Clinical trial NCT04858425
Conditions: Covid19
Keywords: SARS-CoV-2 Covid Covid19 Diarrhea Covid19 GI Infection
Sponsor: Entero Therapeutics
Start date: 2021-04-30; Completion date: 2023-09-10
Enrollment: 166 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a 2-part, 2-arm, Phase 2 , multicentre, randomized, double-blind, placebo-controlled study in adults with COVID-19 with gastrointestinal infection.

Detailed description:

Arms: arm 1: Niclosamide tablets 400 mg 3 times daily for 14 days arm 2: Matching placebo tablets 3 times daily for 14 days
Interventions: intervention 1: Niclosamide intervention 2: Placebo
Intervention descriptions: intervention 1: Niclosamide tablets 400 mg 3 times daily for 14 days intervention 2: Matched placebo tablets 400 mg 3 times daily for 14 days

Protocol documents:
Prot_000.pdf: 
Official Title: 
Clinical Study Protocol 
A Phase 2, Randomized, Double-Blind, 
Placebo-Controlled Study on the Safety and 
Efficacy of Niclosamide in Patients with 
COVID-19 with Gastrointestinal Infection 
NCT 04858425 
Date of Document 
15DEC2021 


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CLINICAL STUDY PROTOCOL 
A 2-Part, 2-Arm, Phase 2, Randomized, Double-Blind, Placebo-Controlled 
Study on the Safety and Efficacy of Niclosamide in Patients with COVID-19 
with Gastrointestinal Infection 
 
Study Name 
RESERVOIR: A Phase 2, Randomized, Double-Blind, 
Placebo-Controlled Study on the Safety and Efficacy of 
Niclosamide in Patients with COVID-19 with 
Gastrointestinal Infection 
Protocol Number 
AZ-NICL-COV-1 
Investigational Product Niclosamide 
Phase 
Phase 2 
Sponsor 
AzurRx BioPharma, Inc. 
777 Yamato Road, Suite 502 
Boca Raton, FL 33431 
Protocol Date 
15 December 2021 
Protocol Version 
3.1 
Previous Versions 
1.0, August 17, 2020 
1.1, March 08, 2021 
1.2, March 29, 2021 
1.3, April 08, 2021 
1.4, April 28, 2021 
1.5, May 14, 2021 
2.0, May 27, 2021 
3.0, July 30, 2021 
 
 
 
This protocol may not be reproduced, or communicated to a third party, 
without the written permission of AzurRx. 




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2 
DECLARATION OF INVESTIGATOR 
I have read and understood all sections of the protocol entitled “A 2-Part, 2-Arm, Phase 2, 
Randomized, Double-Blind, Placebo-Controlled Study on the Safety and Efficacy of 
Niclosamide in Patients with COVID-19 with Gastrointestinal Infection” and the accompanying 
investigator’s brochure. 
I agree to supervise all aspects of the protocol and to conduct the clinical investigation in 
accordance with the Final Protocol Version 3.0, dated 30 July 2021, the International Council for 
Harmonisation harmonised tripartite guideline E6(R2): Good Clinical Practice and all applicable 
government regulations. I will not make changes to the protocol before consulting with AzurRx 
BioPharma, Inc. or implement protocol changes without independent ethics committee approval 
except to eliminate an immediate risk to participants. I agree to administer study treatment only 
to participants under my personal supervision or the supervision of a sub investigator. 
I will not supply the investigational product to any person not authorized to receive it. 
Confidentiality will be protected. Participant identity will not be disclosed to third parties or 
appear in any study reports or publications. 
I will not disclose information regarding this clinical investigation or publish results of the 
investigation without authorization from AzurRx BioPharma, Inc. 
 
 
 
 
Signature of Principal Investigator 
 
Date 
 
 
 
Printed Name of Principal Investigator 
 
 
 
 
 


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PROTOCOL SYNOPSIS 
Name of Sponsor/Company: AzurRx BioPharma, Inc. 
 
Name of Investigational Product: Niclosamide 
Protocol Number: AZ-NICL-COV-1 (Niclosamide in COVID-19) 
Study Name: RESERVOIR: A Phase 2, Randomized, Double-Blind, Placebo-Controlled 
Study on the Safety and Efficacy of Niclosamide in Patients with COVID-19 with 
Gastrointestinal Infection 
Study Sites: This study will be conducted at approximately 30 sites globally. 
Number of Patients: Up to approximately 168 
Phase of Development: 2 
Objectives 
The primary objective for Part 1 of the study is to evaluate the safety of niclosamide 
administered to patients with COVID-19. 
The primary objective for Part 2 of the study is to evaluate the effect of niclosamide in 
addition to Standard of Care (SoC) compared to placebo in addition to SoC on fecal clearance 
of SARS-CoV-2 RNA. 
The secondary objective of the study is to evaluate the clinical efficacy, safety, and tolerability 
of oral niclosamide in addition to SoC compared to placebo in addition to SoC. 
The exploratory objectives include characterization of the effect of niclosamide on disease 
progression and severity 4 and 6 months after starting treatment, and possible genotypic 
resistance analysis using the nasopharyngeal swabs and/or stool samples 
Study Design 
This is a 2-part, 2-arm, Phase 2, multicenter, randomized, double-blind, placebo-controlled 
study in adults with COVID-19.  
Part 1 will enroll approximately 9 patients. After treatment is concluded for all 9 patients, a 
Data Monitoring Committee (DMC) will review the safety data and determine if the study 
may proceed to Part 2 or if additional patients are needed to assess tolerability of the study 
drug. If additional patients are needed, approximately 9 more patients will be enrolled in Part 
1, and then the DMC will meet again after all patients are treated to determine if the study may 
proceed to Part 2.  
Part 2 will enroll up to approximately 150 patients receiving at least 1 dose of study treatment.  
Each part will include 2 study arms with randomized enrollment. Randomization of patients in 
Part 2 will be stratified by age and sex. 
I 


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Inclusion Criteria 
Subjects meeting all the following inclusion criteria will be considered eligible for the study: 
1. Patients who give their written consent for participation in the study and for personal data 
processing and are willing and able to comply with all study procedures. 
2. Patients of any gender who are at least 18 years of age. 
3. Part 1 only: Patients with a primary diagnosis of COVID-19, with or without pneumonia, 
who agree to be monitored daily for at least 7 days after randomization and who accept 
continuing to be assessed for the study procedures. 
4. Part 2 only: Patients with a primary diagnosis of COVID-19, with or without pneumonia. 
5. Patients who are reasonably expected to maintain and adhere to SoC treatments prescribed 
by their physician.  
6. Patients who had SARS-CoV-2 RNA presence in nasopharyngeal swab ≤5 days before 
randomization as confirmed by local or central laboratory. The assay used for testing at the 
laboratory should be approved or authorized for use by the FDA or local regulatory agency 
for diagnosing patients with COVID-19 at the time the test is used.  
7. Patients who are considered reliable and capable of adhering to the protocol, according to 
the judgment of the investigator. 
Exclusion Criteria 
Patients will be excluded from the study if one or more of the following criteria are applicable: 
1. At the time of randomization, patients who require intensive care unit (ICU) admission or 
patients with severe respiratory insufficiency who require mechanical ventilation or with 
rapid worsening of respiratory function leading to expectation for mechanical ventilation 
or ICU admission. 
2. Evidence of rapid clinical deterioration or existence of any life-threatening co-morbidity 
or any other medical condition that, in the opinion of the investigator, makes the patient 
unsuitable for inclusion. 
3. Patients who, at the time of enrollment, are not in a clinical condition compatible with the 
oral administration of the study drug. 
4. Patients with serum alanine transaminase (ALT) or aspartate transaminase (AST) >3 times 
upper limit of normal (ULN) detected within 24 hours prior to randomization or with other 
evidence of severe hepatic impairment (Child-Pugh Class C). 
5. Patients with an estimated GFR (eGFR) ≤30 mL/min/1.73m2 (based on CKD-EPI formula) 
at screening. 
6. Patients with a history of hypersensitivity or allergy to any component of the study drug. 
7. Enrollment in another concurrent clinical interventional study, intake of an investigational 
drug within 30 days prior to randomization, or intake of an investigational drug for 
COVID-19 within 3 months prior to randomization. Drugs approved under a US Food and 


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Drug Administration Emergency Use Authorization are not considered investigational 
under this exclusion. 
8. Pregnant or lactating women or women with a positive pregnancy test (urine or serum). 
Concomitant and Prohibited Medications 
Concomitant Medications: 
Other than study drugs, SoC as directed by the patient’s physician will be allowed. 
Vaccination status for COVID-19 will not influence eligibility for the study and will be 
considered SoC while the patient is on study. After randomization and treatment allocation, 
the SoC therapy can be modified by the investigator according to the patient’s needs. 
In case of worsening or need of mechanical ventilation or admission to ICU, patients will be 
treated with any medication or treatment based on the physicians’ judgment, without any 
constraint from the sponsor, including, but not limited to, antibiotics, antimycotics, steroids, 
alpha interferon, and immunoglobulins. 
Prohibited Medications: 
Investigational drugs received through participation in another clinical trial are prohibited 
through the Day 43 follow-up visit.  
Investigational Product, Dosage, Duration and Mode of Administration 
Niclosamide (active), supplied as 400-mg tablets, or placebo will be administered orally 3 
times per day (TID). Patients who are able to comply with the oral treatment must take, for 
each administration, 1 tablet (400-mg niclosamide or placebo) TID for 14 days. It is 
recommended to take the tablets after meals, with a glass of water to facilitate swallowing.  
Arm A (active): Continued SoC therapy together with niclosamide 400-mg tablets TID (total 
daily dose 1,200 mg) for 14 days. 
Arm B (placebo): Continued SoC therapy together with placebo tablets matching 
niclosamide TID for 14 days. 
Randomization and Stratification 
In Part 1: Patients will be randomized 2:1 between Arm A (active) and Arm B (placebo). 
In Part 2: Patients will be randomized 1:1 between Arm A (active) and Arm B (placebo) 
following stratification based on age and sex. 
Duration of Study 
Each patient will remain in the study for approximately 6 months, including 2 weeks of 
treatment and approximately 5.5 months of follow-up. The recruitment period will last 
approximately 5 months. 
The total study duration from first patient first visit (FPFV) to last patient last visit (LPLV) is 
expected to be approximately 11 months. 


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Criteria for Evaluation 
The primary endpoint of Part 1 is summarization of the safety results (adverse events 
[AEs], clinical laboratory results, and vital signs) comparing the niclosamide arm to the 
placebo arm.  
The primary endpoint in Part 2 is the time to fecal viral RNA clearance for patients with a 
positive Day 1 stool test for SARS-CoV-2 assessed by RT-qPCR in the niclosamide arm 
compared to the placebo arm. 
The secondary endpoints will all compare the niclosamide arm to the placebo arm. These 
secondary endpoints will be assessed for both Part 1 and Part 2: 
Gastrointestinal efficacy secondary endpoints are: (a) Part 1: time to fecal viral RNA 
clearance for patients with a positive Day 1 stool test for SARS-CoV-2 assessed by 
RT-qPCR; (b) time from the first dose of study treatment to the first formed stool (this 
formed stool must have been followed by a non-watery stool) in patients with loose or 
watery stool (Bristol Stool Scale Types 5-7) at Day 1; (c) time from the first dose of study 
treatment to the last loose or watery stool in patients with loose or watery stool (Bristol 
Stool Scale Types 5-7) at Day 1; (d) proportion of patients administered any anti-diarrheal 
agent from the first dose of study treatment to Day 15 and from Day 16 to 29; (e) time 
from first dose of study treatment to improvement of abdominal symptoms, if abdominal 
symptoms are present at Day 1 and (f) proportion of patients with a negative Day 1 stool 
test for SARS-CoV-2 who acquire SARS-CoV-2 in stool through Day 43. 
Systemic and respiratory efficacy secondary endpoints are: (g) proportion of patients 
with each clinical severity score as recommended by the World Health Organization 
(WHO) for COVID-19 studies by study visit; (h) total duration, type of administration, 
and quantity of supplemental oxygen treatment; (i) changes in body temperature; (j) SaO2 
on room air over time; (k) proportion of patients requiring ICU admission and length of 
ICU stay; (l) time to SARS-CoV-2 viral clearance from the nasopharynx (assessed by 
RT-qPCR); and (m) proportion of patients requiring hospitalization and duration of 
hospitalization. 
Safety and tolerability secondary endpoints are: (n) all-cause mortality 6 weeks after 
randomization; (o) proportion of patients with treatment-emergent adverse events 
(TEAEs) leading to study drug discontinuation; (p) serious adverse events (SAEs); (q) 
clinically significant changes in laboratory measurements; and (r) clinically significant 
changes in vital sign measurements. 
The exploratory endpoints will all compare the niclosamide arm to the placebo arm. These 
exploratory endpoints will be assessed for both Part 1 and Part 2: 
(r) all-cause mortality 4 months and 6 months after randomization; (s) proportion of 
patients with recurrence of COVID-19 symptoms after Day 43, at 4 months and 6 months 
after randomization; (t) proportion of patients with persistence of COVID-19 symptoms 
beyond Day 43, at 4 months and 6 months after randomization (u) proportion of patients 
with new hospitalization or rehospitalization after Day 43, at 4 months and 6 months after 
randomization; and (v) summarization of genotypic resistance analysis data. 


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TABLE OF CONTENTS 
CLINICAL STUDY PROTOCOL ............................................................................................1 
1 
PROTOCOL APPROVAL SIGNATURES ............................................................2 
2 
DECLARATION OF INVESTIGATOR .................................................................3 
3 
PROTOCOL SYNOPSIS.........................................................................................4 
TABLE OF CONTENTS ...........................................................................................................9 
LIST OF TABLES ...................................................................................................................12 
LIST OF FIGURES .................................................................................................................12 
4 
LIST OF ABBREVIATIONS ................................................................................13 
5 
BACKGROUND AND RATIONALE ..................................................................14 
5.1 
Background ......................................................................................................14 
5.2 
Background and Rationale Update ..................................................................14 
5.3 
Clinical Evidence of GI Involvement in COVID-19 .......................................15 
5.4 
Evidence for the GI System as a Reservoir .....................................................16 
5.5 
Fecal-Oral Transmission ..................................................................................17 
5.6 
Niclosamide .....................................................................................................17 
5.7 
Rationale for Dose Selection of Niclosamide ..................................................22 
5.8 
Dose Selection of Niclosamide in the Treatment of COVID-19 .....................23 
5.9 
Other Clinical Trials on COVID-19 Using Niclosamide .................................23 
5.10 
Rationale for the Study ....................................................................................24 
6 
RISK/BENEFIT ASSESSMENT ..........................................................................25 
6.1 
Risk for the Patient ...........................................................................................25 
6.2 
Other Risks.......................................................................................................25 
6.3 
Potential Benefit for the Patient .......................................................................25 
6.4 
Potential Benefit for the Community ...............................................................26 
6.5 
Risk Mitigation ................................................................................................26 
6.6 
Regulatory Compliance ...................................................................................26 
7 
OBJECTIVES ........................................................................................................27 
7.1 
Primary Objective ............................................................................................27 
7.2 
Secondary Objective ........................................................................................27 
7.3 
Exploratory Objective ......................................................................................27 
8 
ENDPOINTS .........................................................................................................28 
8.1 
Primary Endpoint .............................................................................................28 
8.2 
Secondary Endpoints .......................................................................................28 
8.3 
Exploratory Endpoints .....................................................................................29 
9 
INVESTIGATIONAL PLAN ................................................................................30 
9.1 
Overall Study Design and Plan: .......................................................................30 
9.1.1 
Study Design, Part 1 ............................................................................30 


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9.1.2 
Study Design, Part 2 ............................................................................30 
9.2 
Study Treatment and Its Duration ....................................................................30 
9.3 
Study Duration and Recruitment Period ..........................................................31 
9.4 
Study Population ..............................................................................................31 
9.5 
Inclusion Criteria .............................................................................................31 
9.6 
Exclusion Criteria ............................................................................................32 
9.7 
Investigational Medicinal Products (IMPs) .....................................................33 
9.7.1 
Formulation and Packaging .................................................................33 
9.7.2 
Allocation to Study Treatment .............................................................33 
9.7.3 
Product Shipment, Storage, Distribution, and Accountability .............33 
9.7.4 
IMP Resupply ......................................................................................34 
9.7.5 
IMP Misuse/Overdose .........................................................................34 
9.7.6 
IMP Administration .............................................................................34 
9.7.7 
IMP Return, Destruction, and Recall ...................................................35 
9.8 
Concomitant Medications and Prohibited Treatments .....................................35 
10 
STUDY PROCEDURES .......................................................................................36 
10.1 
Day -3, -2, or -1: Screening .............................................................................36 
10.2 
Day 1: Treatment .............................................................................................37 
10.3 
Part 1 Only: Days 2, 3, 5, 6, and 7: Safety Monitoring ...................................37 
10.4 
Days 4 (±1 day), 8 (±1 day), and 15 (±2 day): Treatment ...............................37 
10.5 
Days 22 (±2 days), 29 (±2 days), 36 (±3 days), and 43 (±3 days): Short-Term 
Follow-Up ........................................................................................................38 
10.6 
Four and Six Months After First Dose (±1 week): Long-Term Follow-Up ....38 
10.7 
Assessments .....................................................................................................38 
10.7.1 
Assessments for Diarrhea ....................................................................39 
10.7.2 
Overall Clinical Assessment ................................................................39 
10.7.3 
Stool Samples and Nasopharyngeal Swabs .........................................39 
10.7.4 
Safety and Laboratory Assessments ....................................................40 
10.8 
Patient Withdrawal ...........................................................................................40 
10.8.1 
Individual Treatment Discontinuation .................................................40 
10.8.2 
Participant Withdrawal from the Study ...............................................40 
10.8.3 
Lost to Follow-Up ................................................................................40 
11 
DATA MANAGEMENT.......................................................................................42 
11.1 
Data Sources ....................................................................................................42 
11.2 
Data Collection ................................................................................................42 
11.3 
Data Verification and Data Cleaning ...............................................................42 
11.4 
Data Coding .....................................................................................................42 
11.5 
Database Closure .............................................................................................43 


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11.6 
Data Storage and Retention .............................................................................43 
12 
STATISTICAL ANALYSIS PLAN AND STATISTICAL ANALYSIS .............44 
12.1 
Statistical Analysis Plan ...................................................................................44 
12.2 
Sample Size Calculation ..................................................................................44 
12.3 
Analysis Sets ....................................................................................................44 
12.4 
Analysis of Efficacy Variables ........................................................................45 
12.5 
Analysis of Safety Variables ............................................................................45 
12.6 
Interim Safety Analysis for Study Continue/Pause Decision Part 1 ................46 
12.7 
Interim Safety Analysis Part 2 .........................................................................46 
12.8 
Handling of Missing Data ................................................................................46 
12.9 
Data Monitoring Committee ............................................................................47 
12.10 
Planned Analyses and Unblinding ...................................................................47 
12.10.1 
Day 43 Final Analysis ..........................................................................47 
12.10.2 
End of Study Final Analysis ................................................................47 
13 
SAFETY REPORTING .........................................................................................48 
13.1 
Definitions of Adverse Events and Serious Adverse Events ...........................48 
13.1.1 
Evaluation of Adverse Events ..............................................................48 
13.1.2 
Definition of Serious and Nonserious Adverse Events ........................48 
13.2 
Reporting/Documentation of Adverse Events .................................................49 
13.3 
Reporting Requirements ..................................................................................50 
13.4 
Special Situations .............................................................................................51 
14 
OTHER ASPECTS ................................................................................................52 
14.1 
Quality Assurance and Quality Control Procedures ........................................52 
14.1.1 
Site Monitoring ....................................................................................52 
14.1.2 
Quality Assurance Audits ....................................................................52 
14.2 
Ethical Considerations .....................................................................................52 
14.3 
Regulatory and Ethical Compliance ................................................................52 
14.4 
Subject Information and Consent.....................................................................53 
14.5 
Subject Confidentiality ....................................................................................53 
14.6 
Protocol Amendments ......................................................................................54 
14.7 
Registration of the Protocol .............................................................................54 
14.8 
Study Report and Communication of Results ..................................................54 
15 
REFERENCES ......................................................................................................55 
16 
APPENDICES .......................................................................................................59 
16.1 
Appendix A - Schedule of Assessments ..........................................................60 
16.2 
Appendix B - Bristol Stool Scale .....................................................................62 
16.3 
Appendix C - WHO Ordinal Scale for Clinical Improvement ........................63 
 


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LIST OF TABLES 
Table 1 
In Vitro Antiviral Activity of Niclosamide Against Coronaviruses That 
Cause SARS and MERS ............................................................................21 
 
LIST OF FIGURES 
Figure 1 
Dose-Response Curve Analysis of Niclosamide by Immunofluorescence 19 
Figure 2 
Concentration-Dependent Inhibition of SARS-CoV-2 Growth by 
Niclosamide ...............................................................................................20 
 


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4 
LIST OF ABBREVIATIONS 
ABBREVIATIONS 
DEFINITIONS 
ACE2 
Angiotensin-converting enzyme 2 
AE 
Adverse event 
ALT 
Alanine transaminase 
AST 
Aspartate transaminase 
BP 
Blood pressure 
CI 
Confidence interval 
COVID-19 
Coronavirus disease 2019 
CRA 
Clinical research associate 
CRO 
Contract research organization 
DMC 
Data Monitoring Committee 
eCRF 
Electronic case report form 
FPFV 
First patient first visit 
GCP 
Good Clinical Practice 
GI 
Gastrointestinal 
GMP 
Good Manufacturing Practice 
ICF 
Informed consent form 
ICU 
Intensive care unit 
IMP 
Investigational medical product 
IWRS 
Interactive web randomization system 
LPLV 
Last patient last visit 
MedDRA 
Medical Dictionary for Regulatory Activities 
MERS 
Middle East respiratory syndrome 
PT 
Preferred term 
RT-qPCR 
Reverse transcriptase-quantitative polymerase chain reaction 
SAE 
Serious adverse event 
SaO2 
Blood oxygen saturation by pulse oximetry 
SAP 
Statistical analysis plan 
SARS 
Severe acute respiratory syndrome 
SARS-CoV-2 
Severe acute respiratory syndrome coronavirus 2 
SoC 
Standard of care 
SOC 
System organ class 
TEAE 
Treatment-emergent adverse event 
TID 
3 times per day (ter in die) 
ULN 
Upper limit of normal 
WHO 
World Health Organization 


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5 
BACKGROUND AND RATIONALE 
5.1 
Background 
The coronavirus disease (COVID-19 2019) is a public health emergency of international concern 
caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus. An 
increasing volume of convergent evidence indicates that gastrointestinal (GI) infection and 
fecal-oral transmission of SARS-CoV-2 are important factors in the clinical presentation, 
virology, and epidemiology of COVID-19. There is no etiological treatment for COVID-19 GI 
effects, representing a potentially unmet therapeutic need. 
5.2 
Background and Rationale Update 
The original protocol was prepared and submitted about one year ago (August 2020).  The 
overall rationale and objective for targeting acute GI infection with SARS-CoV-2 remains the 
same.  The compelling set of epidemiological studies referenced in the Section below confirm 
that GI infection with SARS-CoV-2 remains an important COVID-19 clinical problem that 
deserves focused attention with a gut targeted pharmacologic agent, such as niclosamide.  
However, it has become apparent that the original design of the clinical trial is too restrictive.  
The use of overt clinical diarrhea coupled with a positive respiratory swab positive for SARS-
CoV-2, which was the original plan, is likely to only capture a subset of the acute cases of GI 
infection. 
The overall incidence of positive stool samples for SARS-CoV-2 is best estimated from two 
large meta-analyses.  These reported that 43% (Wong et al., 2020) and 43% (van Dorn et al., 
2020) of patients had stool specimens positive for virus.  These reports included thousands of 
patients who were screened from multiple hospital centers.  Wong et al., 2020 reported that 
among the patients with positive stool samples, only 77% reported overt GI symptoms.  In 
separate smaller studies, prospective screening of stool specimens for SARS-CoV-2 detected 
virus in 55% of patients with positive respiratory disease (Wu et al., 2020) and 67% of patients 
with respiratory disease (Chen et al., 2020).  In the latter report only 19% of patients presented 
with GI symptoms. 
Important learnings from these reports are that: 1.  In patients with SARS-CoV-2 infection of the 
GI tract, overt clinical signs and symptoms of GI infection, including diarrhea, are present in 
only a fraction of the cases.  Thus, enrolling patients for treatment of GI infection based solely 
on diarrhea will miss a majority of infected patients; 2.  In every study in which prospective 
monitoring of stool cultures was conducted, the presence of virus in stool lasted considerably 
longer than it lasted in the respiratory tract.  In some cases, virus was detected in stool over one 
month after the respiratory episode was resolved.  A reservoir of virus likely remained silently in 
the gut, without persistence of GI symptoms.  It is also currently unknown if the GI infection 
results in prolonging the course and spread of the infection. 
This updated (version 3.0, July 2021) protocol will therefore enroll any patient with positive 
respiratory swabs for SARS-CoV-2, regardless of overt GI symptoms.  This will allow 
enrollment of patients with acute symptomatic as well as clinically silent GI infection.  Stool 
samples from all enrolled patients will be screened just prior to beginning treatment for presence 


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of virus.  The primary efficacy endpoint of time to resolution of stool SARS-CoV-2 positivity 
will remain the same and will be conducted in the subgroup with positive stools at the time of 
enrollment.  The patients who do not have SARS-CoV-2 in stool at baseline will remain on study 
for the full two week treatment, and will be followed per protocol with serial stool assays.  In 
addition to adding safety data, these tests will allow the detection of virus in stool, appearing 
after baseline.  Since ‘Long COVID Syndrome’ has been reported to include 50 to 60% of 
patients with GI symptoms (Davis et al., 2020; Dennis et al., 2021), we will follow all enrollees 
for 4 and 6 month clinical follow-ups to ascertain the potential impact of our treatment on long 
haul COVID.  The addition of clinically silent GI infections to our protocol may be of particular 
value for this observation.  
5.3 
Clinical Evidence of GI Involvement in COVID-19 
The prevalence of GI signs and symptoms associated with SAR-CoV-2 infections (probably 
underestimated), the time course of GI symptoms often occurring early in infection, frequent 
liver involvement, and detection of viral RNA in stool samples and bathroom surfaces 
underscore the importance of the GI tract in the clinical course and epidemiology of COVID-19. 
Moreover, GI involvement in the clinical course and transmission of similar viruses (SARS-CoV 
and Middle East respiratory syndrome coronavirus [MERS-CoV]) highlight the potential 
significance of GI infection in COVID-19 pathogenesis. 
Prevalence of GI Symptoms in COVID-19. A meta-analysis of 60 clinical studies and case 
series involving 4,243 patients indicates that GI manifestations, mainly diarrhea, nausea, and 
vomiting, affect 17.6% (95% confidence interval [CI]: 12.3 to 24.5; range: 0 to 100) of patients 
with diagnosis of COVID-19, with diarrhea present in 12.5% (95% CI: 9.6 to 16.0) of the 
reported cases (Cheung et al., 2020). Other epidemiological reviews, which were conducted on 
smaller, but robust, samples or observational studies not included in the above-mentioned meta-
analysis, confirm these observations (Han et al., 2020; Tian et al., 2020; Jin et al., 2020; 
Kujawski et al., 2020; D'Amico et al., 2020). In particular, it has been reported that 28.4% of 
COVID-19 patients present only with GI symptoms (nausea, vomiting, and diarrhea) without 
respiratory symptoms (Jin et al., 2020). 
The critical nature of respiratory symptoms has made them the primary focus for COVID-19 
diagnosis and treatment, while the GI effects of the virus are underestimated. The progressive 
increase of the proportion of patients with diarrhea reported in Wuhan in the later stage of the 
outbreak (Tian et al., 2020; Jin et al., 2020) suggests that as a more complete understanding of 
the clinical features of COVID-19 has developed, GI effects are becoming better recognized. 
Importantly, the prevalence of GI symptoms in COVID-19 is related to severity of respiratory 
impairment, which is 17.1% (95% CI: 6.9 to 36.7) in patients with severe respiratory disease and 
11.8% (95% CI: 4.1 to 29.1) in patients with non-severe disease (Cheung et al., 2020). This 
relationship suggests that possibility that GI infection with SARS-CoV-2 is a factor that 
determines overall disease severity. 
Time Course of GI Symptoms. An average of 19.4% of the patients with COVID-19 
experience diarrhea as their first symptom, even before the onset of respiratory symptoms or 
signs (Han et al., 2020). The importance of the GI tract in SARS-CoV-2 infection is also 
highlighted by several case series and case reports indicating that, in patients infected with 


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SARS-CoV-2, diarrhea usually precedes development of pneumonia (Pan L et al., 2020; Jin et 
al., 2020; Ferrey et al., 2020) or can be the only symptom reported by COVID-19 patients 
(Pan Q et al., 2020; Jin et al., 2020; Lo et al., 2020). In general, patients with diarrhea have 
longer hospital stays, longer duration of the symptoms, and longer period for complete viral 
clearance (44.3 vs 33.7 days; p = 0.003) compared to patients without diarrhea (Han et al., 2020; 
Pan L et al., 2020). 
Since clinicians commonly rely on the presence of respiratory symptoms to diagnose COVID-19, 
patients who present with only GI symptoms may go undiagnosed and therefore may potentially 
remain untreated and more likely to spread the virus. 
5.4 
Evidence for the GI System as a Reservoir 
Although GI symptoms in COVID-19 patients cannot be attributed with certainty to the presence 
of the virus in the GI tract, the fact that positive testing for viral RNA in stool, anal swabs, and 
rectal swabs and viral load are associated with a higher prevalence than GI symptoms makes it 
likely that a GI reservoir of infection causes the GI symptoms associated with COVID-19. 
It has been demonstrated that, like SARS-CoV, SARS-CoV-2 binds to angiotensin-converting 
enzyme 2 (ACE2) receptors present in the respiratory and intestinal tracts and that these 
receptors represent the entry point for the virus to the epithelial cells (Wan et al., 2020). 
It is well documented that ACE2 is likely the receptor that allows the SARS-CoV-2 to infect the 
cells. The ACE2 mRNA is detectable in the entire digestive tract (Harmer et al., 2002); however, 
protein expression may be greatest in the brush border of the enterocytes of the small intestine 
(Hamming et al., 2004). 
The ACE2-expressing enterocytes are invaded by SARS-CoV-2, leading to malabsorption, 
unbalanced intestinal secretion, and activated enteric nervous system, resulting in diarrhea 
(Zhang et al., 2020). Secondly, SARS-CoV-2 indirectly damages the digestive system through a 
chain of inflammatory responses (Pan Q et al., 2020). 
The ACE2 receptors are also expressed in the esophagus and in the colon (Zhang et al., 2020; 
Hamming et al., 2004), but the microvilli of the small intestine amplify its surface area by 60 to 
120 times; consequently, the small intestine represents approximately 92% of the entire surface 
of the digestive tract (Helander et al., 2014). For this reason, the target organ of the oral 
niclosamide can be considered the small intestine. 
Intestinal Virus. As shown in another study, patients without GI symptoms seem more likely to 
be cured and discharged than patients with digestive symptoms (60% vs 34.3%). This could be 
due either to viral replication in the GI tract causing more severe disease or to patients who do 
not initially have typical respiratory symptoms presenting with later stages of disease (Pan Q et 
al., 2020). 
Active viral replication was observed for SARS-CoV in biopsies obtained via colonoscopy up 
10 weeks after the onset of symptoms of both small and large intestine (Leung et al., 2003). This 
observation fits with staining of viral nucleocapsid protein of SARS-CoV-2 visualized in the 
cytoplasm of the GI epithelium of patients who tested positive to viral RNA in the feces, 


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suggesting that the continuous positive detection of viral RNA in the feces results from secretion 
of the nucleic acid from infected intestinal cells (Xiao et al., 2020). 
In an already mentioned meta-analysis (Section 5.3), the pooled prevalence of stool samples 
positive for virus RNA after hospitalization was 48.1% (95% CI: 38.3% to 57.9%) (Cheung et 
al., 2020). Similar data are also confirmed from other epidemiological reviews or cross-sectional 
studies (Tian et al., 2020; Lei et al., 2020). Remarkably, 1 study demonstrated that 70.3% 
(95% CI: 49.6% to 85.1%) of positive GI samples were collected after virus clearance from 
respiratory specimens and up to 33 days from the onset of the illness (Cheung et al., 2020). 
Moreover, stool viral clearance is significantly delayed (p < 0.001) in patients treated with 
steroids compared to patients not taking steroids, with mean clearance time of 20 days versus 
11 days (Ling et al., 2020). These conclusions are supported by other studies (Xiao et al., 2020) 
and reports characterizing the disease specifically in children (Tang et al., 2020). 
In a sample of 59 patients with COVID-19 in Hong Kong, the median fecal viral load was 5.1 
log10 copies per mL in patients with diarrhea versus 3.9 log10 cpm in patients without diarrhea 
(p = 0.06) (Cheung et al., 2020). Similar values were reported in a European study that 
documented positive detection of SARS-CoV-2 in stools, with viral load of 6.8 and 8.1 log10 
copies per gram of stool in 2 patients (Lescure et al., 2020). 
Irrespective of whether the intestine is the primary site of infection or acts as a reservoir for viral 
replication, the intestine appears to be important in the pathogenesis of SARS-CoV-2. 
5.5 
Fecal-Oral Transmission 
A number of observations support the risk of fecal-oral transmission of SARS-CoV-2 and the 
potentially important role that GI infection has transmissibility and epidemiology of COVID-19. 
• Family clusters. Lin at al. identified 23 (31.08%) patients with GI symptoms who had 
family clustering. This percentage was significantly higher than that in patients without GI 
symptoms (20.45%, p = 0.037) (Lin et al., 2020). 
• Fecal-oral transmission in larger communities of the closely related SARS virus. In 
2003, a housing estate known as Amoy Garden, nearby Hong Kong, experienced a severe 
SARS outbreak affecting 329 residents (33 deaths) that was traced to poor design and faulty 
maintenance of stacks collecting effluent from the plumbing system in the housing systems 
bathrooms (Leung et al., 2003). 
• Transmission in hospitals. Multiple SARS-CoV-2 outbreaks have been reported among 
healthcare workers, including physicians, nurses, and healthcare assistants, despite the use of 
surgical masks (Ho et al., 2020). It can be speculated that fecal-oral transmission plays a role 
in community hospital spread. 
 
5.6 
Niclosamide 
Niclosamide is currently approved in the European Union to treat infection with cestodes and it 
is included on the core list of minimum medicine needs for a basic healthcare system, as 


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published in the most current World Health Organization (WHO) list of essential medicines 
(WHO 2020). Niclosamide’s activity as an anti-helminthic treatment results from direct action in 
the intestinal lumen where it disrupts parasite oxidative metabolism, killing parasites. 
Niclosamide has been commercially available worldwide for more than 50 years as 500-mg 
tablets intended for use in pediatric and adult populations, at a dose of 2 g per adult or child over 
6 years of age. No significant safety issues have been reported. 
Drug repurposing/repositioning aimed at identifying new therapeutic applications for existing 
clinically approved drugs is a critical strategy to accelerate drug discovery for the COVID-19 
pandemic. Multiple laboratories across the globe have now identified and validated niclosamide 
to have potent antiviral activity against SARS-CoV-2. 
A small set (n = 49) of US Food and Drug Administration (FDA)-approved drugs was examined 
(selected based on either having known activity against SARS-CoV or being recommended by 
infectious disease experts) for activity against SARS-CoV-2 (Jeon et al, 2020). 
Niclosamide was the most potent of all agents tested in a Vero cell cytopathic assay (half 
maximal inhibitory concentration [IC50] = 0.28 μM) (Figure 1). For comparison in terms of 
potency, niclosamide outperformed reference compounds chloroquine, lopinavir, and remdesivir 
with IC50 values of 7.28, 9.12, and 11.41 μM, respectively. Thus, niclosamide is approximately 
25-fold more potent in vitro than remdesivir, a drug authorized for use against SARS-CoV-2 
(Jeon et al., 2020). 


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Figure 1 
Dose-Response Curve Analysis of Niclosamide by Immunofluorescence 
 
IC50 = half maximum inhibitory concentration, CC50 = half maximum cytotoxic concentration, SI = selectivity 
index 
The blue squares represent inhibition of virus infection (%) and the red triangles represent cell viability (%). Means 
± standard deviation were calculated from duplicate experiments. 
Source: Jeon et al., 2020. 
 
Gassen et al. reported studies aimed at understanding metabolic changes induced by SARS-CoV-
2 infection that are required for viral propagation. They demonstrated that similar to other 
coronaviruses, SARS-CoV-2 inhibits autophagy as a means of survival and propagation. 
Niclosamide, known previously to be an inducer of autophagy, was tested and shown to reverse 
the effect of the virus on autophagy and, in so doing, to inhibit viral propagation with a maximal 
inhibition of >99% and an IC50 of 0.17 µM (Figure 2) (Gassen et al., 2020). 
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Figure 2 
Concentration-Dependent Inhibition of SARS-CoV-2 Growth by 
Niclosamide 
 
IC50 = half maximal inhibitory concentration, R2 = coefficient of determination, PFU = plaque forming unit, 
SARS-CoV-2= severe acute respiratory syndrome coronavirus 2. 
SARS-CoV-2 plaque forming units (PFU) were determined at 48 hours (after niclosamide treatment was started) by 
plaque assay. Data are presented as virus growth (shown as percent of untreated control) plotted against niclosamide 
concentration. Error bars denote standard error of mean derived from n = 3 biologically independent experiments.  
Source: Gassen et al., 2020. 
 
Zeng et al. reported on a deep-learning approach mining data from 24 million PubMed 
publications followed by systematic validation using transcriptomics and proteomics data 
generated from SARS-CoV-2–infected human cells that identified niclosamide as 1 of 41 drug 
candidates for further testing in clinical trials for COVID-19 (Zeng et al., 2020). 
In addition to studies demonstrating antiviral effects on SARS-CoV-2, in vitro cellular assays 
demonstrate that niclosamide also blocks replication of the closely related coronaviruses 
SARS-CoV-1 and MERS-CoV; relevant published studies are summarized in Table 1. For 
example, the IC100 for SARS-CoV-2 antiviral activity, determined on a widely used in vitro 
model (Vero cell) is <3.0 µM (Figure 2), approximately the same magnitude as the IC100 of 
SARS-CoV, which is 94.6% similar in amino acid sequence and 80% similar in nucleotide 
sequence (Zhou et al., 2020). Moreover, earlier publications have also reported on niclosamide’s 
potent and broad-spectrum antiviral properties against Zika, Ebola, Rhinovirus, Chikungunya, 
and Epstein-Barr virus (Xu et al., 2020). 
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Table 1 
In Vitro Antiviral Activity of Niclosamide Against Coronaviruses That 
Cause SARS and MERS 
Reference Year 
Virus 
Cell Type 
Substrate or Model 
EC50 
EC100 
Wu et al., 2004 
SARS-CoV-1 
Vero E6 
Viral antigens S and N 
proteins (immunoblot) 
0.78 µM to 
1.56 µM 
1.56 µM 
Wu et al., 2004 
SARS-CoV-1 
Vero E6 
Viral antigens S and N 
proteins (IFA) 
1.56 µM to 
3.12 µM 
3.12 µM 
Wu et al., 2004 
SARS-CoV-1 
Vero E6 
Viral RNA replication 
(PCR) 
1.56 µM to 
3.12 µM 
3.12 µM 
Wen et al., 2007 
SARS-CoV-1 
Vero E6 
Expression of S protein 
(ELISA) 
<0.1 µM 
- 
Gassen et al., 2019 
MERS-CoV 
Vero B4 
Autophagic stimulation by 
SKP2 inhibition 
0.32 µM 
3 µM* 
Jeon et al., 2020 
SARS-CoV-2 
Vero E6 
Viral N protein (IFA) 
0.28 µM 
- 
Gassen et al., 2020 SARS-CoV-2 
Vero FM 
Viral RNA replication 
(PFU) 
0.17 µM 
1.24 µM** 
EC50 = half maximal effective concentration; EC100 = maximal effective concentration; ELISA = enzyme-linked 
immunosorbent assay; IFA = immunofluorescence assay; MERS = Middle East respiratory syndrome; MERS-CoV 
= Middle East respiratory syndrome coronavirus; N = nucleocapsid protein; PFU = plaque-forming units; S = spike 
protein; SARS = severe acute respiratory syndrome; SARS-CoV = severe acute respiratory syndrome coronavirus. 
* >99.99<99.999 viral growth inhibition; ** >99.99% viral growth inhibition 
 
The mechanistic basis for activity of niclosamide against SARS-CoV-2 has been investigated. 
Gassen et al. show that SARS-CoV-2 viral replication is linked to the ability of SARS-CoV-2 to 
activate SPK2 (S-Phase Kinase-Associated Protein 2), which, in turn, induces the degradation of 
a critical autophagy protein, Beclin-1 (BECN1). The overall consequence of this series of steps is 
that the virus limits autophagy as a survival mechanism. Niclosamide treatment overcomes this 
by inhibiting SPK2, thereby preventing Beclin-1 degradation, which enhances autophagy and 
restricts viral replication (Gassen et al., 2020). 
Niclosamide’s antiviral activity against SARS-CoV-2 is reproducible across studies, 
mechanistically well-defined, and approximately 25-fold more potent than other antiviral agents 
(chloroquine or remdesivir) that have already been clinically tested and used against SARS-CoV-
2 infection. Moreover, studies showing it inhibits replication of the related viruses SARS-CoV-1 
and MERS-CoV further support activity against pathogenic coronaviruses. 
At present, no animal models of SARS-CoV-2 have been validated as being able to predict 
clinical response of test articles in human disease. Studies of niclosamide in animal models of 
SARS-CoV-2, therefore, cannot be used to judge the likelihood of benefit in COVID-19 patients. 
This is underscored by differences in the role of the GI site of infection (target tissue for 
niclosamide therapy) in disease in animals versus humans that are expected based on 
animal-specific behaviors such as coprophagia that cause the virus in the stool to be continually 
and uncontrollably reintroduced through the oral route. Based on these considerations, 
preclinical efficacy studies of niclosamide in animal models of SARS-CoV-2 have not been 
performed by the sponsor. 


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Independent expert opinions have concluded that available evidence of niclosamide’s antiviral 
effects is sufficient to support clinical testing in COVID-19 (Kupferschmidt, 2020). Multiple 
other Phase 2/3 clinical trials evaluating standard formulation (non-micronized) niclosamide in 
COVID-19 have been announced (NCT04644705, NCT04749173, NCT04558021, 
NCT04753619, NCT04603924, and NCT04399356). This further indicates that available data on 
niclosamide’s antiviral properties against SARS-CoV-2 is widely considered sufficient to 
proceed with clinical testing. 
Niclosamide is poorly absorbed following oral administration, leaving the majority of the dose in 
the GI tract. This fact, together with the use of micronized niclosamide in the drug product to 
accelerate dissolution, allows this drug product to achieve pharmacologically effective 
concentrations of niclosamide in the GI tract while having almost no bioavailability, enhancing 
efficacy and safety. These properties make it ideal for treating GI disease and infections, 
including SARS-CoV-2 infection and GI symptoms of COVID-19. 
In summary, AzurRx BioPharma Inc. is developing a drug product containing micronized 
niclosamide in an immediate-release tablet formulation as treatment for SARS-CoV-2 intestinal 
infection in patients presenting with GI symptoms of COVID-19 disease. Evidence of 
niclosamide’s antiviral properties is sufficient to expect a clinical pharmacodynamic response 
against viral replication and clinical benefit, justifying the proposed clinical study in COVID-19 
patients and favorable benefit-risk assessment. 
5.7 
Rationale for Dose Selection of Niclosamide 
The rationale for determining the dose of niclosamide is based on the following path and data. 
The primary factor differentiating the current formulation from standard niclosamide 
formulations is rate of solubilization. The apparent increase in solubilization rate increases the 
potential for the current formulation to treat SARS-CoV-2. The rate of solubilization is low with 
only approximately 13% of the maximum amount entering solution in 90 minutes as reported by 
Devarakonda et al. (Devarakonda et al., 2005). The long time needed for solubilization is 
believed to be the source of differences between reports of solubility. 
The upper limit of niclosamide solubility in water is reported between 15 and 24 µmol/L 
(Devarakonda et al., 2005), while other references report lower concentrations. Experiments 
suggest that a standard formulation of niclosamide may not be able to achieve the concentration 
at the limit of solubility within 1 hour as may be required to treat the small intestine, but the 
micronized formulation is able to achieve approximately the upper limit of solubility 
concentrations in rat colonic mucosa within 1 hour after administration in the rectum as a 
suspension enema, whereas the standard formulation only achieves approximately 1% of that 
concentration in intestinal mucosa. 
The target location for prevention of SARS-CoV-2 infection in the current study is the gastric 
and intestinal epithelium. While the stomach, small and large intestines may be targets, based on 
ACE2 receptor expression levels, the small intestine is likely the most relevant target. 


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5.8 
Dose Selection of Niclosamide in the Treatment of COVID-19 
Dose selection for micronized niclosamide in the current study is made on the basis of safety and 
anticipated efficacy. The selected dose is 400-mg micronized niclosamide 3 times per day (TID) 
with meals, yielding a total daily dose of 1,200 mg (Schiller et al., 2005; Mudie et al., 2014).  
Safety of niclosamide is based on the long history of administration of niclosamide at doses up to 
2,000 mg/day, typically administered to adults as 2,000 mg once daily after breakfast 
(Bayer, Yomesan label). While the micronized formulation is anticipated to decrease the time to 
dissolve, it is not anticipated to significantly increase the extent of absorption. This is due to 
extensive first-pass metabolism in the intestine and liver in conjunction with the low solubility. 
Therefore, systemic toxicity is anticipated to be minimal (similar to standard formulations of 
niclosamide). 
To maximize potential efficacy, the goal of dose selection is to maintain coverage of the 
stomach, small intestine, and potentially the large intestine with a ≥3-μM dissolved niclosamide 
concentration for complete inhibition of in vitro viral replication (Gassen et al., 2020; Jeon et al., 
2020). A 400-mg niclosamide dose is approximately 1,220 μmol. When administered with a 
typical meal, approximately 750 mL (Schiller et al., 2005), this dose will achieve a nominal 
concentration of approximately 1,630 μM, but due to solubility limitations, the dissolved 
concentration would be approximately 20 μM (Devarakonda et al., 2005). The dynamics of 
transit through the small intestine (with decreasing concentrations starting approximately 2 hours 
after dose due to gastric half-emptying times) warrant increased concentrations relative to those 
required for viral inhibition. The concentration above the target allows for variability between 
patients along with both potential absorption and metabolism (both anticipated to be minimal) 
and for continued coverage during the transit of the dose from the stomach through the small 
intestine and to the colon. Dosing with meals is selected to increase the duration of stomach and 
small intestinal exposure to niclosamide. 
The dosing duration of 14 days is based on typical fecal viral shedding dynamics observed in 
COVID-19 (He et al., 2020). 
The micronized formulation is required to achieve efficacy in treatment of SARS-CoV-2 
infection rather than the standard formulation to increase the rate of dissolution, as the standard 
formulation is not observed to achieve a significant amount of dissolution prior to entering the 
colon: 13% of the saturating concentration is achieved in 90 minutes (Devarakonda et al., 2005). 
5.9 
Other Clinical Trials on COVID-19 Using Niclosamide 
Currently (as of February 2021), the ClinicalTrial.gov database reports 6 interventional studies 
that are recruiting: 
• NCT04644705: Phase 1 study. A 3-part Study to Investigate the Safety and Pharmacokinetics 
of a Novel Niclosamide Solution as a Treatment Option for COVID-19 in Combination With 
Camostat. 
• NCT04749173: Phase 1 study. A Double-blind, Randomized, Placebo-Controlled, Single-
Ascending Dose Phase I Study to Evaluate the Safety, Tolerability and Pharmacokinetic 


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Properties of Niclosamide Injectable (DWRX2003) Following Intramuscular Administration 
in Healthy Volunteers. Injectable formulation of niclosamide.  
• NCT04558021: Phase 3 study. A Phase III, Randomized, Placebo-Controlled, Clinical Trial 
to Evaluate the Efficacy and Safety of Co-administered Niclosamide in Patients Treated With 
an Established Regimen for Novel Coronavirus Infectious Disease (COVID-19).  
• NCT04753619: Phase 2 study. Effectiveness of Niclosamide as Add-on Therapy to the 
Standard of Care Measures in COVID-19 Management.  
• NCT04603924: Phase 2/3 study. A Phase 2/3 Randomized and Placebo-Controlled Study of 
ANA001 in Moderate and Severe COVID-19 Patients.  
• NCT04399356. Phase 2 study. Niclosamide for Patients With Mild to Moderate Disease 
From Novel Coronavirus (COVID-19). Standard formulation of niclosamide. 
 
None of these studies have intestinal viral clearance as a primary endpoint. The oral niclosamide 
used in these other studies is non-micronized material, whereas this study investigates 
micronized niclosamide that is expected to provide significant advantages by achieving greater 
soluble drug levels in the GI tract without significantly increasing systemic bioavailability and 
exposure. 
5.10 
Rationale for the Study 
There are currently no approved or investigational treatments with demonstrated clinical efficacy 
for control of the intestinal SARS-CoV-2 viral shedding and fecal positivity. The evaluation of a 
safe and effective antiviral agent that is able to potently block SARS-CoV-2 replication in the 
intestine addresses serious unmet medical and epidemiological needs. Considering the objective 
of this protocol, the overall risks to participants are outweighed by the potential benefits of 
niclosamide experimental therapy. For these reasons, the benefit-risk balance for this study is 
considered positive. 


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6 
RISK/BENEFIT ASSESSMENT 
6.1 
Risk for the Patient 
A specific risk for a patient participating in this study is the exposure to the adverse reactions of 
niclosamide. This drug was approved for use in humans as an anti-helminthic treatment in the 
early 1980s and is included in the WHO's list of essential medicines (WHO, 2007). 
To date, niclosamide has been administered to millions of people, including children, and 
appears to have a very good safety profile: GI disturbance is occasionally reported, whereas 
light-headedness and pruritus have been reported less frequently (Sweetman, 2012). Nausea, 
retching, and abdominal pain are also reported (WHO, 2008). 
Other reported AEs (1%-4% of patients) are vomiting, abdominal discomfort possibly associated 
with anorexia, diarrhea, drowsiness, dizziness, and headache. Less frequently reported AEs (<1% 
of patients) are rash, oral irritation, fever, rectal bleeding, weakness, bad taste in mouth, 
sweating, palpitation, constipation, alopecia, edema of an arm, backache, and irritability. A 
transient increase in serum AST has reportedly occurred in at least 1 patient who was physically 
dependent on opiate agonists. Urticaria, which may be caused by the presence of breakdown 
products of the dead or dying worms, has occurred rarely (McEvoy et al., 1995). 
6.2 
Other Risks 
The examinations and procedures required by the study do not expose the investigator or 
healthcare professionals to risks other than those that would normally involve the management of 
COVID-19 patients, assuming that the collection and treatment of biological samples (about 9 
pharyngeal swabs, 9 stool samples, and 6 blood draws per patient over 43 days) are performed 
using the standard safety procedures. 
6.3 
Potential Benefit for the Patient 
If the gut-selective antiviral activity of niclosamide were confirmed, the potential therapeutic or 
prophylactic return for the patient would be: 
a.
Effects on GI symptoms, and diarrhea in particular, due to the control of the viral replication
within the epithelial cells and reduced interaction with ACE2 receptors.
b. Effects on liver complications, likely as a consequence of the spread of the virus through the
enterohepatic circulation.
c.
Possible effects on respiratory and systemic symptoms due to the reduction of circulating
viral load of enteric origin.
d. Potential systemic effects due to, even if limited, intestinal absorption and potential model
for the development of formulations acting at systemic level.
e.
No expected pharmacokinetic drug interactions when used with other systemic treatments for
COVID-19, as niclosamide acts locally at the intestinal level and has poor systemic
absorption.


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6.4 
Potential Benefit for the Community 
If the gut-selective antiviral activity of niclosamide were confirmed, the potential returns for the 
community, from a prophylactic point of view, would be: 
a. Reduction of the viral load of enteric origin and of the probability of fecal-oral transmission, 
with repercussions for the risk for health personnel during hospitalization periods, staff in the 
GI department during the flares, and for members of the family after hospital discharge. 
b. Potentially greater control of infections in the event of outbreaks that affect restricted 
communities. 
c. Possible reduction, especially in those at risk, of relapses if these were sustained by self-
reinfection. 
d. Reduction of the number of viral replications and, consequently, lower probability of 
introducing new mutations and potential effects on virulence and clinical presentation 
(Jin et al., 2020). 
 
6.5 
Risk Mitigation 
The risk mitigation strategy for this study includes: 
a. Reduction of the total standard daily dose in adults. Niclosamide is typically administered to 
adults as 2,000 mg once daily. Even if the available data are only in vitro and in rats, the 
micronized formulation is anticipated to decrease the time to dissolve and not significantly 
increase the extent of absorption. However, for precaution micronized formulation of 
niclosamide will be administered at a total daily dose of 1,200 mg (400 mg TID). 
b. Restriction of the study population to those patients without a history or evidence of acute 
and chronic hepatic impairment or failure, history of significant renal dysfunction, or patients 
in critical condition (see Section 9.6). 
c. No limitation in the treatments, including antiviral drugs, that the doctor decides to use in 
relation to the clinical conditions of the patients (see Section 9.8). 
d. An independent Data Monitoring Committee (DMC), including 2 physicians, will be 
appointed to provide recommendations about the individual safety assessment, early closures, 
or protocol modifications. Due to the double-blind design of the study, the members of the 
DMC will have unblinded access to the data. 
 
6.6 
Regulatory Compliance 
This study will be conducted in compliance with this protocol, Good Clinical Practice (ICH 
GCP), and all applicable national and local regulatory requirements and in accordance with the 
ethical principles that have their origin in the Declaration of Helsinki and following revisions. 
The investigator is responsible for ensuring that the study is conducted in accordance with the 
procedures described in this protocol. 


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7 
OBJECTIVES 
7.1 
Primary Objective 
The primary objective for Part 1 of the study is to evaluate the safety of niclosamide 
administered to patients with COVID-19. 
The primary objective for Part 2 of the study is to evaluate the effect of niclosamide in addition 
to standard of care (SoC) compared to placebo in addition to SoC on fecal clearance of 
SARS-CoV-2 RNA. 
7.2 
Secondary Objective 
The secondary objective of the study is to evaluate the clinical efficacy, safety, and tolerability of 
oral niclosamide in addition to SoC compared to placebo in addition to SoC. 
7.3 
Exploratory Objective 
The exploratory objectives include characterization of the effect of niclosamide on disease 
progression and severity 4 and 6 months after starting treatment, and possible genotypic 
resistance analysis using the nasopharyngeal swabs and/or stool samples.   


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9 
INVESTIGATIONAL PLAN 
9.1 
Overall Study Design and Plan:  
Patients will be recruited and randomized to niclosamide oral formulation plus SoC or placebo 
matching niclosamide tablets plus SoC. 
This is a 2-part, 2-arm, Phase 2, multicenter, randomized, double-blind, placebo-controlled study 
in adults with COVID-19. 
The study will initiate with Part 1 and, upon safety review, the study may proceed to Part 2. 
9.1.1 
Study Design, Part 1 
Part 1 will enroll approximately 9 patients. After treatment is concluded for all 9 patients, a 
DMC will review the safety data and determine if the study may proceed to Part 2 or if additional 
patients are needed to assess tolerability of the study drug. If additional patients are needed, 
approximately 9 more patients will be enrolled in Part 1, and then the DMC will meet again after 
all patients are treated to determine if the study may proceed to Part 2.  
Arm A and Arm B will be randomized in a 2:1 ratio for active treatment versus placebo using an 
interactive web-based randomization system (IWRS). 
9.1.2 
Study Design, Part 2 
Part 2 will enroll up to approximately 150 patients receiving at least 1 dose of study treatment. 
Arm A and Arm B will be randomized in a 1:1 ratio using an IWRS and balanced and stratified 
by age and sex: 
1. Age: 
a. <65 years old 
b. ≥65 years old 
2. Sex: 
a. Female 
b. Male 
 
9.2 
Study Treatment and Its Duration 
Patients will be randomized into 1 of the following 2 treatment arms: 
Arm A (active): Continued SoC therapy together with niclosamide 400-mg tablets TID, 
equivalent to a total daily dose 1,200 mg, for 14 days. 
Arm B (placebo): Continued SoC therapy together with placebo tablets matching niclosamide 
TID for 14 days. 


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Treatment may begin at any time of day; if only 1 or 2 doses are administered on Day 1, the 
planned total number of doses should be administered (42 total doses) and the final doses may be 
administered on Day 15. The total study duration for a patient will not be extended if the final 
dose occurs on Day 15 for this reason. 
The long-term care of the participant will remain the responsibility of their primary treating 
physician and there is no provision for post-study availability of niclosamide. 
9.3 
Study Duration and Recruitment Period 
Each patient will remain in the study for approximately 6 months, including 2 weeks of treatment 
and approximately 5.5 months of follow-up. The recruitment period will last approximately 5 
months. 
The total study duration from first patient first visit (FPFV) to last patient last visit (LPLV) is 
expected to be approximately 11 months. 
9.4 
Study Population 
Both Parts: 
Eligible patients will have a diagnosis of COVID-19 with or without respiratory symptoms. No 
gender and/or ethnicity restrictions will apply. Each patient should meet all the inclusion and 
none of the exclusion criteria in order to be eligible for the study. 
Part 1: 
The study population will include 1 or 2 cohorts of approximately 9 patients (up to 
approximately 18 patients) randomized in a ratio of 2 active to 1 placebo. Patients will have a 
primary diagnosis of COVID-19. Patients may be hospitalized, inpatient in a research unit, or 
seen in an outpatient clinic or in a home care setting. At-home assessments may be performed 
using a combination of remote digital monitoring of patient-reported information, home visits by 
qualified research team staff (include nurses or medical assistants), and telehealth evaluation by 
study investigators. Implementation of the home-based outpatient assessment, including remote 
digital monitoring and telehealth evaluation, may include use of a digital application. 
Part 2: 
Part 2 will enroll up to approximately 150 patients receiving at least one dose of study treatment. 
Patients may be hospitalized, inpatient in a research unit, or seen in an outpatient clinic or in a 
home care setting. 
If a patient begins treatment but is not confirmed to have a positive SARS-CoV-2 result from the 
pre-treatment stool sample by the central lab, the patient will remain on randomized treatment 
and will continue study assessments. 
9.5 
Inclusion Criteria 
Subjects meeting all the following inclusion criteria will be considered eligible for the study: 


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1. Patients who give their written consent for participation in the study and for personal data 
processing and are willing and able to comply with all study procedures. 
2. Patients of any gender who are at least 18 years of age. 
3. Part 1 only: Patients with a primary diagnosis of COVID-19, with or without pneumonia, 
who agree to be monitored daily for at least 7 days after randomization and who accept 
continuing to be assessed for the study procedures. 
4. Part 2 only: Patients with a primary diagnosis of COVID-19, with or without pneumonia. 
5. Patients who are reasonably expected to maintain and adhere to SoC treatments prescribed by 
their physician.  
6. Patients who had SARS-CoV-2 RNA presence in nasopharyngeal swab ≤5 days before 
randomization as confirmed by local or central laboratory. The assay used for testing at the 
laboratory should be approved or authorized for use by the FDA or local regulatory agency 
for diagnosing patients with COVID-19 at the time the test is used.  
7. Patients who are considered reliable and capable of adhering to the protocol, according to the 
judgment of the investigator. 
 
9.6 
Exclusion Criteria 
Patients will be excluded from the study if one or more of the following criteria are applicable: 
1. At the time of randomization, patients requiring ICU admission or patients with severe 
respiratory insufficiency requiring mechanical ventilation or with rapid worsening of 
respiratory function leading to expectation for mechanical ventilation or ICU admission. 
2. Evidence of rapid clinical deterioration or existence of any life-threatening co-morbidity or 
any other medical condition that, in the opinion of the investigator, makes the patient 
unsuitable for inclusion. 
3. Patients who, at the time of enrollment, are not in a clinical condition compatible with the 
oral administration of the study drug. 
4. Patients with serum alanine transaminase (ALT) or aspartate transaminase (AST) >3 times 
upper limit of normal (ULN) detected within 24 hours prior to randomization or other 
evidence of severe hepatic impairment (Child-Pugh Class C). 
5. Patients with an estimated GFR (eGFR) ≤30 mL/min/1.73m2 (based on CKD-EPI formula) at 
screening. 
6. Patients with a history of hypersensitivity or allergy to any component of the study drug. 
7. Enrollment in another concurrent clinical interventional study, intake of an investigational 
drug within 30 days prior to randomization, or intake of an investigational drug for 
COVID-19 within 3 months prior to randomization. Drugs approved under a US Food and 
Drug Administration Emergency Use Authorization are not considered investigational under 
this exclusion. 
8. Pregnant or lactating women or women with a positive pregnancy test (urine or serum). 


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9.7 
Investigational Medicinal Products (IMPs) 
Niclosamide and Placebo 
The chemical name of niclosamide is 5-chloro-N-(2-chloro-4-nitrophenyl)-2-hydroxybenzamide. 
The IMPs are in the form of white yellowish oval 400-mg uncoated immediate-release (IR) 
tablets containing the active ingredient micronized niclosamide or a matched placebo.  
The IMPs will be supplied by the sponsor for use in the protocol and are limited to 
investigational use only. Please refer to the current investigator’s brochure for additional 
information.  
9.7.1 
Formulation and Packaging 
The IMPs (active and matched placebo) are manufactured according to applicable Good 
Manufacturing Practice (GMP) rules. The primary packaging consists of high-density 
polypropylene white bottles of 75-mL capacity with polyethylene (PE) white screw caps (child-
proof and safety closure).  
Clinical kits will be identified by means of a label, as required by current GMPs (Annex 13) and 
law on IMP locally in force. 
9.7.2 
Allocation to Study Treatment 
Patients will be randomized to the niclosamide and placebo arms using a computer-generated 
randomization list generated by the sponsor or designee and using an IWRS. 
The treatment assignment is performed by pre-assigning the subject’s number to the treatment 
kits corresponding to the randomization list. 
9.7.3 
Product Shipment, Storage, Distribution, and Accountability 
The IMPs will be supplied in bottles to the sites by the sponsor, in accordance with local 
requirements. The IMPs will be shipped at room temperature.  
The IMPs must be stored in a secured limited-access area and maintained at room temperature 
≤25°C. The IMPs will be stored according to the storage conditions identified on the drug label. 
The investigator, or pharmacist as applicable, is responsible for receipt, proper storage, and 
usage of the study drug. On receipt, the pharmacist or delegated site staff will record the date, 
details of the bottle, and quantity of tablets. 
The investigator, or pharmacist as applicable, will keep a cumulative inventory and dispensing 
records and will maintain all supplies under adequate security. Adequate record of receipt, use, 
or loss of study drug will be retained.  
The IMP inventory and accountability records will be kept by the investigator or designee using 
an IMP Accountability Log and will include details of IMP received and a clear record of when 
it was dispensed and to which subjects. The investigator or designee will perform the drug 


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accountability to calculate the number of tablets remaining after the returns the study drug bottle. 
The investigator agrees not to supply IMPs to any person except subjects enrolled in this study. 
9.7.4 
IMP Resupply 
The investigational sites will be re-supplied with IMPs according to their respective recruitment 
rates. The pharmacist or delegated site staff will be provided with specific forms for 
accountability of the IMP (including the returned bottles). Records will be kept up to date 
throughout the study and must be complete and accurate. 
Used and unused IMPs must be made available to the monitor or sponsor designee, who will 
verify the IMP accountability and cross-check pharmacy and investigator records for compliance 
with the protocol requirements. Any discrepancy must be accounted for and documented. 
9.7.5 
IMP Misuse/Overdose 
Any IMP misuse or overdose associated or not associated with any AE should be reported to the 
sponsor or designee. Overdose is considered as dose taken above the prescribed daily dose for 
the current dosing phase. 
9.7.6 
IMP Administration 
Patients who are able to comply with the oral treatment must take, for each administration, 
1 tablet (400-mg niclosamide or placebo) TID for 14 days. It is recommended to take the tablets 
after meals, with a glass of water to facilitate swallowing. 
Treatment may begin at any time of day; if only 1 or 2 doses are administered on Day 1, the 
planned total number of doses should be administered (42 total doses) and the final doses may be 
administered on Day 15. The total study duration for a patient will not be extended if the final 
dose occurs on Day 15 for this reason. 
Management of patient who discontinues therapy. Patients may discontinue therapy due to 
progression to more severe illness if they are unable to tolerate oral niclosamide or placebo. If 
the patient recovers and is willing and able to resume treatment, the patient will be allowed to 
resume and complete the course of treatment. The duration when the patient could not tolerate 
study drug will be considered a dose delay and only the planned number of doses will be 
administered; it will not count as a restart of dosing. 
Management of vomiting after dose administration. If vomiting occurs within 1 hour after 
dosing, the dose should be re-administered. The re-administration should only occur once per 
planned dose; if vomiting occurs a second time after the same planned dose, it should not be 
administered a third time. The times and dose amount below are selected based on published 
gastric half-emptying times (Maes et al., 1994). In case of re-administration, the next dose should 
still be taken on schedule. 
Diarrhea. No dose adjustment is required in the case of diarrhea, as diarrhea primarily affects 
large intestinal transit, which is less sensitive to transient dose effects (Read et al., 1980). 


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Inability to tolerate oral tablet administration. For patients who are unable to tolerate or 
swallow tablets, it is possible, based on the judgment of the investigator, to administer the IMP 
through a nasogastric tube dispersing, for each administration, one 400-mg tablet in 50 mL of 
drinking water in a suitable glass container and to administer the mixture to the patient through a 
nasogastric tube using a needle-free syringe. 
9.7.7 
IMP Return, Destruction, and Recall 
Return of IMP: 
Unused, partially used, or empty bottles will be returned by the patient to the site at the end of 
each cycle.  
At the end of the study, the sponsor will conduct a final reconciliation between delivered, 
dispensed, and used/unused IMPs. 
Destruction of IMP: 
Unused, partially used, or empty bottles must not be destroyed at the investigative sites without 
written authorization from the sponsor. 
Recall: 
If an IMP batch is suspected to be defective, then the sponsor will immediately inform the 
investigator and the hospital pharmacist. 
The monitor will coordinate with the investigative site staff for the return of the concerned 
batches as per the return procedure. Depending on the study status, new batches may be sent to 
the investigational site. 
9.8 
Concomitant Medications and Prohibited Treatments 
Other than study drugs, SoC as directed by the patient’s physician will be allowed. Vaccination 
status for COVID-19 will not influence eligibility for the study and will be considered SoC while 
the patient is on study. After randomization and treatment allocation, the SoC therapy can be 
modified by the investigator according to the patient’s needs. 
In case of worsening or need of mechanical ventilation or admission to ICU, patients will be 
treated with any medication or treatment based on the physicians’ judgment, without any 
constraint from the sponsor, including, but not limited to, antibiotics, antimycotics, steroids, 
alpha interferon, and immunoglobulins. 
All prior and concomitant medication and treatments taken or received during the study, from 
screening visit to discharge, must be recorded. For concomitant or rescue medication: dose, 
posology, frequency of administration, start and end dates, and reason for use will be required 
and collected. 
Investigational drugs received through participation in another clinical trial are prohibited 
through the Day 43 follow-up visit. 


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10 
STUDY PROCEDURES 
Clinical or laboratory procedures for the assessment of the inclusion and exclusion criteria will 
be performed after the patient provides informed consent. Procedures may be conducted in a 
hospital, in a clinic, or at home. 
The Schedule of Assessments of the study is in Appendix A. 
10.1 
Day -3, -2, or -1: Screening 
The following procedures and tests will be performed at the screening/baseline visit (V1): 
 Informed consent/privacy (it must be signed prior to the initiation of any study-related 
activities). 
 Evaluation of inclusion/exclusion criteria 
 Demography 
 Significant medical history, including primary diagnosis 
• 
Initial medical history will collect date of initial COVID-19 symptom onset.  
• 
Documentation of concomitant and previous medications or treatments. 
 Pregnancy test (urine or serum) 
 Nasopharyngeal swab for SARS-CoV-2 viral RNA analysis to determine eligibility at the 
local laboratory. Only one screening sample is required and can be determined by local 
requirements. If the local laboratory is not able to run the analysis, the sample or samples 
may be sent to the central laboratory to confirm eligibility as long as the central laboratory 
can perform the analysis before the screening period ends. The sampling method used for 
testing at the laboratory should be approved or authorized for use by the FDA or local 
regulatory agency for diagnosing patients with COVID-19 at the time the test is used.  
 Clinical assessment of diarrhea (including anti-diarrheal agents) 
 Stool sample for infection analysis at the local laboratory. Results are not required prior to 
randomization. 
 Laboratory assessments: 
• 
Central: None required 
• 
Local: At least AST, ALT, and serum creatinine to determine eligibility. Any other 
laboratory tests may be conducted for the physician’s safety assessment according to the 
local practice and patient’s clinical needs. 
 Overall clinical assessment 
 AE monitoring after the patient has signed the informed consent form (ICF) 
 
Rescreening may be considered. The investigator should discuss the case with the medical 
monitor before rescreening a patient.  


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10.2 
Day 1: Treatment 
The following procedures and tests will be performed on Day 1. If screening and Day 1 occur on 
the same day, assessments completed for screening are not required to be repeated on Day 1. 
 Pre-dose 
• 
Confirmation of eligibility 
• 
Changes in the medical history and concomitant medications 
• 
Stool sample for the central laboratory 
• 
Clinical assessment of diarrhea (including anti-diarrheal agents) 
• 
Nasopharyngeal swab for the central laboratory 
• 
Laboratory assessments:  
• Central: Obtain samples for central laboratory. 
• Local: Any other laboratory tests may be conducted for the physician’s safety 
assessment according to the local practice and patient’s clinical needs. 
• 
Overall clinical assessment 
 Randomization by means of an IWRS (randomization should occur after eligibility is 
confirmed, including all required laboratory tests) 
 Administration of first dose and other TID doses, as they apply for the time of day 
 Part 1 patients, who are not hospitalized, will be observed for approximately 30 minutes after 
receiving their first dose. 
 Daily diary 
 AE monitoring 
 
10.3 
Part 1 Only: Days 2, 3, 5, 6, and 7: Safety Monitoring 
 Vital signs (For safety monitoring only. Vital signs do not need to be entered into the CRF, 
though detected adverse events should be entered in the CRF.) 
 AE monitoring 
 Concomitant medications 
 
10.4 
Days 4 (±1 day), 8 (±1 day), and 15 (±2 day): Treatment 
 Changes in the medical history and concomitant medications since previous visit 
 Pregnancy test (urine or serum) on Day 15 
 Stool sample for the central laboratory 
 Clinical assessment of diarrhea (including anti-diarrheal agents) since previous visit 
 Nasopharyngeal swab for the central laboratory 
 Laboratory assessments:  
• 
Central: Obtain samples for central laboratory at Day 8 and Day 15. 


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• 
Local: Any other laboratory tests may be conducted for the physician’s safety assessment 
according to the local practice and patient’s clinical needs. 
 Overall clinical assessment 
 Continued TID daily dosing 
 Daily diary 
 AE monitoring 
 Concomitant medications 
 
10.5 
Days 22 (±2 days), 29 (±2 days), 36 (±3 days), and 43 (±3 days): Short-Term 
Follow-Up 
The following procedures and tests will be performed at the days noted above or upon early 
termination if the patient discontinues the study less than 4 weeks after the last dose of study 
drug. 
 Changes in the medical history and concomitant medications since previous visit 
 Stool sample for the central laboratory 
 Clinical assessment of diarrhea (including anti-diarrheal agents) since previous visit 
 Nasopharyngeal swab for the central laboratory 
 Laboratory assessments:  
• 
Central: Obtain samples for central laboratory at Day 29 and 43. 
• 
Local: Any other laboratory tests may be conducted for the physician’s safety assessment 
according to the local practice and patient’s clinical needs. 
 Overall clinical assessment 
 Daily diary, with diary collection on Day 43 
 AE monitoring 
 Concomitant medications 
 
10.6 
Four and Six Months After First Dose (±1 week): Long-Term Follow-Up  
The patient will be contacted 4 months and 6 months after the first dose of study drug (±1 week) 
to collect: 
 Survival status 
 Persistence of COVID-19 symptoms beyond Day 43 
 Recurrence of COVID-19 symptoms after Day 43 
 Hospitalization or rehospitalization due to COVID-19 after Day 43 
 
10.7 
Assessments 
Patients may be hospitalized, inpatient in a research unit, or seen in an outpatient clinic or in a 
home care setting. At-home assessments may be performed using a combination of remote 


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digital monitoring of patient-reported information, home visits by qualified research team staff 
(include nurses or medical assistants), and telehealth evaluation by study investigators. 
Implementation of the home-based outpatient assessment, including remote digital monitoring 
and telehealth evaluation, may include use of a digital application. 
10.7.1 
Assessments for Diarrhea 
Assessments for the evaluation of diarrhea will be performed at all the study time points (except 
the long-term follow-up visits at months 4 and 6) and include: 
 Number of watery episodes per day according to Type 6 or 7 of the Bristol Stool Scale, as 
reported in Appendix B (Lewis at al., 1997) 
 Number of evacuations with formed stool 
 Use of anti-diarrheal agents 
 Daily presence of other GI signs and symptoms: vomiting, nausea, anorexia, gastralgia, 
abdominal pain or discomfort, flatulence 
 
In the hospital or inpatient setting, the clinical assessment of diarrhea will be performed by the 
investigator, whereas after discharge or in an outpatient setting, it will be assessed daily and at 
defined study time points based on information entered by the patient using either a digital 
application or paper home diary. 
10.7.2 
Overall Clinical Assessment 
The following information and clinical data will be captured as appropriate by the investigator, 
the study nurse, or a digital application daily and at defined study time points: 
 Death 
 ICU admission and discharge 
 Hospitalization admission and discharge dates, including hospital readmission 
 WHO severity score as reported in Appendix C 
 Duration, type of administration, and quantity of supplemental oxygen treatment 
 SaO2 on room air (if available, fingertip pulse oximeter) 
 Vital signs, including blood pressure (BP), pulse, SaO2, and temperature, with temperature 
including method of measurement (axillary, oral, rectal, or tympanic) 
 
10.7.3 
Stool Samples and Nasopharyngeal Swabs 
Stool samples and nasopharyngeal swabs will be collected in the hospital or clinic or at patient’s 
home, according to written instructions using a pre-labeled patient’s kit and shipped to a central 
laboratory for RT-qPCR analysis of the endpoints related to viral RNA. At screening, the sample 
will be collected for testing at the local laboratory of viral RNA to determine eligibility. Samples 
that are obtained in the outpatient setting will be collected by appropriately trained and qualified 
personnel, for example, a home-visiting medical assistant, or by the patient after the patient 
receives adequate training that has been documented by qualified personnel.  


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10.7.4 
Safety and Laboratory Assessments 
 Stool infection analysis at the local laboratory at screening. Clostridium difficile toxin, 
Salmonella, Shigella, Yersinia, Plesiomonas Campylobacter, and intestinal parasites are 
recommended tests, but the specific bacteria or parasites to be tested can be based on local 
standard of care testing. 
 Safety (SAEs and AEs) 
 Central laboratory testing will include complete blood count (CBC), blood urea nitrogen 
(BUN), blood sugar, electrolytes (sodium, chloride, potassium, and bicarbonate [HCO3]), 
alkaline phosphatase, AST, ALT, lactate dehydrogenase (LDH), total bilirubin, serum 
creatinine, C-reactive protein, and fecal calprotectin.  
 Any other laboratory assessment may be conducted at the local laboratory for the physician’s 
safety assessment according to the local practice and patient’s clinical needs. 
 
10.8 
Patient Withdrawal 
10.8.1 
Individual Treatment Discontinuation 
The assigned study treatment might be permanently discontinued at any time by the investigator 
for safety or medically justified reasons. 
There are several other reasons the patient may withdraw from treatment, including, but not 
limited to, patient withdrawal of consent to treatment, the sponsor terminating the study, or the 
patient being lost to follow-up. The reason for early discontinuation of treatment will be 
documented in the patient’s medical records and the electronic case report form (eCRF). Patients 
who discontinue treatment early will continue to be followed through the end of the study. 
10.8.2 
Participant Withdrawal from the Study 
There are several reasons the patient may withdraw from the study, including, but not limited to, 
patient withdrawal of consent for participation in the study, the sponsor terminating the study, or 
the patient being lost to follow-up. The reason for early discontinuation of treatment will be 
documented in the patient’s medical records and the eCRF. 
10.8.3 
Lost to Follow-Up 
A participant will be considered lost to follow-up if he/she fails to provide data or biologic 
samples after the discharge at the time points described in the protocol before the completion of 
the study. 
The site should attempt to contact the patient (eg, by phone or last known mailing address) in 
order to: 
a. Determine if the patient is deceased and the reason of the death; 


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b. Reschedule, if still alive, the missed hospital or home visit as soon as possible; counsel the 
participant on the importance of maintaining the assigned visit schedule; and ascertain 
whether the participant wishes to and/or should continue in the study. 
 
Should the participant continue to be unreachable, he/she will be considered lost to follow-up. 
 


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11 
DATA MANAGEMENT 
11.1 
Data Sources  
Data required by the protocol will be collected both at the hospital or at the subject’s home, as 
applicable. 
11.2 
Data Collection 
Data collection is the responsibility of the clinical study staff at the site, under the supervision of 
the principal investigator. The study eCRF is the primary data collection instrument for the 
study. The investigator should ensure the accuracy, completeness, legibility, and timeliness of 
the data reported in the eCRFs and all other required reports. The investigator must ensure that 
the clinical data required by the study protocol are carefully reported in the subject’s source 
documents detailing the unique identification number and date and time of the study procedures 
performed. Data reported in the eCRF that are derived from source documents should be 
consistent with the source documents or the discrepancies should be explained. Any correction to 
the source data entries must be carried out by the investigator or a designated member of the 
staff. Incorrect entries must not be covered with correcting fluid, obliterated, or made illegible in 
any way. 
All data requested on the eCRF must be recorded. Any missing data must be explained. An audit 
trail will be maintained by the eCRF system. 
An internet-based, study-specific eCRF will be designed, validated (FDA CRF 21 Part 11 
compliant), and set-up for data storage and remote data entry by the principal investigator. All 
the information included into the eCRF should accurately reflect the source documents. Patient-
reported data captured by a digital application and self-reported by study patients may be 
organized into reports that can be used as source data for entry into the eCRF, or the application 
may be linked directly to the eCRF. The investigator is responsible for the management and 
accuracy of the information collected in the eCRF. 
Access to, consultation with, and use of the eCRF will be password protected, with restrictions 
tailored for the function of the users (eg, read-only, read and write). The eCRF will be designed 
to generate automatic alerts and queries in case of inconsistencies or errors during data entry. 
Any changes in the dataset will be tracked (eg, user, date and time, old entry, new entry). 
11.3 
Data Verification and Data Cleaning 
The sponsor or designee will review the data over the course of the study to identify data 
inconsistencies and prepare the queries to resolve such inconsistencies. The investigator will be 
asked to resolve queries by making changes directly in the eCRF. 
11.4 
Data Coding 
Concomitant diseases and events in the medical history, such as safety-related events, and 
relevant additional records related to the medical history will be coded using MedDRA (latest 
version in use). 


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Medications (products under study and concomitant medications) will be entered in the eCRF by 
the investigator, and they will be coded using the WHO-DRUG dictionary (latest version in use). 
11.5 
Database Closure 
Prior to study database lock, all tasks or processes described in relevant study plans, such as data 
entry and check of all data, resolution of all queries, coding validation, and data review, must be 
completed and documented. The study database must be locked before generation of any results. 
The database lock will be documented and approved by relevant study personnel and all edit 
accesses will be removed. Following database closure, the study database can only be unlocked 
in case critical errors that affect the main conclusions of the study are discovered. The unlock 
justification and process must be documented. 
11.6 
Data Storage and Retention 
Investigators are reminded that all sponsor representatives keep professional confidentiality with 
regards to the patient data. Source documents along with all other trial-related documents (copies 
of all ICFs and personal data processing consent, product inventories, and any correspondence 
related to the study) must be kept in the investigator’s file throughout the study and then must be 
stored for a period of at least 15 years or as per local legal requirements on force, whichever is 
longer. 
Records and documents, including signed ICFs, pertaining to the conduct of this study must be 
retained by the investigator as indicated in the contract. No records may be destroyed during the 
retention period without the written approval of the sponsor. No records may be transferred to 
another location or party without written notification to the sponsor. 


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12 
STATISTICAL ANALYSIS PLAN AND STATISTICAL ANALYSIS 
12.1 
Statistical Analysis Plan 
All statistical methodology will be described in detail in the statistical analysis plan (SAP) which 
will be finalized prior to database lock. All variables collected in the eCRF and/or other 
recordings (if applicable) and all derived parameters will be used in the statistical analysis. 
12.2 
Sample Size Calculation 
Part 1: 
The sample size was selected empirically for an initial evaluation of safety in patients with 
COVID-19. 
Part 2: 
The sample size for Part 2 of the study was determined by simulations based on the following 
assumptions: 
• The time to fecal viral clearance has an exponential distribution for each treatment arm. 
• The median time to fecal viral clearance is anticipated to be approximately 21 days for 
placebo arm and 10 days for niclosamide arm.  
• Fecal viral clearance assessments are performed at Day 3, 7, 14, 28, 42 after first dose. 
• Log-rank test (2-sided) is conducted to compare treatment difference.  
 
Using a 1:1 randomization ratio, a sample size of 30 patients per treatment arm (60 patients total 
with a positive stool test for SARS-CoV-2 on Day 1) provides 74% power to detect a significant 
treatment difference for alpha=0.05 and 83% power for alpha=0.10. It is expected that 
approximately 40% of COVID-19 patients will be positive for SARS-CoV-2 in the stool sample. 
Therefore, approximately 150 patients with COVID-19 are needed to be enrolled/randomized to 
ensure 60 patients have a positive stool test for SARS-CoV-2 on Day 1. 
12.3 
Analysis Sets 
The following analysis sets will be defined: 
Safety Set will consist of all randomized patients who received at least 1 dose of the IMP and 
will be used to present results on safety data. The Safety Set will be used for safety summaries 
and will be analyzed according to the study treatment actually received. 
Full Analysis Set will consist of all randomized patients who received at least 1 dose of the IMP. 
The Full Analysis Set will be used for systemic and respiratory efficacy secondary endpoints and 
will be analyzed according to the study treatment as randomized. 
 


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Efficacy Evaluable Set will consist of all randomized patients who received at least 1 dose of 
the IMP, and who had a positive stool test for SARS-CoV-2 on Day 1 assessed by RT-PCR, and 
who did not test positive for bacteria or parasites in the screening stool analysis. The Efficacy 
Evaluable Set will be used for the primary efficacy endpoint and relevant gastrointestinal 
efficacy secondary endpoints and will be analyzed according to the study treatment as 
randomized.  
Per-Protocol Set will consist of patients in the Efficacy Evaluable Set who did not have major 
protocol deviations affecting the primary efficacy endpoint. The Per-Protocol Set will be used as 
a supportive analysis set for gastrointestinal efficacy analyses and will be analyzed according to 
the study treatment as randomized. 
12.4 
Analysis of Efficacy Variables 
The primary endpoint for Part 2, as well as the key secondary efficacy endpoint for Part 1, will 
be the time from first drug administration to the first fecal RT-qPCR sample negative for 
SARS-CoV-2 as defined as a quantitative test either below the limit of quantification or above a 
number of cycles equivalent to a limit of quantification. Secondary efficacy endpoints for Part 1 
and Part 2 will be analysed separately. 
The primary analysis of the study will be a stratified log-rank test. Stratification will be based on 
strata defined for randomization. Kaplan-Meier curve figures with 95% CIs will be generated for 
the total population by treatment and for each stratum by treatment. Tables will present summary 
statistics of fraction of subjects not cleared by planned visit, and these summary tables will 
illustrate the total population and each stratum by treatment. Listings of all patients and the time 
to the primary endpoint along with stratum levels and clarifications required for sensitivity 
analyses will be generated. 
Secondary and exploratory endpoints, along with safety and baseline characteristics, will be 
summarized with tables, figures, and listings appropriate for each measure. 
Full details for all analyses will be provided in the SAP. 
12.5 
Analysis of Safety Variables 
The primary endpoint of Part 1 is summarization of safety (AEs, clinical laboratory results, and 
vital signs) comparing the niclosamide arm to the placebo arm. 
The TEAEs, SAEs, and AEs will be presented for each treatment arm in terms of number of AEs 
and their incidence by SOC and preferred term (PT) using MedDRA. Analyses will be provided 
also by severity and relationship to the treatment. 
Laboratory tests will be presented using descriptive statistics at each available visit. 
Additionally, the frequency of subjects reporting an abnormal or abnormal clinically significant 
laboratory value at each available visit will be presented for each laboratory parameter. 


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12.6 
Interim Safety Analysis for Study Continue/Pause Decision Part 1 
The interim safety analysis for Part 1 will be performed by the DMC (see Section 12.9 below). 
Due to the relatively small number of subjects in Part 1, the decision for DMC review of Part 1 
will be based on medical judgment of niclosamide tolerability compared to placebo and will not 
require specific statistics. 
12.7 
Interim Safety Analysis Part 2 
The interim safety analysis for Part 2 will be performed by the DMC (see Section 12.9 below). 
The DMC will be unblinded to study data and will operate under a DMC charter. The planned 
interim analysis will occur when 75 patients have been enrolled and completed the 2-week 
treatment period. The outcome from the DMC to be delivered to the sponsor will be: (1) continue 
as planned; (2) pause enrollment and undertake further evaluation of safety; or (3) recommend 
that the study be terminated due to safety concerns. No rigid statistical stopping rules will be 
used to make these decisions. While the DMC statistician may perform statistical analyses to 
examine adverse trends in safety, such as excess deaths and SAEs in the active arm, the decision 
to recommend a pause in enrollment or termination of the study will be reached by clinical 
consensus of the DMC. 
The chairperson of the DMC will be apprised of SAEs and other important safety events in real 
time and may elect to convene an ad hoc DMC meeting at any time. 
12.8 
Handling of Missing Data 
All reasonable efforts will be made to reduce the rate of missing data. Investigators will be 
trained about the importance of patient retention and full data capture. In addition, reasonable 
attempts should be made by the investigators to emphasize continued subject’s participation for 
the full duration of the trial. 
Missing data for the primary endpoint will be handled as follows: 
1. In the case of death of any cause, the patient will be considered to have the worst outcome 
with censoring at the planned follow-up visit (Day 43). 
2. In the case of patients who are hospitalized for any reason and withdraw consent, the patient 
will be considered to have the worst outcome with censoring at the planned follow-up visit 
(Day 43). 
3. In the case of loss to follow-up or other reasons unrelated to COVID-19 for discontinuing the 
study, the data will be considered missing at random and will be censored at the last available 
visit if the patient does not have fecal viral RNA clearance before discontinuation from the 
study. 
 


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12.9 
Data Monitoring Committee 
An independent DMC, including 2 physicians and a statistician, will be appointed to provide 
recommendations about the individual safety assessments, early closures, or protocol 
modifications to the sponsor. 
Due to the double-blind design of the study, the members of the DMC will have unblinded 
access to the data. The members of the DMC will not be allowed to be in contact with the study 
staff at the sites. 
12.10 
Planned Analyses and Unblinding 
12.10.1 
Day 43 Final Analysis 
This analysis will be carried out for the main clinical study report (CSR) when the last patient 
has completed the Day 43 follow-up visit. This CSR will contain all clean efficacy data (primary 
and secondary) and safety data through Day 43 for all randomized patients. At the time of the 
Day 43 analysis for writing the main CSR, the randomization will be unblinded to the central 
study team. However, the investigators, other site study staff, and patients will remain blinded to 
their treatment for as long as they are participating in the study. 
12.10.2 
End of Study Final Analysis 
This analysis will be provided in an addendum to the main CSR. It will include limited 
exploratory data collected at the Month 4 and Month 6 long-term follow-up visits. 


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13 
SAFETY REPORTING 
13.1 
Definitions of Adverse Events and Serious Adverse Events 
13.1.1 
Evaluation of Adverse Events 
An adverse event (AE) is any untoward medical occurrence in a patient or study patient 
administered a pharmaceutical product that does not necessarily have a causal relationship with 
this treatment. An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease temporally associated with the use of an 
investigational product, whether or not it is related to the investigational product. 
The period of observation for AEs extends from the time the patient gives informed consent until 
the patient completes the study. Adverse events that are still present after the patient’s last 
scheduled visit will be followed up by means of a phone call or visit, as considered appropriate. 
After that time point, the need for additional follow-up of ongoing AEs/SAEs will be discussed 
between the investigator and the sponsor, although in the event of discrepancies, the 
investigator’s criteria will prevail. Adverse events occurring after the end of the clinical trial 
must be reported if the investigator considers there is a causal relationship with the 
investigational product. 
The investigator will be responsible for the necessary acute medical treatment of any AEs 
required during the study and will ensure that appropriate medical care will be maintained 
thereafter, if necessary. 
All patients experiencing AEs, whether considered related to the use of the IMP or not, will be 
monitored periodically until symptoms subside and any abnormal laboratory values have 
returned to baseline, or until there is a satisfactory explanation for the changes observed, or until 
death, in which case a full pathologist's report will be supplied, if possible. 
All AEs, including intercurrent illnesses, will be reported and documented as described below. 
Adverse events are divided into the categories "serious" and "nonserious." This determines the 
procedure that will be used to report/document the AE (see below). 
Surgical procedures themselves are not AEs; they are therapeutic measures for conditions that 
require surgery. The condition for which the surgery is required is an AE if it occurs or is 
detected during the study period. Planned surgical measures permitted by the clinical trial 
protocol and the condition(s) leading to these measures are not AEs if the condition(s) were 
known before the start of treatment with investigational product. In the latter case, the condition 
should be reported as medical history. 
13.1.2 
Definition of Serious and Nonserious Adverse Events  
An SAE is any untoward medical occurrence that at any dose: 
• results in death or is life-threatening. 


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• results in permanent or significant disability/incapacity. 
• requires inpatient hospitalization or prolongation of hospitalization. 
• results in a congenital abnormality/birth defect. 
 
Hospitalization solely for the purpose of diagnostic tests, even if related to an AE, elective 
hospitalization for an intervention that was already planned before the inclusion of the patient in 
the clinical trial, and admission to a daycare facility may not themselves constitute sufficient 
grounds to be considered an SAE. 
Medical and scientific judgment will be exercised in the classification of other important medical 
events that may not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the patient or require intervention to prevent one of the other outcomes listed in the 
definition above. These should also usually be considered serious. 
Adverse events that do not fall into these categories are defined as nonserious. 
13.2 
Reporting/Documentation of Adverse Events 
The investigator or qualified sub-investigator is responsible for assessing AEs and SAEs for 
causality and severity and for final review and confirmation of accuracy of event information and 
assessments. 
Adverse events either reported by the patient or observed by the investigator must be recorded on 
the AE section of the eCRF and should be described in the following manner: 
The nature of the event will be described in precise, standard medical terminology. If known, a 
specific diagnosis should be stated (eg, allergic contact dermatitis). 
The severity of the AE will be described in terms of mild, moderate, or severe according to the 
investigator’s clinical judgment. 
Mild: The AE does not interfere in a significant manner with the patient’s normal functioning 
level but may be an annoyance. 
Moderate: The AE produces some impairment of functioning but is not hazardous to health but is 
uncomfortable and/or an embarrassment. These events are usually ameliorated by simple 
therapeutic measures. 
Severe: The AE produces significant impairment of functioning or incapacitation and is a hazard 
to the patient. 
The duration of the event will be described by the start date and end date. 
The location for cutaneous AEs will be described as at or just around the application area (≤2 cm 
from the application area) or distant (>2 cm from the application area). 


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For the causal relationship of the event to the use of the IMP, the investigator or qualified sub-
investigator is responsible for assessing the relationship to study drug using clinical judgment 
and the following considerations: 
• Certain: The AE occurs in a plausible time relationship to IMP administration, cannot be 
explained by concurrent disease or other drugs or chemicals, follows a clinically plausible 
response to withdrawal of the IMP, is definitive based on recognized pharmacological or 
other parameter associated with the IMP, and is confirmed by re-challenge procedure, if 
performed. 
• Probable: The AE follows a reasonable temporal sequence from administration of the IMP, is 
unlikely to be attributed to a disease or other drug/s and disappears or decreases upon 
withdrawal of the IMP. 
• Possible: The AE follows a reasonable temporal sequence from administration of the IMP 
but can also be explained by disease or other drugs, and information on drug withdrawal may 
be lacking or unclear. 
• Unlikely: The AE does not follow a reasonable temporal sequence from administration of the 
IMP, can be reasonably explained by disease or other drugs, does not follow a known pattern 
of response to the IMP, and does not reappear or worsen upon re-challenge, if performed. 
• Not related: The AE occurs prior to IMP administration. 
 
The outcome of the event will be described in terms of (a) Recovered/resolved; (b) 
Recovering/resolving; (c) Recovered/resolved with sequelae; (d) Not recovered/not resolved; (e) 
Fatal; and (f) Unknown. It will also be recorded if the study product use is continued, 
interrupted, or discontinued. 
13.3 
Reporting Requirements 
All AEs, SAEs, and clinically significant laboratory abnormalities will be recorded in the eCRF 
in a timely manner and will be followed until resolution or stability of the AE, SAE, or 
laboratory abnormality has been demonstrated, whenever possible. Laboratory abnormalities 
without clinical significance are not recorded as AEs or SAEs. 
Site personnel record all SAE data in the applicable eCRFs and, from there, transmit the SAE 
information to the sponsor-designated pharmacovigilance unit within 24 hours of the 
investigator’s knowledge of the event. 
Transmission of such documents should occur without personal subject identification, 
maintaining the traceability of a document to the subject identifiers. 


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13.4 
Special Situations 
Special situation reports include all reports of medication error, abuse, misuse, overdose, 
occupational exposure, drug interactions, unexpected benefit, transmission of infectious agents 
via the product, and pregnancy, regardless of an associated AE. 
• Medication error is any unintentional error in the prescribing, dispensing, preparation for 
administration, or administration of an investigational product while the medication is in the 
control of a healthcare professional, patient, or consumer. Medication errors may be 
classified as a medication error without an AE, which includes situations of missed dose, 
medication error with an AE, intercepted medication error, and potential medication error. 
• Abuse is defined as persistent or sporadic intentional excessive use of an investigational 
product by a subject. 
• Misuse is defined as any intentional and inappropriate use of an investigational product that 
is not in accordance with the protocol instructions or the local prescribing information. 
• Overdose is defined as an accidental or intentional administration of a quantity of an 
investigational product given per administration or cumulatively, which is above the 
maximum recommended dose as per protocol or in the product labeling (as it applies to the 
daily dose of the subject in question). In cases of a discrepancy in drug accountability, 
overdose will be established only when it is clear that the subject has taken the excess 
dose(s). Overdose cannot be established when the subject cannot account for the discrepancy, 
except in cases in which the investigator has reason to suspect that the subject has taken the 
additional dose(s). 
• Occupational exposure is defined as exposure to an investigational product as a result of 
one’s professional or non-professional occupation. 
• Drug interaction is defined as any drug-drug, drug-food, or drug-device interaction. 
• Unexpected benefit is defined as an unintended therapeutic effect where the results are 
judged to be desirable and beneficial. 
• Transmission of infectious agents is defined as any suspected transmission of an infected 
agent through the IMP. 
• Pregnancy itself is not considered an AE, nor is an induced elective abortion to terminate a 
pregnancy without medical reasons. Any premature termination of pregnancy such as a 
spontaneous abortion, an induced therapeutic abortion due to complications, or other medical 
reasons should be considered an SAE. 
 
The investigator should report special situations, pregnancies and premature termination of 
pregnancies, study subjects who are identified after initiation of study drug and throughout the 
study, including the post-study drug follow-up period, to the sponsor. 


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14 
OTHER ASPECTS 
14.1 
Quality Assurance and Quality Control Procedures 
The strategy to ensure data quality and integrity will include remote and/or on-site monitoring 
and procedures for data management and may include a Quality Assurance (QA) audit. 
14.1.1 
Site Monitoring 
The clinical research associate (CRA) is responsible for routine review of the eCRF at regular 
intervals during the study in order to verify adherence to the protocol and the completeness, 
accuracy, and consistency of the data collected by the investigator or his/her staff and entered by 
them in the eCRF. The CRA should have access directly or remotely, as appropriate, to any 
subject records needed to verify the entries in the eCRF. 
The investigator agrees to cooperate with the CRA to ensure that any problems detected through 
remote or on-site monitoring are resolved. 
14.1.2 
Quality Assurance Audits 
Quality Assurance audits might be performed by 1 or more auditors if considered necessary by 
the sponsor or by the contract research organization (CRO). The QA audits will imply the 
examination and evaluation of the accuracy of information obtained and collected by the 
investigator or managed by the CRO. Study facilities and equipment might be also subjected to 
QA audits. 
14.2 
Ethical Considerations 
The study will be conducted in accordance with the Declaration of Helsinki, Ethical Principles 
for Medical Research Involving Human Subjects, and applicable GCP principles. 
14.3 
Regulatory and Ethical Compliance 
This protocol, subject information, and ICF, and personal data processing consent, if applicable, 
will be submitted to an Institutional Review Board (IRB) along with a notification to regulatory 
authorities according to the local regulations. Notification in writing of ethical approval must be 
obtained from the IRB by the investigator before study initiation. 
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by the sponsor, IRB, and/or health authority(ies) according to applicable 
regulations. 
The study will be conducted at each approved site under the scientific, clinical, and operative 
responsibility and supervision of the principal investigator by the medically and scientifically 
trained qualified person appointed by him/her. 


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14.4 
Subject Information and Consent 
Informed consent will be obtained in accordance with the Declaration of Helsinki, ICH GCP, US 
Code of Federal Regulations (CFR) for Protection of Human Subjects (21 CFR 50.26[a,b], CFR 
50.27, and CFR Part 56, Subpart A), and the Health Insurance Portability and Accountability 
Act. 
Before entering the study, written informed consent will be obtained from all subjects. 
Investigators are responsible for the correctness of the recruitment procedure and for using 
comprehensible verbal communication when providing information to subjects. 
The investigators will also clearly inform the patient that he/she can leave the study at any time 
and for any reason without giving an explanation, and that this discontinuation would not in any 
case deteriorate the patient’s relationship with the physician. 
This information is exhaustively reported in the information sheet enclosed with the study ICF. 
A copy of the ICF, including the information sheet, will be given to the patient, together with any 
needed clarification. Sufficient time will be given to enable the patient to take a decision whether 
to participate in the study. 
14.5 
Subject Confidentiality 
Before entering the study, the written informed consent will be obtained from the subjects. 
Patient confidentiality is strictly held in trust by the participating investigators, their staff, and the 
sponsor and their agents. This confidentiality is extended to cover testing of samples in addition 
to the clinical information relating to participants. Therefore, the study protocol, documentation, 
data, and all other information generated will be held in strict confidence. No information 
concerning the study or the data will be released to any unauthorized third party without prior 
written approval of the sponsor. 
Patient will be assigned a unique identifier by the sponsor. Any patient’s record or dataset that is 
transferred to the sponsor will contain the identifier only; the patient’s name or any information 
that would make the participant identifiable will not be transferred. 
The patient will be informed that his/her personal study-related data will be used by the sponsor. 
The level of disclosure will also be explained to the patient. The patient will be informed on the 
nature of the data, processing mechanisms, period of data retention, and exercising of their 
rights. 
The patient will be informed that his/her medical records may be examined by Clinical Quality 
Assurance auditors or other authorized personnel appointed by the sponsor, by appropriate IRB 
members, and by inspectors from regulatory authorities. 
A copy of the ICF will be given to the patient, together with any needed clarification. The 
patient’s data will be collected only if informed consent has been obtained in writing. 


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14.6 
Protocol Amendments 
Any amendment to this protocol must be approved by AzurRx. Amendments will be submitted 
to the IRB for written approval. Written approval must be obtained before implementation of the 
amended version occurs. The written signed approval from the IRB should specifically reference 
the investigator name, protocol number, study title, and amendment number(s) that is applicable. 
Amendments that are administrative in nature do not require IRB approval but will be submitted 
to the IRB for information purposes. 
14.7 
Registration of the Protocol 
In order to ensure that information on clinical trials reaches the public in a timely manner and to 
comply with applicable law, regulation, and guidance, the protocol will be registered in and 
publicly disclosed on ClinicalTrials.gov. 
14.8 
Study Report and Communication of Results 
A clinical study report will be prepared according to standards set out in the ICH Guideline for 
Structure and Content of Clinical Study Reports (ICH E3) and provided to the regulatory 
agency(ies), regardless of the use or otherwise of these results for regulatory purposes. 
AzurRx is committed to report at scientific meetings or to publish the results of the study in a 
complete and transparent manner, following the recommendations of the International 
Committee of Medical Journal Editors. 
The results of the study, or any part thereof, shall not be published without the prior review or 
written consent and approval of AzurRx, and such consent and approval is not to be 
unreasonably withheld. However, no communication or publication will include AzurRx’s 
confidential information. 
AzurRx will register the study on a publicly accessible website (eg, ClinicalTrials.gov or 
EudraCT) in accordance with applicable laws and regulations. 


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Zhou P, Yang XL, Wang XG, et al. Discovery of a novel coronavirus associated with the recent 
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APPENDICES 
Appendix A - Schedule of Assessments 
Appendix B - Bristol Stool Scale 
Appendix C - WHO Ordinal Scale for Clinical Improvement 


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Appendix A - Schedule of Assessments 
Visit1 
Screening2 
Treatment 
Follow-up 
Short-term 
Long-term 
Timing (D=day, M=month) 
D -3 to -1 
D1 
D4 
D8 
D15 
D22 
D29 
D36 
D43 
M4 
M6 
Deviation vs randomization day 
 
 
±1 day ±1 day ±2 days ±2 days ±2 days ±3 days ±3 days ±1 week ±1 week 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
Eligibility (inclusion/exclusion criteria) 
X 
X 
 
 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
 
 
Medical history (or changes) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Pregnancy test (urine or serum) 
X 
 
 
 
X 
 
 
 
 
 
 
Stool analysis 
X 
 
 
 
 
 
 
 
 
 
 
Stool sample for SARS-CoV-2 RNA3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Diarrhea clinical assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Nasopharyngeal swab for SARS-CoV-2 
RNA3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Laboratory assessments4(L=local, 
C=central) 
L 
C 
 
C 
C 
 
C 
 
C 
 
 
Overall clinical assessment5 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
Dosing study drug 
 
Daily TID, with last dose 
on D14 or 15 
 
 
 
 
 
 
Daily diary 
 
Daily 
 
 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Concomitant medications 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Survival status 
 
 
 
 
 
 
 
 
 
X 
X 
Persistence of COVID-19 symptoms 
 
 
 
 
 
 
 
 
 
X 
X 
Recurrence of COVID-19 symptoms 
 
 
 
 
 
 
 
 
 
X 
X 
(Re)Hospitalization due to COVID-19 
 
 
 
 
 
 
 
 
 
X 
X 


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1 
Patients may be hospitalized, inpatient in a research unit, or seen in an outpatient clinic or in a home care setting.  
2 
Screening may occur on the same day as randomization, if all procedures may be completed. If they occur on the same day, procedures scheduled for both visits are not 
required to be duplicated. 
3 
At screening, eligibility can be determined by local SARS-CoV-2 viral RNA analysis on a nasopharyngeal swab. Only one screening sample is required and can be 
determined by local requirements.  Eligibility can be determined at a local laboratory at screening; however, a central laboratory may be used at screening if needed. On 
Days 1 to 43, the nasopharyngeal swab and stool sample will be collected and sent to the central lab.  
4 
Local laboratory testing at screening should include at least AST, ALT, and serum creatinine to determine eligibility. Central laboratory testing will include CBC, BUN, 
blood sugar, electrolytes (sodium, chloride, potassium, and bicarbonate [HCO3]), alkaline phosphatase, AST, ALT, LDH, total bilirubin, serum creatinine, C-reactive 
protein, and fecal calprotectin. When only central testing is required, any other laboratory assessment may be conducted at the local laboratory for the physician’s safety 
assessment according to the local practice and patient’s clinical needs 
5 
Including: mortality; hospital admission and discharge; ICU admission and discharge; WHO severity score and duration, type of administration, vital signs, and quantity 
of supplemental oxygen treatment. Vital signs should be completed on Days 1-8, 10, and 12 for Part 1 patients, but only need to be recorded in the CRF when the full 
Overall Clinical Assessment is due at the study visits above.  
* Initial medical history will collect date of initial symptom onset. If date is uncertain, verbatim response from patient will be collected. 


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16.2 
Appendix B - Bristol Stool Scale 
Type 
Descriptor 
Type 1 
Separate hard lumps, like nuts (difficult to pass and can be black) 
Type 2 
Sausage-shaped, but lumpy 
Type 3 
Like a sausage but with cracks on its surface (can be black) 
Type 4 
Like a sausage or snake, smooth and soft (average stool) 
Type 5 
Soft blobs with clear-cut edges 
Type 6 
Fluffy pieces with ragged edges, a mushy stool (diarrhea) 
Type 7 
Watery, no solid pieces, entirely liquid (diarrhea) 
Source: Lewis et al., 1997. 
 


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16.3 
Appendix C - WHO Ordinal Scale for Clinical Improvement 
Patient State 
Descriptor 
Score 
Uninfected 
No clinical or virologic evidence of infection 
0 
Ambulatory 
No limitation of activities 
1 
Ambulatory 
Limitation of activities 
2 
Hospitalized, Mild Disease 
Hospitalized, no oxygen therapy 
3 
Hospitalized, Mild Disease 
Oxygen by mask or nasal prongs 
4 
Hospitalized, Severe Disease 
Non-invasive ventilation or high-flow oxygen 
5 
Hospitalized, Severe Disease 
Intubation and mechanical ventilation 
6 
Hospitalized, Severe Disease 
Ventilation + additional organ support – pressors, RRT, ECMO 
7 
Dead 
Dead 
8 
A special WHO (2020) committee arrived at the ordinal scale that measures illness severity over time. 
 

SAP_001.pdf: 
 
Official Title: 
Statistical Analysis Plan 
A Phase 2, Randomized, Double-Blind, 
Placebo-Controlled Study on the Safety and 
Efficacy of Niclosamide in Patients with 
COVID-19 with Gastrointestinal Infection 
 
NCT 04858425 
 
 
Date of Document 
14MAR2022 


 
Page 1 of 33 
 
 
 
 
   
 
 
 
 
 
AzurRx BioPharma, Inc. 
 
AZ-NICL-COV-1 
 
A 2-Part, 2-Arm, Phase 2, Randomized, Double-Blind, Placebo-Controlled Study 
on the Safety and Efficacy of Niclosamide in Patients with COVID-19 with 
Gastrointestinal Infection 
 
14MAR2022 
Final Statistical Analysis Plan 
 
Version 1.0 
 
 
Prepared by: 
 
 
PPD, part of Thermo Fisher Scientific 
929 North Front Street 
Wilmington, NC 28401 
 
 
 


AzurRx BioPharma, Inc. 
 
 Final Statistical Analysis Plan, Version 1.0 
 
AZ-NICL-COV-1 
 
Date Issued: 14MAR2022 
 
  
Page 2 of 33 
 
TABLE OF CONTENTS 
LIST OF ABBREVIATIONS ...................................................................................................... 5 
1. 
INTRODUCTION ............................................................................................................ 6 
2. 
OBJECTIVES ................................................................................................................... 6 
2.1. PRIMARY OBJECTIVE .......................................................................................................... 6 
2.2. SECONDARY OBJECTIVE ..................................................................................................... 6 
2.3. EXPLORATORY OBJECTIVE ................................................................................................. 6 
3. 
INVESTIGATIONAL PLAN .......................................................................................... 7 
3.1. OVERALL STUDY DESIGN AND PLAN .................................................................................. 7 
3.2. STUDY ENDPOINTS ............................................................................................................. 7 
3.2.1. 
Primary Endpoint........................................................................................................ 7 
3.2.2. 
Secondary Endpoints .................................................................................................. 8 
3.2.3. 
Exploratory Endpoints ................................................................................................ 9 
3.3. TREATMENTS ...................................................................................................................... 9 
4. 
GENERAL STATISTICAL CONSIDERATIONS ....................................................... 9 
4.1. SAMPLE SIZE .................................................................................................................... 11 
4.2. RANDOMIZATION, STRATIFICATION, AND BLINDING ........................................................ 11 
4.3. ANALYSIS SETS ................................................................................................................ 12 
4.3.1. 
Full Analysis Set (FAS) ............................................................................................. 12 
4.3.2. 
Efficacy Evaluable (EE) Set ...................................................................................... 12 
4.3.3. 
Per Protocol (PP) Set ............................................................................................... 12 
4.3.4. 
Safety (SAF) Set ........................................................................................................ 13 
5. 
SUBJECT DISPOSITION ............................................................................................. 13 
5.1. DISPOSITION ..................................................................................................................... 13 
5.2. PROTOCOL DEVIATIONS ................................................................................................... 13 
6. 
DEMOGRAPHICS AND BASELINE CHARACTERISTICS .................................. 14 
6.1. DEMOGRAPHICS ................................................................................................................ 14 
6.2. MEDICAL HISTORY ........................................................................................................... 15 
6.2.1. 
General Medical History .......................................................................................... 15 
7. 
TREATMENTS AND MEDICATIONS ....................................................................... 15 
7.1. PRIOR AND CONCOMITANT MEDICATIONS ........................................................................ 15 
7.2. STUDY TREATMENTS ........................................................................................................ 16 
7.2.1. 
Extent of Exposure .................................................................................................... 16 
7.2.2. 
Treatment Compliance .............................................................................................. 16 
8. 
EFFICACY ANALYSIS................................................................................................. 16 
8.1. PRIMARY EFFICACY ENDPOINT ......................................................................................... 17 
8.1.1. 
Primary Analysis ....................................................................................................... 17 
8.1.2. 
Sensitivity Analysis.................................................................................................... 18 
8.1.3. 
Subgroup Analysis .................................................................................................... 18 


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8.2. GASTROINTESTINAL SECONDARY EFFICACY ENDPOINTS ................................................. 18 
8.2.1. 
Time to fecal viral RNA clearance assessed by RT-qPCR (Part 1) .......................... 18 
8.2.2. 
Time from the first dose of study treatment to the first formed stool ........................ 18 
8.2.3. 
Time from the first dose of study treatment to the last watery stool ......................... 19 
8.2.4. 
Proportion of subjects administered any anti-diarrheal agent during designated time 
periods ....................................................................................................................................19 
8.2.5. 
Time from first dose of study treatment to improvement of abdominal symptoms ... 20 
8.2.6. 
Proportion of subjects with a negative stool test for SARS-CoV-2 on Day 1 who 
acquire SARS-CoV-2 in stool through Day 43 ....................................................................... 20 
8.3. SYSTEMIC AND RESPIRATORY SECONDARY EFFICACY ENDPOINTS .................................. 20 
8.3.1. 
Proportion of subjects with each WHO severity score by study visit ....................... 20 
8.3.2. 
Total duration, method of administration, and quantity of supplemental oxygen 
treatment................................................................................................................................. 21 
8.3.3. 
Proportion of subjects with normal body temperature by study visit ....................... 21 
8.3.4. 
Proportion of subjects with normal blood oxygen saturation by pulse oximetry 
(SpO2) on room air by study visit .......................................................................................... 21 
8.3.5. 
Proportion of subjects admitted to the intensive care unit (ICU) and length of ICU 
stay 
....................................................................................................................................21 
8.3.6. 
Time to nasopharyngeal viral clearance assessed by RT-PCR ................................ 22 
8.3.7. 
Proportion of subjects requiring hospitalization and duration of hospitalization from 
first dose through Day 43 ....................................................................................................... 22 
9. 
SAFETY ANALYSIS ..................................................................................................... 22 
9.1. ADVERSE EVENTS ................................................................................................................ 23 
9.2. CLINICAL LABORATORY EVALUATIONS .............................................................................. 24 
9.2.1 Hematology ................................................................................................................... 24 
9.2.2 Chemistry ...................................................................................................................... 24 
9.3 VITAL SIGNS ......................................................................................................................... 24 
10. 
EXPLORATORY ANALYSIS ...................................................................................... 25 
10.1. PROPORTION OF SUBJECTS WITH RECURRENCE OF COVID-19 SYMPTOMS DURING LONG 
TERM FOLLOW-UP ....................................................................................................................... 25 
10.2. PROPORTION OF SUBJECTS WITH PERSISTENCE OF COVID-19 SYMPTOMS DURING LONG 
TERM FOLLOW-UP ....................................................................................................................... 25 
10.3. 
PROPORTION OF SUBJECTS WITH NEW HOSPITALIZATION OR REHOSPITALIZATION DURING 
LONG-TERM FOLLOW-UP ............................................................................................................. 25 
10.4. SUMMARIZATION OF GENOTYPIC RESISTANCE ANALYSIS DATA ......................................... 26 
11. 
INTERIM SAFETY ANALYSIS .................................................................................. 26 
12. 
DATA MONITORING COMMITTEE (DMC) ........................................................... 26 
13. 
FINAL ANALYSES AND UNBLINDING ................................................................... 27 
13.1.  DAY 43 FINAL ANALYSIS .................................................................................................. 27 
13.2. END OF STUDY FINAL ANALYSIS ....................................................................................... 27 
13.3. UNBLINDING ...................................................................................................................... 27 
14. 
CHANGES IN THE PLANNED ANALYSIS .............................................................. 27 


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15. 
REFERENCES ................................................................................................................ 27 
16. 
APPENDICES ................................................................................................................. 29 
16.1. SCHEDULE OF ASSESSMENTS ............................................................................................. 29 
16.2. WHO ORDINAL SCALE FOR CLINICAL IMPROVEMENT ....................................................... 31 
16.3. MISSING DATE IMPUTATION .............................................................................................. 32 


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List of Abbreviations 
AE 
Adverse event 
BMI 
Body mass index 
CI 
Confidence interval 
CMH 
Cochran mantel-Haenszel 
COVID-19 
Coronavirus disease 2019 
CSR 
Clinical study report 
DMC 
Data Monitoring Committee 
eCRF 
Electronic case report form 
FAS 
Full analysis set 
GI 
Gastrointestinal 
ICU 
Intensive care unit 
IMP 
Investigational medical product 
IWRS 
Interactive web randomization system 
MedDRA 
Medical Dictionary for Regulatory Activities 
PP 
Per-protocol (analysis set) 
PT 
Preferred term 
RT-qPCR 
Reverse transcriptase-quantitative polymerase chain reaction 
SAE 
Serious adverse event 
SAF 
Safety (analysis set) 
SaO2 
Blood oxygen saturation by pulse oximetry 
SAP 
Statistical analysis plan 
SARS 
Severe acute respiratory syndrome 
SARS-CoV-2 
Severe acute respiratory syndrome coronavirus 2 
SD 
Standard deviation 
SE 
Standard error 
SoC 
Standard of care 
SOC 
System organ class 
TEAE 
Treatment-emergent adverse event 
TID 
3 times per day (ter in die) 
WHO 
World Health Organization 
 
 
 


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1. Introduction 
 
The coronavirus disease (COVID-19 2019) is a public health emergency of international concern 
caused by the severe acute respiratory syndrome coronavirus 2 (SARS CoV-2) virus. An 
increasing volume of convergent evidence indicates that gastrointestinal (GI) infection and fecal 
oral transmission of SARS-CoV-2 are important factors in the clinical presentation, virology, and 
epidemiology of COVID-19. There are currently no approved or investigational treatments with 
demonstrated clinical efficacy for control of the intestinal SARS-CoV-2 viral shedding and fecal 
positivity. The evaluation of a safe and effective antiviral agent that is able to potently block 
SARS-CoV-2 replication in the intestine would address serious unmet medical and 
epidemiological needs. 
 
To address this unmet need, AzurRx BioPharma Inc. is developing a drug product containing 
micronized niclosamide in an immediate-release tablet formulation as treatment for SARS-CoV-
2 intestinal infection in patients presenting with GI symptoms of COVID-19 disease. Evidence of 
niclosamide’s antiviral properties is sufficient to expect a clinical pharmacodynamic response 
against viral replication and clinical benefit, justifying the proposed clinical study in COVID-19 
patients and favorable benefit-risk assessment. 
 
This statistical analysis plan (SAP) is based upon Section 12 (Statistical Analysis Plan and 
Statistical Analysis) of the clinical study protocol (version 3.0, dated 30July2021), and is 
prepared in compliance with International Conference on Harmonisation (ICH) E9. Furthermore, 
this SAP contains definitions for analysis sets, derived variables, and statistical methods and data 
presentations for the analysis of efficacy and safety endpoints. 
2. Objectives 
2.1. Primary Objective 
The primary objective for Part 1 of the study is to evaluate the safety of niclosamide 
administered to subjects with COVID-19. 
 
The primary objective for Part 2 of the study is to evaluate the effect of niclosamide in addition 
to standard of care (SoC) compared to placebo in addition to SoC on fecal clearance of SARS-
CoV-2 RNA. 
2.2. Secondary Objective 
The secondary objective of the study is to evaluate the clinical efficacy, safety, and tolerability of 
oral niclosamide in addition to SoC compared to placebo in addition to SoC. 
2.3. Exploratory Objective 
The exploratory objectives include characterization of the effect of niclosamide on disease 
progression and severity 4 and 6 months after starting treatment, and possible genotypic 
resistance analysis using the nasopharyngeal swabs, and/or stool samples. 


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3. Investigational Plan 
3.1. Overall Study Design and Plan 
 
This a 2-part, 2-arm, Phase 2, multicenter, randomized, double-blind, placebo-controlled study in 
adults with COVID-19. Subjects will be recruited and randomized to niclosamide oral 
formulation plus SoC or placebo matching niclosamide tablets plus SoC. The study will initiate 
with Part 1 and, upon safety review, the study may proceed to Part 2. 
 
Part 1 will enroll approximately 9 subjects. After treatment is concluded for all 9 subjects, a 
DMC will review the safety data and determine if the study may proceed to Part 2 or if additional 
subjects are needed to assess tolerability of the study drug. If additional subjects are needed, 
approximately 9 more subjects will be enrolled in Part 1, and then the DMC will meet again after 
all subjects are treated to determine if the study may proceed to Part 2. 
 
Part 2 will enroll up to approximately 150 subjects receiving at least 1 dose of study treatment.  
 
Each part will include 2 study arms with randomized enrollment. Randomization of subjects in 
Part 2 will be stratified by age and sex. An overview of the study design is shown in Figure 1 and 
the Schedule of Assessments for the study is detailed in Appendix 16.1. 
 
Figure 1: Study Design 
 
 
3.2. Study Endpoints 
3.2.1. Primary Endpoint 
The primary endpoint of Part 1 is summarization of safety (AEs, clinical laboratory results, and 
vital signs) from Day 1 (first dose) to Day 43 comparing the niclosamide arm to placebo arm. 
 


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The primary endpoint of Part 2 is time to fecal viral RNA clearance for subjects with a positive 
Day 1 stool test assessed by RT-qPCR from Day 1 (first dose) to Day 43 in the niclosamide arm 
compared to the placebo arm. 
3.2.2. Secondary Endpoints 
The secondary endpoints will all compare the niclosamide arm to the placebo arm. These 
secondary endpoints will be assessed for both Part 1 and Part 2 from Day 1 (first dose) to Day 
43, as applicable. 
 
• Gastrointestinal Efficacy Secondary Endpoints 
 
a) Part 1: Time to fecal viral RNA clearance for subjects with a positive Day stool test 
for SARS-CoV-2 assessed by RT-qPCR. 
b) Time from the first dose of study treatment to the first formed stool (this formed stool 
must have been followed by a non-watery stool) in subjects with loose or watery stool 
(Bristol Stool Scale Types 6-7) on Day 1. 
c) Time from the first dose of study treatment to the last loose or watery stool in subjects 
with loose or watery stool (Bristol Stool Scale Types 6-7) on Day 1. 
d) Proportion of subjects administered any anti-diarrheal agent from the first dose of 
study treatment to Day 8, first dose of study treatment to Day 15 and from Day 16 to 
29. 
e) Time from the first dose of study treatment to improvement of abdominal symptoms 
in subjects with adnominal symptoms on Day 1. 
f) Proportion of patients with a negative Day 1 stool test for SARS-CoV-2 who acquire 
SARS-CoV-2 in stool through Day 43. 
 
• Systemic and Respiratory Efficacy Secondary Endpoints 
 
g) Proportion of subjects with each clinical severity score as recommended by the WHO 
for COVID-19 studies by study visit. 
h) Total duration, type of administration (e.g., mean increased room oxygen, nasal tubes, 
ventilator, or ECMO), and quantity of supplemental oxygen treatment, whenever 
possible. 
i) Body temperature and proportion of subjects with normal body temperature by study 
visit. Criteria for normalization was temperature: ≤36.9ºC axillary, ≤37.4ºC oral, 
≤37.8ºC rectal, and ≤37.5ºC tympanic (Geneva et al., 2019). 
j) Proportion of subjects with normal blood oxygen saturation by pulse oximeter (SaO2) 
>90% on room air by study visit. 
k) Proportion of subjects admitted to the intensive care unit (ICU) and length of ICU 
stay. 
l) Time to nasopharyngeal viral clearance assessed by RT-PCR. 
m) Proportion of subjects requiring hospitalization and duration of hospitalization. 
 
• Safety and Tolerability Secondary Endpoints 
 


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n) All-cause mortality 6 weeks after randomization. 
o) Proportion of subjects with treatment-emergent adverse events (TEAEs) leading to 
study drug discontinuation. 
p) Serious adverse events (SAEs) coded by system organ class (SOC) and preferred term 
(PT) using the Medical Dictionary for Regulatory Activities (MedDRA). 
q) Clinically significant changes in laboratory measurements. 
r) Clinically significant changes in vital sign measurements. 
3.2.3. Exploratory Endpoints 
s) All-cause mortality 4 months and 6 months after randomization. 
t) Proportion of subjects with recurrence of COVID-19 symptoms after Day 43 at 4 
months and 6 months after randomization. 
u) Proportion of subjects with persistence of COVID-19 symptoms beyond Day 43 at 4 
months and 6 months after randomization. 
v) Proportion of subjects with new hospitalization or rehospitalization due to COVID-19 
at 4 months and 6 months after randomization. 
w) Summarization of genotypic resistance analysis data.  
3.3. Treatments   
The chemical name of niclosamide is 5-chloro-N-(2-chloro-4-nitrophenyl)-2-hydroxybenzamide. 
The IMPs are in the form of white yellowish oval 400-mg uncoated immediate-release (IR) 
tablets containing the active ingredient micronized niclosamide or a matched placebo.  
 
Subjects who are able to comply with the oral treatment must take, for each administration, 1 
tablet (400-mg niclosamide or placebo) TID for 14 days. Treatment may begin at any time of 
day; if only 1 or 2 doses are administered on Day 1, the planned total number of doses should be 
administered (42 total doses) and the final doses may be administered on Day 15. The total study 
duration for a subject will not be extended if the final dose occurs on Day 15 for this reason. 
4. General Statistical Considerations 
Continuous data will be described using descriptive statistics (i.e., number of subjects, mean, 
standard deviation, median, 25th percentile, 75th percentile, minimum, and maximum). Unless 
otherwise specified, minimum and maximum will be displayed to the same level of precision as 
reported. Mean and median will be displayed to one level of precision greater than the data 
collected. Standard deviation (SD) and standard error (SE) will be displayed to two levels of 
precision greater than the data collected. If the precision of the values being summarized are too 
large (e.g., 3 or more decimal places), then limit the precision to two decimal places and follow 
the rules previously stated above. If n=0, then display n and leave all other statistics blank. If 
n=1, then display “N/A” for SD and SE.  
 
Categorical data will be described using the subject count and percentage in each category. 
When count data are presented, the percentage will be suppressed when the count is zero. A row 
denoted “Missing” will be included in count tabulations where specified on the shells to account 
for dropouts and missing values where applicable. The denominator for all percentages will be 


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the number of subjects in that treatment within the analysis set of interest, unless otherwise 
specified. Non-zero percentages will be rounded to one decimal place, except 100% will be 
displayed without any decimal places. 
 
All subject data collected at scheduled and unscheduled visits, excluding data collected in the 
daily diary, will be presented in individual subject data listings. Dates will be shown in subject 
listings as they have been recorded. Data listings will be sorted by treatment group, subject 
identification number, date/time and visit where applicable. The treatment group (randomized) as 
well as subject’s sex and age will be stated on each listing where applicable. Unless otherwise 
stated, data listings will be based on all subjects randomized. When no data are available for a 
table or listing, an empty page with the title will be produced with suitable text (e.g., “There are 
no records for this table/listing.”).  
 
Unless otherwise specified, baseline will be defined as the last non-missing assessment prior to 
or on the date that the first dose of treatment is taken. For subjects who are randomized, but not 
treated, the baseline will be defined as the last non-missing assessment prior to or on the date of 
randomization. Assessments from both scheduled and unscheduled visits will be used to 
determine baseline. The date of first and last dose will be collected on the End of Treatment 
eCRF. 
 
Study day will be calculated relative to the first dose date:  
• Day 1 is defined as the first dose date 
• Assessments before the first dose date: Study Day = Assessment Date – First Dose Date 
• Assessments after the first dose date: Study Day = Assessment Date – First Dose Date +1 
 
Summaries or analyses by study visit will be based on data collected at scheduled visits (i.e., 
nominal visits as collected on eCRF) and data from unscheduled visits will not be included. 
Efficacy analyses for time to viral clearance or clinical improvement will include data from both 
scheduled and unscheduled visits. Laboratory treatment emergent summaries will also include 
data from both scheduled and unscheduled visits. 
 
A two-sided hypothesis test will be used at a significance level of 0.05 for comparison between 
the niclosamide and the placebo group for the primary efficacy analysis. All other statistical 
analyses will also be performed using a two-sided hypothesis test at a nominal significance level 
of 0.05. No adjustment for Type I error will be made for multiple comparisons. Models will 
include stratification factors, age (<65 years or ≥65 years) and sex (female or male), unless an 
insufficient amount of data exists where convergence or the analysis cannot be performed. 
 
Confidence intervals will be presented as two-sided 95% CI for the primary efficacy analysis 
secondary efficacy analyses. P-values will be rounded to three decimal places. If a p-value is less 
than 0.001 it will be reported as “<0.001.” If a p-value is greater than 0.999 it will be reported as 
“>0.999.” For analyses where convergence or the analysis cannot be performed, “NC” (not 
calculable) will be presented.   
 
For all Tables, Listings, and Figures, treatment group will be labelled as follows: “Niclosamide + 
SoC” and “Placebo + SoC”. All analyses will be conducted using SAS Version 9.4 or higher.  


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4.1. Sample Size 
The sample size for Part 1 of the study was selected empirically for an initial evaluation of safety 
in subjects with COVID-19. 
 
The sample size for Part 2 of the study was determined by simulations based on the following 
assumptions: 
• The time to fecal viral clearance has an exponential distribution for each treatment arm. 
• The median time to fecal viral clearance is anticipated to be approximately 21 days for 
placebo arm and 10 days for niclosamide arm.  
• Fecal viral clearance assessments are performed at Day 3, 7, 14, 28, 42 after first dose. 
• Log-rank test (2-sided) is conducted to compare treatment difference.  
Using a 1:1 randomization ratio, a sample size of 30 patients per treatment arm (60 patients total 
with a positive stool test for SARS-CoV-2 on Day 1) provides 74% power to detect a significant 
treatment difference for alpha=0.05 and 83% power for alpha=0.10. It is expected that 
approximately 40% of COVID-19 patients will be positive for SARS-CoV-2 in the stool sample. 
Therefore, approximately 150 patients with COVID-19 are needed to be enrolled/randomized to 
ensure 60 patients have a positive stool test for SARS-CoV-2 on Day 1. 
To assess the sensitivity analysis of the above power calculation, additional scenarios of 
assumptions of stool positivity rate and longer time to fecal viral clearance for niclosamide arm 
(i.e. less treatment effect) are also evaluated in the below table. 
4.2. Randomization, Stratification, and Blinding 
 
Subjects will be randomized to the niclosamide plus SoC or placebo plus SoC arms using a 
computer-generated randomization list generated by the PPD unblinded randomization team and 
using an IWRS. The treatment assignment is performed by pre-assigning the subject’s number to 
the treatment kits corresponding to the randomization list. 
 
Subjects will be randomized for Part 1 of the study in a 2:1 ratio to niclosamide plus SoC or 
placebo plus SoC. Subjects will be randomized for Part 2 of the study in a 1:1 ratio to 
Total Sample 
Size for 
Enrollment 
Stool 
Positivity 
Rate 
Niclosamide: 
Median Time to 
Fecal Clearance 
in Days 
Placebo:  
Median Time to 
Fecal Clearance 
in Days 
2-sided 
Significance 
Level (Alpha) 
Statistical 
Power (%) 
150 
0.3 
10 
21 
0.05 
61 
150 
0.4 
10 
21 
0.05 
74 
150 
0.5 
10 
21 
0.05 
84 
150 
0.3 
12 
21 
0.05 
40 
150 
0.4 
12 
21 
0.05 
49 
150 
0.5 
12 
21 
0.05 
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niclosamide plus SoC or placebo plus SoC and balanced and stratified by age (<65 years, ≥65 
years) and sex (Female, Male).  
 
This study will be double-blinded, meaning that the subjects, investigators, and site staff will be 
blinded to the subject treatment assignments until the completion of the long-term follow-up at 
Month 6. Any member of the study team involved in study conduct or participation in data 
handling decisions will also be blinded to the subject treatment assignments, but only until the 
completion of the short-term follow-up at Day 43.  
 
At the initiation of the study, the study site will be given instructions on the method for breaking 
the blind. The method for breaking the blind will use the IWRS process. Unblinding of 
individual subject treatment by the Investigator should be limited to medical emergencies or 
urgent clinical situations in which knowledge of the subject’s study treatment is necessary for 
clinical management. In such cases, the Investigator must first attempt to contact the PPD 
Medical Monitor to discuss and agree to the need for unblinding. In situations which the 
Investigator has attempted and failed to contact the PPD Medical Monitor and/or the urgency of 
the case requires immediate action, investigators should use their best judgment, based on the 
nature and urgency of the clinical situation, and proceed with unblinding.  
 
Once a subject’s treatment assignment has been unblinded for a medical emergency or urgent 
clinical situation, the PPD Medical Monitor should be notified within 24 hours of unblinding of 
the treatment. Information relating to unblinding (e.g., the reason, date) should be clearly 
recorded in the subject’s study file. 
4.3. Analysis Sets 
4.3.1. Full Analysis Set (FAS) 
The full analysis set (FAS) will consist of all randomized subjects who received at least one dose 
of study drug. The FAS will be used for systemic and respiratory efficacy secondary endpoints as 
well as exploratory endpoints and will be analyzed according to the study treatment as 
randomized.  
4.3.2. Efficacy Evaluable (EE) Set  
The efficacy evaluable (EE) set will consist of all randomized subjects who received at least one 
dose of study drug, had a positive stool test for SARS-CoV-2 on Day 1 assessed by RT-PCR, 
and did not test positive for bacteria or parasites in the screening stool analysis by the local 
laboratory. The EE set will be used for the primary efficacy endpoint and relevant 
gastrointestinal efficacy secondary endpoints and will be analyzed according to the study 
treatment as randomized. 
4.3.3. Per Protocol (PP) Set 
The per-protocol (PP) set will consist of subjects in the evaluable efficacy set who had at least 
80% exposure of study drug (i.e., at least 12 days with any dose administered) and do not have 
major protocol deviations that may affect the primary efficacy endpoint (time to fecal viral RNA 


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clearance). The PP set will be used as a supportive analysis set for gastrointestinal efficacy 
analyses and will be analyzed according to the study treatment as randomized.  
4.3.4. Safety (SAF) Set 
 
The safety (SAF) set will include all randomized subjects who received at least one dose of study 
drug. The SAF set will be used for safety summaries and will be analyzed according to the study 
treatment actually received. 
5. Subject Disposition  
 
Subject disposition will be presented separately for Part 1 and Part 2 of the study.  
5.1. Disposition 
 
Subject disposition will be summarized by treatment group and overall for all subjects who 
provided informed consent and were screened. The subject disposition summary includes the 
number and percentage of subjects for the following categories: screened, randomized, treated, 
completed study treatment and discontinued study treatment, completed Day 43 follow-up visit 
and discontinued before Day 43 follow-up visit. The reasons for discontinuation of study 
treatment and discontinuation before Day 43 follow-up visit will be summarized in this table. In 
addition, reasons for screen failures will also be summarized overall. All percentages will be 
based on the number of subjects randomized, except for screen failures. 
 
For subjects who completed Day 43 follow-up visit, a separate disposition summary will be 
provided to present the number and percentages of subjects who completed the long-term follow-
up and subjects who discontinued from the long-term follow-up and reasons for discontinuation.  
 
Study drug completion data will be collected on the End of Treatment eCRF. Disposition data for 
randomized subjects will be collected on the End of Study Day 43 and the End of Long Term 
Follow Up eCRFs. For screen failures, reasons will be collected on the Inclusion Exclusion 
eCRF or End of Study Day 43 eCRF. 
 
Additionally, a summary of the analysis sets will be provided to include the number and 
percentage of subjects in each analysis set (FAS, EE, PP, and SAF) by treatment group and 
overall. The number and percentage of subjects excluded from each analysis set and the reasons 
for exclusion will also be presented. All percentages will be based on the number of subjects 
randomized. 
 
Subject disposition and exclusions from analysis sets will also be presented in a listing.  
5.2. Protocol Deviations 
All protocol deviations will be entered and tracked within the PPD Clinical Trial Management 
System (CTMS) by the study team throughout the conduct of the study in accordance with 
PPD’s Study Deviation Rules Document. A significant deviation is any deviation that may affect 
primary efficacy and safety assessments (as applicable), the safety or mental integrity of a 


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subject, or the scientific value of the trial. A significant deviation does not necessarily affect the 
primary endpoint and be excluded from the PP set. 
 
Data will be reviewed by the study team prior to unblinding and official database lock for final 
analysis at Day 43 to ensure all significant deviations are captured and properly categorized. 
Particularly, a final list of significant protocol deviations leading to exclusion from the PP set 
(also referred to as major protocol deviations) will also be determined by the study team and 
flagged in the final CTMS deviation data file. 
  
Major protocol deviations are defined as significant deviations that might directly or indirectly 
impact the primary efficacy endpoint (time to fecal viral RNA clearance) and may include (but 
are not limited to) the following: 
• Did not meet the key inclusion or exclusion criteria 
• Had poor compliance with study treatment (< 80%) 
• Received prohibited concomitant medications through the Day 43 follow-up visit 
• Had a randomization error 
• Received incorrect study drug 
 
Significant protocol deviations will be summarized by treatment group and overall. A listing will 
also be provided for significant protocol deviations with a flag indicating major protocol 
deviations. Non-significant protocol deviations will be just listed. Summaries will be conducted 
on all subjects that were randomized.  
6. Demographics and Baseline Characteristics 
All summaries will be based on the safety set and presented separately for Part 1 and Part 2 of 
the study. 
6.1. Demographics 
A summary of demographics and baseline information will be presented by treatment group and 
overall. The demographic characteristics consist of age, sex, race, and ethnicity. The baseline 
characteristics consist of the WHO severity score as reported in Appendix 16.2, loose or watery 
stool on Day 1, abdominal symptom(s) on Day 1, stool test for SARS-CoV-2 by RT-qPCR on 
Day 1, stool test for bacteria or parasites at Screening (local laboratory) and COVID-19 
vaccination(s) prior to Screening. 
 
Age (years) will be summarized using descriptive statistics. The number and percentage of 
subjects will be presented for each of the following variables and its associated categories:  
• Age (<65, ≥65) 
• Sex (Male, Female) 
• Race (White, African American, Asian, American Indian or Alaska Native, Native 
Hawaiian or Other Pacific Islander, Other), 
• Ethnicity (Hispanic or Latino, Not Hispanic or Latino), 
• WHO severity score (ordinal categorical scores of 1 to 7) 


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• Loose or watery stool on Day 1 (Yes, No) as collected on the Diarrhea Clinical 
Assessment at Randomization eCRF 
• Abdominal symptom(s) on Day 1 (Yes, No) 
• Stool test for SARS-CoV-2 by RT-qPCR on Day 1 (Positive, Negative) 
• Stool test for bacteria or parasites at Screening (Positive, Negative) 
• COVID-19 vaccination(s) prior to Screening (Yes, No)  
 
Subject demographic and baseline characteristics will also be presented in a listing. 
6.2. Medical History 
6.2.1. General Medical History 
Medical history will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
Version 24.0. The number and percentage of subjects with any medical history will be 
summarized overall and for each system organ class and preferred term by treatment group and 
overall. Percentages will be calculated based on number of subjects in the safety set.  
 
Subject medical history data including specific details, will also be presented in a listing.  
7. Treatments and Medications 
All summaries will be based on the safety set and presented separately for Part 1 and Part 2 of 
the study. 
7.1. Prior and Concomitant Medications 
All medications taken during the study, from screening visit to short-term follow-up (Day 43), 
will be collected. All medications will be coded according to the World Health Organization 
(WHO) drug dictionary (WHODrug Global B3 2021 MAR or higher version). Details for 
imputing missing or partial start and/or stop dates of medications are described in Appendix 
16.3. 
 
 
A prior medication is defined as any medication with a start date prior to the first dose of study 
drug. A concomitant medication is defined as any medication that has a start date that is on or 
after the first dose of study drug or any medication with a start date prior to the first dose and a 
stop date after the first dose of study drug. Furthermore, a medication could be labeled as both a 
prior and concomitant medication if it was started prior to the first dose of study drug and 
continued after the first dose of study drug. 
 
The number and percentages of subjects with at least one prior medication will be summarized 
by treatment group and overall. The number and percentages of all prior medications will be 
summarized by treatment group and overall and listed by Anatomical Therapeutic Chemical 
(ATC) level 2 and preferred term. 
 
The number and percentages of subjects with at least one concomitant medication will be 
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medications will be summarized by treatment group and overall and listed by Anatomical 
Therapeutic Chemical (ATC) level 2 and preferred term. 
 
Prior and concomitant medications, including prohibited medication, will also be presented in a 
listing.   
7.2. Study Treatments 
7.2.1. Extent of Exposure 
Duration of study drug in days will be calculated as: last dose date – first dose date + 1 day, 
regardless of study drug interruption (i.e., missed dose). Study drug exposure will be 
summarized by treatment group and overall using the safety set. 
 
A summary of each subject’s exposure will also be presented in a listing.  
7.2.2. Treatment Compliance 
The study drug compliance will be calculated as: 100 * [1 – (total number of days with any 
missed dose / duration of study drug in days)]. Days of missed dose (full or partial dose) will be 
based on the Missed Dose eCRF.  
 
Study drug compliance will be summarized for all subjects in the safety set with descriptive 
statics by treatment group and overall. Additionally, the number and percentages of subjects in 
each compliance category (<80% and ≥80%) will be also presented by treatment group and 
overall.   
 
A summary of each subject’s compliance will also be presented in a listing. 
8. Efficacy Analysis 
Primary and secondary efficacy analyses will be conducted on efficacy data collected through 
the Day 43 follow-up visit for all randomized subjects and will be included as part of the Day 43 
Final Analysis for the main clinical study report (CSR).  
 
All efficacy analyses will be performed using the FAS or EE set and will be presented separately 
for Part 1 and Part 2 of the study unless otherwise specified. For Part 1, due to the small sample, 
only descriptive summary statistics will be provided by treatment group and no inferential 
statistical tests will be performed. For Part 2, all efficacy data will be summarized descriptively 
and also analyzed using appropriate inferential statistical tests as applicable.  Relevant subject 
data listings will also be provided to support all efficacy analyses and will be presented 
separately for Part 1 and Part 2 of the study unless otherwise specified. 
 
Missing data will not be imputed.  


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8.1. Primary Efficacy Endpoint 
The primary endpoint for Part 2 of the study is the time to fecal viral RNA clearance for subjects 
with a positive stool test for SARS-CoV-2 on Day 1 assessed by RT-qPCR in the niclosamide 
arm compared to the placebo arm.  
 
Time to fecal viral RNA clearance is defined as the time (days) from the first dose of study 
treatment to the first stool RT-qPCR sample negative for SARS-CoV-2, after which all stool 
samples (if any) are negative. A stool sample is considered negative for SARS-CoV-2 if the test 
result is reported as “Not Detected”; otherwise, the stool sample is positive if the test result is 
reported as “Detected”. Furthermore, an “Inconclusive” test result is considered positive if it is 
followed directly by a positive test result; an “Inconclusive” test result is considered negative if it 
is followed directly by a negative test result. Subjects without fecal viral RNA clearance will be 
censored as follows: 
• In the case of death of any cause, the subject will be considered to have the worst 
outcome with censoring at the planned Day 43 follow-up visit. 
• In the case of hospitalization for any reason and withdrawal of consent, the subject will 
be considered to have the worse outcome with censoring at the planned Day 43 follow-
up visit. 
• In the case of study discontinuation prior to Day 43 follow-up visit due to any other 
reasons, the subject will be censored at the last available visit.  
• In the case of study completion for Day 43, the subject will be censored at the date of the 
actual Day 43 follow-up visit. 
8.1.1. Primary Analysis 
 
The analysis of the primary efficacy endpoint, time to fecal viral RNA clearance, will be 
conducted on the EE set.  
 
The number and percentages of subjects achieving and not achieving the first fecal viral RNA 
clearance will be summarized up to each post-first dose study visit (Days 4, 8, 15, 22, 29, 36, and 
43) by treatment group. For each study visit, only subjects with available assessment at the visit 
or having a negative stool test before the visit will be included in the summary and counted in the 
denominator for the percentages.   
 
A stratified log-rank test will be used to compare time to fecal viral RNA clearance between 
niclosamide and placebo treatment groups adjusting for stratification factors, age (<65 years or 
≥65 years) and sex (female or male). The two-sided p-value will be reported. The estimate of the 
hazard ratio (niclosamide vs. placebo) and the associated 95% confidence interval (CI) will be 
obtained from a Cox Proportional Hazards model adjusting for stratification factors and will also 
be reported. 
 
Kaplan-Meier curves with 95% CIs will be generated for the total population by treatment group. 
Summary statistics obtained from Kaplan-Meier estimates, including the median time to fecal 
viral clearance with corresponding 95% CI and the proportion of subjects achieving fecal viral 
clearance at 3, 7, 14, 21, 28, 35, and 42 days post first dose (Day 1), will be summarized by 
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8.1.2. Sensitivity Analysis 
The analysis of the primary efficacy endpoint, time to fecal viral RNA clearance assessed by RT-
qPCR, will also be conducted on the PP set. 
8.1.3. Subgroup Analysis 
The primary efficacy endpoint, time to fecal viral RNA clearance assessed by RT-qPCR, will be 
analyzed in the same manner as the primary analysis for age group (<65 years, ≥65 years) and 
gender. For the subgroup analysis of age group, the primary endpoint will be analyzed by the 
log-rank test and Cox Proportional Hazards model adjusting only for gender. For the subgroup 
analysis of gender, the primary endpoint will be analyzed by the log-rank test and Cox 
Proportional Hazards model adjusting only for age group. 
8.2. Gastrointestinal Secondary Efficacy Endpoints 
The analysis of the gastrointestinal secondary efficacy endpoints will be conducted on the EE set 
unless otherwise specified. 
8.2.1. Time to fecal viral RNA clearance assessed by RT-qPCR (Part 1)  
The number of subjects with and without fecal viral RNA clearance assessed by RT-qPCR (as 
defined in Section 8.1.) will be summarized up to each post-first dose study visit (Days 4, 8, 15, 
22, 29, 36, and 43) by treatment group. For each study visit, only subjects with available 
assessment at the visit or having a negative stool test before the visit will be included in the 
summary and counted in the denominator for the percentages.    
8.2.2. Time from the first dose of study treatment to the first formed stool 
Only subjects with loose or watery stool (Bristol Stool Scale Types 6-7) on Day 1 will be 
included in this analysis. This data was collected on the Diarrhea Clinical Assessment at 
Randomization eCRF.  
 
Date of the earliest formed stool (followed by a non-watery stool) between study visits will be 
collected on the Diarrhea Clinical Assessment eCRF. A summary table will include the number 
and percentage of subjects achieving and not achieving the first formed stool (followed by a non-
watery stool) up to each post-first dose study visit (Days 4, 8, 15, 22, 29, 36, and 43) by 
treatment group. For each study visit, only subjects with available assessment at the visit or 
having a formed stool test before the visit will be included in the summary and counted in the 
denominator for the percentages. 
 
Time to the first formed stool is defined as the time in days from the first dose of study treatment 
to the first formed stool (followed by a non-watery stool). If subjects experienced a formed stool 
on the first day of treatment, time to first formed stool will be imputed as 0.5 days. Subjects 
without a first formed stool will be censored using the same rules as described for the primary 
efficacy endpoint in Section 8.1. Time to the first formed stool (followed by a non-watery stool) 
will be analyzed using the same time to event methods described for the analysis of the primary 
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8.2.3. Time from the first dose of study treatment to the last watery stool 
 
Only subjects with loose or watery stool (Bristol Stool Scale Types 6-7) on Day 1 will be 
included in this analysis. This data was collected on the Diarrhea Clinical Assessment at 
Randomization eCRF.  
 
Date of the last watery stool between study visits will be collected on the Diarrhea Clinical 
Assessment eCRF. A summary table of events will include the number and percentage of 
subjects achieving and not achieving the last watery stool (followed by all formed stools) up to 
each post-first dose study visit (Days 4, 8, 15, 22, 29, 36, and 43) by treatment group. For each 
study visit, only subjects with available assessment at the visit or having the last watery stool 
before the visit will be included in the summary and counted in the denominator for the 
percentages.  
 
Time to the last watery stool is defined as the time in days from the first dose of study treatment 
to the last watery stool (followed by all formed stools). Only subjects with baseline and at least 
one non-missing post-baseline will be included. Time to the last loose/watery stool during the 
course of the study will utilize the last visit at which a subject had watery stool. If a subject did 
not experience watery stool at any timepoint post-baseline, we impute time as 0.5 days. Subjects 
will not be censored because relapse cases of watery stool will be included in the analysis (i.e. 
subject experienced watery stool again after formed stool) and in such cases, the last visit at 
which relapse occurred is considered to be the last visit at which watery stool is experienced. 
Time to the last watery stool will be analyzed using the same time to event methods described 
for the analysis of the primary endpoint in Section 8.1.1. 
8.2.4. Proportion of subjects administered any anti-diarrheal agent during 
designated time periods 
A summary table of anti-diarrheal agent administration will include the number and percentage 
(proportion) of subjects administered any anti-diarrheal agent during the following time periods 
by treatment group: first dose (Day 1) to Day 43 (inclusive), first dose (Day 1) to Day 8 
(inclusive), first dose (Day 1) to Day 15 (inclusive), Day 16 to Day 29 (inclusive), and Day 30 to 
Day 43 (inclusive).A time period is defined if at least one visit unique to the time period exists. 
An anti-diarrheal agent will be considered administered during a specific time period if the 
calculation of days between the date of the first dose of study treatment and the start date of the 
anti-diarrheal agent falls within the specific time period. The use of anti-diarrheal agents along 
with start and end dates will be recorded on the Concomitant Medications eCRF at all study 
visits up to Day 43.   
 
A Cochran Mantel-Haenszel (CMH) test will be used to compare the proportion of subjects 
administered any anti-diarrheal agent during each specified time period [first dose to Day 8 
(inclusive), first dose to Day 15 (inclusive), and Day 16 to Day 29 (inclusive)] between 
niclosamide and placebo treatment groups adjusting for stratification factors, age (<65 years or 
≥65 years) and sex (female or male). The two-sided p-value will be reported. The adjusted 
difference in proportions between the 2 treatment groups (niclosamide vs. placebo) will be 
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Haenszel weights, and the associated 95% CI will also be provided using the Sato variance 
estimator (Sato, 1989). 
8.2.5. Time from first dose of study treatment to improvement of abdominal 
symptoms 
 
Only subjects with abdominal symptom(s) on Day 1 will be included in this analysis. 
 
The overall severity of abdominal symptoms and the date of assessment will be collected on the 
Diarrhea Clinical Assessment. A summary table of severity will include the number of subjects 
with an assessment available and the number and percentage of subjects within each severity 
category at each study visit (Baseline, Days 4, 8, 15, 22, 29, 36, and 43) by treatment group. The 
proportion of subjects with any improvement from baseline of abdominal symptoms will also be 
provided in the summary table by treatment group. Improvement of abdominal symptoms is 
defined as any severity reduction from baseline by at least one level (i.e., mild to normal, 
moderate to mild or normal, or severe to moderate or mild or normal).  
 
Time to the first improvement of abdominal symptoms is defined as the time in days from the 
first dose of study treatment to the first improvement of abdominal symptoms. Subjects without 
improvement of abdominal symptoms will be censored using the same rules as described for the 
primary efficacy endpoint in Section 8.1. Time to improvement of abdominal symptoms will be 
analyzed using the same time to event methods as described for the analysis of the primary 
endpoint in Section 8.1.1. 
8.2.6. Proportion of subjects with a negative stool test for SARS-CoV-2 on Day 1 
who acquire SARS-CoV-2 in stool through Day 43 
This analysis will be conducted on the FAS and include only all subjects with a negative stool 
test for SAS2-CoV-2 on Day 1. 
 
A summary table will include the number and percentage (proportion) of subjects acquiring 
SARS-CoV-2 by treatment group first overall after Day 1 through Day 43 visit, then for each 
post-first dose study visit (Days 4, 8, 15, 22, 29, 36, and 43). For each study visit, only subjects 
with available assessment at the visit or having a positive stool test before the visit will be 
included in the summary and counted in the denominator for the percentages. 
8.3. Systemic and Respiratory Secondary Efficacy Endpoints  
The analysis of the systemic and respiratory secondary efficacy endpoints will be conducted on 
the FAS. 
8.3.1. Proportion of subjects with each WHO severity score by study visit 
The WHO severity score and the date of assessment will be collected on the WHO Ordinal Scale 
for Clinical Improvement eCRF. A summary table severity will include the number of subjects 
with an assessment available and the number and percentage (proportion) of subjects with each 
WHO severity score at each study visit (Baseline, Days  4, 8, 15, 22, 29, 36, and 43) by treatment 


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group. The proportion of subjects with any clinical improvement or clinical worsening of illness 
severity from baseline will also be provided in the summary table by treatment group. Clinical 
improvement of illness severity is defined as a 1-point or greater reduction from baseline in 
WHO severity score. Clinical worsening of illness severity is defined as a 1-point or greater 
increase from baseline in WHO severity score. 
 
Time to first clinical improvement of illness severity is defined as the time in days from the first 
dose of study treatment to the first clinical improvement of illness severity. Subjects without 
clinical improvement of illness severity will be censored using the same rules as described for 
the primary efficacy endpoint in Section 8.1. As a supportive analysis, time to clinical 
improvement of illness severity will be analyzed using the same time to event methods as 
described for the primary endpoint in Section 8.1.1. 
8.3.2. Total duration, method of administration, and quantity of supplemental 
oxygen treatment 
A summary table by treatment group will include the following: 
• Number and percentage of subjects who require supplemental oxygen 
• Number and percentage of subjects with each method of oxygen administration 
• Descriptive statistics for the total number of days requiring supplemental oxygen 
A subject will be considered as requiring supplemental oxygen if the subject is administered any 
supplemental oxygen from first dose through Day 43. The total number of days requiring 
supplemental oxygen will be calculated by taking the sum of the duration (stop date – start date 
+1) for each supplemental oxygen treatment. The start and stop date of supplemental oxygen 
treatment, oxygen type, method of oxygen supplementation, oxygen flow rate and FiO2 will be 
collected on the Supplemental Oxygen Treatment eCRF at all study visits up to Day 43. 
8.3.3. Proportion of subjects with normal body temperature by study visit 
 
A summary table will include the number of subjects with an assessment available and the 
number and percentage of subjects with normal body temperature at each study visit (Baseline, 
Days 4, 8, 15, 22, 29, 36, and 43) by treatment group. Normal body temperature is defined for 
each method of measurement as follows: ≤36.9ºC axillary, ≤37.4ºC oral, ≤37.8ºC rectal, and 
≤37.5ºC tympanic (Geneva et al., 2019).  
8.3.4. Proportion of subjects with normal blood oxygen saturation by pulse 
oximetry (SpO2) on room air by study visit 
 
A summary table will include the number of subjects with an assessment available and the 
number and percentage (proportion) of subjects with normal SpO2 on room air, defined as SpO2 
>90%, at each study visit (Baseline, Days 4, 8, 15, 22, 29, 36, and 43) by treatment group. The 
oxygen saturation (%) on room air will be collected on the Vital Sign eCRF.   
8.3.5. Proportion of subjects admitted to the intensive care unit (ICU) and length of 
ICU stay 
 


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A summary table containing the proportion of subjects admitted to the ICU from the first dose 
through Day 43 and the length of ICU stay for each treatment group will be presented. The 
length of ICU stay in days will be calculated by taking the sum of the duration (discharge date – 
admission date + 1) for each ICU admission. ICU admissions and dates of stay will be captured 
on the Hospitalizations eCRF. 
8.3.6. Time to nasopharyngeal viral clearance assessed by RT-PCR 
 
Only subjects with positive test on Day 1 will be included in this analysis. 
 
Time to nasopharyngeal viral clearance is defined as the time in days from the first dose of study 
treatment to the first nasopharyngeal RT-PCR sample negative for SARS-CoV-2. Subjects 
without nasopharyngeal clearance will be censored using the same rules as described for the 
primary efficacy endpoint in Section 8.1.  
 
A summary table will include the number and percentage of subjects achieving and not achieving 
the first nasopharyngeal viral clearance up to each post-first dose study visit (Days 4, 8, 15, 22, 
29, 36, and 43) by treatment group. For each study visit, only subjects with available assessment 
at the visit or having a negative nasopharyngeal test before the visit will be included in the 
summary and counted in the denominator for the percentages.   
 
Time to nasopharyngeal viral clearance will be analyzed using the same time to event methods as 
described for the analysis of the primary endpoint in Section 8.1.1.. 
8.3.7. Proportion of subjects requiring hospitalization and duration of 
hospitalization from first dose through Day 43 
Hospital admissions and dates of stay will be captured on the Hospitalizations eCRF. 
 
Summary table containing the proportion of subjects requiring any hospitalization and the 
duration of hospitalization will be presented for each treatment group. A subject will be 
considered as requiring hospitalization if the subject has at least one hospital admission with an 
admission date between the first dose date and the Day 43 follow-up visit date (inclusive). The 
duration of hospitalization in days will be calculated by taking the sum of the duration (discharge 
date – admission date + 1) for each hospitalization. 
9. 
Safety Analysis 
Safety analyses will be conducted on safety data collected through the Day 43 follow-up visit for 
all randomized subjects and will be included as part of the Day 43 Final Analysis for the main 
CSR. All safety analyses will be performed using the SAF set and will be presented separately 
for Part 1 and Part 2 of the study unless otherwise specified. 


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9.1. Adverse Events 
Adverse events (AEs) will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) Version 23.0 and classified by system organ class (SOC) and preferred term (PT) for 
all summaries. 
 
The period of observation for AEs extends from the time the subject gives informed consent until 
the subject completes the Day 43 follow-up visit. AEs will be classified as pre-treatment AEs 
and treatment emergent adverse events (TEAEs) and are defined as follows:  
• A pre-treatment event is any event that meets the criteria for an AE/SAE and occurs after 
the subject signs the informed consent form but before receiving the first administration 
of study drug.  
• A TEAE is defined as an AE occurring or worsening on or after the date of first dose of 
study drug.  
 
A treatment-related AE will be defined as related if causality is definitely, probably, or possibly 
related. AEs where the causality is missing will be assumed to be related in table summaries.  
 
TEAEs leading to study drug discontinuation will be identified as TEAEs with a study drug 
action taken of “Drug Withdrawn”. TEAEs leading to death will be identified as TEAEs   
with an outcome of “Death Related to Adverse Event”.  
 
The severity of AEs (serious and non-serious) will be graded in accordance with the 
investigator’s clinical judgement as follows:  
• Mild: The AE dose not interfere in a significant manner with normal functioning but may 
be an annoyance. 
• Moderate: The AE produces some impairment of functioning but is not hazardous to 
health but is uncomfortable and/or an embarrassment. These events are usually 
ameliorated by simple therapeutic measures. 
• Severe: The AE produces significant impairment of functioning or incapacitation and is a 
hazard. 
AEs with missing severity will be assumed to be severe in table summaries. 
 
Details for imputing missing or partial start and/or stop dates of AEs are described in Appendix 
16.3. 
 
All summaries of AEs will be based on treatment-emergent adverse events (TEAEs) in the safety 
set. The following summaries of TEAEs will be provided by treatment group: 
 
• An overall summary of TEAEs including the number of TEAEs and the number and 
percentage of subjects with any of the following: TEAEs, study drug related TEAEs, 
TEAEs by maximum severity, TEAEs leading to study drug discontinuation, TEAEs 
leading to death, serious TEAEs, and study drug related serious TEAEs. 
• TEAEs (by SOC and PT) 
• Study Drug-Related TEAEs - by SOC and PT 
• TEAEs by Maximum Severity – by SOC and PT 


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• TEAEs leading to study drug discontinuation – by SOC and PT 
• AEs leading to death – by SOC and PT 
• Serious TEAEs – by SOC and PT  
• Study Drug-Related Serious TEAEs – by SOC and PT 
 
For the above summaries by SOC and PT, each subject is counted once within each unique 
category. For the summary by maximum severity, subjects who experience the same event 
several times, with different severity levels, will only be counted with the maximum severity. 
AEs will be sorted in descending order of frequency of SOC based on the total of all treatment 
groups. Within each SOC, AEs will be sorted in alphabetical order of preferred terms.  
 
All AEs, including pre-treatment AEs and TEAEs, will also be presented in a listing. 
9.2. Clinical Laboratory Evaluations 
Safety laboratory tests include chemistry and hematology on Days 1, 8, 15, 29, and 43 and will 
performed by a central laboratory. All summaries will be based on the units provided by the 
central laboratory; no conversion will be made. 
 
Summary tables displaying observed values and changes from baseline will be presented for 
numeric clinical laboratory tests by treatment group for subjects in the Safety set. Changes from 
baseline to each scheduled post-baseline visit (Days 8, 15, 29, and 43) will be presented. Box-
and-whisker plots will also be displayed for each laboratory test at baseline and each scheduled 
post-baseline visit by treatment group. 
 
All safety laboratory data will be included in separate listings and all test values outside the 
normal range will be flagged. 
9.2.1 Hematology 
The following laboratory tests will be included: complete blood count (CBC).  
9.2.2 Chemistry 
The following laboratory tests will be included: blood urea nitrogen (BUN), blood sugar, 
electrolytes (sodium, chloride, and bicarbonate [HCO3]), alkaline phosphatase, AST, ALT, 
lactate dehydrogenase (LDH), total bilirubin, serum creatinine, C-reactive protein, and fecal 
calprotectin. 
9.3 Vital Signs 
Vital signs will be measured on Days 1, 4, 8, 15, 22, 29, 36, and 43. Vital signs include systolic 
and diastolic blood pressure (mmHg), pulse rate (beats/min), blood oxygen saturation SpO2, and 
temperature (ºC) with method of measurement (axillary, oral, rectal, or tympanic). 
 


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Summary tables displaying observed values and changes from baseline will be presented for 
numeric vital sign data by treatment group for subjects in the Safety set. Changes from baseline 
to each scheduled post-baseline visit (Days 4, 8, 15, 22, 29, 36, and 43) will be presented.  
 
All vital sign data will also be presented in a listing. 
10. Exploratory Analysis 
Exploratory analyses will be conducted on exploratory data collected at the Month 4 and Month 
6 visits during the long term follow-up and will be included as the End of Study Final Analysis 
in an addendum to the main CSR. 
 
All exploratory analyses will be performed using the FAS and will be presented separately for 
Part 1 and Part 2 of the study unless otherwise specified. Due the exploratory nature of these 
analyses, only descriptive summary statistics will be provided by treatment group and no 
inferential statistical tests will be performed.  
 
All exploratory data including deaths will also be presented in separate listings.  
10.1. Proportion of subjects with recurrence of COVID-19 symptoms during long term 
follow-up 
A summary table will include the number and percentage (proportion) of subjects with any 
recurrent COVID-19 symptoms during the entire long term follow-up, after Day 43 visit to 
Month 4 visit and after Month 4 visit to Month 6 visit by treatment group. Only subjects who 
continued into the long term follow-up will be included in the summary and counted as the 
denominator for proportion. Additionally, the summary table will also include the number and 
percentage of subjects reporting each individual recurrent COVID-19 symptom by treatment 
group.  
10.2. Proportion of subjects with persistence of COVID-19 symptoms during long term 
follow-up 
A summary table will include the number and percentage (proportion) of subjects with any 
persistent COVID-19 symptoms during the entire long term follow-up, beyond Day 43 visit to 
Month 4 visit and beyond Month 4 visit to Month 6 visit by treatment group. Only subjects who 
continued into the long term follow-up will be included in the summary and counted as the 
denominator for proportion. Additionally, the summary table will also include the number and 
percentage of subjects reporting each individual persistent COVID-19 symptom by treatment 
group.  
10.3. Proportion of subjects with new hospitalization or rehospitalization during long-
term follow-up 
A summary table will include the number and percentage (proportion) of subjects with any new 
hospitalization or rehospitalization during the entire long term follow-up, after Day 43 visit to 
Month 4 visit and after Month 4 visit to Month 6 visit by treatment group. Only subjects who 


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continued into the long term follow-up will be included in the summary and counted as the 
denominator for proportion. A subject will be considered as having a new hospitalization or 
rehospitalization if the subject has at least one hospitalization with an admission date after the 
Day 43 follow-up visit. Hospital admissions and dates of stay are collected on the 
Hospitalizations eCRF.  
10.4. Summarization of genotypic resistance analysis data  
Nasopharyngeal swabs and stool samples will be collected and stored for possible genotypic 
resistance analysis. The summary results will be provided when data become available.  
11. Interim Safety Analysis 
The interim safety data review for Part 1 and 2 of the study will be performed by the DMC (see 
Section 12. below). Data to be reviewed includes subject disposition, demographics, medical 
history, concomitant medications, study drug Exposure and compliance, adverse Events, safety 
clinical laboratory and vital signs. The DMC will be unblinded to study data and will operate 
under a DMC charter. Blinded and unblinded PPD Biostatisticians will produce and provide 
tables, listings, and figures requested by the DMC. 
 
Part 1 will enroll approximately 9 hospitalized subjects. After treatment is concluded for all 9 
subjects, the DMC will review the safety data and determine if the study may proceed to Part 2 
or if additional subjects are needed to assess tolerability of the study drug. If additional subjects 
are needed, approximately 9 more subjects will be enrolled in Part 1, and then the DMC will 
meet again after all subjects are treated to determine if the study may proceed to Part 2. Due to 
the relatively small number of subjects in Part 1, the decision for DMC review of Part 1 will be 
based on medical judgment of niclosamide tolerability compared to placebo and will not require 
specific statistics. 
 
For Part 2, the planned interim safety data review will occur when 50 subjects have been 
randomized and completed the 2-week treatment period. The outcome from the DMC to be 
delivered to the sponsor will be: (1) continue as planned; (2) pause enrollment and undertake 
further evaluation of safety; or (3) recommend that the study be terminated due to safety 
concerns. No rigid statistical stopping rules will be used to make these decisions. While the 
DMC statistician may perform statistical analyses to examine adverse trends in safety, such as 
excess deaths and SAEs in the active arm, the decision to recommend a pause in enrollment or 
termination of the study will be reached by clinical consensus of the DMC. 
 
No formal interim analysis for efficacy is planned to stop the study early for benefit or futility. 
12. Data Monitoring Committee (DMC) 
An independent Data Monitoring Committee (DMC) will be established to review the safety data 
throughout the study to ensure the safety of study subjects, the ethical continuation of the study, 
and provide recommendations regarding continuation or termination of the study or protocol 
modifications. The DMC will be headed by a DMC Chair and will consist of 2 clinicians and 1 
biostatistician, who, collectively, have experience in the management of patients with infectious 


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diseases and in the conduct and monitoring of randomized clinical trials. The DMC will consist 
of experts independent from the Sponsor.  
 
The roles, responsibilities and rules governing operation of the DMC are discussed in full in the 
DMC charter, which will be finalized prior to the administration of investigational product. The 
DMC charter will define the primary responsibilities of the DMC; guide its activities, its 
relationship with other study components, its membership, and the purpose and timings of its 
meetings.  It will provide the procedures for ensuring confidentiality, formal communication, and 
outline of the content of reports that will be provided by the DMC.   
13. Final Analyses and Unblinding 
13.1.  Day 43 Final Analysis 
This analysis will be carried out for the main clinical study report (CSR) when the last subject 
has completed the Day 43 follow-up visit. The main CSR will contain all efficacy (primary and 
secondary) and safety data through Day 43 as specified per protocol for all randomized patients. 
An official database lock with PI sign off will be implemented prior to this final analysis at Day 
43.  
13.2. End of Study Final Analysis 
This analysis will be provided in an addendum to the main CSR. It will include only exploratory 
data collected at Month 4 and Month 6 long-term follow-up visits. Specifically, the exploratory 
data contains subject survival status, recurrence of COVID-19 symptoms and associated 
hospitalization(s) and treatments/therapies. A second official database lock with PI sign off will 
be performed but only for exploratory data prior to this final analysis at end of long-term follow-
up. 
13.3. Unblinding 
At the time of the final analysis at Day 43, the randomization will be unblinded to the central 
study team after the official database lock. However, the investigators, other site study staff, and 
subjects will remain blinded to their treatment allocation(s) for as long as they are participating 
in the study. 
14. Changes in the Planned Analysis 
Bristol Stool Scale Types 5-7 has been updated to 6-7 for the secondary endpoint in section 
3.2.2,  section 8.2.2, and section 8.2.3 to be consistent with Appendix B of the protocol. 
Furthermore, for both analyses if the day of the formed stool/last watery stool was the same as 
the first day of treatment, then the time to event was imputed as 0.5 days. In the time to last 
watery stool analysis, there was no censoring necessary. 
15.  References 
Geneva II, Cuzzo B, Fazili T, et al. Normal body temperature: a systematic review. Open Forum 
Infect Dis. 2019;6(4):ofz032. 


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He X, Lau EHY, Wu P, et al. Temporal dynamics in viral shedding and transmissibility of 
COVID-19. Nat Med. 2020;26(5):672-5. 
Sato, T. (1989). On the variance estimator for the Mantel-Haenszel risk difference, Biometrics 
45, 1323-1324. Letter to the editor. 


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16. Appendices 
16.1. Schedule of Assessments 
 
Visit1 
Screening2 
Treatment 
Follow-Up 
Short-term 
Long-term 
Timing (D=day, M=month) 
D -3 to -1 D1 
D4 
D8 
D15 
D22 
D29 
D36 
D43 
M4 
M6 
Deviation vs randomization day 
±1 day 
±1 day ±2 days 
±2 days 
±2 days ±3 days 
±3 days 
±1 week ±1 week 
Informed consent 
X 
Eligibility (inclusion/exclusion criteria) 
X 
X 
Demography 
X 
Medical history (or changes) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Stool analysis 
X 
 
 
 
 
 
 
 
 
 
 
Stool sample for      SARS-CoV-2 RNA3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Diarrhea clinical assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Nasopharyngeal swab for               
SARS-CoV-2 RNA3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Laboratory assessments4                    
(L=local, C=central) 
L 
C 
 
 C 
 C 
 
 C 
 
 C 
 
 
Overall clinical assessment5 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Randomization 
X 


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Dosing study drug 
Daily TID, with last dose on       
D14 or 15  
Daily diary 
 
Daily 
 
 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Survival status 
 
 
 
 
 
 
 
 
X 
X 
Persistence of COVID-19 symptoms 
 
 
 
 
 
 
 
 
X 
X 
Recurrence of COVID-19 symptoms 
 
 
 
 
 
 
 
 
X 
X 
(Re)Hospitalization due to COVID-19 
 
 
 
 
 
 
 
 
X 
X 
1. 
Patients may be hospitalized, inpatient in a research unit, or seen in an outpatient clinic or in a home care setting.  
2. 
Screening may occur on the same day as randomization, if all procedures may be completed. If they occur on the same day, procedures scheduled for both visits are 
not required to be duplicated. 
3. 
At screening, eligibility can be determined by local SARS-CoV-2 viral RNA analysis on a nasopharyngeal swab. Only one screening sample is required and can be 
determined by local requirements.  Eligibility can be determined at a local laboratory at screening; however, a central laboratory may be used at screening if needed. 
On Days 1 to 43, the nasopharyngeal swab and stool sample will be collected and sent to the central lab.  
4. 
Local laboratory testing at screening should include at least AST, ALT, and serum creatinine to determine eligibility. Central laboratory testing will include CBC, 
BUN, blood sugar, electrolytes (sodium, chloride, potassium, and bicarbonate [HCO3]), alkaline phosphatase, AST, ALT, LDH, total bilirubin, serum creatinine, 
C-reactive protein, and fecal calprotectin. When only central testing is required, any other laboratory assessment may be conducted at the local laboratory for the 
physician’s safety assessment according to the local practice and patient’s clinical needs. 
5. 
Including: mortality; hospital admission and discharge; ICU admission and discharge; WHO severity score and duration, type of administration, vital signs, and 
quantity of supplemental oxygen treatment. Vital signs should be completed on Days 1-8, 10, and 12 for Part 1 patients, but only need to be recorded in the CRF 
when the full Overall Clinical Assessment is due at the study visits above.  
* Initial medical history will collect date of initial symptom onset. If date is uncertain, verbatim response from patient will be collected. 
 
 


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16.2. WHO Ordinal Scale for Clinical Improvement 
 
Patient State 
Descriptor 
Score 
Uninfected 
No clinical or virologic evidence of infection 
0 
Ambulatory 
No limitation of activities 
1 
Ambulatory 
Limitation of activities 
2 
Hospitalized, Mild Disease 
Hospitalized, no oxygen therapy 
3 
Hospitalized, Mild Disease 
Oxygen by mask or nasal prongs 
4 
Hospitalized, Severe Disease 
Non-invasive ventilation or high-flow oxygen 
5 
Hospitalized, Severe Disease 
Intubation and mechanical ventilation 
6 
Hospitalized, Severe Disease 
Ventilation + additional organ support – pressors, RRT, ECMO 
7 
Dead 
Dead 
8 
A special WHO (2020) committee arrived at the ordinal scale that measures illness severity over time. 
 
 
 
 


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16.3. Missing Date Imputation 
 
Imputation rules for missing or partial AE start/end dates are defined as:  
• Only Day of AE start date is missing:  
o If the AE start year and month are the same as that for the first dose date, then:   
▪ If the full (or partial) AE end date is NOT before the first dose date or AE end date is missing, then impute the 
AE start day as the day of first dose date.  
o Otherwise, impute the AE start day as 1.  
• If Day and Month of AE start date are missing:  
o If AE start year = first dose year, then:   
▪ If the full (or partial) AE end date is NOT before the first dose date or AE end date is missing, then impute the 
AE start Month and Day as the Month and Day of first dose date.   
o Otherwise, impute the AE start MONTH as January and the DAY as 1.  
• If Year of AE start date is missing:  
o If the year of AE start is missing or AE start date is completely missing, then query site and leave as missing.  
• For missing and partial adverse event end dates, imputation will be performed as follows:  
o If only the day of the month is missing, the last day of the month will be used to replace the missing day.  
o If the day and month are missing or a date is completely missing, it will be considered as missing.  
 
Imputation rules for missing or partial medication start/stop dates are defined below:  
• If only Day of CM start date is missing:  
o If the CM start year and month are the same as that for the first dose date, then:   


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▪ If the full (or partial) CM end date is NOT before the first dose date or CM end date is missing, then impute the 
CM start day as the day of first dose date.   
o Otherwise, impute the CM start day as 1.  
• If Day and Month of CM start date are missing:  
o If CM start year = first dose year, then:   
▪ If the full (or partial) CM end date is NOT before the first dose date or CM end date is missing, then impute the 
CM start Month and Day as the Month and Day of first dose date.   
o Otherwise, impute the CM start MONTH as January and the DAY as 1.  
• If Year of CM start date is missing:  
o If the year of CM start is missing or CM start date is completely missing, then query site and leave as missing. 
• For missing and partial CM end dates, imputation will be performed as follows:  
o If only the day of the month is missing, the last day of the month will be used to replace the missing day.  
If the day and month are missing or a date is completely missing, it will be considered as missing.