maximum Severity, Relationship, and Treatment Group – 
Nitazoxanide 500 mg, Safety Population, N=x ........................................................107 


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Table 57: Unsolicited Adverse Events by MedDRA System Organ Class and Preferred 
Term, Maximum Severity, Relationship, and Treatment Group – Placebo, 
Safety Population, N=x .............................................................................................107 
Table 58: Unsolicited Adverse Events by MedDRA System Organ Class and Preferred 
Term, Maximum Severity, Relationship, and Treatment Group – All 
Subjects, Safety Population, N=x .............................................................................107 
Table 59: Related Unsolicited Adverse Events During Treatment Phase (Days 1 – 28) 
by MedDRA System Organ Class, Preferred Term, and Treatment Group – 
Safety Population ......................................................................................................108 
Table 60: Listing of Serious Adverse Events ...........................................................................109 
Table 61: Listing of Non-Serious, Unsolicited, Moderate or Severe Adverse Events .............110 
Table 62: Listing of Abnormal Laboratory Results - Chemistry ..............................................112 
Table 63: Listing of Abnormal Laboratory Results - Hematology ...........................................113 
Table 64: Laboratory Results by Parameter, Maximum Severity, Time Point, and 
Treatment Group – Any Chemistry Parameter .........................................................114 
Table 65: Laboratory Results by Parameter, Maximum Severity, Time Point, and 
Treatment Group – Creatinine ..................................................................................115 
Table 66: Laboratory Results by Parameter, Maximum Severity, Time Point, and 
Treatment Group – BUN ..........................................................................................115 
Table 67: Laboratory Results by Parameter, Maximum Severity, Time Point, and 
Treatment Group – Alkaline Phosphatase ................................................................115 
Table 68: Laboratory Results by Parameter, Maximum Severity, Time Point, and 
Treatment Group – AST ...........................................................................................115 
Table 69: Laboratory Results by Parameter, Maximum Severity, Time Point, and 
Treatment Group – ALT ...........................................................................................115 
Table 70: Laboratory Results by Parameter, Maximum Severity, Time Point, and 
Treatment Group – Total Bilirubin ...........................................................................115 
Table 71: Abnormal Laboratory Results Related to Study Treatment by Parameter, 
Maximum Severity, Time Point, and Treatment Group – Any Chemistry 
Parameter ..................................................................................................................116 
Table 72: Abnormal Laboratory Results Related to Study Treatment by Parameter, 
Maximum Severity, Time Point, and Treatment Group – Creatinine ......................117 
Table 73: Abnormal Laboratory Results Related to Study Treatment by Parameter, 
Maximum Severity, Time Point, and Treatment Group – BUN ...............................117 
Table 74: Abnormal Laboratory Results Related to Study Treatment by Parameter, 
Maximum Severity, Time Point, and Treatment Group – Alkaline 
Phosphatase ...............................................................................................................117 


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Table 75: Abnormal Laboratory Results Related to Study Treatment by Parameter, 
Maximum Severity, Time Point, and Treatment Group – AST ...............................117 
Table 76: Abnormal Laboratory Results Related to Study Treatment by Parameter, 
Maximum Severity, Time Point, and Treatment Group – ALT ...............................117 
Table 77: Abnormal Laboratory Results Related to Study Treatment by Parameter, 
Maximum Severity, Time Point, and Treatment Group – Total Bilirubin ...............117 
Table 78: Laboratory Summary Statistics by Parameter, Time Point, and Treatment 
Group – Creatinine (mg/dL) .....................................................................................118 
Table 79: Laboratory Summary Statistics by Parameter, Time Point, and Treatment 
Group – BUN (mg/dL) .............................................................................................118 
Table 80: Laboratory Summary Statistics by Parameter, Time Point, and Treatment 
Group – Alkaline Phosphatase (U/L) .......................................................................118 
Table 81: Laboratory Summary Statistics by Parameter, Time Point, and Treatment 
Group – AST (U/L) ..................................................................................................118 
Table 82: Laboratory Summary Statistics by Parameter, Time Point, and Treatment 
Group – ALT (U/L) ..................................................................................................118 
Table 83: Laboratory Summary Statistics by Parameter Time Point, and Treatment 
Group – Total Bilirubin (mg/dL) ..............................................................................118 
Table 84: Laboratory Results by Parameter, Maximum Severity, Time Point, and 
Treatment Group – Any Hematology Parameter ......................................................119 
Table 85: Laboratory Results by Parameter, Maximum Severity, Time Point, and 
Treatment Group – WBC ..........................................................................................120 
Table 86: Laboratory Results by Parameter, Maximum Severity, Time Point, and 
Treatment Group – Hemoglobin ...............................................................................121 
Table 87: Laboratory Results by Parameter, Maximum Severity, Time Point, and 
Treatment Group – Platelets .....................................................................................121 
Table 88: Abnormal Laboratory Results Related to Study Treatment by Parameter, 
Maximum Severity, Time Point, and Treatment Group – Any Hematology 
Parameter ..................................................................................................................122 
Table 89: Abnormal Laboratory Results Related to Study Treatment by Parameter, 
Maximum Severity, Time Point, and Treatment Group – WBC ..............................123 
Table 90: Abnormal Laboratory Results Related to Study Treatment by Parameter, 
Maximum Severity, Time Point, and Treatment Group – Hemoglobin ...................124 
Table 91: Abnormal Laboratory Results Related to Study Treatment by Parameter, 
Maximum Severity, Time Point, and Treatment Group – Platelets .........................124 
Table 92: Laboratory Summary Statistics by Parameter, Time Point, and Treatment 
Group – WBC (109/L) ..............................................................................................125 


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Table 93: Laboratory Summary Statistics by Parameter, Time Point, and Treatment 
Group – Hemoglobin (g/dL) .....................................................................................125 
Table 94: Laboratory Summary Statistics by Parameter, Time Point, and Treatment 
Group – Platelets (109/L) ..........................................................................................125 
Table 95: Laboratory Summary Statistics by Parameter, Time Point, and Treatment 
Group – Monocytes (109/L) ......................................................................................125 
Table 96: Laboratory Summary Statistics by Parameter, Time Point, and Treatment 
Group – Hematocrit (%) ...........................................................................................125 
Table 97: Laboratory Summary Statistics by Parameter, Time Point, and Treatment 
Group – Mean Corpuscular Volume (fL) .................................................................125 
Table 98: Laboratory Summary Statistics by Parameter, Time Point, and Treatment 
Group – Neutrophils (109/L) .....................................................................................125 
Table 99: Laboratory Summary Statistics by Parameter, Time Point, and Treatment 
Group – Lymphocytes (109/L) ..................................................................................126 
Table 100: Laboratory Summary Statistics by Parameter, Time Point, and Treatment 
Group – Eosinophils (109/L) .....................................................................................126 
Table 101: Laboratory Summary Statistics by Parameter, Time Point, and Treatment 
Group – CD3+ Cells (106/L).....................................................................................126 
Table 102: Laboratory Summary Statistics by Parameter, Time Point, and Treatment 
Group – CD3+ Cells/Lymphocytes (%) ...................................................................126 
Table 103: Laboratory Summary Statistics by Parameter, Time Point, and Treatment 
Group – CD4+ Cells (106/L).....................................................................................126 
Table 104: Laboratory Summary Statistics by Parameter, Time Point, and Treatment 
Group – CD4+ Cells/Lymphocytes (%) ...................................................................126 
Table 105: Laboratory Summary Statistics by Parameter, Time Point, and Treatment 
Group – CD8+ Cells (106/L).....................................................................................126 
Table 106: Laboratory Summary Statistics by Parameter, Time Point, and Treatment 
Group – CD8+ Cells/Lymphocytes (%) ...................................................................126 
Table 107: Duration of Hospitalization (Days) Summary Statistics by Treatment Group 
and Study Day – Safety Population ..........................................................................127 
Table 108: Natural History of Disease Time to Event by Treatment Group and Duration 
of Symptoms – mITT Population .............................................................................128 
Table 109: Vital Signs Summary Statistics by Parameter, Time Point, and Treatment 
Group – Temperature (°F) ........................................................................................129 
Table 110: Vital Signs Summary Statistics by Parameter, Time Point, and Treatment 
Group – Weight (kg) .................................................................................................130 
Table 111: Vital Signs Summary Statistics by Parameter, Time Point, and Treatment 
Group – Systolic Blood Pressure (mmHg) ...............................................................130 


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Table 112: Vital Signs Summary Statistics by Parameter, Time Point, and Treatment 
Group – Diastolic Blood Pressure (mmHg) ..............................................................130 
Table 113: Vital Signs Summary Statistics by Parameter, Time Point, and Treatment 
Group – Respiration (breaths/minute) ......................................................................130 
Table 114: Vital Signs Summary Statistics by Parameter, Time Point, and Treatment 
Group – Pulse (beats/minute) ...................................................................................130 
Table 115: Number and Percentage of Subjects with Prior and Concurrent Medications 
by WHO Drug Classification and Treatment Group ................................................131 
 


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9.5.1 Efficacy/Immunogenicity and Safety Measurements Assessed and Flow Chart 
Table 1: 
Schedule of Study Procedures 
[Implementation Note: Include a graphic display of the frequency and timing of efficacy and safety measures including visit numbers. The schedule of 
procedures from the protocol may be excerpted and included here, as appropriate.] 
Phase 
Treatment Phase 
Longitudinal Monitoring Phase 
Procedure 
Screen/
Enroll/ 
Day 1 
Day 7 
(±3 d) 
Day 14 
(±3 d) 
Day 21 
(±3d) 
Day 28 
(+3 d) 
Day 
35 
Day 53 
( ± 7d) 
Day 60 
(±14 d) 
Day 
113 
 (± 7d) 
Day 
120 
(±14 d) 
Day 
173 
( ± 7d) 
Day 
180 
(±14 d) 
Unscheduled 
Visit 
Early 
Termination 
visit 
Visit 
01 
02 
03 
04 
05 
06 
07 
08 
09 
10 
11 
12 
 
 
Consent1 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine Pregnancy2 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
WBC, TLC, Hb, Platelets 3#₱  
4 mL₱ 
4 mL3 
 
 
4 mL3 
 
 
 
 
 
 
4 mL3 
 
4 mL3 
Creatinine, Alk Phos, AST, 
ALT, BUN, Bilirubin.3€₱  
4.5 mL₱ 
4.5 mL3 
 
 
4.5 mL3 
 
 
 
 
 
 
4.5 mL3 
 
4.5 mL3 
T-Cell Subsets3 
4 mL 
 
 
 
 
 
 
 
 
 
 
4 mL 
 
4 mL 
Pill Count  
 
X 
X 
X 
X 
 
 
X10 
 
 
 
 
 
 
Vital Signs*  
X 
X 
X 
X 
X 
 
 
X 
 
X 
 
X 
X 
X 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Exam 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
Inquiry about hospitalization 
since last Assessment 
 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
Stool for Pathogen Screen¥ 
X 
X7 
X7 
X7 
X7 
 
 
X7 
 
X7 
 
X7 
X7 
X7 
Stool Norovirus Testing 
X8¶ 
X¶ 
X¶ 
X¶ 
X8¶ 
 
 
X8¶ 
 
X¶ 
 
X¶ 
X¶ 
X¶ 
Stool Ig Study 
X 
 
X¶ 
 
X 
 
 
X 
 
X¶ 
 
X¶ 
 
X¶ 
Serum Ig Study  
10 mL 
 
 
 
10 mL 
 
 
10 mL 
 
 
 
10 mL¶ 
 
10¶ mL 
Buccal Swab/Saliva 
Collection 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Nitazoxanide PK4 
 
4.5 mL 
 
4.5 mL 
 
 
 
 
 
 
 
 
 
 


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Phase 
Treatment Phase 
Longitudinal Monitoring Phase 
Procedure 
Screen/
Enroll/ 
Day 1 
Day 7 
(±3 d) 
Day 14 
(±3 d) 
Day 21 
(±3d) 
Day 28 
(+3 d) 
Day 
35 
Day 53 
( ± 7d) 
Day 60 
(±14 d) 
Day 
113 
 (± 7d) 
Day 
120 
(±14 d) 
Day 
173 
( ± 7d) 
Day 
180 
(±14 d) 
Unscheduled 
Visit 
Early 
Termination 
visit 
Nitazoxanide or placebo5 
X 
X  
X  
X  
X  
 
 
 
 
 
 
 
 
 
Return residual medication 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
Review concomitant 
medications 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
Assess for adverse events 
 
X 
X 
X 
X 
X 
 
X 
 
 
 
 
X 
X 
Administer Detailed PROs 
Packet 
X 
 
 
 
X 
 
 
X 
 
X 
 
X 
 
X 
Administer Weekly Packet 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Collect Daily Diary6 
 
X 
X 
X 
X 
 
 
X 
 
X 
 
X 
X 
X 
Phone Call for Status Update 
 
 
 
 
 
X 
X 
 
X 
 
X 
 
 
 
Phone Call for Appt Reminder 
 
 
 
 
 
 
X 
 
X 
 
X 
 
 
 
Total Blood Volume 
22.5 mL 
13 mL 
-- 
4.5 mL 
18.5 mL 
-- 
-- 
10 mL 
-- 
-- 
-- 
22.5 
mL 
-- 
22.5 mL 
1Consent/Assent must be obtained from eligible subjects, consistent with local IRB policy for consent and assent of subjects and must be obtained prior to any study procedures being performed  
2 Urine pregnancy test will be obtained from women of childbearing potential, results of test must be known and negative prior to dosing. 
3Locally performed assay; values obtained within 7 days of the study visit, if obtained for clinical indication, can be utilized during the treatment phase and within 14 days of the study visit for the 
longitudinal monitoring phase. T cell subset will be drawn unless CBC shows an ALC<100. 
4 The PK specimen on Day 7 will be collected 1-4 hours after the subject takes the study dose and on Day 21 will be a pre-dose trough and will be drawn only in subjects consenting to this optional 
assessment. 
5 Nitazoxanide or placebo kit will be provided to the subject. Study drug (Nitazoxanide or placebo) given BID for 28 days. 
6 Diary recorded once a day during the treatment phase and once a day during the longitudinal monitoring phase.  Copies of completed pages are collected at each study visit. One pack give an 
enrollment and additional copies provided at Day 28. 
7 Stool for pathogen screen will not be performed for formed stool except on Day 1 and 180.  An aliquot will be retained for later testing if indicated.  Norovirus testing includes quantitative viral load at 
all time points. 
8 Sequencing at selected time points. 
10Day 60 pill count only needs to be conducted if the dosing was not completed and medications returned during Study Day 28. 
§ If diarrhea recurs after stopping therapy, would have subject provide a stool specimen for pathogen screen and Norovirus PCR; therapy is at the discretion of the site.  
¥ The sample must have been produced within 24 hours of the visit and if it exceeds 24 hours it must be disposed.  After collection in the stool hat, the subjects can wipe down and disinfect the outside 
of the container and place it in a bag for   transport then refrigerate until they come to their visit with the research staff. Subjects would be encouraged to provide another sample within the visit 
window and if not, rectal swab may be used for all assays related to stool collection.  
*Vital Signs include weight, Blood Pressure, Respiration, Pulse, Temperature and Height. Height is only measured at Screening/Enrollment/Baseline visit.  
#Derived from Complete Blood Count.  
€Derived from Complete Metabolic Panel. 
¶Specimen also stored for future use. 
₱Must be within 3 days of enrollment 


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9.7.1 Sample Size 
Table 2: 
Sample Size/Probability Estimates  
 
Proportion Receiving Additional Treatment in the Placebo Group 
0% 
5% 
10% 
15% 
20% 
25% 
30% 
Proportion re-treated in 
the nitazoxanide Group 
0% 
91.3% 
91.6% 
91.7% 
91.6% 
91.8% 
92.0% 
92.3% 
5% 
91.4% 
91.5% 
91.6% 
91.2% 
91.2% 
91.8% 
92.5% 
10% 
- 
91.5% 
92.0% 
91.2% 
91.8% 
91.2% 
92.2% 
15% 
- 
- 
90.7% 
90.7% 
91.0% 
91.6% 
91.8% 
20% 
- 
- 
- 
87.3% 
87.1% 
87.0% 
87.7% 
25% 
- 
- 
- 
- 
74.0% 
73.9% 
75.2% 
30% 
- 
- 
- 
- 
- 
40.0% 
40.9% 


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10.2 Protocol Deviations 
Table 3: 
Missing Diary Days by Treatment Group 
Diary Days 
Statistic (days/subject) 
Nitazoxanide 500 mg 
(N = X) 
Placebo 
(N = X) 
All Subjects 
(N = X) 
Imputed a 
n 
x 
x 
x 
Mean 
xx.x 
xx.x 
xx.x 
Median 
xx.x 
xx.x 
xx.x 
Standard Deviation 
xx.x 
xx.x 
xx.x 
Minimum 
x 
x 
x 
Maximum 
x 
x 
x 
Total Missing b 
n 
x 
x 
x 
Mean 
xx.x 
xx.x 
xx.x 
Median 
xx.x 
xx.x 
xx.x 
Standard Deviation 
xx.x 
xx.x 
xx.x 
Minimum 
x 
x 
x 
Maximum 
x 
x 
x 
N=Number of subjects enrolled. 
n = Number of subjects with imputed/missing diary days. 
a Includes subjects with imputed diary days per imputation rules given in Section 9.7.2.2. 
b Includes subjects with any missing diary days  


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Table 4: 
Distribution of Protocol Deviations by Category, Type, and Treatment Group 
Category 
Deviation Type 
Nitazoxanide 500 mg  
(N=X) 
Placebo 
(N=X) 
All Subjects 
(N=X) 
No. of 
Subj. 
No. of 
Dev. 
No. of 
Subj. 
No. of 
Dev. 
No. of 
Subj. 
No. of 
Dev. 
Eligibility 
/enrollment 
Any type 
 
 
 
 
 
 
Did not meet inclusion criterion 
x 
x 
x 
x 
x 
x 
Met exclusion criterion 
 
 
 
 
 
 
ICF not signed prior to study procedures 
 
 
 
 
 
 
Other 
 
 
 
 
 
 
Treatment 
administration 
schedule 
Any type 
 
 
 
 
 
 
Out of window visit 
 
 
 
 
 
 
Missed visit/visit not conducted 
 
 
 
 
 
 
Missed treatment administration 
 
 
 
 
 
 
Delayed treatment administration 
 
 
 
 
 
 
Other 
 
 
 
 
 
 
Follow-up visit 
schedule 
Any type 
 
 
 
 
 
 
Out of window visit 
 
 
 
 
 
 
Missed visit/visit not conducted 
 
 
 
 
 
 
Other 
 
 
 
 
 
 
Protocol 
procedure/ 
assessment 
Any type 
 
 
 
 
 
 
Incorrect version of ICF signed 
 
 
 
 
 
 
Blood not collected 
 
 
 
 
 
 
Urine not collected 
 
 
 
 
 
 
Stool not collected 
 
 
 
 
 
 
Other specimen not collected 
 
 
 
 
 
 
Too few aliquots obtained 
 
 
 
 
 
 
Specimen result not obtained 
 
 
 
 
 
 
Required procedure not conducted 
 
 
 
 
 
 
Required procedure done incorrectly 
 
 
 
 
 
 
Study product temperature excursion 
 
 
 
 
 
 
Specimen temperature excursion 
 
 
 
 
 
 
Other 
 
 
 
 
 
 
Treatment 
administration 
Any type 
 
 
 
 
 
 
Required procedure done incorrectly 
 
 
 
 
 
 
Study product temperature excursion 
 
 
 
 
 
 
Other 
 
 
 
 
 
 
Blinding policy/ 
procedure 
Any type 
 
 
 
 
 
 
Treatment unblinded 
 
 
 
 
 
 
Other 
 
 
 
 
 
 
N=Number of subjects in the Safety Population 


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12.4.1 Individual Laboratory Measurements and Abnormal Laboratory Values 
Table 5: 
Laboratory Adverse Event Grading Scale 
Blood, Serum, or Plasma Chemistries1 
Reference Range2 
LO/HI/N3 
Mild (Grade 1) 
Moderate (Grade 2) 
Severe (Grade 3) 
Creatinine (mg/dL) 
 
HI 
>ULN - 1.5 x ULN 
>1.5 – 3.0 x ULN 
>3.0 x ULN 
Blood Urea Nitrogen (BUN, mg/dL) 
 
HI 
>ULN - 26 
27 - 31 
>31 
Alkaline phosphatase (U/L) 
 
HI 
>ULN – 2.5 x ULN 
>2.5 – 5.0 x ULN 
>5.0 x ULN 
AST (U/L) 
 
HI 
>ULN – 3.0 x ULN 
>3.0 – 5.0 x ULN 
>5.0 x ULN 
ALT (U/L) 
 
HI 
>ULN – 3.0 x ULN 
>3.0 – 5.0 x ULN 
>5.0 x ULN 
Bilirubin, serum total (mg/dL)  
 
HI 
>ULN – 1.5 x ULN 
>1.5 – 3.0 x ULN 
>3.0 x ULN  
Hematology 
Reference Range2 
LO/HI/N3 
Mild (Grade 1) 
Moderate (Grade 2) 
Severe (Grade 3) 
Hemoglobin  (g/dL) 
 
LO 
<LLN – 10.0 
<10.0 – 8.0 
<8.0  
 
 
 
 
 
 
White Blood Cell Count (WBC, K/CUMM ) 
 
HI 
>ULN - 15.00 
15.00 - 20.00 
>20.00 
 
 
LO 
<LLN – 3.0 
<3.0 – 2.0 
<2.0 
Platelets (K/CUMM) 
 
LO 
<LLN - 75 
<75 - 50 
<50 
 
Other Laboratory Parameters 
 
LO/HI 
Test result is associated with a 
mild sign or symptom. 
Test result requires minimal, 
local or non-invasive 
intervention. 
Test result requires an invasive 
medical or surgical intervention, 
or change in study dosing 
outside of the protocol defined 
dosing or discontinuation from 
the study treatment, or addition 
of new medication. 
1 Depending upon the lab used, references ranges, eligibility ranges and grading may be split out by sex and/or age. 
2 Reference range of individual study site laboratory 
3 High, Low, Not Graded 
ULN – upper limit of normal; LLN – lower limit of normal 


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14.1.1 Disposition of Subjects 
Table 6: 
Subject Disposition by Treatment Group 
Subject 
Disposition  
Nitazoxanide 500 mg 
(N=X) 
Placebo 
(N=X) 
All Subjects 
(N=X) 
n 
% 
n 
% 
n 
% 
Enrolled/Randomized 
x 
100 
x 
100 
x 
100 
Received Any Treatment  
x 
x.x 
x 
x.x 
x 
x.x 
Received All Scheduled Treatments through Day 7b 
x 
x.x 
x 
x.x 
x 
x.x 
Received All Scheduled Treatments through Day 14b 
 
 
 
 
 
 
Received All Scheduled Treatments through Day 21b 
 
 
 
 
 
 
Received All Scheduled Treatments through Day 28b 
 
 
 
 
 
 
Received any additional Nitazoxanide 
 
 
 
 
 
 
Received additional Nitazoxanide after Day 28 
 
 
 
 
 
 
Completed Study Day 60 
 
 
 
 
 
 
Completed Study Day 120 
 
 
 
 
 
 
Completed All Blood Drawsc   
 
 
 
 
 
 
Completed All Stool Collectionsd 
 
 
 
 
 
 
Completed Follow-up (Study Day 180)b 
 
 
 
 
 
 
Terminated Early b 
 
 
 
 
 
 
Death 
 
 
 
 
 
 
Lost to Follow-Up 
 
 
 
 
 
 
Voluntary Withdrawal by Subject 
 
 
 
 
 
 
Withdrawal by Investigator   
 
 
 
 
 
 
Termination of Site/Study by Sponsor 
 
 
 
 
 
 
Other 
 
 
 
 
 
 
N = Number of subjects enrolled. 
a Subjects are included if they have data indicating the study treatment was distributed and at least one pill count completed. 
b Refer to Section 16.2.1 for reasons subjects discontinued or terminated early. 
c Blood draws for serum Ig assays. 
d Stool or rectal swabs collected for virus detection and stool for Norovirus specific Ig assays. 


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Table 7: 
Analysis Populations by Treatment Group 
[Implementation Note: The reasons listed here should match the SAP text that describes who will be excluded from analyses. Although subjects may 
meet multiple criteria for exclusion, they should be counted under only one reason for exclusion in this table. Priority for assigning reasons for 
exclusions will be defined in the SAP text.] 
Analysis Populations 
Reason Subjects Excluded 
Nitazoxanide 500 mg 
(N=X) 
Placebo 
(N=X) 
All Subjects 
(N=X) 
n 
% 
n 
% 
% 
n 
Modified Intention-to-Treat Population 
Any Reason 
x 
xx 
x 
xx 
x 
xx 
 
Found to be ineligible at baseline 
 
 
 
 
 
 
 
Did not receive at least one dose of study product 
 
 
 
 
 
 
Per Protocol Population 
Any Reason 
 
 
 
 
 
 
 
Found to be ineligible at baseline 
 
 
 
 
 
 
 
Received less than 75% of scheduled doses through 28 
days 
 
 
 
 
 
 
 
Received additional Nitazoxanide 500 mg before primary 
outcome observed 
 
 
 
 
 
 
 
Missed more than 1.5/7 days per week of the daily diary 
through 8 weeks (through Day 60) 
 
 
 
 
 
 
 
Did not complete follow up 
 
 
 
 
 
 
Safety Population 
Any Reason 
 
 
 
 
 
 
 
Did not receive at least one dose of study product 
 
 
 
 
 
 
 
Do not have a safety assessment 
 
 
 
 
 
 
Immunogenicity Population 
Any Reason 
 
 
 
 
 
 
 
Did not receive at least one dose of study product 
 
 
 
 
 
 
 
Did not have at least one stool or serum immunoglobulin 
test result 
 
 
 
 
 
 
N=Number of subjects enrolled. 
Note: Subjects who were excluded for more than one reason are only counted once. Reason excluded is prioritized as follows: ineligible at baseline, treatment compliance, additional Nitazoxanide 500 mg, 
diary compliance, and did not complete follow-up. 


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Table 8: 
Dates of First Treatment by Site and Treatment Group 
[Implementation Note: Each site that enrolled subjects will have columns for Nitazoxanide 500 mg and placebo treatment groups.] 
Site 
Treatment Group 
Date of First Dose 
OCT2018-
DEC2018 
JAN2019-
MAR2019 
APR2019-
JUN2019 
… 
… 
… 
JAN2021-
MAR2021 
Site 1 
Nitazoxanide 500 mg (N = X) 
x 
x 
x 
x 
x 
x 
x 
 
Placebo (N = X) 
 
 
 
 
 
 
 
 
All Subjects (N = X) 
 
 
 
 
 
 
 
Site 2 
Nitazoxanide 500 mg (N = X) 
 
 
 
 
 
 
 
 
Placebo (N = X) 
 
 
 
 
 
 
 
 
All Subjects (N = X) 
 
 
 
 
 
 
 
(Continue for All Sites that Enrolled 
Subjects) 
 
 
 
 
 
 
 
 
N = Number of subjects enrolled. 
 


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Table 9: 
Ineligibility Summary of Screen Failures 
Inclusion/Exclusion Category 
Inclusion/Exclusion Criterion 
na 
%b 
Inclusion and Exclusion 
Number of subjects failing any eligibility criterion 
x 
100 
Inclusion 
Any inclusion criterion 
x 
xx 
 
[inclusion criterion 1] 
x 
xx 
 
[inclusion criterion 2] 
x 
xx 
 
[inclusion criterion 3] 
x 
xx 
Exclusion 
Any exclusion criterion 
x 
xx 
 
[exclusion criterion 1] 
x 
xx 
 
[exclusion criterion 2] 
x 
xx 
 
[exclusion criterion 3] 
x 
xx 
a More than one criterion may be marked per subject. 
b Denominator for percentages is the total number of screen failures. 


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Table 10: 
Treatment Compliance by Study Day and Treatment Group, Safety Population 
Summary  
Nitazoxanide 500 mg 
(N=X) 
Placebo 
(N=X) 
Visit 2 
Day 7 
Visit 3 
Day 14 
Visit 4 
Day 21 
Visit 5 
Day 28 
Final Pill 
Count a 
Visit 2 
Day 7 
Visit 3 
Day 14 
Visit 4 
Day 21 
Visit 5 
Day 28 
Final Pill 
Count a 
Number of Subjects Completing Visit 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Number of Subjects Compliant with Study Treatment 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Mean Cumulative Number of Pills Taken 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
Mean Percentage of Pills Taken 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
N = Number of subjects in the Safety Population. 
Note: To be considered compliant at a visit, subjects must have taken at least 75% of their expected pills. Compliance for final pill count requires subjects take at least 42 pills. 
a Final pill count will include Day 28 and Day 60 pill counts. Subjects with pill counts at both visits will use the Day 60 pill count as the final pill count.  


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14.1.2 Demographic Data by Study Group 
Table 11: 
Summary of Categorical Demographic and Baseline Characteristics by Treatment Group 
Variable 
Characteristic 
Nitazoxanide 500 mg 
(N=X) 
Placebo 
(N=X) 
All Subjects 
(N=X) 
n 
% 
n 
% 
n 
% 
Sex  
Male 
x 
xx 
x 
xx 
x 
xx 
Female 
 
 
 
 
 
 
Ethnicity  
Not Hispanic or Latino 
x 
xx 
x 
xx 
x 
xx 
Hispanic or Latino 
 
 
 
 
 
 
Not Reported 
 
 
 
 
 
 
Unknown 
 
 
 
 
 
 
Race  
American Indian or Alaska Native 
x 
xx 
x 
xx 
x 
xx 
Asian 
 
 
 
 
 
 
Native Hawaiian or Other Pacific 
Islander 
 
 
 
 
 
 
Black or African American 
 
 
 
 
 
 
White 
 
 
 
 
 
 
Multi-Racial 
 
 
 
 
 
 
Unknown 
 
 
 
 
 
 
Duration of Symptoms 
Acute (less than 14 days) 
x 
xx 
x 
xx 
x 
xx 
Chronic (14 days or greater) 
 
 
 
 
 
 
Transplant Type 
Solid organ 
x 
xx 
x 
xx 
x 
xx 
Hematopoietic Stem Cell Transplant 
 
 
 
 
 
 
Age Range 
Pediatric (12-17 years) 
x 
xx 
x 
xx 
x 
xx 
Adult (≥ 18 years) 
 
 
 
 
 
 
N = Number of subjects enrolled. 
Tables with similar format: 
Table 12: 
Summary of Categorical Demographic and Baseline Characteristics by Site 
[Implementation Note:  Treatment Groups will be replaced with Site Names.]


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Table 13: 
Summary of Continuous Demographic and Baseline Characteristics by Treatment Group 
Variable 
Statistic 
Nitazoxanide 500 mg 
(N=X) 
Placebo 
(N=X) 
All Subjects 
(N=X) 
Age 
Mean 
xx 
xx 
xx 
Standard Deviation 
xx 
xx 
xx 
Median 
xx 
xx 
xx 
Minimum 
x 
x 
x 
Maximum 
x 
x 
x 
N = Number of subjects enrolled. 
 
Tables with similar format: 
Table 14: 
Summary of Continuous Demographic and Baseline Characteristics by Site 
[Implementation Note:  Treatment Groups will be replaced with Site Names.]


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14.1.3 Prior and Concurrent Medical Conditions 
Table 15: 
Summary of Subjects with Pre-Existing Medical Conditions by MedDRA System Organ 
Class and Treatment Group 
MedDRA System Organ Class 
Nitazoxanide 500 mg 
(N=X) 
Placebo 
 (N=X) 
All Subjects 
(N=X) 
n 
% 
n 
% 
n 
% 
Any SOC 
x 
xx 
x 
xx 
x 
xx 
[SOC 1] 
 
 
 
 
 
 
[SOC 2] 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
N = Number of subjects in the Safety Population.  
n = Number of subjects reporting medical history within the specified SOC.  
Note: A subject is only counted once per SOC. 


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14.2.1 Efficacy/Immunogenicity Response Tabular Summaries by Measure, Treatment and Time Point 
Table 16: 
Time to Initial Clinical Resolution by Treatment Group and Duration of Symptoms 
Implementation Note: If an estimate is not calculable, insert “NC” in the cell and add a footnote “NC = Not 
calculable. If a subgroup has less than 5 subjects per treatment group, then remove rows and add footnote 
specifying which group(s) are excluded from analyses.” 
Analysis 
Population 
Treatment 
Group 
Duration of 
Symptoms 
n 
Median Time to Initial 
Clinical Resolution 
HR 
P-value 
Estimate 
95% CI 
Estimate 
95% CI 
mITT 
Population 
Nitazoxanide 500 
mg (N=X) 
Acute 
x 
x.x 
x.x, x.x 
x.x 
x.x, x.x 
-- 
Placebo (N=X) 
x 
x.x 
x.x, x.x 
Nitazoxanide 500 
mg (N=X) 
Chronic 
x 
x.x 
x.x, x.x 
x.x 
x.x, x.x 
-- 
Placebo (N=X) 
x 
x.x 
x.x, x.x 
Nitazoxanide 500 
mg (N=X) 
Any Duration 
x 
x.x 
x.x, x.x 
x.x 
x.x, x.x 
0.xxx 
Placebo (N=X) 
x 
x.x 
x.x, x.x 
Implementation note: Repeat for the Per Protocol Population. 
N = Number of subjects in the specified treatment group, duration of symptoms strata, and analysis population. 
n = Number of subjects with initial clinical resolution of symptoms. 
Note: HR is the ratio of the hazard of initial clinical resolution in each treatment group estimated from the Cox model. The ratio is Nitazoxanide 
500 mg to Placebo. 
HR for the ‘Any Duration’ group is the hazard ratio from the stratified Cox Model. 
P-value calculated using the likelihood ratio test. 
Additional table with similar format: 
Table 17: 
Time to Initial Clinical Resolution by Treatment Group and Duration of Symptoms:  
Worst Case Scenario Sensitivity Analysis  


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Table 18: 
Time to Initial Clinical Resolution by Treatment Group and Duration of Symptoms:  
Subgroup Sensitivity Analysis – mITT Population 
Implementation Note: If an estimate is not calculable, insert “NC” in the cell and add a footnote “NC = Not 
calculable. If a subgroup has less than 5 subjects per treatment group, then remove rows and add footnote 
specifying which group(s) are excluded from analyses.” 
Subgroup 
Treatment 
Group 
Duration of 
Symptoms 
n 
Median Time to Initial 
Clinical Resolution 
HR 
P-value 
Estimate 
95% CI 
Estimate 
95% CI 
Additional 
Nitazoxanide 
500 mga 
Nitazoxanide 
500 mg (N=X) 
Acute 
x 
x.x 
x.x, x.x 
x.x 
x.x, x.x 
-- 
Placebo (N=X) 
x 
x.x 
x.x, x.x 
Nitazoxanide 
500 mg (N=X) 
Chronic 
x 
x.x 
x.x, x.x 
x.x 
x.x, x.x 
-- 
Placebo (N=X) 
x 
x.x 
x.x, x.x 
Nitazoxanide 
500 mg (N=X) 
Any Duration 
x 
x.x 
x.x, x.x 
x.x 
x.x, x.x 
0.xxx 
Placebo (N=X) 
x 
x.x 
x.x, x.x 
Chromaturiab 
Nitazoxanide 
500 mg (N=X) 
Acute 
x 
x.x 
x.x, x.x 
x.x 
x.x, x.x 
-- 
Placebo (N=X) 
x 
x.x 
x.x, x.x 
Nitazoxanide 
500 mg (N=X) 
Chronic 
x 
x.x 
x.x, x.x 
x.x 
x.x, x.x 
-- 
Placebo (N=X) 
x 
x.x 
x.x, x.x 
Nitazoxanide 
500 mg (N=X) 
Any Duration 
x 
x.x 
x.x, x.x 
x.x 
x.x, x.x 
0.xxx 
Placebo (N=X) 
x 
x.x 
x.x, x.x 
N = Number of subjects in the specified treatment group, subgroup, and duration of symptoms strata. 
n = Number of subjects with initial clinical resolution of symptoms. 
a Subjects that took additional Nitazoxanide 500 mg are excluded from the analyses. 
b Subjects with unsolicited self-reported chromaturia (discoloration of urine) are excluded from the analyses. 
Note: HR is the ratio of the hazard of initial clinical resolution in each treatment group estimated from the Cox model. The ratio 
is Nitazoxanide 500 mg to Placebo. 
HR for the ‘Any Duration’ group is the hazard ratio from the stratified Cox Model. 
P-value calculated using the likelihood ratio test. 


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Table 19: 
Time to Initial Clinical Resolution by Treatment Group and Diary Compliance – mITT 
Population 
Implementation Note: If an estimate is not calculable, insert “NC” in the cell and add a footnote “NC = Not 
calculable. If a subgroup has less than 5 subjects per treatment group, then remove rows and add footnote 
specifying which group(s) are excluded from analyses.” 
Treatment Group 
Diary 
Compliance 
n 
Median Time to Initial Clinical 
Resolution 
HR 
Estimate 
95% CI 
Estimate 
95% CI 
Nitazoxanide 500 mg 
(N=X) 
Missing < 2 per 
week 
x 
x.x 
x.x, x.x 
x.xx 
x.xx, x.xx 
Placebo (N=X) 
x 
x.x 
x.x, x.x 
Nitazoxanide 500 mg 
(N=X) 
Missing >= 2 per 
week 
x 
x.x 
x.x, x.x 
x.xx 
x.xx, x.xx 
Placebo (N=X) 
x 
x.x 
x.x, x.x 
N = Number of subjects in the specified treatment group and diary compliance strata. 
n = Number of subjects with initial clinical resolution of symptoms. 
Note: HR is the ratio of the hazard of initial clinical resolution in each treatment group estimated from the Cox model. The ratio is Nitazoxanide 
500 mg to Placebo. 


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Table 20: 
Summary of Virologic Improvement by Test Type, Treatment Group, and Study Day – mITT Population 
Implementation Note: If an estimate is not calculable, insert “NC” in the cell and add a footnote “NC = Not calculable. If a subgroup has less than 5 
subjects per treatment group, then remove rows and add footnote specifying which group(s) are excluded from analyses.” 
Test Type 
Summary  
Nitazoxanide 500 mg 
(N=XX) 
Placebo 
(N=XX) 
Visit 1 
Day 1 
Visit 5 
Day 28 
Visit 8 
Day 60 
Visit 10 
Day 120 
Visit 12 
Day 180 
Visit 1 
Day 1 
Visit 5 
Day 28 
Visit 8 
Day 60 
Visit 10 
Day 120 
Visit 12 
Day 180 
Norovirus GII 
Number of Subjects with Positive Viral Load 
n/N (x%) 
n/N (x%) 
n/N (x%) 
n/N (x%) 
n/N (x%) 
n/N (x%) 
n/N (x%) n/N (x%) 
n/N (x%) 
n/N (x%) 
Geometric Mean Viral Titer in Positive Subjects (95% 
CI) 
x.x 
(x.x,x.x) 
x.x 
(x.x,x.x) 
x.x 
(x.x,x.x) x.x (x.x,x.x) x.x (x.x,x.x) x.x (x.x,x.x) 
x.x 
(x.x,x.x) 
x.x 
(x.x,x.x) 
x.x 
(x.x,x.x) x.x (x.x,x.x) 
Norovirus GI 
Number of Subjects with Positive Viral Load 
n/N (x%) 
n/N (x%) 
n/N (x%) 
n/N (x%) 
n/N (x%) 
n/N (x%) 
n/N (x%) 
n/N (x%) 
n/N (x%) 
n/N (x%) 
Geometric Mean Viral Titer in Positive Subjects (95% 
CI) 
x.x 
(x.x,x.x) 
x.x 
(x.x,x.x) 
x.x 
(x.x,x.x) x.x (x.x,x.x) x.x (x.x,x.x) x.x (x.x,x.x) 
x.x 
(x.x,x.x) 
x.x 
(x.x,x.x) 
x.x 
(x.x,x.x) x.x (x.x,x.x) 
N = Number of subjects in the mITT population. Subjects will only be included in the denominators if they have a valid result for the specified test type at the given visit. 
n = Number of subjects with positive viral load for the specified test type at the given visit. 


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Table 21: 
Time to First Negative Viral Load by Treatment Group and Duration of Symptoms – Norovirus GII  
Implementation Note: If an estimate is not calculable, insert “NC” in the cell and add a footnote “NC = Not calculable.” If a subgroup has less than 5 
subjects per treatment group, then remove rows and add footnote specifying which group(s) are excluded from analyses. 
Analysis 
Population 
Treatment Group 
Duration of 
Symptoms 
n 
Median Time to First Negative Viral 
Load 
HR 
P-value 
Estimate 
95% CI 
Estimate 
95% CI 
mITT Population 
Nitazoxanide 500 mg 
(N=X) 
Acute 
x 
x.x 
x.x, x.x 
x.xx 
x.xx, x.xx 
-- 
Placebo (N=X) 
x 
x.x 
x.x, x.x 
Nitazoxanide 500 mg 
(N=X) 
Chronic 
x 
x.x 
x.x, x.x 
x.xx 
x.xx, x.xx 
-- 
Placebo (N=X) 
x 
x.x 
x.x, x.x 
Nitazoxanide 500 mg 
(N=X) 
Any Duration 
x 
x.x 
x.x, x.x 
x.xx 
x.xx, x.xx 
0.xxx 
Placebo (N=X) 
x 
x.x 
x.x, x.x 
Implementation note: Repeat for the Per Protocol Population. 
N = Number of subjects in the specified treatment group, duration of symptoms strata, and analysis population with positive Norovirus GII test results at baseline. 
n = Number of subjects with first negative Norovirus GII viral load test result. 
Note: HR is the ratio of the hazard of first negative Norovirus GII viral load in each treatment group estimated from the Cox model. The ratio is Nitazoxanide 500 mg to Placebo. 
HR for the ‘Any Duration’ group is the hazard ratio from the stratified Cox Model. 
P-value calculated using the likelihood ratio test. 
Table with similar format: 
Table 22: 
Time to First Negative Viral Load by Treatment Group and Duration of Symptoms – Norovirus GI  
 


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Table 23: 
Time to First Negative Viral Load by Treatment Group and Duration of Symptoms:  Subgroup Sensitivity Analysis – Norovirus 
GII, mITT Population 
Implementation Note: If an estimate is not calculable, insert “NC” in the cell and add a footnote “NC = Not calculable.” If a subgroup has less than 5 
subjects per treatment group, then remove rows and add footnote specifying which group(s) are excluded from analyses. 
Subgroup 
Treatment Group 
Duration of 
Symptoms 
n 
Median Time to First Negative Viral 
Load 
HR 
P-value 
Estimate 
95% CI 
Estimate 
95% CI 
Additional 
Nitazoxanide 500 mga 
Nitazoxanide 500 mg (N=X) 
Acute 
x 
x.x 
x.x, x.x 
x.xx 
x.xx, x.xx 
-- 
Placebo (N=X) 
x 
x.x 
x.x, x.x 
Nitazoxanide 500 mg (N=X) 
Chronic 
x 
x.x 
x.x, x.x 
x.xx 
x.xx, x.xx 
-- 
Placebo (N=X) 
x 
x.x 
x.x, x.x 
Nitazoxanide 500 mg (N=X) 
Any Duration 
x 
x.x 
x.x, x.x 
x.xx 
x.xx, x.xx 
0.xxx 
Placebo (N=X) 
x 
x.x 
x.x, x.x 
Chromaturiab 
Nitazoxanide 500 mg (N=X) 
Acute 
x 
x.x 
x.x, x.x 
x.xx 
x.xx, x.xx 
-- 
Placebo (N=X) 
x 
x.x 
x.x, x.x 
Nitazoxanide 500 mg (N=X) 
Chronic 
x 
x.x 
x.x, x.x 
x.xx 
x.xx, x.xx 
-- 
Placebo (N=X) 
x 
x.x 
x.x, x.x 
Nitazoxanide 500 mg (N=X) 
Any Duration 
x 
x.x 
x.x, x.x 
x.xx 
x.xx, x.xx 
0.xxx 
Placebo (N=X) 
x 
x.x 
x.x, x.x 
N = Number of subjects in the specified treatment group, subgroup, and duration of symptoms strata with positive GII test results at baseline. 
n = Number of subjects with first negative GII viral load test result. 
a Subjects that took additional Nitazoxanide 500 mg are excluded from the analyses. 
b Subjects with unsolicited self-reported chromaturia (discoloration of urine) are excluded from the analyses. 
Note: HR is the ratio of the hazard of first negative GII viral load in each treatment group estimated from the Cox model. The ratio is Nitazoxanide to Placebo. 
HR for the ‘Any Duration’ group is the hazard ratio from the stratified Cox Model. 
P-value calculated using the likelihood ratio test. 
Table with similar format: 
Table 24: 
Time to First Negative Viral Load by Treatment Group and Duration of Symptoms:  Subgroup Sensitivity Analysis – Norovirus 
GI, mITT Population 


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Table 25: 
Change in Viral Titer between Day 1 and Day 180 by Treatment Group and Duration of Symptoms – Norovirus GII  
[Implementation Note: If a transformation of the dependent variable is used, a footnote in the table will denote which transformation was used in the 
analyses. If the assumptions of ANCOVA cannot be met, only the observed mean, standard deviation and 95% confidence intervals of the unadjusted 
change in viral titer between Day 1 and Day 180 will be reported. If an estimate is not calculable, insert “NC” in the cell and add a footnote “NC = Not 
calculable.” If a subgroup has less than 5 subjects per treatment group, then remove rows and add footnote specifying which group(s) are excluded from 
analyses.] 
Analysis Population 
Treatment Group 
Duration of Symptoms 
n 
Observed 
Mean 
Standard 
Deviation 
Adjusted 
Mean 
Standard 
Error 
95% CI 
P-value 
mITT Population 
Nitazoxanide 500 mg (N=X) 
Acute  
(Baseline Mean = xx.x) 
x 
x.x 
x.x 
x.x 
x.x 
x.x, x.x 
--- 
Placebo (N=X) 
x 
x.x 
x.x 
x.x 
x.x 
x.x, x.x 
Nitazoxanide 500 mg (N=X) 
Chronic 
(Baseline Mean = xx.x) 
x 
x.x 
x.x 
x.x 
x.x 
x.x, x.x 
--- 
Placebo (N=X) 
x 
x.x 
x.x 
x.x 
x.x 
x.x, x.x 
Nitazoxanide 500 mg (N=X) 
Any Duration 
(Baseline Mean = xx.x) 
x 
x.x 
x.x 
x.x 
x.x 
x.x, x.x 
0.xxx 
Placebo (N=X) 
x 
x.x 
x.x 
x.x 
x.x 
x.x, x.x 
Implementation note: Repeat for the Per Protocol Population. 
N = Number of subjects in the specified treatment group, duration of symptoms strata, and analysis population with positive GII test results at baseline. 
n = Number of subjects with Norovirus GII results at Day 1 and Day 180. 
Note: Adjustments based on Baseline Viral Titer. 
P-value is the test of between-treatment differences for change in viral titer from Day 1 to Day 180. 
Table with similar format: 
Table 26: 
Change in Viral Titer between Day 1 and Day 180 by Treatment Group and Duration of Symptoms – Norovirus GI  


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Table 27: 
Change in Viral Titer between Day 1 and Day 180 by Treatment Group and Duration of Symptoms: Subgroup Sensitivity 
Analysis – Norovirus GII, mITT Population 
 
[Implementation Note: If a transformation of the dependent variable is used, a footnote in the table will denote which transformation was used in the 
analyses. If the assumptions of ANCOVA cannot be met, only the observed mean, standard deviation and 95% confidence intervals of the unadjusted 
change in viral titer between Day 1 and Day 180 will be reported. If an estimate is not calculable, insert “NC” in the cell and add a footnote “NC = Not 
calculable.” If a subgroup has less than 5 subjects per treatment group, then remove rows and add footnote specifying which group(s) are excluded from 
analyses.] 
Subgroup 
Treatment Group 
Duration of Symptoms 
n 
Observed 
Mean 
Standard 
Deviation 
Adjusted 
Mean 
Standard 
Error 
95% CI 
P-value 
Additional 
Nitazoxanide 500 
mga 
Nitazoxanide 500 mg (N=X) 
Acute 
(Baseline Mean = xx.x) 
x 
x.x 
x.x 
x.x 
x.x 
x.x, x.x 
--- 
Placebo (N=X) 
x 
x.x 
x.x 
x.x 
x.x 
x.x, x.x 
Nitazoxanide 500 mg (N=X) 
Chronic 
(Baseline Mean = xx.x) 
x 
x.x 
x.x 
x.x 
x.x 
x.x, x.x 
--- 
Placebo (N=X) 
x 
x.x 
x.x 
x.x 
x.x 
x.x, x.x 
Nitazoxanide 500 mg (N=X) 
Any Duration 
(Baseline Mean = xx.x) 
x 
x.x 
x.x 
x.x 
x.x 
x.x, x.x 
0.xxx 
Placebo (N=X) 
x 
x.x 
x.x 
x.x 
x.x 
x.x, x.x 
Chromaturiab 
Nitazoxanide 500 mg (N=X) 
Acute 
(Baseline Mean = xx.x) 
x 
x.x 
x.x 
x.x 
x.x 
x.x, x.x 
--- 
Placebo (N=X) 
x 
x.x 
x.x 
x.x 
x.x 
x.x, x.x 
Nitazoxanide 500 mg (N=X) 
Chronic 
(Baseline Mean = xx.x) 
x 
x.x 
x.x 
x.x 
x.x 
x.x, x.x 
--- 
Placebo (N=X) 
x 
x.x 
x.x 
x.x 
x.x 
x.x, x.x 
Nitazoxanide 500 mg (N=X) 
Any Duration 
(Baseline Mean = xx.x) 
x 
x.x 
x.x 
x.x 
x.x 
x.x, x.x 
0.xxx 
Placebo (N=X) 
x 
x.x 
x.x 
x.x 
x.x 
x.x, x.x 
N = Number of subjects in the specified treatment group, subgroup, and duration of symptoms strata with positive GII test results at baseline. 
n = Number of subjects with Norovirus GII results at Day 1 and Day 180. 
a Subjects that took additional Nitazoxanide 500 mg are excluded from the analyses. 
b Subjects with unsolicited self-reported chromaturia (discoloration of urine) are excluded from the analyses. 
Note: Adjustments based on Baseline Viral Titer Mean = xx.xx. 
P-value is the test of between-treatment differences for change in viral titer from Day 1 to Day 180 for each subgroup. 
Table with similar format: 
Table 28: 
Change in Viral Titer between Day 1 and Day 180 by Treatment Group and Duration of Symptoms: Subgroup Sensitivity 
Analysis – Norovirus GI, mITT Population 


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Table 29: 
Exploratory Time to Event by Treatment Group and Duration of Symptoms – mITT Population 
Implementation Note: If an estimate is not calculable, insert “NC” in the cell and add a footnote “NC = Not calculable.” If a subgroup has less than 5 
subjects per treatment group, then remove rows and add footnote specifying which group(s) are excluded from analyses. 
Event 
Treatment Group 
Duration of 
Symptoms 
n 
Median Time to Event 
HR 
P-value 
Estimate 
95% CI 
Estimate 
95% CI 
Clinical 
Improvement  
(Day 28) 
Nitazoxanide 500 mg (N=X) 
Acute 
x 
x.x 
x.x, x.x 
x.xx 
x.xx, x.xx 
-- 
Placebo (N=X) 
x 
x.x 
x.x, x.x 
Nitazoxanide 500 mg (N=X) 
Chronic 
x 
x.x 
x.x, x.x 
x.xx 
x.xx, x.xx 
-- 
Placebo (N=X) 
x 
x.x 
x.x, x.x 
Nitazoxanide 500 mg (N=X) 
Any Duration 
x 
x.x 
x.x, x.x 
x.xx 
x.xx, x.xx 
0.xxx 
Placebo (N=X) 
x 
x.x 
x.x, x.x 
Clinical 
Improvement  
(Day 180) 
Nitazoxanide 500 mg (N=X) 
Acute 
x 
x.x 
x.x, x.x 
x.xx 
x.xx, x.xx 
-- 
Placebo (N=X) 
x 
x.x 
x.x, x.x 
Nitazoxanide 500 mg (N=X) 
Chronic 
x 
x.x 
x.x, x.x 
x.xx 
x.xx, x.xx 
-- 
Placebo (N=X) 
x 
x.x 
x.x, x.x 
Nitazoxanide 500 mg (N=X) 
Any Duration 
x 
x.x 
x.x, x.x 
x.xx 
x.xx, x.xx 
0.xxx 
Placebo (N=X) 
x 
x.x 
x.x, x.x 
Repeat for Cessation of Vomiting, No Loss of Appetite, Cessation of Diarrhea, and 50% Reduction in Antimotility Agents 
N = Number of subjects in the specified treatment group, duration of symptoms strata, and analysis population. 
n = Number of subjects with initial clinical resolution of symptoms. 
Note: HR is the ratio of the hazard of the given event in each treatment group estimated from the Cox model. The ratio is Nitazoxanide 500 mg to Placebo. 
HR for the ‘Any Duration’ group is the hazard ratio from the stratified Cox Model. 
P-value calculated using the likelihood ratio test. 


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Table 30: 
Exploratory Summary Statistics of Clinical Improvement Measures by Treatment Group – mITT Population 
Clinical Improvement Measure 
Statistic 
Nitazoxanide 500 mg 
(N=X) 
Placebo 
(N=X) 
Days of Diarrhea (Day 28) 
Mean  
x.x  
x.x  
Median  
x.x  
x.x  
Standard Deviation  
x.x  
x.x  
Minimum  
X 
x 
Maximum 
X 
x 
P-valuea 
 
0.xxx 
Days of Diarrhea (Day 180) 
Mean  
x.x  
x.x  
Median  
x.x  
x.x  
Standard Deviation  
x.x  
x.x  
Minimum  
X 
x 
Maximum 
X 
x 
P-valuea 
 
0.xxx 
Implementation note: Repeat for Number of Type 6 or 7 stools and Days of IV Hydration/TPN Therapy 
N = Number of subjects in the specified treatment group and analysis population. 
P-value is based on Wilcoxon-Mann-Whitney exact rank sum test. 


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Table 31: 
Patient-Reported Quality of Life by EuroQOL-5 Dimension and Study Day – Nitazoxanide 500 mg, mITT Population 
EuroQOL-5 Dimension 
Study Day 
Total 
Day 1 
Day 28 
Day 60 
Day 120 
Day 180 
Mobility 
No problems 
n/N (x%) 
n/N (x%) 
n/N (x%) 
n/N (x%) 
n/N (x%) 
n/N (x%) 
Problems 
n/N (x%) 
n/N (x%) 
n/N (x%) 
n/N (x%) 
n/N (x%) 
n/N (x%) 
Self-Care 
No problems 
n/N (x%) 
n/N (x%) 
n/N (x%) 
n/N (x%) 
n/N (x%) 
n/N (x%) 
Problems 
n/N (x%) 
n/N (x%) 
n/N (x%) 
n/N (x%) 
n/N (x%) 
n/N (x%) 
Usual Activities 
No problems 
n/N (x%) 
n/N (x%) 
n/N (x%) 
n/N (x%) 
n/N (x%) 
n/N (x%) 
Problems 
n/N (x%) 
n/N (x%) 
n/N (x%) 
n/N (x%) 
n/N (x%) 
n/N (x%) 
Pain/Discomfort 
No problems 
n/N (x%) 
n/N (x%) 
n/N (x%) 
n/N (x%) 
n/N (x%) 
n/N (x%) 
Problems 
n/N (x%) 
n/N (x%) 
n/N (x%) 
n/N (x%) 
n/N (x%) 
n/N (x%) 
Anxiety/Depression 
No problems 
n/N (x%) 
n/N (x%) 
n/N (x%) 
n/N (x%) 
n/N (x%) 
n/N (x%) 
Problems 
n/N (x%) 
n/N (x%) 
n/N (x%) 
n/N (x%) 
n/N (x%) 
n/N (x%) 
Note: Number of questions answered as ‘No Problems’ (level 1) or ‘Problems’ (levels 2 or 3) for each EuroQOL-5 dimension at each given study day over the number of questions that were completed 
for the EuroQOL-5 dimension for the given study day. 
Table with similar format: 
Table 32: 
Patient-Reported Quality of Life by EuroQOL-5 Dimension and Study Day – Placebo, mITT Population 


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Table 33: 
Change in Patient-Reported Measures from Baseline to Day 28, 60, 120, and 180 by Treatment Group – mITT Population 
[Implementation Note: If a transformation of the dependent variable is used, a footnote in the table will denote which transformation was used in the 
analyses for each patient-reported measure. If the assumptions of ANCOVA cannot be met, only the observed mean, standard deviation and 95% 
confidence intervals of the unadjusted change in patient reported measures will be reported.] 
Patient-Reported Measure 
Treatment Group 
Study Day 
Observed 
Mean 
Standard 
Deviation 
Adjusted 
Mean 
Standard 
Error 
95% CI 
p-value 
IBSQOL Quality of Life   
(Baseline QOL Mean = xx.xx) 
Nitazoxanide 500 mg (N =X) 
Day 28 
x.x 
x.x 
x.x 
x.x 
x.x, x.x 
--- 
Placebo (N=X) 
x.x 
x.x 
x.x 
x.x 
x.x, x.x 
Nitazoxanide 500 mg (N =X) 
Day 60 
x.x 
x.x 
x.x 
x.x 
x.x, x.x 
--- 
Placebo (N=X) 
x.x 
x.x 
x.x 
x.x 
x.x, x.x 
Nitazoxanide 500 mg (N =X) 
Day 120 
x.x 
x.x 
x.x 
x.x 
x.x, x.x 
--- 
Placebo (N=X) 
x.x 
x.x 
x.x 
x.x 
x.x, x.x 
Nitazoxanide 500 mg (N =X) 
Day 180 
x.x 
x.x 
x.x 
x.x 
x.x, x.x 
0.xxx 
Placebo (N=X) 
x.x 
x.x 
x.x 
x.x 
x.x, x.x 
Implementation note: Repeat for Physical Function, Depression, Anxiety, Fatigue, GI Symptoms: Diarrhea, GI Symptoms: Nausea, GI Symptoms: Fecal Incontinence, GI Symptoms: Belly Pain. 
N = Number of subjects in the specified treatment group and analysis population with patient-reported measure on the given study day. 
Note: Adjustments based on baseline mean values for each patient-reported measure. 
P-value is the test of between-treatment differences for change in each patient-reported measure from baseline to Day 180. 


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Table 34: 
Time to Initial Clinical Resolution by Treatment Group and Co-Pathogen – mITT Population 
Implementation Note: If an estimate is not calculable, insert “NC” in the cell and add a footnote “NC = Not calculable. If a subgroup has less than 5 
subjects per treatment group, then remove rows and add footnote specifying which group(s) are excluded from analyses.” 
Treatment Group 
Co-Pathogens 
n 
Median Time to Initial Clinical 
Resolution 
HR 
P-value 
Estimate 
95% CI 
Estimate 
95% CI 
Nitazoxanide 500 mg (N=X) 
Present 
x 
x.x 
x.x, x.x 
x.xx 
x.xx, x.xx 
-- 
Placebo (N=X) 
x 
x.x 
x.x, x.x 
Nitazoxanide 500 mg (N=X) 
Absent 
x 
x.x 
x.x, x.x 
x.xx 
x.xx, x.xx 
-- 
Placebo (N=X) 
x 
x.x 
x.x, x.x 
Nitazoxanide 500 mg (N=X) 
Any Status 
x 
x.x 
x.x, x.x 
x.xx 
x.xx, x.xx 
0.xxx 
Placebo (N=X) 
x 
x.x 
x.x, x.x 
N = Number of subjects in the specified treatment group, co-pathogen status strata, and analysis population. 
n = Number of subjects with initial clinical resolution of symptoms. 
Note: HR is the ratio of the hazard of initial clinical resolution in each treatment group estimated from the Cox model. The ratio is Nitazoxanide 500 mg to Placebo. 
HR for the ‘Any Status’ group is the hazard ratio from the stratified Cox Model. 
P-value calculated using the likelihood ratio test. 


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Table 35: 
Time to First Negative Viral Load by Treatment Group and Co-Pathogen – Norovirus GII, mITT Population 
Implementation Note: If an estimate is not calculable, insert “NC” in the cell and add a footnote “NC = Not calculable.” If a subgroup has less than 5 
subjects per treatment group, then remove rows and add footnote specifying which group(s) are excluded from analyses. 
Treatment Group 
Co-Pathogens 
n 
Median Time to First Negative Viral 
Load 
HR 
P-value 
Estimate 
95% CI 
Estimate 
95% CI 
Nitazoxanide 500 mg (N=X) 
Present 
x 
x.x 
x.x, x.x 
x.xx 
x.xx, x.xx 
-- 
Placebo (N=X) 
x 
x.x 
x.x, x.x 
Nitazoxanide 500 mg (N=X) 
Absent 
x 
x.x 
x.x, x.x 
x.xx 
x.xx, x.xx 
-- 
Placebo (N=X) 
x 
x.x 
x.x, x.x 
Nitazoxanide 500 mg (N=X) 
Any Status 
x 
x.x 
x.x, x.x 
x.xx 
x.xx, x.xx 
0.xxx 
Placebo (N=X) 
x 
x.x 
x.x, x.x 
N = Number of subjects in the specified treatment group, co-pathogen strata, and analysis population with positive GII test results at baseline. 
n = Number of subjects with first negative GII viral load test result. 
Note: HR is the ratio of the hazard of first negative GII viral load in each treatment group estimated from the Cox model. The ratio is Nitazoxanide 500 mg to Placebo. 
HR for the ‘Any Status’ group is the hazard ratio from the stratified Cox Model. 
P-value calculated using the likelihood ratio test. 
Table with similar format: 
Table 36: 
Time to First Negative Viral Load by Treatment Group and Co-Pathogens – Norovirus GI, mITT Population 


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Table 37: 
Summary Statistics of Norovirus-Specific Serum and Stool IgA, IgM, and IgG Results by Study Day and Treatment Group – 
Immunogenicity Population 
Assay 
Study Day 
Statistic 
Nitazoxanide 500 mg 
(N=X) 
Placebo 
(N=X) 
NoV-Specific Serum IgA 
Day 1 
n 
x 
x 
GMT (95% CI) 
x.x (x.x, x.x) 
x.x (x.x, x.x)  
Median  
x.x  
x.x  
Minimum  
x 
x 
Maximum 
x 
x 
Day 28 
n 
x 
x 
GMT (95% CI) 
x.x (x.x, x.x) 
x.x (x.x, x.x)  
Median  
x.x  
x.x  
Minimum  
x 
x 
Maximum 
x 
x 
Day 60 
n 
x 
x 
GMT (95% CI) 
x.x (x.x, x.x) 
x.x (x.x, x.x)  
Median  
x.x  
x.x  
Minimum  
x 
x 
Maximum 
x 
x 
Implementation note: Repeat for NoV-Specific Serum IgG, Total Serum IgG, NoV-Specific/Total Serum IgG, NoV-Specific Serum IgM, NoV-Specific Stool IgA, NoV-Specific Stool IgG, and NoV-
Specific Stool IgM. 
N = Number of subjects in the specified treatment group and analysis population. 
n = Number of subjects with valid results at the given timepoint for the given assay. 


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Table 38: 
Norovirus-Specific Serum and Stool IgA, IgM, and IgG Results by Study Day and Treatment Group – Immunogenicity 
Population 
Assay 
Study Day 
Statistic 
Nitazoxanide 500 mg 
(N=X) 
Placebo 
(N=X) 
NoV-Specific Serum IgA 
Day 28 
n 
x 
x 
GMFR (95% CI) 
x.x (x.x, x.x) 
x.x (x.x, x.x) 
Proportion Seroresponders (95% CI)a 
x.x (x.x, x.x) 
x.x (x.x, x.x) 
Day 60 
n 
x 
x 
GMFR (95% CI) 
x.x (x.x, x.x) 
x.x (x.x, x.x) 
Proportion Seroresponders (95% CI)a 
x.x (x.x, x.x) 
x.x (x.x, x.x) 
Implementation note: Repeat for NoV-Specific Serum IgG, Total Serum IgG, NoV-Specific/Total Serum IgG, NoV-Specific Serum IgM, NoV-Specific Stool IgA, NoV-Specific Stool IgG, and NoV-
Specific Stool IgM. 
N = Number of subjects in the specified treatment group and analysis population. 
n = Number of subjects with valid results at the given timepoint for the given assay.  
a95% CIs are Wilson score two-sided confidence intervals. 


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Table 39: 
Change in Norovirus-Specific Immunoglobulin Assays between Day 1 and Study Day 28 and 60 by Treatment Group – 
Immunogenicity Population 
[Implementation Note: If a transformation of the dependent variable is used, a footnote in the table will denote which transformation was used in the 
analyses. If the assumptions of ANCOVA cannot be met, only the observed mean, standard deviation and 95% confidence intervals of the unadjusted 
change in assays between Day 1 and Day 28 and Day 1 and Day 60 will be reported.] 
Norovirus-Specific 
Assay 
Treatment Group 
Study Day 
Observed 
Mean 
Standard 
Deviation 
Adjusted Mean 
Standard 
Error 
95% CI 
P-value 
Serum IgA (Baseline 
Serum IgA Mean = 
xx.xx) 
Nitazoxanide 500 mg (N=X) 
Day 28 
x.x 
x.x 
x.x 
x.x 
x.x, x.x 
0.xxx 
Placebo (N=X) 
x.x 
x.x 
x.x 
x.x 
x.x, x.x 
Nitazoxanide 500 mg (N=X) 
Day 60 
x.x 
x.x 
x.x 
x.x 
x.x, x.x 
0.xxx 
Placebo (N=X) 
x.x 
x.x 
x.x 
x.x 
x.x, x.x 
Implementation note: Repeat for Serum IgG, Serum IgM, Stool IgA, Stool IgG, and Stool IgM. 
N = Number of subjects in the specified treatment group and analysis population. 
Note: Adjustments based on baseline mean values for each assay type. 
P-value is the test of between-treatment differences for change in each assay type from Day 1 to the given study day. 


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Table 40: 
Mixed Effects Model Coefficient Estimates – Norovirus-Specific Serum IgA, Immunogenicity Population 
[Implementation Note: If a transformation is used, a footnote in the table will denote which transformation was used in the analyses. If the relationship 
between Norovirus-specific serum IgA and time is linear, the coefficients listed in the table will only include β0 - β3 and the descriptions of the 
coefficients will be “Intercept”, “Slope”, “Intercept * Treatment”, and “Slope * Treatment”, respectively.] 
Coefficient 
Estimate 
Standard Error 
P-value 
β0: Intercept 
 
 
 
β1: Treatment 
 
 
 
β2: Day 28 
 
 
 
β3: Day 28 * Treatment 
 
 
 
β4: Day 60 
 
 
 
β5: Day 60 * Treatment 
 
 
 
Tables with similar format: 
Table 41: 
Mixed Effects Model Coefficient Estimates – Norovirus-Specific Stool IgA, Immunogenicity Population 
Table 42: 
Mixed Effects Model Coefficient Estimates – Norovirus-Specific Serum IgG, Immunogenicity Population 
Table 43: 
Mixed Effects Model Coefficient Estimates – Norovirus-Specific Stool IgG, Immunogenicity Population 
Table 44: 
Mixed Effects Model Coefficient Estimates – Norovirus-Specific Serum IgM, Immunogenicity Population 
Table 45: 
Mixed Effects Model Coefficient Estimates – Norovirus-Specific Stool IgM, Immunogenicity Population 


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Table 46: 
Correlation of Change in T-Cell Subset from Day 1 to Day 180 vs Clinical Resolution of Symptoms and Negative PCR by 
Treatment Group – Immunogenicity Population 
T-Cell Subset 
First Day of Clinical Resolution 
First Day with Negative PCR 
Pearson Correlation (95% CI) 
P-value 
Pearson Correlation (95% CI) 
P-value 
Nitazoxanide 500 mg 
Placebo 
Nitazoxanide 500 mg 
Placebo 
Total Lymphocyte Count 
x.xx (x.xxx, x.xxx) 
x.xx (x.xxx, x.xxx) 
0.xxx 
x.xx (x.xxx, x.xxx) 
x.xx (x.xxx, x.xxx) 
0.xxx 
CD3 + Cells 
x.xx (x.xxx, x.xxx) 
x.xx (x.xxx, x.xxx) 
0.xxx 
x.xx (x.xxx, x.xxx) 
x.xx (x.xxx, x.xxx) 
0.xxx 
CD3+ Cells/Lymphocytes 
x.xx (x.xxx, x.xxx) 
x.xx (x.xxx, x.xxx) 
0.xxx 
x.xx (x.xxx, x.xxx) 
x.xx (x.xxx, x.xxx) 
0.xxx 
CD4+ Cells 
x.xx (x.xxx, x.xxx) 
x.xx (x.xxx, x.xxx) 
0.xxx 
x.xx (x.xxx, x.xxx) 
x.xx (x.xxx, x.xxx) 
0.xxx 
CD4+ Cells/Lymphocytes 
x.xx (x.xxx, x.xxx) 
x.xx (x.xxx, x.xxx) 
0.xxx 
x.xx (x.xxx, x.xxx) 
x.xx (x.xxx, x.xxx) 
0.xxx 
CD8+ Cells 
x.xx (x.xxx, x.xxx) 
x.xx (x.xxx, x.xxx) 
0.xxx 
x.xx (x.xxx, x.xxx) 
x.xx (x.xxx, x.xxx) 
0.xxx 
CD8+ Cells/Lymphocytes 
x.xx (x.xxx, x.xxx) 
x.xx (x.xxx, x.xxx) 
0.xxx 
x.xx (x.xxx, x.xxx) 
x.xx (x.xxx, x.xxx) 
0.xxx 


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Table 47: 
Correlation of Change in Norovirus-Specific Immunoglobulin Assays vs Clinical Resolution of Symptoms and Negative PCR by 
Study Day and Treatment Group – Immunogenicity Population 
Norovirus-Specific Assay 
First Day of Clinical Resolution 
First Day with Negative PCR 
Pearson Correlation (95% CI) 
P-value 
Pearson Correlation (95% CI) 
P-value 
Nitazoxanide 500 mg 
Placebo 
Nitazoxanide 500 mg 
Placebo 
Serum IgA (Day 28) 
x.xx (x.xxx, x.xxx) 
x.xx (x.xxx, x.xxx) 
0.xxx 
x.xx (x.xxx, x.xxx) 
x.xx (x.xxx, x.xxx) 
0.xxx 
Serum IgA (Day 60) 
x.xx (x.xxx, x.xxx) 
x.xx (x.xxx, x.xxx) 
0.xxx 
x.xx (x.xxx, x.xxx) 
x.xx (x.xxx, x.xxx) 
0.xxx 
Stool IgA (Day 28) 
x.xx (x.xxx, x.xxx) 
x.xx (x.xxx, x.xxx) 
0.xxx 
x.xx (x.xxx, x.xxx) 
x.xx (x.xxx, x.xxx) 
0.xxx 
Stool IgA (Day 60) 
x.xx (x.xxx, x.xxx) 
x.xx (x.xxx, x.xxx) 
0.xxx 
x.xx (x.xxx, x.xxx) 
x.xx (x.xxx, x.xxx) 
0.xxx 
Implementation note: Repeat for Serum IgG (Day 28), Serum IgG (Day 60), Stool IgG (Day 28), Stool IgG (Day 60), Serum IgM (Day 28), Serum IgM (Day 60), Stool IgM (Day 28), and Stool IgM 
(Day 60). 
Note: Change in Norovirus-specific assay is the change Day 1 to the given study day (Day 28 or Day 60). 


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Table 48: 
Time to Initial Clinical Resolution by Test, Treatment Group and Secretor Status – mITT Population 
Implementation Note: If an estimate is not calculable, insert “NC” in the cell and add a footnote “NC = Not calculable.” If a subgroup has less than 5 
subjects per treatment group, then remove rows and add footnote specifying which group(s) are excluded from analyses. 
Test 
Treatment Group 
Secretor Status 
n 
Median Time to Initial Clinical 
Resolution 
HR 
P-value 
Estimate 
95% CI 
Estimate 
95% CI 
Genotype 
Nitazoxanide 500 mg 
(N=X) 
Secretor 
x 
x.x 
x.x, x.x 
x.xx 
x.xx, x.xx 
-- 
Placebo (N=X) 
x 
x.x 
x.x, x.x 
Nitazoxanide 500 mg 
(N=X) 
Non-Secretor 
x 
x.x 
x.x, x.x 
x.xx 
x.xx, x.xx 
-- 
Placebo (N=X) 
x 
x.x 
x.x, x.x 
Nitazoxanide 500 mg 
(N=X) 
Any Status 
x 
x.x 
x.x, x.x 
x.xx 
x.xx, x.xx 
0.xxx 
Placebo (N=X) 
x 
x.x 
x.x, x.x 
Phenotype 
Nitazoxanide 500 mg 
(N=X) 
Secretor 
x 
x.x 
x.x, x.x 
x.xx 
x.xx, x.xx 
-- 
Placebo (N=X) 
x 
x.x 
x.x, x.x 
Nitazoxanide 500 mg 
(N=X) 
Non-Secretor 
x 
x.x 
x.x, x.x 
x.xx 
x.xx, x.xx 
-- 
Placebo (N=X) 
x 
x.x 
x.x, x.x 
Nitazoxanide 500 mg 
(N=X) 
Any Status 
x 
x.x 
x.x, x.x 
x.xx 
x.xx, x.xx 
0.xxx 
Placebo (N=X) 
x 
x.x 
x.x, x.x 
N = Number of subjects in the specified treatment group and secretor status strata with valid results for the given test type. 
n = Number of subjects with initial clinical resolution of symptoms. 
Note: HR is the ratio of the hazard of initial clinical resolution in each treatment group estimated from the Cox model. The ratio is Nitazoxanide 500 mg to Placebo. 
HR for the ‘Any Status’ group is the hazard ratio from the stratified Cox Model. 
P-value calculated using the likelihood ratio test. 


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14.3 
Safety Data 
14.3.1 Displays of Adverse Events 
Table 49: 
Overall Summary of Adverse Events 
 
Nitazoxanide 500 mg 
(N = X) 
Placebo 
(N = X) 
All Subjects 
(N = X) 
Subjectsa with 
n 
% 
n 
% 
n 
% 
 
 
 
 
 
 
 
At least one unsolicited adverse event 
x 
x 
x 
x 
x 
x 
At least one unsolicited non-serious adverse event through 60 days 
x 
x 
x 
x 
x 
x 
 
 
 
 
 
 
 
At least one related unsolicited adverse event 
x 
x 
x 
x 
x 
x 
     Mild (Grade 1) 
x 
x 
x 
x 
x 
x 
     Moderate (Grade 2)  
x 
x 
x 
x 
x 
x 
     Severe (Grade 3)  
x 
x 
x 
x 
x 
x 
     Not yet assessed 
 
 
 
 
 
 
 
 
 
 
 
 
 
At least one severe (Grade 3) unsolicited adverse event 
x 
x 
x 
x 
x 
x 
     Related  
x 
x 
x 
x 
x 
x 
     Unrelated 
x 
x 
x 
x 
x 
x 
 
 
 
 
 
 
 
At least one serious adverse eventb 
x 
x 
x 
x 
x 
x 
At least one serious adverse event through 60 daysb 
x 
x 
x 
x 
x 
x 
At least one related, serious adverse event 
x 
x 
x 
x 
x 
x 
At least one adverse event leading to early terminationc  
x 
x 
x 
x 
x 
x 
 
 
 
 
 
 
 
At least one laboratory adverse eventd through 60 days 
x 
x 
x 
x 
x 
x 
 
 
 
 
 
 
 
At least one hospitalization 
x 
x 
x 
x 
x 
x 
At least one hospitalization through 60 days 
x 
x 
x 
x 
x 
x 
N = Number of subjects in the Safety Population 
a Subjects are counted once for each category regardless of the number of events. 
b A listing of Serious Adverse Events is included in Section 14.3.2. 
c As reported on the Adverse Event eCRF. 
d Laboratory adverse events include WBC, Hemoglobin, Platelet count, Creatinine, Alkaline Phosphatase, ALT, AST, BUN, and Bilirubin. 


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Table 50: 
Subject-Level Rates of Adverse Events through Day 60 and Differences between Treatment Groups – Safety Population 
Subjectsa with at least one: 
Nitazoxanide 500 mg 
(N=X) 
Placebo 
(N = X) 
Differenceb 
p-valuec 
n 
% 
n 
% 
Estimate 
95% CI 
Unsolicited Non-Serious Adverse Event 
x 
x 
x 
x 
x.xx 
(x.xx,x.xx) 
0.xxxx 
Laboratory Adverse Eventd 
 
 
 
 
 
 
 
Serious Adverse Event 
 
 
 
 
 
 
 
Hospitalization 
 
 
 
 
 
 
 
N = Number of subjects in the Safety Population. 
a Subjects are counted once for each category regardless of the number of events. 
b Difference is the difference in proportions of subjects with at least one adverse event in the specified category between Nitazoxanide 500 mg and Placebo. 
c P-value is based on Barnard’s exact test at the 5% two-sided level of significance. 
d Laboratory adverse events include WBC, Hemoglobin, Platelet count, Creatinine, Alkaline Phosphatase, ALT, AST, BUN, and Bilirubin. 


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Table 51: 
Subject-Level Rates of Adverse Events through Day 60 and Differences between Treatment Groups: Chromaturia Sensitivity 
Analysis – Safety Population 
Subjectsa with at least one: 
Nitazoxanide 500 mg  
(N=X) 
Placebo 
(N = X) 
Differenceb 
p-valuec 
n 
% 
n 
% 
Estimate 
95% CI 
Unsolicited Non-Serious Adverse Event 
x 
x 
x 
x 
x.xx 
(x.xx,x.xx) 
0.xxxx 
Laboratory Adverse Eventd 
 
 
 
 
 
 
 
Serious Adverse Event 
 
 
 
 
 
 
 
Hospitalization 
 
 
 
 
 
 
 
N = Number of subjects in the Safety Population who do not report chromaturia. 
a Subjects are counted once for each category regardless of the number of events. 
b Difference is the difference in proportions of subjects with at least one adverse event in the specified category between Nitazoxanide 500 mg and Placebo. 
c P-value is based on Barnard’s exact test at the 5% two-sided level of significance.  
d Laboratory adverse events include WBC, Hemoglobin, Platelet count, Creatinine, Alkaline Phosphatase, ALT, AST, BUN, and Bilirubin. 


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Table 52: 
Adverse Events Occurring in 5% of Subjects in Any Treatment Group by MedDRA Preferred Term, System Organ Class, and 
Treatment Group – Safety Population 
MedDRA Preferred Term 
MedDRA System Organ Class 
Nitazoxanide 500 mg  
(N=X) 
Placebo 
(N=X) 
All Subjects 
(N=X) 
 
 
n 
% 
Events 
n 
% 
Events 
n 
% 
Events 
Serious Adverse Events 
All  
All 
x 
x 
x 
x 
x 
x 
x 
x 
x 
PT1 
SOC1 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Etc. 
Etc. 
 
 
 
 
 
 
 
 
 
Other (Non-serious) Adverse Events 
All  
All 
x 
x 
x 
x 
x 
x 
x 
x 
x 
PT1 
SOC1 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Etc 
Etc 
 
 
 
 
 
 
 
 
 
N = number of subjects in the Safety Population (number of subjects at risk).  
n= number of subjects reporting event.  
Events= total frequency of events reported. 


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Table 53: 
Summary of Unsolicited Adverse Events by MedDRA System Organ Class, Preferred Term, and Study Phase – Nitazoxanide 500 
mg, Safety Population 
MedDRA 
System Organ 
Class 
MedDRA 
Preferred Term 
Day 1 - 28 
Treatment Phase 
(N=X) 
Day 29 - 60 
Longitudinal Phase 
(N=X) 
Any Time  
(N=X) 
n 
% 
95% CI 
Events 
n 
% 
95% CI 
Events 
n 
% 
95% CI 
Events 
Any SOC 
Any PT 
x 
xx 
xx, xx 
x 
x 
xx 
xx, xx 
x 
x 
xx 
xx, xx 
x 
[SOC 1] 
Any PT 
 
 
 
 
 
 
 
 
 
 
 
 
 
[PT 1] 
 
 
 
 
 
 
 
 
 
 
 
 
 
[PT 2] 
 
 
 
 
 
 
 
 
 
 
 
 
[SOC 2] 
Any PT 
 
 
 
 
 
 
 
 
 
 
 
 
 
[PT 1] 
 
 
 
 
 
 
 
 
 
 
 
 
 
[PT 2] 
 
 
 
 
 
 
 
 
 
 
 
 
N = Number of subjects in the Safety Population. 
n = number of subjects reporting event. A subject is only counted once per PT/time point. 
Events = total frequency of events reported.  
Note: 95% CIs are Wilson score two-sided confidence intervals. 
Tables with similar format: 
Table 54: 
Summary of Unsolicited Adverse Events by MedDRA System Organ Class, Preferred Term, and Study Phase – Placebo, Safety 
Population 
Table 55: 
Summary of Unsolicited Adverse Events by MedDRA System Organ Class, Preferred Term, and Study Phase – All Subjects, 
Safety Population 


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Table 56: 
Unsolicited Adverse Events by MedDRA System Organ Class and Preferred Term, Maximum Severity, Relationship, and 
Treatment Group – Nitazoxanide 500 mg, Safety Population, N=x 
MedDRA System Organ Class 
MedDRA Preferred Term 
Any Incidence 
Severity 
Relationship to Treatment 
Mild 
Moderate 
Severe 
Related 
Not Related 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
Any SOC 
Any PT 
x  
xx 
x  
xx 
x  
xx 
x  
xx 
x  
xx 
x  
xx 
SOC 1 
PT 1 
x  
xx 
x  
xx 
x  
xx 
x  
xx 
x  
xx 
x  
xx 
 
PT 2 
x  
xx 
x  
xx 
x  
xx 
x  
xx 
x  
xx 
x  
xx 
N = Number of subjects in the Safety Population. 
n = number of subjects reporting event. A subject is only counted once per PT/time point. 
Tables with similar format: 
Table 57: 
Unsolicited Adverse Events by MedDRA System Organ Class and Preferred Term, Maximum Severity, Relationship, and 
Treatment Group – Placebo, Safety Population, N=x 
Table 58: 
Unsolicited Adverse Events by MedDRA System Organ Class and Preferred Term, Maximum Severity, Relationship, and 
Treatment Group – All Subjects, Safety Population, N=x 
 


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Table 59: 
Related Unsolicited Adverse Events During Treatment Phase (Days 1 – 28) by MedDRA System Organ Class, Preferred Term, 
and Treatment Group – Safety Population 
MedDRA System Organ 
Class 
MedDRA 
Preferred Term 
Nitazoxanide 500 mg 
 (N = X) 
Placebo 
 (N = X) 
All Subjects 
(N = X) 
n 
% 
Events 
n 
% 
Events 
n 
% 
Events 
Any SOC 
Any PT 
x 
xx 
x 
x 
xx 
x 
x 
xx 
x 
[SOC 1] 
Any PT 
 
 
 
 
 
 
 
 
 
 
[PT 1] 
 
 
 
 
 
 
 
 
 
 
[PT 2] 
 
 
 
 
 
 
 
 
 
[SOC 2] 
Any PT 
x 
xx 
x 
x 
xx 
x 
x 
xx 
x 
 
[PT 1] 
 
 
 
 
 
 
 
 
 
 
[PT 2] 
 
 
 
 
 
 
 
 
 
N = Number of subjects in the Safety Population. 
n = number of subjects reporting event. A subject is only counted once per PT/time point. 
Events = total frequency of events reported. 


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14.3.2 Listing of Deaths, Other Serious and Significant Adverse Events 
Table 60: 
Listing of Serious Adverse Events 
[Implementation Note: This listing is included in the table shells document, as it is included in the body of the CSR. If the event is ongoing (no stop 
date), indicate “ongoing” for the “Duration”. If more than one reason is selected for the reason reported as an SAE, list all reasons in the column, 
separated by a comma. In the “If Not Related, Alternate Etiology” column, merge the 2 data fields for collecting alternate etiology, separate by a colon. 
If there are no comments for an event, populate ‘Comments’ row with ‘None’. Add columns for MedDRA HLT or LLT depending on halting criteria or 
other study needs. In the CSR, Subject ID should be USUBJID (not PATID) for purposes of de-identification. Listing should be sorted by Subject ID, 
Associated with Dose No., and No. of Days Post Associated Dose.] 
Adverse 
Event 
No. of Days 
Post First 
Dose 
(Duration) 
No. of Days 
Post First Dose 
the Event 
Became 
Serious 
Reason 
Reported 
as an SAE 
Severity 
Relationship 
to Study 
Treatment 
If Not Related, 
Alternative 
Etiology 
Action Taken 
with Study 
Treatment 
Subject 
Discontinued 
Due to AE 
Outcome 
MedDRA 
System Organ 
Class 
MedDRA 
Preferred 
Term 
Treatment Group: , Subject ID: , Transplant Type, Duration of Symptoms Strata, AE Number:  
 
 
 
 
 
 
 
 
 
 
 
 
Comments: 
Treatment Group: , Subject ID: , Transplant Type, Duration of Symptoms Strata, AE Number:  
 
 
 
 
 
 
 
 
 
 
 
 
Comments: 


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Table 61: 
Listing of Non-Serious, Unsolicited, Moderate or Severe Adverse Events 
[Implementation Note: This listing is included in the tables document, as it is included in the body of the CSR. If the event is ongoing (no stop date), 
indicate “ongoing” in the “Duration” column. In the “If Not Related, Alternate Etiology” column, merge the 2 data fields for collecting alternate 
etiology, separate by a colon. If there are no comments for an event, populate ‘Comments’ row with ‘None’. Add columns for MedDRA HLT or LLT 
depending on halting criteria or other study needs. In the CSR, Subject ID should be USUBJID (not PATID) for purposes of de-identification. Listing 
should be sorted by Subject ID, Associated with Dose No., and No. of Days Post Associated Dose. If the event is related, show N/A in the Alternative 
Etiology column and add a footnote defining N/A = Not applicable.] 
Adverse Event 
No. of Days 
Post First Dose 
(Duration) 
Severity 
Relationship to 
Study 
Treatment 
If Not Related, 
Alternative 
Etiology 
Action Taken 
with Study 
Treatment 
Subject 
Discontinued 
Due to AE 
Outcome 
MedDRA 
System Organ 
Class 
MedDRA 
Preferred Term 
Treatment Group: , Subject ID: , Transplant Type, Duration of Symptoms Strata, AE Number:  
 
 
 
 
 
 
 
 
 
 
Comments: 
Treatment Group: , Subject ID: , Transplant Type, Duration of Symptoms Strata, AE Number:  
 
 
 
 
 
 
 
 
 
 
Comments: 


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14.3.3 Narratives of Deaths, Other Serious and Significant Adverse Events 
(not included in SAP, but this is a placeholder for the CSR) 


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14.3.4 Abnormal Laboratory Value Listings (by Subject) 
Table 62: 
Listing of Abnormal Laboratory Results - Chemistry 
Subject 
ID 
Treatment 
Group 
Sex 
Age 
(years) 
Planned 
Time Point 
Actual 
Study Day 
Laboratory 
Parameter 
(Units) 
Result 
(Severity) 
Relationship to 
Treatment 
If Not Related, 
Alternate 
Etiology 
Action Taken 
with Study 
Treatment 
Subject 
Discontinued Due 
to Result? 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Table 63: 
Listing of Abnormal Laboratory Results - Hematology 
Subject 
ID 
Treatment 
Group 
Sex 
Age 
(years) 
Planned 
Time Point 
Actual 
Study Day 
Laboratory 
Parameter 
(Units) 
Result 
(Severity) 
Relationship to 
Treatment 
If Not Related, 
Alternate 
Etiology 
Action Taken 
with Study 
Treatment 
Subject 
Discontinued Due 
to Result? 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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14.3.4 Displays of Laboratory Results 
14.3.4.1 
Chemistry Results 
Table 64: 
Laboratory Results by Parameter, Maximum Severity, Time Point, and Treatment Group – Any Chemistry Parameter 
[Implementation Note: Generate one table for “Any Chemistry Parameter” and one table for each chemistry parameter. If a parameter has a grading scale 
that includes grading for both high and low, then include one column for each severity for high and low, as shown in the second sample table below. If 
not, then just include one column per severity, as shown in the first sample table. The “Any Parameter” table will just summarize one column per 
severity.] 
Any Chemistry Parameter 
 
Time Point 
Treatment Group 
N 
None 
Mild / 
Grade 1 
Moderate/ 
Grade 2 
Severe/ 
Grade 3 
Missing 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
Baseline 
Nitazoxanide 500 mg 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Placebo 
 
 
 
 
 
 
 
 
 
 
 
Day 7 
Nitazoxanide 500 mg 
 
 
 
 
 
 
 
 
 
 
 
Placebo 
 
 
 
 
 
 
 
 
 
 
 
Day 28 
Nitazoxanide 500 mg 
 
 
 
 
 
 
 
 
 
 
 
Placebo 
 
 
 
 
 
 
 
 
 
 
 
Day 180 
Nitazoxanide 500 mg 
 
 
 
 
 
 
 
 
 
 
 
Placebo 
 
 
 
 
 
 
 
 
 
 
 
Max Severity Post Baseline 
Nitazoxanide 500 mg 
 
 
 
 
 
 
 
 
 
 
 
Placebo 
 
 
 
 
 
 
 
 
 
 
 
Note: The “Max Post Baseline” rows indicate the maximum severity experienced by each subject at any time point post baseline, including unscheduled assessments.  
N = Number of subjects in the Safety Population and in study for the given time point. 
 
 


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Table 65: 
Laboratory Results by Parameter, Maximum Severity, Time Point, and Treatment Group – Creatinine  
Time Point 
Treatment Group 
N 
None 
Mild / 
Grade 1 
Moderate/ 
Grade 2 
Severe/ 
Grade 3 
Missing 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
Baseline 
Nitazoxanide 500 mg 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Placebo 
 
 
 
 
 
 
 
 
 
 
 
Day 7 
Nitazoxanide 500 mg 
 
 
 
 
 
 
 
 
 
 
 
Placebo 
 
 
 
 
 
 
 
 
 
 
 
Day 28 
Nitazoxanide 500 mg 
 
 
 
 
 
 
 
 
 
 
 
Placebo 
 
 
 
 
 
 
 
 
 
 
 
Day 180 
Nitazoxanide 500 mg 
 
 
 
 
 
 
 
 
 
 
 
Placebo 
 
 
 
 
 
 
 
 
 
 
 
Max Severity Post Baseline 
Nitazoxanide 500 mg 
 
 
 
 
 
 
 
 
 
 
 
Placebo 
 
 
 
 
 
 
 
 
 
 
 
Note: The “Max Post Baseline” rows indicate the maximum severity experienced by each subject at any time point post baseline, including unscheduled assessments.  
N = Number of subjects in the Safety Population and in study for the given time point. 
Tables with similar format: 
Table 66: 
Laboratory Results by Parameter, Maximum Severity, Time Point, and Treatment Group – BUN  
Table 67: 
Laboratory Results by Parameter, Maximum Severity, Time Point, and Treatment Group – Alkaline Phosphatase  
Table 68: 
Laboratory Results by Parameter, Maximum Severity, Time Point, and Treatment Group – AST  
Table 69: 
Laboratory Results by Parameter, Maximum Severity, Time Point, and Treatment Group – ALT  
Table 70: 
Laboratory Results by Parameter, Maximum Severity, Time Point, and Treatment Group – Total Bilirubin  
 
 


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Table 71: 
Abnormal Laboratory Results Related to Study Treatment by Parameter, Maximum Severity, Time Point, and Treatment Group 
– Any Chemistry Parameter 
[Implementation Note: Generate one table for “Any Chemistry Parameter” and one table for each chemistry parameter. If a parameter has a grading scale 
that includes grading for both high and low, then include one column for each severity for high and low, as shown in the second sample table below. If 
not, then just include one column per severity, as shown in the first sample table. The “Any Parameter” table will just summarize one column per 
severity.] 
Any Chemistry Parameter 
 
Time Point 
Treatment Group 
N 
None 
Mild / 
Grade 1 
Moderate/ 
Grade 2 
Severe/ 
Grade 3 
n 
% 
n 
% 
n 
% 
n 
% 
Baseline 
Nitazoxanide 500 mg 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Placebo 
 
 
 
 
 
 
 
 
 
Day 7 
Nitazoxanide 500 mg 
 
 
 
 
 
 
 
 
 
Placebo 
 
 
 
 
 
 
 
 
 
Day 28 
Nitazoxanide 500 mg 
 
 
 
 
 
 
 
 
 
Placebo 
 
 
 
 
 
 
 
 
 
Day 180 
Nitazoxanide 500 mg 
 
 
 
 
 
 
 
 
 
Placebo 
 
 
 
 
 
 
 
 
 
Max Severity Post Baseline 
Nitazoxanide 500 mg 
 
 
 
 
 
 
 
 
 
Placebo 
 
 
 
 
 
 
 
 
 
Note: The “Max Post Baseline” rows indicate the maximum severity experienced by each subject at any time point post baseline, including unscheduled assessments.  
N = Number of subjects in the Safety Population and in study for the given time point. 


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Table 72: 
Abnormal Laboratory Results Related to Study Treatment by Parameter, Maximum Severity, Time Point, and Treatment Group 
– Creatinine  
[Implementation Note: Generate one table for “Any Chemistry Parameter” and one table for each chemistry parameter. If a parameter has a grading scale 
that includes grading for both high and low, then include one column for each severity for high and low, as shown in the second sample table below. If 
not, then just include one column per severity, as shown in the first sample table. The “Any Parameter” table will just summarize one column per 
severity.] 
Time Point 
Treatment Group 
N 
None 
Mild / 
Grade 1 
Moderate/ 
Grade 2 
Severe/ 
Grade 3 
n 
% 
n 
% 
n 
% 
n 
% 
Baseline 
Nitazoxanide 500 mg 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Placebo 
 
 
 
 
 
 
 
 
 
Day 7 
Nitazoxanide 500 mg 
 
 
 
 
 
 
 
 
 
Placebo 
 
 
 
 
 
 
 
 
 
Day 28 
Nitazoxanide 500 mg 
 
 
 
 
 
 
 
 
 
Placebo 
 
 
 
 
 
 
 
 
 
Day 180 
Nitazoxanide 500 mg 
 
 
 
 
 
 
 
 
 
Placebo 
 
 
 
 
 
 
 
 
 
Max Severity Post Baseline 
Nitazoxanide 500 mg 
 
 
 
 
 
 
 
 
 
Placebo 
 
 
 
 
 
 
 
 
 
Note: The “Max Post Baseline” rows indicate the maximum severity experienced by each subject at any time point post baseline, including unscheduled assessments.  
N = Number of subjects in the Safety Population and in study for the given time point. 
Tables with similar format: 
Table 73: 
Abnormal Laboratory Results Related to Study Treatment by Parameter, Maximum Severity, Time Point, and Treatment Group 
– BUN  
Table 74: 
Abnormal Laboratory Results Related to Study Treatment by Parameter, Maximum Severity, Time Point, and Treatment Group 
– Alkaline Phosphatase  
Table 75: 
Abnormal Laboratory Results Related to Study Treatment by Parameter, Maximum Severity, Time Point, and Treatment Group 
– AST  
Table 76: 
Abnormal Laboratory Results Related to Study Treatment by Parameter, Maximum Severity, Time Point, and Treatment Group 
– ALT  
Table 77: 
Abnormal Laboratory Results Related to Study Treatment by Parameter, Maximum Severity, Time Point, and Treatment Group 
– Total Bilirubin  


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Table 78: 
Laboratory Summary Statistics by Parameter, Time Point, and Treatment Group – Creatinine (mg/dL)  
[Implementation Note: Generate one table for each chemistry parameter. For calculated fields (Mean, SD, Median), decimal place should be the format 
in which the data were collected + 1 extra place. For Min, Max, decimal place should be in the same format in which the data were collected.] 
[Repeat for each Chemistry Laboratory Parameter, number each table separately] 
Time Point 
Treatment Group 
N 
Mean 
Standard Deviation 
Median 
Min, Max 
Baseline 
Nitazoxanide 500 mg 
x 
xx.x 
xx.x 
xx.x 
xx.x, xx.x 
 
Placebo 
 
 
 
 
 
Day 7 
Nitazoxanide 500 mg 
 
 
 
 
 
 
Placebo 
 
 
 
 
 
Day 7, Change from Baseline 
Nitazoxanide 500 mg 
 
 
 
 
 
 
Placebo 
 
 
 
 
 
Day 28 
Nitazoxanide 500 mg 
 
 
 
 
 
 
Placebo 
 
 
 
 
 
Day 28, Change from Baseline 
Nitazoxanide 500 mg 
 
 
 
 
 
 
Placebo 
 
 
 
 
 
Day 180 
Nitazoxanide 500 mg 
 
 
 
 
 
 
Placebo 
 
 
 
 
 
Day 180, Change from Baseline 
Nitazoxanide 500 mg 
 
 
 
 
 
 
Placebo 
 
 
 
 
 
N = Number of subjects in the Safety Population with reported results at the specified time point. 
Tables with similar format: 
Table 79: 
Laboratory Summary Statistics by Parameter, Time Point, and Treatment Group – BUN (mg/dL) 
Table 80: 
Laboratory Summary Statistics by Parameter, Time Point, and Treatment Group – Alkaline Phosphatase (U/L) 
Table 81: 
Laboratory Summary Statistics by Parameter, Time Point, and Treatment Group – AST (U/L) 
Table 82: 
Laboratory Summary Statistics by Parameter, Time Point, and Treatment Group – ALT (U/L) 
Table 83: 
Laboratory Summary Statistics by Parameter Time Point, and Treatment Group – Total Bilirubin (mg/dL) 


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14.3.4.2 
Hematology Results 
Table 84: 
Laboratory Results by Parameter, Maximum Severity, Time Point, and Treatment Group – Any Hematology Parameter 
[Implementation Note: Generate one table for “Any Hematology Parameter” and one table for each hematology parameter. If a parameter has a grading 
scale that includes grading for both high and low, then include one column for each severity for high and low, as shown in the second sample table 
below. If not, then just include one column per severity, as shown in the first sample table. The “Any Parameter” table will just summarize one column 
per severity.] 
Any Hematology Parameter 
 
Time Point 
Treatment Group 
N 
None 
Mild / 
Grade 1 
Moderate/ 
Grade 2 
Severe/ 
Grade 3 
Missing 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
Baseline 
Nitazoxanide 500 mg 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Placebo 
 
 
 
 
 
 
 
 
 
 
 
Day 7 
Nitazoxanide 500 mg 
 
 
 
 
 
 
 
 
 
 
 
Placebo 
 
 
 
 
 
 
 
 
 
 
 
Day 28 
Nitazoxanide 500 mg 
 
 
 
 
 
 
 
 
 
 
 
Placebo 
 
 
 
 
 
 
 
 
 
 
 
Day 180 
Nitazoxanide 500 mg 
 
 
 
 
 
 
 
 
 
 
 
Placebo 
 
 
 
 
 
 
 
 
 
 
 
Max Severity Post Baseline 
Nitazoxanide 500 mg 
 
 
 
 
 
 
 
 
 
 
 
Placebo 
 
 
 
 
 
 
 
 
 
 
 
Note: The “Max Post Baseline” rows indicate the maximum severity experienced by each subject at any time point post baseline, including unscheduled assessments.  
N = Number of subjects in the Safety Population and in study for the given time point. 
 


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Table 85: 
Laboratory Results by Parameter, Maximum Severity, Time Point, and Treatment Group – WBC 
Time Point 
Treatment Group 
N 
None 
Mild/ 
Grade 1 
(Low) 
Mild/ 
Grade 1 
(High) 
Moderate/ 
Grade 2 
(Low) 
Moderate/ 
Grade 2 
(High) 
Severe/ 
Grade 3 
(Low) 
Severe/ 
Grade 3 
(High) 
Missing 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
Baseline 
Nitazoxanide 500 mg 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Placebo 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Day 7 
Nitazoxanide 500 mg 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Placebo 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Day 28 
Nitazoxanide 500 mg 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Placebo 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Day 180 
Nitazoxanide 500 mg 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Placebo 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Max Severity Post 
Baseline 
Nitazoxanide 500 mg 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Placebo 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: The “Max Post Baseline” rows indicate the maximum severity experienced by each subject at any time point post baseline, including unscheduled assessments.  
N = Number of subjects in the Safety Population and in study for the given time point. 


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Table 86: 
Laboratory Results by Parameter, Maximum Severity, Time Point, and Treatment Group – Hemoglobin  
[Implementation Note: Generate one table for “Any Hematology Parameter” and one table for each hematology parameter. If a parameter has a grading 
scale that includes grading for both high and low, then include one column for each severity for high and low, as shown in the second sample table 
below. If not, then just include one column per severity, as shown in the first sample table. The “Any Parameter” table will just summarize one column 
per severity.] 
Time Point 
Treatment Group 
N 
None 
Mild / 
Grade 1 
Moderate/ 
Grade 2 
Severe/ 
Grade 3 
Missing 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
Baseline 
Nitazoxanide 500 mg 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Placebo 
 
 
 
 
 
 
 
 
 
 
 
Day 7 
Nitazoxanide 500 mg 
 
 
 
 
 
 
 
 
 
 
 
Placebo 
 
 
 
 
 
 
 
 
 
 
 
Day 28 
Nitazoxanide 500 mg 
 
 
 
 
 
 
 
 
 
 
 
Placebo 
 
 
 
 
 
 
 
 
 
 
 
Day 180 
Nitazoxanide 500 mg 
 
 
 
 
 
 
 
 
 
 
 
Placebo 
 
 
 
 
 
 
 
 
 
 
 
Max Severity Post Baseline 
Nitazoxanide 500 mg 
 
 
 
 
 
 
 
 
 
 
 
Placebo 
 
 
 
 
 
 
 
 
 
 
 
Note: The “Max Post Baseline” rows indicate the maximum severity experienced by each subject at any time point post baseline, including unscheduled assessments.  
N = Number of subjects in the Safety Population and in study for the given time point. 
Table with similar format: 
Table 87: 
Laboratory Results by Parameter, Maximum Severity, Time Point, and Treatment Group – Platelets 
 


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Table 88: 
Abnormal Laboratory Results Related to Study Treatment by Parameter, Maximum Severity, Time Point, and Treatment Group 
– Any Hematology Parameter 
[Implementation Note: Generate one table for “Any Chemistry Parameter” and one table for each chemistry parameter. If a parameter has a grading scale 
that includes grading for both high and low, then include one column for each severity for high and low, as shown in the second sample table below. If 
not, then just include one column per severity, as shown in the first sample table. The “Any Parameter” table will just summarize one column per 
severity.] 
Any Hematology Parameter 
 
Time Point 
Treatment Group 
N 
None 
Mild / 
Grade 1 
Moderate/ 
Grade 2 
Severe/ 
Grade 3 
n 
% 
n 
% 
n 
% 
n 
% 
Baseline 
Nitazoxanide 500 mg 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Placebo 
 
 
 
 
 
 
 
 
 
Day 7 
Nitazoxanide 500 mg 
 
 
 
 
 
 
 
 
 
Placebo 
 
 
 
 
 
 
 
 
 
Day 28 
Nitazoxanide 500 mg 
 
 
 
 
 
 
 
 
 
Placebo 
 
 
 
 
 
 
 
 
 
Day 180 
Nitazoxanide 500 mg 
 
 
 
 
 
 
 
 
 
Placebo 
 
 
 
 
 
 
 
 
 
Max Severity Post Baseline 
Nitazoxanide 500 mg 
 
 
 
 
 
 
 
 
 
Placebo 
 
 
 
 
 
 
 
 
 
Note: The “Max Post Baseline” rows indicate the maximum severity experienced by each subject at any time point post baseline, including unscheduled assessments.  
N = Number of subjects in the Safety Population and in study for the given time point. 


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Table 89: 
Abnormal Laboratory Results Related to Study Treatment by Parameter, Maximum Severity, Time Point, and Treatment Group 
– WBC 
Time Point 
Treatment Group 
N 
None 
Mild/ 
Grade 1 
(Low) 
Mild/ 
Grade 1 
(High) 
Moderate/ 
Grade 2 
(Low) 
Moderate/ 
Grade 2 
(High) 
Severe/ 
Grade 3 
(Low) 
Severe/ 
Grade 3 
(High) 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
Baseline 
Nitazoxanide 500 mg 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Placebo 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Day 7 
Nitazoxanide 500 mg 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Placebo 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Day 28 
Nitazoxanide 500 mg 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Placebo 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Day 180 
Nitazoxanide 500 mg 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Placebo 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Max Severity Post 
Baseline 
Nitazoxanide 500 mg 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Placebo 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: The “Max Post Baseline” rows indicate the maximum severity experienced by each subject at any time point post baseline, including unscheduled assessments.  
N = Number of subjects in the Safety Population and in study for the given time point. 


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Table 90: 
Abnormal Laboratory Results Related to Study Treatment by Parameter, Maximum Severity, Time Point, and Treatment Group 
– Hemoglobin  
[Implementation Note: Generate one table for “Any Chemistry Parameter” and one table for each chemistry parameter. If a parameter has a grading scale 
that includes grading for both high and low, then include one column for each severity for high and low, as shown in the second sample table below. If 
not, then just include one column per severity, as shown in the first sample table. The “Any Parameter” table will just summarize one column per 
severity.] 
 
Time Point 
Treatment Group 
N 
None 
Mild / 
Grade 1 
Moderate/ 
Grade 2 
Severe/ 
Grade 3 
n 
% 
n 
% 
n 
% 
n 
% 
Baseline 
Nitazoxanide 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Placebo 
 
 
 
 
 
 
 
 
 
Day 7 
Nitazoxanide 
 
 
 
 
 
 
 
 
 
Placebo 
 
 
 
 
 
 
 
 
 
Day 28 
Nitazoxanide 
 
 
 
 
 
 
 
 
 
Placebo 
 
 
 
 
 
 
 
 
 
Day 180 
Nitazoxanide 
 
 
 
 
 
 
 
 
 
Placebo 
 
 
 
 
 
 
 
 
 
Max Severity Post Baseline 
Nitazoxanide 
 
 
 
 
 
 
 
 
 
Placebo 
 
 
 
 
 
 
 
 
 
Note: The “Max Post Baseline” rows indicate the maximum severity experienced by each subject at any time point post baseline, including unscheduled assessments.  
N = Number of subjects in the Safety Population and in study for the given time point. 
Table with similar format: 
Table 91: 
Abnormal Laboratory Results Related to Study Treatment by Parameter, Maximum Severity, Time Point, and Treatment Group 
– Platelets 
 


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Table 92: 
Laboratory Summary Statistics by Parameter, Time Point, and Treatment Group – WBC (109/L) 
[Implementation Note: Generate one table for each hematology parameter. For calculated fields (Mean, SD, Median), decimal place should be the format 
in which the data were collected + 1 extra place. For Min, Max, decimal place should be in the same format in which the data were collected.] 
[Repeat for each Hematology Laboratory Parameter and a table for each Parameter’s Change from Baseline, number each table separately] 
Time Point 
Treatment Group 
N 
Mean 
Standard Deviation 
Median 
Min, Max 
Baseline 
Nitazoxanide 500 mg 
x 
xx.x 
xx.x 
xx.x 
xx.x, xx.x 
 
Placebo 
 
 
 
 
 
Day 7 
Nitazoxanide 500 mg 
 
 
 
 
 
 
Placebo 
 
 
 
 
 
Day 7, Change from Baseline 
Nitazoxanide 500 mg 
 
 
 
 
 
 
Placebo 
 
 
 
 
 
Day 28 
Nitazoxanide 500 mg 
 
 
 
 
 
 
Placebo 
 
 
 
 
 
Day 28, Change from Baseline 
Nitazoxanide 500 mg 
 
 
 
 
 
 
Placebo 
 
 
 
 
 
Day 180 
Nitazoxanide 500 mg 
 
 
 
 
 
 
Placebo 
 
 
 
 
 
Day 180, Change from Baseline 
Nitazoxanide 500 mg 
 
 
 
 
 
 
Placebo 
 
 
 
 
 
N = Number of subjects in the Safety Population with reported results at the specified time point. 
Table with similar format: 
Table 93: 
Laboratory Summary Statistics by Parameter, Time Point, and Treatment Group – Hemoglobin (g/dL) 
Table 94: 
Laboratory Summary Statistics by Parameter, Time Point, and Treatment Group – Platelets (109/L) 
Table 95: 
Laboratory Summary Statistics by Parameter, Time Point, and Treatment Group – Monocytes (109/L) 
Table 96: 
Laboratory Summary Statistics by Parameter, Time Point, and Treatment Group – Hematocrit (%) 
Table 97: 
Laboratory Summary Statistics by Parameter, Time Point, and Treatment Group – Mean Corpuscular Volume (fL) 
Table 98: 
Laboratory Summary Statistics by Parameter, Time Point, and Treatment Group – Neutrophils (109/L) 


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Table 99: 
Laboratory Summary Statistics by Parameter, Time Point, and Treatment Group – Lymphocytes (109/L) 
Table 100: 
Laboratory Summary Statistics by Parameter, Time Point, and Treatment Group – Eosinophils (109/L) 
Table 101: 
Laboratory Summary Statistics by Parameter, Time Point, and Treatment Group – CD3+ Cells (106/L) 
Table 102: 
Laboratory Summary Statistics by Parameter, Time Point, and Treatment Group – CD3+ Cells/Lymphocytes (%) 
Table 103: 
Laboratory Summary Statistics by Parameter, Time Point, and Treatment Group – CD4+ Cells (106/L) 
Table 104: 
Laboratory Summary Statistics by Parameter, Time Point, and Treatment Group – CD4+ Cells/Lymphocytes (%) 
Table 105: 
Laboratory Summary Statistics by Parameter, Time Point, and Treatment Group – CD8+ Cells (106/L) 
Table 106: 
Laboratory Summary Statistics by Parameter, Time Point, and Treatment Group – CD8+ Cells/Lymphocytes (%) 


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Section 14.3.4.4 Displays of Hospitalizations, Allograft Rejection, Graft Loss, Death 
Table 107: 
Duration of Hospitalization (Days) Summary Statistics by Treatment Group and Study Day – Safety Population 
Study Day 
Statistic 
Nitazoxanide 500 mg 
(N=X) 
Placebo 
(N=X) 
Day 28 
n 
x 
x 
Mean  
x.x  
x.x  
Median  
x.x  
x.x  
Standard Deviation  
x.x  
x.x  
Minimum  
x 
x 
Maximum 
x 
x 
P-valuea 
 
0.xxx 
Day 180 
N 
x 
x 
Mean  
x.x  
x.x  
Median  
x.x  
x.x  
Standard Deviation  
x.x  
x.x  
Minimum  
x 
x 
Maximum 
x 
x 
P-valuea 
 
0.xxx 
N = Number of subjects in the specified treatment group and analysis population. 
n = Number of subjects in each treatment group who were hospitalized by the given timepoint. 
a P-value is based on Wilcoxon Mann-Whitney exact rank sum test. 


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Table 108: 
Natural History of Disease Time to Event by Treatment Group and Duration of Symptoms – mITT Population 
Event 
Treatment Group 
Duration of 
Symptoms 
n 
Median Time to Event 
HR 
P-value 
Estimate 
95% CI 
Estimate 
95% CI 
Allograft Rejection 
Nitazoxanide 500 mg (N=X) 
Acute 
x 
x.x 
x.x, x.x 
x.xx 
x.xx, x.xx 
-- 
Placebo (N=X) 
x 
x.x 
x.x, x.x 
Nitazoxanide 500 mg (N=X) 
Chronic 
x 
x.x 
x.x, x.x 
x.xx 
x.xx, x.xx 
-- 
Placebo (N=X) 
x 
x.x 
x.x, x.x 
Nitazoxanide 500 mg (N=X) 
Any Duration 
x 
x.x 
x.x, x.x 
x.xx 
x.xx, x.xx 
0.xxx 
Placebo (N=X) 
x 
x.x 
x.x, x.x 
Graft Loss 
Nitazoxanide 500 mg (N=X) 
Acute 
x 
x.x 
x.x, x.x 
x.xx 
x.xx, x.xx 
-- 
Placebo (N=X) 
x 
x.x 
x.x, x.x 
Nitazoxanide 500 mg (N=X) 
Chronic 
x 
x.x 
x.x, x.x 
x.xx 
x.xx, x.xx 
-- 
Placebo (N=X) 
x 
x.x 
x.x, x.x 
Nitazoxanide 500 mg (N=X) 
Any Duration 
x 
x.x 
x.x, x.x 
x.xx 
x.xx, x.xx 
0.xxx 
Placebo (N=X) 
x 
x.x 
x.x, x.x 
Implementation note: Repeat for Death and Withdrawal from Study. 
N = Number of subjects in the specified treatment group, duration of symptoms strata, and analysis population. 
n = Number of subjects with initial clinical resolution of symptoms. 
Note: HR is the ratio of the hazard of the given event in each treatment group estimated from the Cox model. The ratio is Nitazoxanide 500 mg to Placebo. 
HR for the ‘Any Duration’ group is the hazard ratio from the stratified Cox Model. 
P-value calculated using the likelihood ratio test. 


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14.3.5 Displays of Vital Signs 
Table 109: 
Vital Signs Summary Statistics by Parameter, Time Point, and Treatment Group – Temperature (°F) 
Time Point 
Treatment Group 
N 
Mean 
Standard Deviation 
Median 
Min, Max 
Baseline 
Nitazoxanide 500 mg 
x 
xx.x 
xx.x 
xx.x 
xx.x, xx.x 
Placebo 
 
 
 
 
 
Day 7 
Nitazoxanide 500 mg 
 
 
 
 
 
Placebo 
 
 
 
 
 
Day 7, Change from Baseline 
Nitazoxanide 500 mg 
 
 
 
 
 
Placebo 
 
 
 
 
 
Day 14 
Nitazoxanide 500 mg 
 
 
 
 
 
Placebo 
 
 
 
 
 
Day 14, Change from Baseline 
Nitazoxanide 500 mg 
 
 
 
 
 
Placebo 
 
 
 
 
 
Day 21 
Nitazoxanide 500 mg 
 
 
 
 
 
Placebo 
 
 
 
 
 
Day 21, Change from Baseline 
Nitazoxanide 500 mg 
 
 
 
 
 
Placebo 
 
 
 
 
 
Day 28 
Nitazoxanide 500 mg 
 
 
 
 
 
Placebo 
 
 
 
 
 
Day 28, Change from Baseline 
Nitazoxanide 500 mg 
 
 
 
 
 
Placebo 
 
 
 
 
 
Day 60 
Nitazoxanide 500 mg 
 
 
 
 
 
Placebo 
 
 
 
 
 
Day 60, Change from Baseline 
Nitazoxanide 500 mg 
 
 
 
 
 
Placebo 
 
 
 
 
 
Day 120 
Nitazoxanide 500 mg 
 
 
 
 
 
Placebo 
 
 
 
 
 


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Time Point 
Treatment Group 
N 
Mean 
Standard Deviation 
Median 
Min, Max 
Day 120, Change from Baseline 
Nitazoxanide 500 mg 
 
 
 
 
 
Placebo 
 
 
 
 
 
Day 180 
Nitazoxanide 500 mg 
 
 
 
 
 
Placebo 
 
 
 
 
 
Day 180, Change from Baseline 
Nitazoxanide 500 mg 
 
 
 
 
 
Placebo 
 
 
 
 
 
N = Number of subjects in the Safety Population with reported results at the specified time point. 
Table with similar format: 
Table 110: 
Vital Signs Summary Statistics by Parameter, Time Point, and Treatment Group – Weight (kg) 
Table 111: 
Vital Signs Summary Statistics by Parameter, Time Point, and Treatment Group – Systolic Blood Pressure (mmHg) 
Table 112: 
Vital Signs Summary Statistics by Parameter, Time Point, and Treatment Group – Diastolic Blood Pressure (mmHg) 
Table 113: 
Vital Signs Summary Statistics by Parameter, Time Point, and Treatment Group – Respiration (breaths/minute) 
Table 114: 
Vital Signs Summary Statistics by Parameter, Time Point, and Treatment Group – Pulse (beats/minute) 


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14.4 
Summary of Concomitant Medications 
Table 115: 
Number and Percentage of Subjects with Prior and Concurrent Medications by WHO 
Drug Classification and Treatment Group 
WHO Drug Code 
Level 1, Anatomic Group 
WHO Drug Code 
Level 2, Therapeutic 
Subgroup 
Nitazoxanide 500 mg 
(N=X) 
Placebo 
(N=X) 
All Subjects 
(N=X) 
n 
% 
n 
% 
n 
% 
Any Level 1 Codes 
Any Level 2 Codes 
x 
xx 
x 
xx 
x 
xx 
[ATC Level 1 - 1] 
Any [ATC 1 – 1] 
 
 
 
 
 
 
 
[ATC 2 - 1] 
 
 
 
 
 
 
 
[ATC 2 - 2] 
 
 
 
 
 
 
 
[ATC 2 - 3] 
 
 
 
 
 
 
[ATC Level 1 – 2] 
Any [ATC 1 – 2  
 
 
 
 
 
 
 
[ATC 2 - 1] 
 
 
 
 
 
 
 
[ATC 2 - 2] 
 
 
 
 
 
 
 
[ATC 2 - 3] 
 
 
 
 
 
 
N = Number of subjects in the Safety Population. n=Number of subjects reporting taking at least one medication in the specific WHO Drug 
Class. 


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APPENDIX 2.  FIGURE MOCK-UPS 
LIST OF FIGURES 
Figure 1: 
Study Design .............................................................................................................134 
Figure 2: 
CONSORT Flow Diagram .......................................................................................135 
Figure 3: 
Kaplan-Meier Curves of Time to Initial Clinical Resolution by Treatment Group – mITT 
Population .................................................................................................................136 
Figure 4: 
Kaplan-Meier Curves of Time to Initial Clinical Resolution by Treatment Group – Per 
Protocol Population ..................................................................................................136 
Figure 5: 
Kaplan-Meier Curves of Time to Initial Clinical Resolution by Treatment Group: Worst 
Case Scenario Sensitivity Analysis – mITT Population ...........................................136 
Figure 6: 
Kaplan-Meier Curves of Time to Initial Clinical Resolution by Treatment Group and 
Duration of Symptoms – mITT Population ..............................................................137 
Figure 7: 
Kaplan-Meier Curves of Time to Initial Clinical Resolution by Treatment Group and 
Duration of Symptoms – Per Protocol Population ...................................................137 
Figure 8: 
Kaplan-Meier Curves of Time to Initial Clinical Resolution by Treatment Group and 
Duration of Symptoms: Worst Case Scenario Sensitivity Analysis – mITT Population
 ..................................................................................................................................137 
Figure 9: 
Kaplan-Meier Curves of Time to Initial Clinical Resolution by Treatment Group and 
Diary Compliance – mITT Population .....................................................................137 
Figure 10: Kaplan-Meier Curves of Time to First Negative Viral Load by Treatment Group – 
Norovirus GII, mITT Population ..............................................................................138 
Figure 11: Kaplan-Meier Curves of Time to First Negative Viral Load by Treatment Group – 
Norovirus GII, Per Protocol Population ...................................................................138 
Figure 12: Kaplan-Meier Curves of Time to First Negative Viral Load by Treatment Group – 
Norovirus GI, mITT Population ...............................................................................138 
Figure 13: Kaplan-Meier Curves of Time to First Negative Viral Load by Treatment Group – 
Norovirus GI, Per Protocol Population .....................................................................138 
Figure 14: Kaplan-Meier Curves of Time to First Negative Viral Load by Treatment Group and 
Duration of Symptoms – Norovirus GII, mITT Population .....................................139 
Figure 15: Kaplan-Meier Curves of Time to First Negative Viral Load by Treatment Group and 
Duration of Symptoms – Norovirus GI, mITT Population.......................................139 
Figure 16: Forest Plot of Change in Viral Titer between Day 1 and Day 180 by Treatment Group and 
Duration of Symptoms – Norovirus GII, mITT Population .....................................140 
Figure 17: Forest Plot of Change in Viral Titer between Day 1 and Day 180 by Treatment Group and 
Duration of Symptoms – Norovirus GI, mITT Population.......................................140 
Figure 18: Forest Plot of Change in Viral Titer between Day 1 and Day 180 by Treatment Group and 
Duration of Symptoms – Norovirus GII, PP Population ..........................................140 


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Figure 19: Forest Plot of Change in Viral Titer between Day 1 and Day 180 by Treatment Group and 
Duration of Symptoms – Norovirus GI, PP Population ...........................................140 
Figure 20: Kaplan-Meier Curves of Time to Initial Clinical Improvement by Treatment Group – 
mITT Population .......................................................................................................141 
Figure 21: Kaplan-Meier Curves of Time to Cessation of Vomiting by Treatment Group – mITT 
Population .................................................................................................................141 
Figure 22: Kaplan-Meier Curves of Time to No Loss of Appetite by Treatment Group – mITT 
Population .................................................................................................................141 
Figure 23: Kaplan-Meier Curves of Time to Cessation of Diarrhea by Treatment Group – mITT 
Population .................................................................................................................141 
Figure 24: Kaplan-Meier Curves of Time to 50% Reduction in Antimotility Agents by Treatment 
Group – mITT Population ........................................................................................141 
Figure 25: Frequency of Related Adverse Events by MedDRA System Organ Class and Severity
 ..................................................................................................................................142 
Figure 26: Incidence of Related Adverse Events by MedDRA® System Organ Class and Maximum 
Severity .....................................................................................................................143 
Figure 27: Kaplan-Meier Curves of Time to Allograft Rejection by Treatment Group – mITT 
Population .................................................................................................................144 
Figure 28: Kaplan-Meier Curves of Time to Graft Loss by Treatment Group – mITT Population144 
Figure 29: Kaplan-Meier Curves of Time to Death by Treatment Group – mITT Population ..144 
Figure 30: Kaplan-Meier Curves of Time to Withdrawal by Treatment Group – mITT Population
 ..................................................................................................................................145 
 


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Figure 1: 
Study Design 


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10.1 
Disposition of Subjects 
Figure 2: 
CONSORT Flow Diagram 
 


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14.2.2 Efficacy/Immunogenicity Response Figures by Measure, Treatment, and Time Point 
Figure 3: 
Kaplan-Meier Curves of Time to Initial Clinical Resolution by Treatment Group – mITT 
Population 
[Implementation Note: Include (N=X) for each group in legend.] 
 
 
Figures with similar format: 
Figure 4: 
Kaplan-Meier Curves of Time to Initial Clinical Resolution by Treatment Group – Per 
Protocol Population 
Figure 5: 
Kaplan-Meier Curves of Time to Initial Clinical Resolution by Treatment Group: Worst 
Case Scenario Sensitivity Analysis – mITT Population 


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Figure 6: 
Kaplan-Meier Curves of Time to Initial Clinical Resolution by Treatment Group and 
Duration of Symptoms – mITT Population 
[Implementation Note: Y axis will be “Proportion Resolved”, x axis will be “Days Since Randomization”. 
Curves will include all subjects in the mITT Population that tested positive for GII at baseline. Include (N=X) 
for each group in legend. If subgroup has less than 5 subjects per treatment group, add footnote describing 
exclusion from figure.] 
 
 
Figures with similar format: 
Figure 7: 
Kaplan-Meier Curves of Time to Initial Clinical Resolution by Treatment Group and 
Duration of Symptoms – Per Protocol Population 
Figure 8: 
Kaplan-Meier Curves of Time to Initial Clinical Resolution by Treatment Group and 
Duration of Symptoms: Worst Case Scenario Sensitivity Analysis – mITT Population 
Figure 9: 
Kaplan-Meier Curves of Time to Initial Clinical Resolution by Treatment Group and 
Diary Compliance – mITT Population 


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Figure 10: 
Kaplan-Meier Curves of Time to First Negative Viral Load by Treatment Group – 
Norovirus GII, mITT Population 
[Implementation Note: Y axis will be “Proportion Negative”, x axis will be “Days Since Randomization”. 
Curves will include all subjects in the mITT Population that tested positive for GII at baseline. Include (N=X) 
for each group in legend.] 
 
 
Tables with similar format: 
Figure 11: 
Kaplan-Meier Curves of Time to First Negative Viral Load by Treatment Group – 
Norovirus GII, Per Protocol Population 
Figure 12: 
Kaplan-Meier Curves of Time to First Negative Viral Load by Treatment Group – 
Norovirus GI, mITT Population 
Figure 13: 
Kaplan-Meier Curves of Time to First Negative Viral Load by Treatment Group – 
Norovirus GI, Per Protocol Population 


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Figure 14: 
Kaplan-Meier Curves of Time to First Negative Viral Load by Treatment Group and 
Duration of Symptoms – Norovirus GII, mITT Population 
[Implementation Note: Y axis will be “Proportion Negative”, x axis will be “Days Since Randomization”. 
Curves will include all subjects in the mITT Population that tested positive for GII at baseline. Include (N=X) 
for each group in legend. If subgroup has less than 5 subjects per treatment group, add footnote describing 
exclusion from figure.] 
 
 
Figures with similar format: 
Figure 15: 
Kaplan-Meier Curves of Time to First Negative Viral Load by Treatment Group and 
Duration of Symptoms – Norovirus GI, mITT Population 


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Figure 16: 
Forest Plot of Change in Viral Titer between Day 1 and Day 180 by Treatment Group 
and Duration of Symptoms – Norovirus GII, mITT Population 
[Implementation Note: Include (N=X) for each group in y axis. If subgroup has less than 5 subjects per 
treatment group, add footnote describing exclusion from figure. X axis title is “Adjusted Mean and 95% CI”.] 
 
 
Figure with similar format: 
Figure 17: 
Forest Plot of Change in Viral Titer between Day 1 and Day 180 by Treatment Group 
and Duration of Symptoms – Norovirus GI, mITT Population 
Figure 18: 
Forest Plot of Change in Viral Titer between Day 1 and Day 180 by Treatment Group 
and Duration of Symptoms – Norovirus GII, PP Population 
Figure 19: 
Forest Plot of Change in Viral Titer between Day 1 and Day 180 by Treatment Group 
and Duration of Symptoms – Norovirus GI, PP Population 


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Figure 20: 
Kaplan-Meier Curves of Time to Initial Clinical Improvement by Treatment Group – 
mITT Population 
[Implementation Note: Y axis will be “Proportion Improved”, x axis will be “Days Since Randomization”. 
Include (N=X) for each group in legend.] 
 
 
 
Figures with similar format: 
Figure 21: 
Kaplan-Meier Curves of Time to Cessation of Vomiting by Treatment Group – mITT 
Population 
Figure 22: 
Kaplan-Meier Curves of Time to No Loss of Appetite by Treatment Group – mITT 
Population 
Figure 23: 
Kaplan-Meier Curves of Time to Cessation of Diarrhea by Treatment Group – mITT 
Population 
Figure 24: 
Kaplan-Meier Curves of Time to 50% Reduction in Antimotility Agents by Treatment 
Group – mITT Population 


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14.3.1.2 
Unsolicited Adverse Events 
Figure 25: 
Frequency of Related Adverse Events by MedDRA System Organ Class and Severity 
[Implementation note: The figure below is an example only. This figure includes serious and non-serious 
unsolicited adverse events deemed related to study product. The SOCs will be sorted in descending frequency. 
Each panel represents a treatment group with Nitazoxanide 500 mg on the left and Placebo on the right.] 
 
 
 


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Figure 26: 
Incidence of Related Adverse Events by MedDRA® System Organ Class and Maximum 
Severity  
[Implementation note: The figure below is an example only. This figure includes serious and non-serious 
unsolicited adverse events deemed related to study product. The SOCs will be sorted in descending incidence. 
Each panel represents a treatment group with Nitazoxanide 500 mg on the left and Placebo on the right.] 
 
 


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14.3.4.4 Displays of Hospitalizations, Allograft Rejection, Graft Loss, Death 
Figure 27: 
Kaplan-Meier Curves of Time to Allograft Rejection by Treatment Group – mITT 
Population 
[Implementation Note: Y axis will be “Proportion Rejected”, x axis will be “Days Since Randomization”. 
Include (N=X) for each group in legend.] 
 
 
Figures with similar format: 
Figure 28: 
Kaplan-Meier Curves of Time to Graft Loss by Treatment Group – mITT Population 
[Implementation Note: Y axis will be “Proportion Lost”, x axis will be “Days Since Randomization”. Include 
(N=X) for each group in legend.] 
Figure 29: 
Kaplan-Meier Curves of Time to Death by Treatment Group – mITT Population 
[Implementation Note: Y axis will be “Proportion Died”, x axis will be “Days Since Randomization”. Include 
(N=X) for each group in legend.] 


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Figure 30: 
Kaplan-Meier Curves of Time to Withdrawal by Treatment Group – mITT Population 
[Implementation Note: Y axis will be “Proportion Withdrawn”, x axis will be “Days Since Randomization”. 
Include (N=X) for each group in legend.]


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APPENDIX 3. LISTINGS MOCK-UPS 
LISTINGS 
Listing 1: 16.1.6: Listing of Subjects Receiving Investigational Product .................................148 
Listing 2: 16.2.1: Early Terminations or Discontinued Subjects ..............................................149 
Listing 3: 16.2.2.1: Subject-Specific Protocol Deviations ........................................................150 
Listing 4: 16.2.2.2: Non-Subject-Specific Protocol Deviations ................................................151 
Listing 5: 16.2.3: Subjects Excluded from Analysis Populations .............................................152 
Listing 6: 16.2.4.1: Demographic Data .....................................................................................153 
Listing 7: 16.2.4.2: Pre-Existing and Concurrent Medical Conditions .....................................154 
Listing 8: 16.2.5.1: Treatment Compliance Data ......................................................................155 
Listing 9: 16.2.5.2: Daily Diary Compliance Data ...................................................................156 
Listing 10: 16.2.5.3: Daily Diary Time of Completion Compliance Data – Treatment 
Phase .........................................................................................................................157 
Listing 11: 16.2.5.4: Individual Additional Nitazoxanide Data ..................................................158 
Listing 12: 16.2.6.1: Individual Treatment Phase Daily Diary Data ..........................................159 
Listing 13: 16.2.6.2: Individual Longitudinal Phase Daily Diary Data ......................................160 
Listing 14: 16.2.6.3: Weekly Recall Diary .................................................................................161 
Listing 15: 16.2.6.3: Individual PROMIS Scores Data – Quality of Life/PANAS ....................162 
Listing 16: 16.2.6.5: Individual PROMIS Scores Data – Physical Function, Emotional, 
and Gastrointestinal Symptoms ................................................................................163 
Listing 17: 16.2.6.4: Individual NoV PCR Results Data ............................................................164 
Listing 18: 16.2.6.7: Individual Co-pathogen Status Data ..........................................................165 
Listing 19: 16.2.6.8: Individual Baseline Secretor Status Data ..................................................166 
Listing 20: 16.2.6.9: Individual Serum Immunology Response Data .........................................167 
Listing 21: 16.2.6.10: Individual Stool Immunology Response Data .........................................168 
Listing 22: 16.2.6.8: Individual Chromaturia Data .....................................................................169 
Listing 23: 16.2.7.1: Unsolicited Adverse Events .......................................................................170 
Listing 24: 16.2.8.1: Clinical Laboratory Results – Chemistry ..................................................171 
Listing 25: 16.2.8.2: Clinical Laboratory Results – Hematology ...............................................172 
Listing 26: 16.2.8.3: Clinical Laboratory Results – T-Cell Subsets ...........................................173 
Listing 27: 16.2.8.2.1: Vital Signs ..............................................................................................174 
Listing 28: 16.2.8.3.1: Hospitalizations ......................................................................................175 


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Listing 29: 16.8.3.2: Individual Graft Loss or Rejection Data ....................................................176 
Listing 30: 16.8.3.3: Deaths ........................................................................................................177 
Listing 31: 16.2.8.4.1: Physical Exam Findings .........................................................................178 
Listing 32: 16.2.8.5.1: Concomitant Medications .......................................................................179 
Listing 33: 16.2.8.6.1: Pregnancy Reports – Maternal Information ...........................................180 
Listing 34: 16.2. 8.6.2: Pregnancy Reports – Gravida and Para .................................................180 
Listing 35: 16.2. 8.6.3: Pregnancy Reports – Live Birth Outcomes ...........................................181 
Listing 36: 16.2. 8.6.4: Pregnancy Reports – Still Birth Outcomes ............................................181 
Listing 37: 16.2. 8.6.5: Pregnancy Reports – Spontaneous, Elective, or Therapeutic 
Abortion Outcomes ...................................................................................................181 


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Listing 1: 
16.1.6: Listing of Subjects Receiving Investigational Product 
[Implementation Note: If all subjects received the treatment they were randomized to then a single “Treatment Group” column will be included. Subject 
ID will be USUBJID (not PATID) for purposes of de-identification.] 
Randomized Treatment Group 
Actual Treatment Group 
 Subject ID 
Enrollment Date 
 


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16.2 
Database Listings by Subject 
16.2.1 Discontinued Subjects 
Listing 2: 
16.2.1: Early Terminations or Discontinued Subjects 
[Implementation Note: Category will be “Early Termination” and/or “Treatment Discontinuation.” A footnote will be added to indicate the cause of 
death for any subjects with early termination reason of “Death, not an AE”.] 
[Implementation Note: Category will be either “Early Termination” or “Treatment Discontinuation.” In the “Reason” column, concatenate any “specify” 
fields, including AE number and DV number. In the CSR, Subject ID should be USUBJID (not PATID) for purposes of de-identification. Sort order: 
Treatment Group, Subject ID, alphabetically by Category (in the case a subject both terminates early and discontinues treatment).] 
Treatment Group 
 Subject ID 
Category 
Reason for Early Termination or Treatment Discontinuation 
Study Day 
 
 
 
 
 
 
Note: EHD.xxxxx: Cause of death was [add cause of death term, if more than one term, separate by commas or “and”]. 
 
 


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16.2.2 Protocol Deviations 
Listing 3: 
16.2.2.1: Subject-Specific Protocol Deviations 
[Implementation Note: In the “Deviation” column, concatenate any and all “specify” fields (including visit number, etc.). If “Reason for Deviation” is 
“Other,” concatenate “specify” field, separate by a colon, e.g., “Other: Subject refusal.” In the CSR, Subject ID should be USUBJID (not PATID) for 
purposes of de-identification. Sort order: Treatment Group, Subject ID, DV Number.] 
Treatment 
Group 
Subject ID 
DV Number 
Deviation 
Deviation 
Category 
Study Day 
Reason for 
Deviation 
Deviation 
Resulted 
in AE? 
Deviation Resulted 
in Subject 
Termination? 
Deviation 
Affected 
Product 
Stability? 
Deviation 
Resolution 
Comments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Listing 4: 
16.2.2.2: Non-Subject-Specific Protocol Deviations 
[Implementation Note: In the “Deviation” column, concatenate any and all “specify” fields (including visit number, etc.). If “Reason for Deviation” is 
“Other,” concatenate “specify” field, separate by a colon, e.g., “Other: Subject refusal.” Sort order: Site, Start Date.] 
Site 
Start Date  
Deviation 
End Date 
Reason for 
Deviation 
Deviation 
Resulted in 
Subject 
Termination? 
Deviation 
Affected 
Product 
Stability? 
Deviation 
Category 
Deviation 
Resolution 
Comments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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16.2.3 Subjects Excluded from the Efficacy Analysis 
Listing 5: 
16.2.3: Subjects Excluded from Analysis Populations 
[Implementation Note: This data in this listing should be congruent with the “Analysis Populations by Treatment Group” table. The reasons included 
here should match the SAP text that describes who will be excluded from analyses. In the CSR, Subject ID should be USUBJID (not PATID) for 
purposes of de-identification.] Sort order: Treatment Group, Subject ID.] 
Treatment Group 
Subject ID 
Analyses in which 
Subject is Included 
Analyses from which  
Subject is Excluded 
Results Available? 
Reason Subject Excluded 
 
 
[e.g., Safety, mITT, PP] 
[e.g., Safety, mITT, PP] 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: “Yes” in the “Results available” column indicates that available data were removed from the analysis. “No” indicates that no data were available for inclusion in the analysis. 
 
 


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16.2.4 Demographic Data 
Listing 6: 
16.2.4.1: Demographic Data 
[Implementation Note: If a subject is multi-racial, in “Race” column, note “Multiple: (list races, separated by a comma).” 
For studies in infants and young children, may be more appropriate to use weeks or months for age at enrollment. In the CSR, Subject ID should be 
USUBJID (not PATID) for purposes of de-identification.] Sort order: Treatment Group, Subject ID.] 
Treatment Group 
 Subject ID 
Transplant Type 
Duration of Symptoms 
Sex 
Age at Enrollment 
(years) 
Ethnicity 
Race 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Listing 7: 
16.2.4.2: Pre-Existing and Concurrent Medical Conditions 
[Implementation Note: “Condition Start Day” and “Condition End Day” are relative to enrollment (which is Day 1, day before enrollment is  
Day -1). Rather than use exact study days, categorize as follows: 
• 5 years prior to enrollment 
• 1-5 years prior to enrollment 
• 1-12 months prior to enrollment 
• Within 1 month of enrollment 
• During study 
• If ongoing, display “Ongoing” in the “Condition End Day” column 
• Within 1 month of enrollment 
• During study 
• If ongoing, display “Ongoing” in the “Condition End Day” column 
It may be appropriate to add another category, based on exclusion criteria that restrict conditions within a particular time period (e.g., within 3 years prior 
to enrollment). In the CSR, Subject ID should be USUBJID (not PATID) for purposes of de-identification. Sort order: Treatment Group, Subject ID, MH 
Number.] 
Treatment 
Group 
 Subject ID 
MH Number 
Medical History Term 
Condition Start Day  
Condition End Day 
MedDRA System Organ Class 
MedDRA Preferred Term 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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16.2.5 Compliance Data  
Listing 8: 
16.2.5.1: Treatment Compliance Data 
[Implementation Note: Each subject will have a single row in the listing. The final pill count column will contain the last pill count entered in the 
Treatment Dispensing Log. The Dose(s) Missed column will list all doses missed per the subject’s daily diary.] 
[Implementation Note: Sort order: Treatment Group, Subject ID, Dose Number.] 
Treatment Group  
Subject ID  
Transplant Type 
Duration of Symptoms 
Final Pill Counta 
Dose(s) Missedb 
 
 
 
 
 
[e.g., Day 3, Day 3 AM, etc.] 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
a Final pill count will include Day 28 and Day 60 pill counts. Subjects with pill counts at both visits will use the Day 60 pill count as the final pill count. 
b Dose(s) Missed includes all missed doses per the subject’s daily diary. Day X AM = Missed Day X Morning Dose; Day X PM = Missed Day X Evening Dose; Day X = Missed Both Doses on Day X. 


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Listing 9: 
16.2.5.2: Daily Diary Compliance Data 
[Implementation Note: Sort order: Treatment Group, Subject ID, Dose Number.] 
Treatment Group 
Subject ID 
Transplant Type 
Duration of 
Symptoms 
Phase 
Week Number 
Number of Diaries 
Missed 
Day(s) Missed 
 
 
 
 
Treatment/Longitudinal  
 
[e.g., Day 3, Day 5, etc.] 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: Weeks are only included if at least one diary was missed for that week. 


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Listing 10: 
16.2.5.3: Daily Diary Time of Completion Compliance Data – Treatment Phase 
[Implementation Note: Sort order: Treatment Group, Subject ID, Dose Number.] 
Treatment 
Group  
Subject ID  
Transplant 
Type 
Duration of 
Symptoms 
Number Completed 
between 6am and 12pm 
Number Completed 
between 12pm and 6pm 
Number Completed 
between 6pm and 12am 
Number Completed 
between 12am and 6am 
Number Completed 
Less than 12 Hours 
after Previous Diary 
Completed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Listing 11: 
16.2.5.4: 
Individual Additional Nitazoxanide Data 
[Implementation Note: Additional Doses of Nitazoxanide will be based on records of Nitazoxanide on the concomitant medication form.] 
[Implementation Note: In the CSR, Subject ID should be USUBJID (not PATID) for purposes of de-identification.] Listing should be sorted by 
Treatment Group, Subject ID, Planned Time Point.] 
Treatment 
Group  
Subject ID  
Transplant Type 
Duration of Symptoms 
Number of Days Post Randomization 
(Duration) 
Number of Additional Doses Taken 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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16.2.6 Individual Efficacy and Immunogenicity Response Data 
Listing 12: 
16.2.6.1: 
Individual Treatment Phase Daily Diary Data 
[Implementation Note: “Too many” will be listed if number of stools was too many to count. If data is missing, it will be denoted as “—“. Rows will not 
be included for missing diary days. Imputation rules will not be included in the listings. Listing should be sorted by Treatment Group, Subject ID, 
Planned Time Point.] 
Treatment 
Group  
Subject ID  
Transplant Type 
Duration of 
Symptoms 
Actual Study Day 
Number of Bristol Type 
6 Stools 
Number of Bristol Type 7 
Stools 
Repeat Dose due 
to Vomiting 
Number of 
Episodes of 
Vomiting 
 
 
 
 
 
[e.g. 7, Too Many] 
[e.g. 7, Too Many] 
Yes/No 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Listing 13: 
16.2.6.2: 
Individual Longitudinal Phase Daily Diary Data 
[Implementation Note: If data is missing, it will be denoted as “—“. Rows will not be included for missing diary days. Imputation rules will not be 
included in the listings. Listing should be sorted by Treatment Group, Subject ID, Planned Time Point.] 
Treatment Group  
Subject ID  
Transplant Type 
Duration of Symptoms 
Actual Study Day 
Diarrhea (At Least 1 Type 6 or 
7 Bowel Movement) 
Vomiting 
 
 
 
 
 
Yes/No 
Yes/No 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Listing 14: 
16.2.6.3: 
Weekly Recall Diary 
[Implementation Note: If data is missing, it will be denoted as “—“. Rows will not be included for missing weeks.] 
Treatment 
Group  
Subject 
ID  
Transplant 
Type 
Duration 
of 
Symptoms 
Week 
Numbera 
Actual Study 
Day 
Average 
Number Bowel 
Movements/Day 
Average 
Number 
Vomiting 
Episodes/Day 
% Type 6 or 
7 Stool 
% Type 3, 
4, or 5 Stool 
Abdominal 
Painb 
Urgency to 
Have Bowel 
Movementb 
Fecal 
Incontinenceb 
Nauseab 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
a Week Number is based off of Planned Time Point. 
b Subjects rated these symptoms as 0 being none and 10 being the worst possible. 
 
 


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Listing 15: 
16.2.6.3: 
Individual PROMIS Scores Data – Quality of Life/PANAS 
[Implementation Note: Listing will provide the PROMIS T-scores for IBSQOL. EurQOL Measures will be reported as ‘Problems’ or ‘No Problems’. 
Positive Affect and Negative Affect will be the reported scores based off of the Definitions in Section 3.3.] 
Treatment 
Group 
Subject 
ID 
Transplant 
Type 
Duration 
of 
Symptoms 
Planned 
Time 
Point 
Actual 
Study 
Day 
Quality of 
Life 
(IBSQOL) 
EuroQOL-
5 Mobility 
EuroQOL-
5 Self-Care 
EuroQOL-
5 Usual 
Activities 
EuroQOL-5 
Pain/Discomfort 
EuroQOL-5 
Anxiety/Depression 
EuroQOL-
5 Health 
State 
Positive 
Affect 
Negative 
Affect 
EuroQOL-
5 Mobility 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Listing 16: 
16.2.6.5: 
Individual PROMIS Scores Data – Physical Function, Emotional, and Gastrointestinal Symptoms 
[Implementation Note: Listing will provide the PROMIS T-scores for Physical Function, Depression, Anxiety, Fatigue, and GI Symptoms.] 
Treatment 
Group 
Subject 
ID 
Transplant 
Type 
Duration of 
Symptoms 
Planned 
Time Point 
Actual Study 
Day 
Physical 
Function 
Depression 
Anxiety 
Fatigue 
GI: 
Diarrhea 
GI: 
Nausea 
GI: Fecal 
Incontinence 
GI: Belly 
Pain 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Listing 17: 
16.2.6.4: 
Individual NoV PCR Results Data 
[Implementation Note: “N/A” will be listed in the NoV GI PCR Test Result column if NoV GI test not conducted.] 
[Implementation Note: Update as appropriate for your study assay/strain and endpoints. In the CSR, Subject ID should be USUBJID (not PATID) for 
purposes of de-identification.] Listing should be sorted by Treatment Group, Subject ID, Planned Time Point.] 
Treatment 
Group  
Subject ID  
Transplant Type 
Duration of Symptoms 
Planned Time Point 
Actual Study Day 
NoV GII PCR Test 
Result 
NoV GI PCR Test 
Result 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Listing 18: 
16.2.6.7: 
Individual Co-pathogen Status Data 
[Implementation Note: Update as appropriate for your study assay/strain and endpoints. In the CSR, Subject ID should be USUBJID (not PATID) for 
purposes of de-identification.] Listing should be sorted by Treatment Group, Subject ID, Planned Time Point.] 
Treatment 
Group  
Subject ID  
Transplant Type 
Duration of Symptoms 
Planned Time Point 
Actual Study Day 
Co-Pathogen Detected 
 
 
 
 
 
 
[e.g. Norovirus GI/GII, 
Norovirus 
GI/GII/Clostridium 
difficile toxin A/B, 
None] 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Listing 19: 
16.2.6.8: 
Individual Baseline Secretor Status Data 
[Implementation Note: Update as appropriate for your study assay/strain and endpoints. In the CSR, Subject ID should be USUBJID (not PATID) for 
purposes of de-identification.] Listing should be sorted by Treatment Group, Subject ID, Planned Time Point.] 
Treatment Group  
Subject ID  
Transplant Type 
Duration of Symptoms 
Phenotype Result 
Genotype Result 
 
 
 
 
Secretor/Non-secretor 
Secretor/Non-secretor 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Listing 20: 
16.2.6.9: 
Individual Serum Immunology Response Data 
[Implementation Note: In the CSR, Subject ID should be USUBJID (not PATID) for purposes of de-identification.] Listing should be sorted by 
Treatment Group, Subject ID, Planned Time Point.] 
Treatment 
Group  
Subject ID  
Transplant Type 
Duration of 
Symptoms 
Planned Time Point 
Actual Study Day 
NoV IgA Result 
NoV IgG Result 
Total IgG 
Result 
NoV IgM 
Result 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Listing 21: 
16.2.6.10: 
Individual Stool Immunology Response Data 
[Implementation Note: In the CSR, Subject ID should be USUBJID (not PATID) for purposes of de-identification.] Listing should be sorted by 
Treatment Group, Subject ID, Planned Time Point.] 
Treatment 
Group  
Subject ID  
Transplant Type 
Duration of Symptoms 
Planned Time Point 
Actual Study Day 
NoV IgA Result 
NoV IgG Result 
NoV IgM Result 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Listing 22: 
16.2.6.8: 
Individual Chromaturia Data 
[Implementation Note: In the CSR, Subject ID should be USUBJID (not PATID) for purposes of de-identification.] Listing should be sorted by 
Treatment Group, Subject ID, Planned Time Point.] 
Treatment Group  
Subject ID  
Transplant Type 
Duration of Symptoms 
Actual Study Day Chromaturia Reported 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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16.2.7 Adverse Events 
Listing 23: 
16.2.7.1: Unsolicited Adverse Events 
[Implementation Note: If the event is ongoing (no stop date), indicate “ongoing” in the “Duration” column. In the “If Not Related, Alternate Etiology” 
column, merge the 2 data fields for collecting alternate etiology, separate by a colon. This listing includes all unsolicited adverse events. If there are no 
comments for an event, populate ‘Comments’ row with ‘None’. Add columns for MedDRA HLT or LLT depending on halting criteria or other study 
needs. In the CSR, Subject ID should be USUBJID (not PATID) for purposes of de-identification. Sort order: Treatment Group, Subject ID, Associated 
with Dose No., No. of Days Post Associated Dose. If the table will be multi-page, move the footnote/explanation to the footer so that it repeats for each 
page of the table.] 
Adverse 
Event 
No. of Days Post 
First Dose 
(Duration) 
Severity 
SAE? 
Relationship 
to Study 
Treatment 
In Not 
Related, 
Alternative 
Etiology 
Action Taken 
with Study 
Treatment 
Subject 
Discontinued 
Due to AE 
Outcome 
MedDRA 
System Organ 
Class 
MedDRA 
Preferred 
Term 
Treatment Group: , Subject ID: , Transplant Type: , Duration of Symptoms: , AE Number:  
 
 
 
 
 
 
 
 
 
 
 
Comments: 
Treatment Group: , Subject ID: , Transplant Type: , Duration of Symptoms: , AE Number:  
 
 
 
 
 
 
 
 
 
 
 
Comments: 
Note: For additional details about SAEs, see Section 14.3.2. 


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16.2.8 Individual Laboratory Measurements 
Listing 24: 
16.2.8.1: Clinical Laboratory Results – Chemistry 
[Implementation Note: Will include results for Creatinine, Alkaline phosphatase, AST, ALT, BUN, and Total bilirubin.] 
[Implementation Note: These listings (for hematology, chemistry, and urinalysis) include all laboratory results, scheduled and unscheduled. These 
listings are not color-coded, but the severity should be included in parentheses after the result for abnormal results, e.g., 16.2 (Mild). The “extra” fields 
that are completed for abnormal results are not included in this listing; they are included in the listing of abnormal laboratory results that is included in 
the table shells document. In the CSR, Subject ID should be USUBJID (not PATID) for purposes of de-identification. Sort oder: Treatment Group, 
Subject ID, Laboratory Parameter, and Planned Time Point.] 
Treatment 
Group 
Subject ID 
Transplant 
Type 
Duration of 
Symptoms 
Planned 
Time Point  
Actual 
Study 
Day  
Sex  
Age (years) 
Laboratory 
Parameter (Units) 
Result 
(Severity 
Grade) 
Reference 
Range Low 
Reference Range 
High 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Listing 25: 
16.2.8.2: Clinical Laboratory Results – Hematology 
[Implementation Note: Will include results for WBC, Hemoglobin, Platelets, Neutrophil, Lymphocyte, Eosinophil, Monocyte, Hematocrit, Mean 
corpuscular volume.] 
Treatment 
Group 
Subject ID 
Transplant 
Type 
Duration of 
Symptoms 
Planned 
Time Point  
Actual 
Study 
Day  
Sex  
Age 
(years) 
Laboratory 
Parameter (Units) 
Result (Severity 
Grade) 
Reference 
Range Low 
Reference Range 
High 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Listing 26: 
16.2.8.3: Clinical Laboratory Results – T-Cell Subsets 
[Implementation Note: Will include results for CD3+, CD3+ %, CD4+, CD4+ %, CD8+, CD8+ %.] 
Treatment 
Group 
Subject ID 
Transplant 
Type 
Duration of 
Symptoms 
Planned Time 
Point  
Actual 
Study Day  
Sex  
Age 
(years) 
Laboratory Parameter 
(Units) 
Result 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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16.2.8.2 
Vital Signs  
Listing 27: 
16.2.8.2.1: Vital Signs 
[Implementation Note: This listing includes all vital sign assessments, scheduled and unscheduled. In the CSR, Subject ID should be USUBJID (not 
PATID) for purposes of de-identification. Sort order: Treatment Group, Subject ID, Planned Time Point.] 
Treatment 
Group 
Subject ID 
Transplant 
Type 
Duration of 
Symptoms 
Planned 
Time Point 
Actual 
Study Day 
Temperature 
(°F) 
Systolic Blood 
Pressure 
(mmHg) 
Diastolic Blood 
Pressure 
(mmHg) 
Heart Rate 
(beats/min) 
Respiratory Rate 
(breaths/min) 
Weight 
(kg) 
Height 
(cm) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Listing 28: 
16.2.8.3.1: Hospitalizations 
Treatment Group 
Subject ID 
Transplant 
Type 
Duration of 
Symptoms 
No. of Days 
Post 
Randomization 
(Duration) 
Diagnosis 
Reason for 
hospitalization 
Discharge 
Status 
MedDRA 
System 
Organ Class 
MedDRA 
Preferred 
Term 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Listing 29: 
16.8.3.2: 
Individual Graft Loss or Rejection Data 
[Implementation Note: In the CSR, Subject ID should be USUBJID (not PATID) for purposes of de-identification.] Listing should be sorted by 
Treatment Group, Subject ID, Planned Time Point. If no resolution date, duration should be listing as ONGOING.] 
Treatment 
Group  
Subject ID  
Transplant Type 
Duration of Symptoms 
Number of Days Post Randomization 
(Duration) 
Event Type 
 
 
 
 
 
Graft Loss/Graft Rejection 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Listing 30: 
16.8.3.3: 
Deaths 
[Implementation Note: Cause of Death will be listed as the Cause of Death on the CRF. If multiple causes listed, Cause of Death field will be populated 
as “Primary/Secondary/Tertiary/Quaternary/Quinary”. Listing should be sorted by Treatment Group, Subject ID, Planned Time Point.] 
Treatment 
Group  
Subject ID  
Transplant Type 
Duration of Symptoms 
Number of Days Post Randomization  
Cause of Death 
 
 
 
 
 
Primary/secondary/etc. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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16.2.8.4 Physical Exam Findings 
Listing 31: 
16.2.8.4.1: Physical Exam Findings 
[Implementation Note: This listing includes all physical exam findings, scheduled and unscheduled. If a subject does not have any findings upon 
examination, they will not be included in this listing. If reported as an AE, display “Yes” with the AE Number in parentheses, e.g., “Yes (7)”. In the 
CSR, Subject ID should be USUBJID (not PATID) for purposes of de-identification. Sort order: Treatment Group, Subject ID, Planned Time Point.] 
Treatment 
Group 
Subject ID 
Transplant 
Type 
Duration of 
Symptoms 
Planned Time 
Point 
Actual Study 
Day 
Body System 
Abnormal Finding 
Reported as an AE? 
(AE Description; 
Number) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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16.2.8.5 Concomitant Medications 
Listing 32: 
16.2.8.5.1: Concomitant Medications 
[Implementation Note: “Medication Start Day” and “Medication End Day” are relative to enrollment (which is Day 1, day before enrollment is Day -1). 
For medication start dates that are > 30 days prior to enrollment, rather than use exact study days, categorize as follows: 
• 5 years prior to enrollment 
• 1-5 years prior to enrollment 
• 1-12 months prior to enrollment 
If ongoing, display “Ongoing” in the “Medication End Day” column. If taken for an AE or MH, display “Yes” with the AE or MH Number in 
parentheses, e.g., “Yes (7)”. In the CSR, Subject ID should be USUBJID (not PATID) for purposes of de-identification. Sort order: Treatment Group, 
Subject ID, and CM Number.] 
Treatment 
Group 
Subject 
ID 
Transplant 
Type 
Duration 
of 
Symptoms 
CM 
Number 
Medication 
Medication Start 
Day 
Medication End 
Day 
Indication 
Taken for an AE? 
(AE Description; 
Number) 
Taken for the 
treatment of 
Norovirus? 
ATC Level 1  
(ATC Level 2) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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16.2.8.6 Pregnancy Reports 
Listing 33: 
16.2.8.6.1: Pregnancy Reports – Maternal Information 
[Implementation Note: Only include the “Pregnancy Number” column if a subject has more than 1 pregnancy. Date of Conception will be calculated 
based on estimated delivery date. BMI will be calculated based on pre-pregnancy height and weight. Mother’s weight gain will be calculated based on 
pre-pregnancy weight and end of pregnancy weight. If a major congenital anomaly with previous pregnancy, display “Yes” and the text from the 
“specify” field, separated by a colon. If any substance use is reported, include a listing of substance use. If autopsy revealed an alternate etiology, display 
“Yes” and the text from the “specify” field, separated by a colon. If abnormality in product of conception, display “Yes” and the text from the “specify” 
field, separated by a colon. In the CSR, Subject ID should be USUBJID (not PATID) for purposes of de-identification. Sort order: Treatment Group, 
Subject ID, Pregnancy Number.] 
` 
Subject 
ID  
Pregnancy 
Number 
Study Day 
Corresponding 
to Estimated 
Date of 
Conception 
Source of 
Maternal 
Information 
Pregnancy 
Status 
Mother’s 
Pre-
Pregnancy 
BMI 
Mother’s 
Weight 
Gain 
During 
Pregnancy 
Tobacco, 
Alcohol, or 
Drug Use 
During 
Pregnancy? 
Medications 
During 
Pregnancy? 
Maternal 
Complications 
During 
Pregnancy? 
Maternal 
Complications 
During Labor, 
Delivery, or 
Post-Partum? 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: Maternal Complications are included in the Adverse Event listing. Medications taken during pregnancy are included in the Concomitant Medications Listing. 
Listing 34: 
16.2. 8.6.2: Pregnancy Reports – Gravida and Para 
 
 
 
Live Births 
 
 
 
 
 
Subject 
ID 
Pregnancy 
Number 
Gravida 
Extremely 
PBa 
Very 
Early 
PBa 
Early 
PBa 
Late 
PBa 
Early 
TBb 
Full 
TBa 
Late 
TBa 
Post 
TBa 
Still 
Births 
Spontaneous 
Abortion/ 
Miscarriage 
Elective 
Abortions 
Therapeutic 
Abortions 
Major 
Congenital 
Anomaly 
with 
Previous 
Pregnancy? 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: Gravida includes the current pregnancy, para events do not. 
a Preterm Birth 
a Term Birth 
 
 


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Listing 35: 
16.2. 8.6.3: Pregnancy Reports – Live Birth Outcomes 
Subject 
ID 
Pregnancy 
Number 
Fetus 
Number 
Pregnancy 
Outcome 
(for this 
Fetus) 
Fetal 
Distress 
During 
Labor and 
Delivery? 
Delivery 
Method 
Gestational 
Age at Live 
Birth  
Size for 
Gestational 
Age 
Apgar 
Score, 1 
minute 
Apgar 
Score, 5 
minutes 
Cord pH 
Congenital 
Anomalies? 
Illnesses/ 
Hospitalizations 
within 1 Month of 
Birth? 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: Congenital Anomalies are included in the Adverse Event listing. 
 
Listing 36: 
16.2. 8.6.4: Pregnancy Reports – Still Birth Outcomes 
Subject 
ID 
Date of 
Initial 
Report 
Fetus 
Number 
Pregnancy 
Outcome 
(for this 
Fetus) 
Fetal Distress 
During 
Labor and 
Delivery? 
Delivery 
Method 
Gestational 
Age at Still 
Birth 
Size for 
Gestational 
Age 
Cord pH 
Congenital 
Anomalies? 
Autopsy 
Performed? 
If Autopsy, Etiology 
for Still Birth 
Identified? 
 
 
 
 
 
 
 
 
 
 
 
 
 
Listing 37: 
16.2. 8.6.5: Pregnancy Reports – Spontaneous, Elective, or Therapeutic Abortion Outcomes 
Subject 
ID 
Date of Initial 
Report 
Fetus Number 
Pregnancy Outcome 
(for this Fetus) 
Gestational Age at 
Termination 
Abnormality in Product of Conception? 
Reason for Therapeutic 
Abortion