Clinical trial NCT04603924
Conditions: COVID-19
Keywords: Corona Virus Disease (COVID-19) Niclosamide Antiviral Immunomodulator Oral Niclosamide Infection Acute Respiratory Distress Syndrome (ARDS) Cytokine dysregulation Virus Viral anthelmintic anti-inflammatory bronchodilator antineoplastic ANA001 Moderate COVID-19 ARDS Acute Respiratory Distress Syndrome Hospitalized COVID-19
Sponsor: NeuroBo Pharmaceuticals Inc.
Start date: 2020-10-07; Completion date: 2022-02-16
Enrollment: 49 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Study of ANA001 in Moderate and Severe COVID-19 Patients

Detailed description:
This is a 2 part, Phase 2/3 multi-center, double blinded, placebo-controlled study to assess the safety, tolerability, and efficacy of oral niclosamide (ANA001) in moderate and severe hospitalized COVID-19 patients compared to placebo.

Arms: arm 1: Subjects in the ANA001 treatment arm will receive 1,000 mg (4 capsules; 250 mg each) by mouth twice per day for 7 consecutive days with a meal. If the participant requires mechanical ventilation over the course of the study, ANA001 may be administered via nasogastric (NG), percutaneous endoscopic gastrostomy (PEG) or orogastric (OG) tube and, if possible, should be administered with a scheduled nasogastric (NG) or orogastric (OG) feeding. arm 2: Subjects in the comparator arm will receive matching placebo (hydroxypropylmethylcellulose (HPMC)) (4 capsules, by mouth twice a day) for the 7-day treatment duration.
Interventions: intervention 1: Niclosamide intervention 2: Placebo
Intervention descriptions: intervention 1: Niclosamide is an antihelmintic with in-vitro antiviral activity intervention 2: Matching hydroxypropylmethylcellulose HPMC capsules with no active ingredients

Protocol documents:
Prot_000.pdf: 
ANA001 - 001 
 
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Confidential 
 
 
 
A Phase 2/3 Randomized and Placebo-Controlled Study of ANA001 
in Moderate and Severe COVID-19 Patients 
 
Investigational Product(s) 
ANA001 (Niclosamide capsules) 
Protocol Number 
ANA001-001 
Version Number 
5.0 (ANA001-001.05) 
Version Date 
03-Feb-2022 
Amendment 
Amendment 4 
Sponsor 
NeuroBo Pharmaceuticals, Inc. 
200 Berkeley Street, 19th Floor  
Boston, MA 02116 
Sponsor Medical Representative 
Douglas Rank, MD 
Director, Clinical Development 
drank@neurobopharma.com 
 
Confidentiality Statement 
The information contained in this protocol and all other information relevant to ANA001 are 
the confidential and proprietary information of NeuroBo Pharmaceuticals Inc., and except as 
may be required by federal, state, or local laws or regulation, may not be disclosed to others 
without prior written permission of NeuroBo Pharmaceuticals Inc. 
 


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STATEMENT OF COMPLIANCE 
The study will be conducted in compliance with this clinical study protocol, Good Clinical 
Practices (GCP) as outlined by International Council for Harmonization (ICH) of Technical 
Requirements for Pharmaceuticals for Human Use E6 (R2), and all applicable local and 
national regulatory requirements. Screening at any clinical study site may not begin prior to 
Ethics Committee (EC) or Institutional Review Board (IRB) approval.
Any amendments to the protocol or changes to the consent document will be approved before 
implementation of that amendment, unless allowed by regulatory guidelines (e.g., when 
necessary to eliminate immediate hazard to the participants). Reconsent of previously enrolled 
participants may be necessary depending on the nature of the amendment. 
The principal investigator will ensure that changes to the study plan as defined by this protocol 
will not be made without prior agreement from the Sponsor and documented approval from the 
IRB of record, unless such a change is necessary to eliminate an immediate hazard to the study 
participants. 
All personnel involved in the conduct of this study have completed Human Subjects Protection 
and GCP Training as outlined by their governing institution. 


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Study Title
A Phase 2/3 Randomized and Placebo-Controlled Study of ANA001 
in Moderate and Severe COVID-19 Patients
Protocol Number
ANA001-001
Version Number
5.0 (ANA001-001.05)
Version Date
03-Feb-2022
Amendment
Amendment 4
The design of this study as outlined by this protocol has been reviewed and approved by the
Sponsors Responsible Personnel 
Name:
Title:
Signature:
Date:
[DD-MMM-YYYY]


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MENT 
I have read the protocol, appendices, and accessory materials related to Study ANA001-001 
and agree to the following: 
 To conduct this study as described by the protocol and any accessory materials 
 To protect the rights, safety, and welfare of the participants under my care 
 To provide oversight to all personnel to whom study activities have been delegated 
 To control all investigational products provided by the Sponsor and maintain records 
of the disposition of those products 
 To conduct the study in accordance with all applicable local and national regulations, 
the requirements of the IRB/EC of record for my clinical site, and GCP as outlined by 
ICH E6 (R2). 
 To obtain approval for the protocol and all written materials provided to participants 
prior to initiating the study at my site 
 To obtain informed consent and updated consent in the event of new information or 
amendments, as required from all participants (or their legally authorized 
representative) enrolled at my study site prior to initiating any study-specific procedures 
or administering investigational products to those participants 
 
protocol 
 To permit monitoring, auditing, and inspection by the Sponsor, its designated 
representatives, and regulatory authorities 
 
Name [Last, First Name] 
Title at Institution 
Site Number 
 
 
 
 
 
 
Signature 
Date [DD-MMM-YYYY] 
 
 
 
Site Name 
Site Address 
 
 
 


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TABLE OF CONTENTS 
TITLE PAGE ........................................................ ERROR! BOOKMARK NOT DEFINED. 
STATEMENT OF COMPLIANCE ........................................................................................... 2 
APPROVAL ........................................................................................................ 3 
MENT ......................................................................................... 4 
TABLE OF CONTENTS ........................................................................................................... 5 
LIST OF TABLES ..................................................................................................................... 8 
LIST OF FIGURES ................................................................................................................... 8 
LIST OF APPENDICES ............................................................................................................ 8 
LIST OF ABBREVIATIONS .................................................................................................... 9 
1 
SYNOPSIS ....................................................................................................................... 12 
1.1 
Study Schematic ...................................................................................................... 16 
1.2 
Schedule of Events .................................................................................................. 17 
2 
INTRODUCTION ............................................................................................................ 22 
2.1 
Background ............................................................................................................. 22 
2.1.1 Target Indication and Population .............................................................. 22 
2.1.2 ANA001 Pharmacology relative to COVID-19 ....................................... 22 
2.1.2.1 
Introduction ..................................................................................... 22 
2.1.2.2 
ANA001 Inhibits SARS-CoV-2 Viral Replication ......................... 23 
2.1.2.3 
ANA001 inhibits NF-
Syndrome ........................................................................................ 23 
2.1.2.4 
STAT3 Mediates IL-6 Associated TH17 Orientation ..................... 24 
2.1.2.5 
STAT3 Upregulates Tissue Factor, the Key Initiator of Blood 
Coagulation ..................................................................................... 25 
2.1.2.6 
Relevance of Tissue Factor in High-Risk Patients with COVID-19
 ......................................................................................................... 25 
2.1.3 Gastrointestinal System ............................................................................ 26 
2.1.3.1 
Introduction ..................................................................................... 26 
2.1.3.2 
Administration Regimen ................................................................. 26 
2.1.3.3 
Justification for Dosing Strategy ..................................................... 26 
2.1.4 Summary of Nonclinical Toxicology and Pharmacokinetics ................... 27 
2.1.5 Summary of Supportive Clinical Data ...................................................... 27 
2.1.5.1 
Clinical Pharmacology and Pharmacokinetics ................................ 28 
2.1.5.2 
Clinical Safety ................................................................................. 28 
2.1.5.3 
Clinical Efficacy.............................................................................. 28 
2.1.6 Other Relevant Data ................................................................................. 29 
2.1.7 Benefit:Risk Assessment .......................................................................... 29 
2.2 
Study Rationale ....................................................................................................... 29 
3 
OBJECTIVES AND ENDPOINTS .................................................................................. 30 
4 
STUDY PLAN.................................................................................................................. 33 
4.1 
Study Design ........................................................................................................... 33 
4.2 
Design Rationale ..................................................................................................... 34 
5 
POPULATION ................................................................................................................. 35 
5.1 
Recruitment ............................................................................................................. 35 


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5.2 
Definitions ............................................................................................................... 35 
5.3 
Inclusion Criteria ..................................................................................................... 35 
5.4 
Exclusion Criteria.................................................................................................... 35 
5.5 
Exceptions to Eligibility Criteria ............................................................................ 36 
6 
STUDY CONDUCT ......................................................................................................... 37 
6.1 
Screening Period Assessments ................................................................................ 37 
6.2 
Randomization (Day 1-Baseline) ............................................................................ 37 
6.3 
Dosing Period (Day 1 through Day 8) .................................................................... 38 
6.3.1 Day 1 Assessments ................................................................................... 38 
6.3.2 Daily Assessments (Day 2 through Day 8) ............................................... 39 
6.3.3 Day 15 (±3 days), and Day 28 (+2 days)Assessments ............................. 40 
6.3.4 Day 60(+2 days)/End of Study (EOS)Assessments.................................. 41 
6.4 
Discontinuation or Withdrawal ............................................................................... 41 
6.4.1 Individual Participants .............................................................................. 41 
6.4.1.1 
Withdrawal from Study and Lost to Follow-up .............................. 41 
6.4.1.2 
Discontinuation of Study Drug ....................................................... 42 
6.4.1.3 
Replacement of Participants ............................................................ 43 
6.4.2 Discontinuation or Termination of the Study ........................................... 43 
7 
STUDY INTERVENTIONS ............................................................................................ 44 
7.1 
Description of Products ........................................................................................... 44 
7.1.1 Active Intervention  ANA001 ................................................................ 44 
7.1.1.1 
Formulation, Storage, Preparation, and Handling ........................... 44 
7.1.1.2 
Dosing and Administration ............................................................. 44 
7.1.2 Control - Placebo ...................................................................................... 44 
7.1.2.1 
Formulation, Storage, Preparation, and Handling ........................... 44 
7.1.2.2 
Dosing and Administration ............................................................. 44 
7.2 
Dosing Assignment and Bias Minimization ........................................................... 44 
7.2.1 Dosing Allocation ..................................................................................... 44 
7.2.2 Randomization Strategy and Procedure .................................................... 45 
7.2.3 Extent and Maintenance of Blinding ........................................................ 45 
7.2.4 Unblinding Procedures ............................................................................. 45 
7.2.4.1 
Planned Unblinding ......................................................................... 45 
7.2.4.2 
Unplanned or Unintentional Unblinding ......................................... 45 
7.3 
Assessment and Verification of Compliance .......................................................... 45 
7.4 
Prior and Concomitant Therapies............................................................................ 45 
7.4.1 Prohibited Therapies ................................................................................. 46 
7.4.2 Permitted Therapies .................................................................................. 46 
7.4.3 Rescue Therapies ...................................................................................... 46 
8 
SAFETY MONITORING ................................................................................................ 47 
8.1 
Definitions ............................................................................................................... 47 
8.2 
Documenting Adverse Events ................................................................................. 48 
8.2.1 Time Frame for Collection ....................................................................... 48 
8.3 
Recording Adverse Events ...................................................................................... 48 
8.4 
Communicating an SAE/SUSAR to the Sponsor and/or CRO ............................... 49 


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8.5 
Expedited Reporting of SAE/SUSAR to IEC/IRB and Regulatory Authorities ..... 49 
8.6 
Adverse Events of Special Interest ......................................................................... 49 
8.7 
Clinical Laboratory Findings .................................................................................. 49 
8.8 
Pregnancy ................................................................................................................ 49 
8.9 
Overdose or Misuse................................................................................................. 49 
9 
DATA ANALYSIS AND STATISTICAL METHODS .................................................. 50 
9.1 
Determination of Sample Size ................................................................................ 50 
9.1.1 Study Part 1............................................................................................... 50 
9.1.2 Study Part 2............................................................................................... 50 
9.2 
Analysis Populations ............................................................................................... 50 
9.3 
Planned Analyses .................................................................................................... 51 
9.3.1 Disposition of the Study Participants ....................................................... 51 
9.3.2 Demographic and Baseline Disease Characteristics ................................. 51 
9.3.3 Exposure to Study Treatment and Compliance ........................................ 51 
9.3.4 Analysis of Primary Efficacy Endpoints of Study Part 2 ......................... 51 
9.3.5 Analysis of Secondary Efficacy Endpoints .............................................. 52 
9.3.6 Safety Analysis ......................................................................................... 52 
9.3.6.1 
Treatment-Emergent Adverse Events ............................................. 52 
9.3.6.2 
Clinical Laboratory Evaluation ....................................................... 52 
9.3.6.3 
Vital Signs ....................................................................................... 53 
9.4 
Interim Analysis ...................................................................................................... 53 
9.5 
Independent Data Monitoring Committee .............................................................. 53 
9.6 
Handling of Missing Data ....................................................................................... 53 
9.7 
Multiplicity Adjustment .......................................................................................... 53 
9.8 
Pharmacokinetic Analysis ....................................................................................... 53 
10 ETHICAL CONSIDERATIONS...................................................................................... 54 
10.1 Good Clinical Practice ............................................................................................ 54 
10.2 Ethics Review.......................................................................................................... 54 
10.3 Informed Consent .................................................................................................... 54 
10.4 Data Privacy ............................................................................................................ 54 
10.5 Disclosure ................................................................................................................ 54 
10.6 Biological Specimens and Data .............................................................................. 54 
11 OVERSIGHT .................................................................................................................... 56 
11.1 Data Monitoring Committee ................................................................................... 56 
11.2 Quality Control and Assurance ............................................................................... 56 
11.2.1 Monitoring ................................................................................................ 56 
11.2.2 Protocol Deviations .................................................................................. 56 
11.2.3 Records ..................................................................................................... 56 
11.2.3.1 Data Capture and Management ....................................................... 56 
11.2.3.2 Records Retention ........................................................................... 57 
11.3 Study Completion/Termination ............................................................................... 57 
12 PUBLICATION POLICY ................................................................................................ 58 
13 FUNDING ........................................................................................................................ 59 
14 REFERENCES ................................................................................................................. 60 


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15 APPENDICES .................................................................................................................. 63 
 
LIST OF TABLES 
Table 1 
Schedule of Events (Study Part 1 and Part 2) .................................................. 18 
Table 2 
Objectives and Endpoints of Study Part 1 ....................................................... 30 
Table 3 
Objectives and Endpoints of Study Part 2 ....................................................... 32 
Table 4 
NEWS2 ............................................................................................................ 64 
 
LIST OF FIGURES 
Figure 1 
Study Schematic............................................................................................... 16 
Figure 2 
Potential Therapeutic Targets to Treat COVID-19 and Anticipated Activity of 
ANA001 (Modified from Hirano and Murakami, 2020) ................................. 24 
 
LIST OF APPENDICES 
APPENDIX 1  NIAID CLINICAL STATUS SCORE (CSS) ................................................. 63 
APPENDIX 2  NATIONAL EARLY WARNING SCORE 2 (NEWS2) ............................... 64 
APPENDIX 3  SEQUENTIAL ORGAN FAILURE ASSESSMENT (SOFA) SCORE ........ 65 
APPENDIX 4 LABORATORY ASSESSMENTS ................................................................. 68 
APPENDIX 5  PK SAMPLE COLLECTION SCHEDULE (PART 1 ONLY) ...................... 69 
 


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LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
ACE2 
Angiotensin converting enzyme 2 
ADAM17 
ADAM Metallopeptidase Domain 17 
AE 
Adverse event 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
AMP 
Amplifier 
ANGII 
Angiotensin II 
aPTT 
Partial thromboplastin 
AR 
Adverse reaction 
ARDS 
Acute respiratory distress syndrome 
AST 
Aspartate aminotransferase 
AT1R 
Angiotensin II receptor type 1 receptor 
BID 
Twice daily 
BL 
Baseline 
BMI 
Body mass index 
BP 
Blood pressure 
BUN 
Blood urea nitrogen 
CATB/L 
Cathepsin B and L 
CBC 
Complete blood count 
CCR 
Chemokine receptor 
Cmax 
Maximum observed serum concentration  
CoV 
Coronavirus 
COVID-19 
Coronavirus disease 2019 
CPE 
Cytopathic effects 
CRF 
Case report form 
CRO 
Contract research organization 
CRP 
C-reactive protein 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
Cytochrome P450 
DAIDS 
Division of AIDS 
DIC 
Disseminated intravascular coagulation 
DG 
Dose group 
DLT 
Dose limiting toxicity 
DMC 
Data Monitoring Committee 
DNA 
Deoxyribonucleic acid 
EC 
Ethics Committee 
ECMO 
Extracorporeal membrane oxygenation 
EC50 
Half maximal effective concentration 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
EOS 
End of study 


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Abbreviation 
Definition 
EOT 
End of treatment 
FIO2 
Fraction of inspired oxygen 
GCP 
Good Clinical Practices 
GI 
Gastrointestinal 
GRAS 
Generally recognized as safe 
GU 
Genitourinary 
HPMC 
Hydroxypropylmethylcellulose 
HR 
Heart rate 
IB 
 
IC50 
Half maximal inhibitory concentration 
IC100 
Total inhibitory concentration 
ICF 
Informed consent form 
ICH 
International Council for Harmonization 
ICU 
Intensive care unit 
IEC 
Independent ethics committee 
IL 
Interleukin 
IL-6 
Interleukin-6 
IND 
Investigational New Drug 
INR 
International normalized ratio 
IRB 
Institutional Review Board 
IV 
Intravenous 
JAK 
Janus kinase 
LDH 
Lactate dehydrogenase 
LRTI 
Lower respiratory tract infection 
LTFU 
Long-term follow-up 
Mabs 
Monoclonal antibodies 
MERS-CoV 
Middle East respiratory syndrome coronavirus 
MODS 
Multiple organ dysfunction syndrome 
N 
Sample size 
NDA 
New Drug Application 
NEWS2 
National Early Warning Score 2 
NF-kB 
Nuclear factor kappa-light-chain-enhancer of activated B cells 
NIPVV 
Noninvasive positive pressure ventilation  
NG 
Nasogastric 
NP 
Nasopharyngeal 
OG 
Orogastric 
PaO2 
Partial pressure of oxygen 
PD 
Pharmacodynamics 
PEG 
Percutaneous endoscopic gastrostomy 
PK 
Pharmacokinetics 
PK/PD 
Pharmacokinetic/Pharmacodynamic 
PO 
By mouth 
PRRs 
Pattern-recognition receptors 


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Abbreviation 
Definition 
PTT 
Prothrombin time 
RR 
Respiratory rate 
RT-PCR 
Reverse transcriptase polymerase chain reaction 
RTSM 
Randomization and Trial Supply Management 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SAR 
Suspected adverse reaction 
SARS-CoV 
Severe acute respiratory syndrome coronavirus 
SARS-CoV-2 
Severe acute respiratory syndrome coronavirus 2 
SD 
Standard deviation 
SOC 
Standard-of-care 
SOE 
Schedule of events 
SOFA 
Sequential Organ Failure Assessment 
SpO2 
Peripheral capillary oxygen saturation 
STAT 
Signal transducers and activators of transcription 
STAT3 
Signal transducer and activator of transcription 3 
SUSAR 
Suspected unexpected serious adverse reaction 
T2D 
Type 2 diabetes 
TEAE 
Treatment-emergent adverse event 
TF 
Tissue factor 
TID 
Thrice daily  
tmax 
Time at which Cmax is observed 
TMPRSS2 
Transmembrane serine protease 2 
TNF-  
Tumor necrosis factor alpha 
WBC 
White blood cell 
WHO 
World Health Organization 
 


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1 
SYNOPSIS 
Title 
A Phase 2/3 Randomized and Placebo-Controlled Study of ANA001 in the 
Treatment of Moderate and Severe COVID-19 Patients
Phase 
2/3 
Study Design 
This is a randomized, double blind, placebo-controlled multicenter study to 
investigate the safety and efficacy of ANA001 in the treatment of subjects with 
moderate and severe coronavirus disease 2019 (COVID-19). A total of 436 
subjects who meet all eligibility criteria at Screening will be randomized to be 
treated with ANA001 1,000 mg twice daily (BID) or matching placebo 
administered orally (PO). Randomization will be stratified by oxygenation 
(SpO2 >93 and <98% on room air versus SpO2 93% on room air), diarrhea
(presence/absence)
. Each subject will be treated for 7
consecutive days. Additionally, every subject will be followed up for safety and 
efficacy up to day 60 (+2 days) after first dose. 
 
The study consists of 2 parts: 
Study Part 1: It includes 60 subjects randomized in 1:1 ratio to receive ANA001 
or matching placebo to assess the safety and tolerability of ANA001 1,000 mg 
BID for 7 days. An independent Data Monitoring Committee will review the 
safety profile of ANA001 1,000 mg PO BID prior to the initiation of Part 2 of 
the study. 
Study Part 2: It includes 376 subjects randomized in 1:1 ratio to receive ANA001 
or matching placebo to demonstrate the statistical superiority of ANA001 1,000
mg PO BID for 7 days compared with matching placebo in the treatment of 
subjects with moderate and severe COVID-19. Additionally, the safety profile
of ANA001 will be assessed compared with placebo. 
Rationale 
Niclosamide has demonstrated both antiviral and immunomodulatory activity 
with possible beneficial downstream effects on coagulation abnormalities 
observed in COVID-19. These effects support the development of ANA001, an 
oral formulation of niclosamide, for the treatment of COVID-19. 
Hypothesis: ANA001 will reduce viral load and inflammation associated with 
cytokine dysregulation, acute respiratory distress syndrome (ARDS), and 
coagulation abnormalities and thus improve time to clinical improvement 
defined as hospital discharge recorded using the WHO Ordinal Scale for Clinical 
Improvement (Appendix 1). 
Target Population 
Patients with moderate and severe COVID-19 who fulfill the study entry 
criteria 
Number of Participants 
Total: Approximately 436 participants 
Part 1 (60 participants): 30 ANA001 + 30 matching placebo 
Part 2 (approximately 376 participants): 188 ANA001 + 188 matching placebo 
Intervention 
ANA001 1,000 mg PO BID or matching placebo for 7 days (i.e., 14 scheduled 
doses comprised of 56 capsules in total): All participants will also receive 
unrestricted access to standard-of-care as defined by the respective study sites.  
Primary Objective and 
Primary 
Endpoints/Parameters 
(Part 1) 
Objective:  
 
To evaluate the safety and tolerability of ANA001 as therapy for moderate 
and severe COVID-19 patients 
Endpoints/Parameters:  
 
Treatment-emergent adverse events (TEAEs), treatment-emergent serious 
adverse events (SAEs), deaths, and discontinuations due to a TEAE 
 
Vital signs and laboratory (hematology, chemistry, and coagulation) 
parameters 
Secondary Objectives and 
Secondary Endpoints 
(Part 1) 
Objectives:  
 
To evaluate the efficacy of ANA001 as therapy in moderate and 
severe COVID-19 patients 


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To evaluate the PK of ANA001 
Endpoints:  
 
Median time (in hours) to hospital discharge (where discharge is 
defined as a score of 1 or 2 in the WHO Ordinal Scale for Clinical 
Improvement 
 
Plasma concentrations of ANA001 will be explored on Day 1, 2, 3, or 
Day 4 
 
Exploratory Objectives and 
Exploratory Endpoints  
(Part 1) 
Objectives:  
 
To evaluate clinical improvement using National Early Warning 
Score 2 (NEWS2) 
 
To evaluate the need and duration of rescue therapy 
 
To evaluate the effect on subjective symptoms of COVID-19 
 
To evaluate progression of COVID-19 from moderate or severe to 
more severe (i.e., moderate to severe, moderate to critical, or severe to 
critical) 
 
To evaluate the effect of ANA001 on requirement for oxygen and/or 
assisted ventilation 
 
To evaluate time to resolution of the WHO Ordinal Scale for Clinical 
Improvement 
 
To evaluate the effect of ANA001 on thromboembolic events 
 
To evaluate the relationship of ANA001 and markers of inflammation 
associated with acute respiratory distress syndrome (ARDS) 
 
To evaluate the relationship between ANA001 plasma concentrations 
and viral dynamics  
Endpoints:  
 
Mean change from baseline (BL) in NEWS2 on Day 15 
 
Mean number of days on rescue treatment (COVID-19 therapies that 
are FDA approved or have emergency-use authorization) within 15 
days after enrollment 
 
Median time (in days) to resolution of subjective symptoms assessed 
by the Investigator to be potentially due to COVID-19 including: 
fever, cough (productive or non-productive), sore throat, malaise, 
headache, muscle pain, gastrointestinal symptoms (i.e., nausea, 
vomiting, or diarrhea), shortness of breath (with or without exertion), 
and respiratory distress 
 
Proportion o
-19 progresses to Severe or 
Critical (Appendix 4) within 15 days after enrollment 
 
Proportion of participants requiring ICU admission within 15 days after 
enrollment 
 
Mean change from baseline (BL) in SOFA score on Day 8 and Day 
15 
 
Proportion of participants requiring supplemental O2, high-flow nasal 
cannula (HFNC) oxygen, noninvasive positive pressure ventilation 
(NIPPV) or mechanical ventilation on Day 8 and Day 15 
 
Mean number of days on mechanical ventilation within 15 days after 
enrollment 
 
Mean number of oxygenation-free days within 15 days after enrollment
 
Proportion of participants who achieve a score of 1 in the WHO Ordinal 
Scale for Clinical Improvement (Appendix 1) on Day 8 and Day 15. 
 
Median time (in hours) to a 2-point improvement in the WHO Ordinal 
Scale for Clinical Improvement 
 
Incidence and severity of thromboembolic events within 15 days after 
enrollment 


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Incidence of abnormal markers of inflammation (CRP, IL-6, TF, 
MCP-1, and IP-10) on Day 8 
 
Mean change in viral load from baseline (BL) on Days 1, 4, 8, 15, and 
28 
 
Mean time (in days) to viral load undetectable by nasopharyngeal 
(NP) swab 
Primary Objectives and 
Primary Endpoints 
(Part 2) 
Objectives:  
 
To evaluate the efficacy of ANA001 as therapy in moderate and severe 
COVID-19 patients 
 
 To evaluate the safety and tolerability of ANA001 as therapy for 
moderate and severe COVID-19 patients 
Endpoints/Parameters:  
 
Time to clinical improvement as measured by median time (in hours) to 
hospital discharge (where discharge is defined as a score of 1 or 2 in the 
WHO Ordinal Scale for Clinical Improvement) 
 
TEAEs, treatment-emergent SAEs, deaths, and discontinuations due to a 
TEAE 
 
Vital signs and laboratory (hematology, chemistry, and coagulation) 
parameters 
Secondary Objectives and 
Secondary Endpoints 
(Part 2) 
Objectives:  
 
To evaluate clinical improvement using NEWS2 
 
To evaluate the need and duration of rescue therapy 
Endpoints:  
 
Mean change from baseline (BL) in NEWS2 on Day 15 
 
Mean number of days on rescue treatment (COVID-19 therapies that are 
FDA approved or have emergency-use authorization) within 15 days after 
enrollment 
Exploratory Objectives and 
Exploratory Endpoints 
(Part 2) 
Objectives:  
 
To evaluate the effect on subjective symptoms of COVID-19 
 
To evaluate progression of COVID-19 from moderate or severe to more 
severe (i.e., moderate to severe, moderate to critical, or severe to critical) 
 
To evaluate the effect of ANA001 on requirement for oxygen and/or 
assisted ventilation 
 
To evaluate time to resolution of the WHO Ordinal Scale for Clinical 
Improvement 
 
To evaluate the effect of ANA001 on thromboembolic events 
 
To evaluate the relationship of ANA001 and markers of inflammation 
associated with acute respiratory distress syndrome (ARDS) 
 
To evaluate the relationship between ANA001 and viral dynamics 
Endpoints:  
 
Median time (in days) to resolution of subjective symptoms assessed by 
the Investigator to be potentially due to COVID-19 including: fever, 
cough (productive or non-productive), sore throat, malaise, headache, 
muscle pain, gastrointestinal symptoms (i.e., nausea, vomiting, or 
diarrhea), shortness of breath (with or without exertion), and respiratory 
distress 
 
-19 progresses to Severe or 
Critical (Appendix 4) within 15 days after enrollment 
 
Proportion of participants requiring ICU admission within 15 days after 
enrollment 
 
Mean change from baseline (BL) in SOFA score on Day 8 and Day 15 


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Proportion of participants requiring supplemental O2, high-flow nasal 
cannula (HFNC) oxygen, noninvasive positive pressure ventilation 
(NIPPV) or mechanical ventilation on Day 8 and Day 15 
 
Mean number of days on mechanical ventilation within 15 days after 
enrollment 
 
Mean number of oxygenation-free days within 15 days after enrollment 
 
Proportion of participants who achieve a score of 1 in the WHO Ordinal 
Scale for Clinical Improvement (Appendix 1) on Day 8 and Day 15. 
 
Median time (in hours) to a 2-point improvement in the WHO Ordinal Scale 
for Clinical Improvement 
 
Incidence and severity of thromboembolic events within 15 days after 
enrollment 
 
Incidence of abnormal markers of inflammation (CRP, IL-6, TF, MCP-1, 
and IP-10) on Day 8 
 
Mean change in viral load from baseline (BL) on Days 1, 4, 8, 15, and 28 
 
Mean time (in days) to viral load undetectable by nasopharyngeal (NP) 
swab 
Number of Sites 
Approximately 20 study sites in the United States 
Participant Duration 
Treatment Duration: 7 consecutive days (defined as 14 doses administered BID)
Total study duration (including screening period through the end of study visit): 
Approximately 60 (+2) days 
Study Duration 
The study will last approximately 1.5 years. 
Inclusion Criteria  
To be included in this study, an individual must satisfy all the following 
criteria: 
1. Willing and able to provide written informed consent (or their legally 
authorized representative) prior to performing study procedures. If
necessary, emergency consent may be obtained per local procedures. 
2. Hospitalized. 
3. Understands and agrees to comply with planned study procedures, 
including ability and willingness to swallow multiple small capsules. 
4. 
 
5. Positive for SARS-CoV-2 by a standard RT-PCR assay or alternative 
Sponsor approved assay within 7 days of randomization and no more than 
36 hours after hospitalization. 
6. Presence of symptoms of lower respiratory tract infection (LRTI) including 
at least 1 of the following: fever, cough, sore throat, malaise, headache, 
muscle pain, or more significant lower respiratory tract symptoms, 
including shortness of breath (at rest or with exertion). 
7. 
 breaths per minute, 
room air SpO2 <98%, requirement for supplemental oxygen, heart rate (HR) 
 beats per minute, or temperature >38.3°C. 
8. Access to a telemedicine platform for outpatient visits in cases where visits 
to the study site are not possible (e.g., telephone, smartphone, tablet, or 
computer). 
9. Women of childbearing potential must agree to abstinence from 
heterosexual intercourse or use at least 1 form of contraception not 
including hormonal contraception from the day of screening through Day 
30. 
Exclusion Criteria 
If an individual meets any of the following criteria at screening, he or she is 
ineligible for this study: 
1. Hospitalized, but no longer requires ongoing inpatient medical care (i.e.,
.  
2. Per the clinical judgment of the Investigator, the patient is not anticipated 
to survive >48 hours OR is under palliative care. 


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1.1 
Study Schematic 
The study schematic is presented in Figure 1. Both Study Part 1 and Part 2 are double-blinded, 
randomized, and placebo-controlled. 
Figure 1 
Study Schematic 
BID=twice daily; DMC=data monitoring committee; N=number of observed participants; 
3. Evidence of critical illness, defined by at least 1 of the following: 
 
Respiratory failure requiring at least 1 of the following:  
a. Endotracheal intubation and mechanical ventilation, oxygen 
delivered by high flow nasal cannula (heated, humidified, oxygen 
delivered via reinforced nasal cannula at flow rates >20 L/min 
 
b. Noninvasive positive pressure ventilation (NIPPV), OR 
c. Extracorporeal membrane oxygenation (ECMO) or clinical 
diagnosis of respiratory failure (i.e., clinical need for 1 of the 
preceding therapies, but preceding therapies not able to be 
administered in setting of resource limitation) 
 
Shock (defined by systolic blood pressure (BP) <90 mm Hg, or 
diastolic BP <60 mm Hg or requiring vasopressors), OR 
 
Multi-organ dysfunction/failure 
4. Severe CNS conditions, e.g., acute stroke, severe confusion, or other acute 
mental status changes that may significantly determine duration of 
hospitalization and patient outcomes. 
5. Chronic kidney disease requiring dialysis. 
6. Anticipated transfer to another facility, which is not a study site, within 72 
hours. 
7. Known allergy to the study drug or salicylate containing medications. 
8. Suspected and/or confirmed pregnancy or breastfeeding. 
9. Current or planned participation in any other interventional clinical trial 
under a US IND or EUA.  
10. Patients receiving chemotherapeutic agents and/or immunomodulators 
(including glucocorticoids, monoclonal antibodies (Mabs), or plasma 
transfusions) for chronic disease conditions (e.g., malignancies, rheumatoid 
arthritis or other autoimmune diseases). 
 


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PO=by mouth. NOTE: In addition to the safety evaluation at the end of Part 1, the DMC will 
conduct periodic evaluations during Part 1 and Part 2. 
 
1.2 
Schedule of Events 
The schedule of events (SOE) for Study Part 1 and Part 2 is presented in Table 1. 


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Table 1 
Schedule of Events (Study Part 1 and Study Part 2) 


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Table 1 
Schedule of Events (Study Part 1 and Study Part 2) 
c
d 


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Table 1 
Schedule of Events (Study Part 1 and Study Part 2) 
eCRF


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Table 1 
Schedule of Events (Study Part 1 and Study Part 2) 


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2 
INTRODUCTION 
2.1 
Background 
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of a global 
pandemic (Huang et al., 2020, Zhu et al., 2020, Chen et al., 2020b). The World Health 
Organization (WHO) named the novel coronavirus SARS-CoV-2 and the disease caused by 
the virus as coronavirus disease 2019 (COVID-19). 
WHO declared the COVID-19 pandemic a Public Health Emergency of International Concern 
on 30 January 2020 (WHO 2020), and the United States (US) declared a national emergency 
on 13 March 2020 (White House Press Release 2020). 
No acquired immunity to this novel viral infection appears to exist in the human population 
globally, and no effective treatment or preventative agent is licensed at this time. 
Rigorous self-isolation and lockdown have been required to contain SARS-CoV-2, causing 
entire societies to abruptly stop normal life.  
COVID-19 presents with a variety of conditions, including acute respiratory distress syndrome 
(ARDS) and rapid multiple organ dysfunction syndrome (MODS) and death. Proposed 
mechanisms for MODS in COVID-19 include a hypercoagulable state with micro- and 
macro-circulatory thrombosis.  
Effective interventions are urgently needed to not only reduce viral load but also to decrease 
the processes that drive morbidity and mortality associated with the infection. 
2.1.1 
Target Indication and Population 
The study population includes hospitalized adults with clinical signs and symptoms of 
moderate and severe COVID-19 and SARS-CoV-2 infection confirmed by the site using 
reverse transcriptase polymerase chain reaction (RT-PCR) or Sponsor approved equivalent 
assay. 
2.1.2 
ANA001 Pharmacology relative to COVID-19 
2.1.2.1 
Introduction 
Niclosamide (5-chloro-N-(2-chloro-4-nitrophenyl)-2-hydroxybenzamide) is an anthelmintic 
that has antiviral activity as well as anti-inflammatory, bronchodilator, and antineoplastic 
activity. 
Niclosamide was approved by the Food and Drug Administration (FDA) for use in humans to 
treat tapeworm infection in 1982 under the New Drug Application (NDA) 018669. It is 
included in the WHO
st of essential medicines and has been used to treat tapeworm in 
thousands of patients in a number of other countries since 1960. The adult dose is 2 g either as 
a single dose or once daily for 7 days, depending on the infection.  
Niclosamide is also a potent antiviral that has been shown to inhibit replication of severe acute 
respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome 
coronavirus (MERS-CoV) in vitro at submicromolar concentrations. SARS-CoV, MERS-CoV, 
and SARS-CoV-2 share 86% homology (Wilder-Smith et al., 2020), and niclosamide is 
therefore being developed as a potential treatment for COVID-19. 


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2.1.2.2 
ANA001 Inhibits SARS-CoV-2 Viral Replication 
Niclosamide efficacy against SARS-CoV-2 replication was shown in 3 independent in vitro 
studies resulting in half maximal inhibitory concentrations (IC50) of 0.15 µM (Shi 2020, 
unpublished results), 0.28 µM (Jeon et al., 2020), and 0.17 µM (Gassen et al., 2020). In 
contrast, the IC50 values of remdesivir, chloroquine, 
, and 
Jeon et al., 2020).  
Niclosamide was found to suppress cytopathic effects (CPE) of SARS-CoV-2 at concentrations 
as low as 1 
half-maximal effective concentration (EC50) 
E6 cells (Xu et al., 2020a, Jeon et al., 2020). 
Niclosamide likely exerts its antiviral activity by enhancing autophagy, which was first shown 
in MERS-CoV-infected cells by Gassen and colleagues. This study demonstrated that 
niclosamide inhibits the activity of SKP2, a small protein that regulates autophagy. Inhibition 
of SKP2 facilitates autophagy and inhibits virus replication. The IC50 of niclosamide to block 
MERS-CoV replication was 0.32 µM (Gassen et al., 2019). This serves as a strong argument 
to expect that niclosamide has the same mechanism of action against SARS-CoV-2.  
Indeed, it was shown recently that pretreatment of VeroFM cells with 5 µM niclosamide for 
24 hours before infection reduced SARS-CoV-2 replication significantly (Gassen et al., 2020). 
2.1.2.3 
ANA001 inhibits NF-
 and STAT3, Drivers of Cytokine Release Syndrome 
Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) is a transcription factor 
that induces the expression of pro-inflammatory cytokines. In vitro experiments with U2OS 
cells demonstrated that niclosamide inhibited NF-kB transcription, its binding to 
deoxyribonucleic acid (DNA), tumor necrosis factor (TNF)-
translocation of p65 into the nucleus, and expression of NF-
-regulated downstream genes. 
The IC50 of niclosamide to inhibit NF-kB transcription was 0.13 µM (42.5 ng/mL) (Jin et al., 
2010).  
Signal transducers and activators of transcription (STATs) are a class of transcription factors 
that regulate cellular and biological processes, including immune responses and angiogenesis, 
by modulating the expression of specific target genes (Yu et al., 2007). Upon stimulation by 
cytokines such as interleukin 6 (IL-6), tyrosine residue 705 (Tyr-705) in the STAT3 SH2 
domain is phosphorylated, consequently inducing STAT3 to dimerize, translocate into the 
nucleus, and induce its binding to specific DNA response elements of target genes (Schuringa 
et al., 2000). Niclosamide was shown to inhibit activation and transcriptional function of 
STAT3 in vitro. HeLa cells were transfected with a luciferase reporter driven by a promoter 
sequence with 7 STAT3 binding sites so that luciferase becomes active upon STAT3 binding. 
Niclosamide prevented binding and thus the transcriptional function of STAT3 with an IC50 of 
100 (total inhibitory concentration) 
 
after a 24-hour incubation (Ren et al., 2010).  
ARDS is a life-threatening condition caused by pneumonia, sepsis, or aspiration. The 
pathogenesis  due in part 
,
release large amounts of pro-inflammatory cytokines (e.g., TNF-
-
-6, and IL-8) that 
cause damage to the host. Hyperactivation of the NF-kB pathway is involved in the phenotype, 
and SARS-CoV-2 is a potential initiator of this scenario (Figure 2). 
Angiotensin converting enzyme II (ACE2) and transmembrane serine protease 2 (TMPRSS2) 
serves as cell entry receptors for SARS-CoV-2. Since ACE2 is either occupied by the virus or 
internalized with it, the density on the cell surface is reduced and angiotensin 2 increases in 
serum. Angiotensin 2 acts as a pro-inflammatory cytokine that activates NF-kB which, in turn, 


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leads to the production of IL-6. IL-6 activates STAT3 that further enhances activation of the 
NF-kB pathway. It is therefore likely that SARS-CoV-2 infection of the respiratory system 
activates both NF-kB and STAT3, which in turn can activate the IL-6 amplifier (IL-6 Amp), a 
mechanism for the hyperactivation of NF-kB by STAT3, leading to multiple inflammatory and 
autoimmune diseases (Hirano and Murakami 2020).
Figure 2
Potential Therapeutic Targets to Treat COVID-19 and Anticipated 
Activity of ANA001 (Modified from Hirano and Murakami, 2020)
ACE2: Angiotensin converting enzyme 2; ADAM17: ADAM Metallopeptidase Domain 17; ANGII: Angiotensin 
II; ARDS: Acute respiratory distress syndrome; AT1R: Angiotensin II receptor type 1 receptor; CATB/L: 
Cathepsin B and L; IL-6: Interleukin-6; AMP: Amplifier; STAT3: Signal transducer and activator of transcription 
3; NF-
: Nuclear factor kappa-light-chain-enhancer of activated B cells; PPRs: Pattern-recognition receptors; 
SARS-COV-2: Severe acute respiratory syndrome coronavirus 2; TMPRSS2: Transmembrane serine protease 2; 
: Tumor necrosis factor alpha.
Although ACE2 as the SARS-CoV-2 receptor for cellular entry provides a key target for 
prophylactic and therapeutic development during the initial phase of the infection, patients will 
often be seen at a later timepoint, many of which are downstream of ACE2-mediated cytokine 
release syndrome. These COVID-19 patients will likely require targeting of cytokine pathways, 
including the NF-
-6-STAT3 axis.
ANA001 (niclosamide) was shown in in vitro experiments to inhibit binding of NF-kB and 
STAT3 to DNA thus blocking the expression of genes that code for inflammatory cytokines. 
This suggests that ANA001 may prevent or reduce the severity of uncontrolled cytokine release 
in COVID-19 patients.
2.1.2.4
STAT3 Mediates IL-6 Associated TH17 Orientation
The janus kinase 2 (JAK2) inhibitor fedratinib is currently in clinical development for reducing 
mortality of COVID-19 in patients with TH17-type immune profiles. 
STAT3 is activated by ILs through JAK1 (IL-6 and IL-21), JAK2 (IL-6 and IL-23), and JAK3 
(IL-23). STAT3 mediates, e.g., IL-6 signals for TH17 cell initial differentiation and effector 
function. IL-6 activates STAT3 through JAK1 and JAK2, IL-23 activates STAT3 through 
JAK2, and IL-21 activates STAT3 through JAK1 and JAK3. It was shown recently that 
peripheral blood of a patient with severe COVID-19 had a strikingly high number of chemokine 
receptor CCR6+ TH17 cells, further supporting a TH17-type cytokine storm in this disease. 
Generally, a TH17-type response contributes to the cytokine storm in pulmonary viral infection 


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that likely promotes pulmonary edema. Therefore, patients with TH17 dominant immune 
profiles may benefit from an intervention that targets the TH17 pathway (Wu and Yang 2020). 
Niclosamide inhibited STAT3 in HeLa cells with an IC50 
100 
 in vitro assay (Ren et al., 2010). These data indicate potential 
for beneficial anti-inflammatory effects of ANA001 in COVID-19 patients independent of its 
anti-viremic effects at similarly low micromolar concentrations. 
2.1.2.5 
STAT3 Upregulates Tissue Factor, the Key Initiator of Blood Coagulation 
IL-6-triggered STAT3 activation induces the expression of tissue factor (TF). TF initiates the 
blood clotting process by thrombin formation (Park et al., 2013, Yeh et al., 2013). Complement 
and neutrophils are sentinels of innate immunity and modulate thrombogenic pathways that are 
likely related to C5a receptor/TF crosstalk mediated by neutrophils. Neutrophilia in COVID-
19 patients could be an index of the extent of complement activation that is associated with a 
poor outcome (Gralinski et al., 2018, Yen et al., 2006, Magro et al., 2020). 
COVID-19 pneumonia triggers the expression of active TF, both on endothelial cells and on 
activated infiltrating macrophages and neutrophils. The net effect is local presentation of 
blood-borne TF within the lungs, which will further amplify activation of the coagulation 
cascade. Endothelial cell disruption, TF expression, and initiation of the coagulation cascade 
will be progressively exacerbated by local hypoxia, leading to a deleterious positive 
thrombo-inflammatory feedback loop within the lung capillaries resulting in thrombosis and 
haemorrhage.  
Thrombin generation and fibrin deposition within the bronchoalveolar system are associated 
with severe pneumonia and ARDS. These changes are mainly driven by upregulation of TF 
expression within the alveoli and correlate with severity of inflammation (McGonagle et al., 
2020). 
ANA001 (niclosamide) is a STAT3 inhibitor and therefore may reduce the increased 
expression of TF and associated blood coagulations abnormalities often observed in COVID-
19 patients. 
2.1.2.6 
Relevance of Tissue Factor in High-Risk Patients with COVID-19 
Coagulopathy is a hallmark of severe COVID-19. In 1 report, 71.4% of patients who died of 
COVID-19 met the International Society on Thrombosis and Haemostasis criteria for 
disseminated intravascular coagulation (DIC), whereas only 0.6% of patients that survive met 
these criteria. This is a predominantly pro-thrombotic DIC with elevated D-dimer levels, high 
venous thromboembolism rates, and elevated fibrinogen levels in combination with low 
antithrombin levels. Additionally, it is accompanied by pulmonary congestion with 
microvascular thrombosis and high rates of central line thrombosis and vascular occlusion (e.g., 
stroke, ischemic limbs, etc.) in patients with severe COVID-19 (Wang et al., 2020). 
ANA001 (niclosamide) is a STAT3 inhibitor and therefore may reduce the increased 
expression of TF and associated blood coagulations abnormalities often observed in COVID-
19 patients. 
2.1.2.6.1 
Acute Respiratory Distress Syndrome 
COVID-19 is associated with the development of ARDS. ARDS is a result of acute 
inflammation within the alveolar space and prevents normal gas exchange. Damaged alveolar 
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STAT3 may be one of the key regulatory genes in the underlying dysfunction of sepsis induced 
ARDS (Zhang et al., 2019). ANA001 (niclosamide) inhibits STAT3 and therefore may reduce 
the severity of ARDS.  
2.1.2.6.2 
Association of Tissue Factor with Obesity and Type 2 Diabetes Mellitus 
Obesity is a major risk factor for the development of type 2 diabetes mellitus (T2D) and 
associated with increased severity of COVID-19. Clinical studies have established an increased 
incidence of thrombosis and cardiovascular disease as a primary cause of mortality in diabetic 
patients. T2D is associated with accelerated and premature atherosclerosis as well as other 
cardiovascular and thrombotic complications including myocardial infarction, ischemic stroke, 
and peripheral vascular disease (Samad and Ruf 2013). 
T2D patients show elevated levels of circulating TF, the main activator of blood coagulation, 
due to hyperglycemia and hyperinsulinemia. This procoagulant state predisposes such 
individuals to acute cardiovascular events (Boden et al., 2007) and may also predispose such 
patients to increased cardiovascular events in COVID-19. 
2.1.3 
Gastrointestinal System and Dosing of Niclosamide 
2.1.3.1 
Introduction 
Interstitial cells of Cajal are important for gastrointestinal (GI) motility and express protein 
transmembrane member 16A (TMEM16A), a calcium-activated chloride channel (Cil et al., 
2019). Given that niclosamide was shown to inhibit TMEM16A in vitro with an IC50 of 0.132 
to 0.3 µM (43 to 98 ng/mL) (Miner et al., 2019), oral administration of 1 to 2 g of ANA001 
may transiently decrease gastric emptying or intestinal motility. This could explain why most 
of the reported transient side effects of niclosamide as an anthelmintic medication are upper 
GI-tract related.  
The clinical implications of the potential inhibition of gastric emptying and intestinal motility 
in intubated patients in the intensive care unit (ICU) setting is currently unknown. Patients 
receiving ANA001 administered with their enteral nutrition in the ICU setting should be closely 
monitored for potential impaired gastric emptying. There was only a low (~10%) incidence of 
documented upper GI adverse events (AEs) reported in the original studies performed with 
niclosamide. According to the NDA 018669 Review Documentation, niclosamide was 
administered to 6365 patients under an Investigational New Drug (IND) in the US between 
1971 and 1978. Of the 2385 evaluable patients, 4.1% reported nausea/emesis, 3.4% reported 
abdominal discomfort/loss of appetite, 1.6% reported diarrhea, and 1.4% reported 
drowsiness/dizziness/headache. 
2.1.3.2 
Administration Regimen 
ANA001 is supplied as a capsule containing 250 mg of niclosamide for oral administration. 
ANA001 should be taken with meal. A placebo capsule that matches the size and appearance 
of the ANA001 drug product capsules is also supplied.  
2.1.3.3 
Justification for Dosing Strategy 
Niclosamide was originally developed as an anthelmintic drug (Perera et al., 1970) but has also 
been found to demonstrate broad antiviral activity in cell culture models.  
Several recent publications have shown that niclosamide has very low IC50 to inhibit replication 
of various coronaviruses: 1.56 µM against SARS-CoV (Wu et al., 2004), 0.32 µM against 
MERS-CoV (Gassen et al., 2019), and 0.15 to 0.28 µM against SARS-CoV-2 (Shi 2020, 


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unpublished results, Jeon et al., 2020, Gassen et al., 2020). These data become relevant in the 
context of the GI and lung exposures projected for niclosamide as both have been demonstrated 
to be sources of viral shedding (He et al., 2020, Chen et al., 2020a).  
Niclosamide pharmacokinetics (PK) information from the literature was extrapolated assuming 
monoexponential elimination to estimate the niclosamide concentrations for the doses planned 
in this study. The physicochemical properties of niclosamide suggest that niclosamide has 
minimal protein binding in plasma and is thus available for distribution into the lungs at 
concentrations that are anticipated to be equivalent to or higher than the free concentrations in 
plasma. Projections based on available clinical data (Schweizer et al., 2018) suggest that oral 
dosing within the dose range to be evaluated in Part 1 of the study can achieve therapeutic 
concentrations in both compartments at or above in vitro IC50 for a substantial portion of, if not 
the entirety of, a dosing interval. 
The proposed dose is the same total daily dose as approved for anthelmintic use (2,000 
mg/day), although it will be given as 1,000 mg twice daily (BID). The Sponsor expects that the 
proposed dosing regimen will achieve therapeutic effects while preserving an adequate safety 
margin.  
2.1.4 Summary of Nonclinical Toxicology and Pharmacokinetics 
ANA001 (niclosamide) is a member of the salicylanilide class of pharmacologic agents and is 
a derivative of salicylic acid. ANA001 contains an aryl beta-hydoxyl-carbonyl pharmacophore 
motif that is resident in a large number of natural products and multiple approved medicines, 
including salicylic acid (aspirin), mycophenolate, doxycycline, and others. Niclosamide has 
pleiotropic activities (Chen et al., 2018, Kadri et al., 2018, Jurgeit et al., 2010), with in vitro 
evidence of benefit in diseases ranging from viral to helminthic disease, as well as 
inflammatory conditions and even diabetes mellitus. 
Daily oral doses of up to 100 mg/kg in rabbits for 11 days, 900 mg/kg in cats for 24 days, and 
4,500 mg/kg in dogs for 24 days were found nontoxic clinically, based on routine laboratory 
tests and toxicology. Male cats were noted to have a mild reduction in white blood cells 
(WBCs), and dogs showed a tendency toward watery stools, but otherwise adverse treatment 
effects were not evident. Other studies reported that doses of 250 mg/kg may cause vomiting 
in dogs and cats. The conclusion of these studies was that niclosamide was low risk for dosing 
orally in humans at the standard therapeutic regimen of 2,000 mg/day (Bayer NDA 018669; 
Summary Basis for Approval). 
In light of the extensive use and safety record niclosamide has shown, several groups have 
subsequently evaluated niclosamide in cell-culture as part of efforts to identify and/or 
repurpose agents with activity against multiple viruses, including SARS-CoV2, the etiologic 
agent of COVID-19. Niclosamide was found to suppress CPE of SARS-CoV-2 at 
concentratio
n EC50 
Vero E6 cells (Xu et al., 2020a). 
Predictions of niclosamide partitioning to the lungs based on its physio-chemical properties 
have suggested that niclosamide partitions into lung with resulting concentrations in excess of 
the in vitro EC50 required to demonstrate a clinical effect. 
2.1.5 Summary of Supportive Clinical Data 
Clinical experience for niclosamide consists primarily of its use as an anthelmintic drug, where 
its success in treating thousands of patients has led it to be included in the WHO list of essential 
medicines. This is the first study we are aware of evaluating niclosamide for use in the 
treatment of moderate and severe COVID-19. 


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2.1.5.1 Clinical Pharmacology and Pharmacokinetics 
Niclosamide, with a hydrophobic structure, is a Biopharmaceutical Classification System class 
II drug, with limited absorption and low bioavailability (F=10%) when administered orally to 
rats, with the absorbed fraction rapidly eliminated by the kidneys (Chang et al., 2006). 
In a cohort of healthy male and female volunteers administered a single 2,000 mg by mouth 
(PO) dose of carbonyl-14C-labeled niclosamide, the fraction of 14C-activity eliminated in the 
urine was 2% to 25% over 4 days. The remainder was eliminated in the feces. Elimination was 
almost complete within 1 to 2 days. In this study, maximum observed serum concentration 
(Cmax) was found to b
Andrews et al., 1982). A study 
with prostate cancer patients showed that 149-182 ng/mL (0.46-0.56 µM) became available 
after a single oral dose of 1,000 mg (Schweizer et al., 2018). Colorectal cancer patients received 
2,000 mg of niclosamide orally once per day until disease progression or toxicity (up to four 
months). Plasma levels mainly peaked 40 minutes after the first niclosamide administration 
with a median Cmax of 0.43-0.85 
 (1.31-2.60 M) (Burock et al., 2020). The lower bounds 
of the reported Cmax values all fall within the range of in vitro concentrations shown to exert an 
antiviral effect on SARS-CoV-2 (0.15-0.28 µM, 49-92 ng/mL) (Shi, 2020, unpublished results, 
Jeon et al., 2020, Gassen et al., 2020). These studies strongly suggest that the dose regimen 
foreseen for clinical development  1,000 mg twice daily (BID) - will provide sufficient 
systemic and intracellular drug levels for effective antiviral and anti-inflammatory activity.  
2.1.5.2 Clinical Safety 
Niclosamide has been used extensively to treat helminthic disease at daily doses of up to 
2,000 mg in both adults and children.  
The primary risks noted in the label include GI upset, including nausea, vomiting, and 
abdominal pain. Additionally, in some cases hypersensitivity reactions have been reported 
(erythema, pruritis, and exanthema). All reported side effects were transitory and did not 
require stopping treatment. ANA001 should be taken with a meal to prevent stomach upset. 
Several studies have explored the use of niclosamide as adjunctive care in patients with 
malignancies (Schweizer et al., 2018). In one of these studies, niclosamide was evaluated at 
doses up to 1500 mg PO TID for up to 28 days and was dosed in conjunction with enzalutamide 
(Schweizer et al., 2018). In this study no dose-limiting toxicities were seen in the cohort treated 
at 500 mg PO TID. Two participants, however, in the 1,000 mg TID regimen were found to 
have a dose limiting toxicity (DLT). One participant had grade 3 nausea, vomiting, and diarrhea 
lasting >72 hours beginning on Day 26 of treatment. The second participant, also on an immune 
checkpoint inhibitor, developed a grade 3 colitis, abdominal pain and diarrhea on Day 8 of 
treatment, with the colitis constituting a dose limiting toxicity (DLT). The participant was 
treated with aggressive intravenous (IV) hydration and antibiotics and the event resolved to 
grade 1 by time of discharge. These observations may be related to a dosing duration (>7 days) 
which exceeds the dosing duration foreseen in the present study, the underlying disease (stage 
4 castration-resistant prostate cancer), and concomitant treatment with enzalutamide 
(XTANDI®). The prescribing information for XTANDI reports that diarrhea and nausea are 
some of the most common adverse reactions (ARs) 
over placebo) in XTANDI-treated patients.  
2.1.5.3 
Clinical Efficacy 
This is the first study of oral niclosamide for this indication. 


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2.1.6 
Other Relevant Data 
Several groups have observed that the primary modes of SARS-CoV-2 shedding are pulmonary 
and GI (Xu et al., 2020b, Ong et al., 2020, Guan et al., 2020) with both sputum and stool 
containing PCR detectable virus. As niclosamide has limited absorption, it is anticipated that 
GI concentrations of niclosamide will be significantly in excess of the IC50 for SARS-CoV-2. 
2.1.7 
Benefit:Risk Assessment 
Niclosamide is typically used to treat helminthic disease. Niclosamide has been found to be 
safe and well tolerated at daily oral doses of up to 2,000 mg and is on the WHO list of essential 
medications.  
As COVID-19 is currently a cause of significant excess global mortality and niclosamide has 
been shown to have potent antiviral and anti-inflammatory effects on key pathways associated 
with cytokine storm and abnormal coagulation in sepsis, at concentrations which are expected 
to be achievable in both the GI tract, systemically and the lungs, the potential benefits of 
ANA001 outweigh the known and potential risks. 
Coadministration of niclosamide with drugs that are metabolized by Cytochrome P450 
(CYP450) 1A2 may prolong plasma concentrations of such drugs. However, such data are 
based on theoretical modeling and to date, no proven drug-drug interactions have been reported 
for niclosamide since its approval by the FDA as an anthelmintic in 1982. Significant effects 
on plasma concentration of concomitant medications metabolized by CYP450 1A2 are not 
expected due to the short duration of ANA001 treatment. 
2.2 
Study Rationale 
There is an urgent need to develop innovative and cost-effective oral therapies to treat 
COVID-19. Based on available data from nonclinical studies and previous experience with 
marketed products, the use of ANA001 could represent a potent and safe oral treatment for 
COVID-19.  


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3 
OBJECTIVES AND ENDPOINTS 
The objectives and endpoints for Part 1 and Part 2 of the study are detailed in Table 2 and 
Table 3, respectively. 
Table 2 
Objectives and Endpoints of Study Part 1  
Objectives 
Endpoints/Parameters 
Primary 
To evaluate the safety and 
tolerability of ANA001 as 
therapy for moderate and severe 
COVID-19 patients 
 
TEAEs, treatment-emergent SAEs, deaths and discontinuations due to a
TEAE 
 
Vital signs and laboratory (hematology, chemistry, and coagulation) 
parameters 
Secondary 
To evaluate the efficacy of 
ANA001 as therapy in 
moderate and severe COVID-
19 patients 
 
Median time (in hours) to hospital discharge (where discharge is defined 
as a score of 1 or 2 in the WHO Ordinal Scale for Clinical Improvement) 
To evaluate PK of ANA001 
 
Plasma concentrations of ANA001 will be explored on Day 1, 2, 3, or Day 
4 
Exploratory 
To evaluate clinical 
improvement using NEWS2 
 
Mean change from baseline (BL) in NEWS2 on Day 15 
To evaluate the need and 
duration of rescue therapy 
 
Mean number of days on rescue treatment (COVID-19 therapies that are 
FDA approved or have emergency-use authorization) within 15 days after 
enrollment 
To evaluate the effect on 
subjective symptoms of 
COVID-19 
 
Median time (in days) to resolution of subjective symptoms assessed by the 
Investigator to be potentially due to COVID-19 including: fever, cough 
(productive or non-productive), sore throat, malaise, headache, muscle 
pain, gastrointestinal symptoms (i.e., nausea, vomiting, or diarrhea), 
shortness of breath (with or without exertion), and respiratory distress 
To evaluate progression of 
COVID-19 from moderate or 
severe to more severe (i.e., 
moderate to severe, moderate to 
critical, or severe to critical) 
 
-19 progresses to Severe or 
Critical (Appendix 4) within 15 days after enrollment 
 
Proportion of participants requiring ICU admission within 15 days after 
enrollment 
 
Mean change from baseline (BL) in SOFA score on Day 8 and Day 15 
To evaluate the effect of 
ANA001 on requirement for 
oxygen and/or assisted 
ventilation 
 
Proportion of participants requiring supplemental O2, high-flow nasal 
cannula (HFNC) oxygen, noninvasive positive pressure ventilation 
(NIPPV) or mechanical ventilation on Day 8 and Day 15 
 
Mean number of days on mechanical ventilation within 15 days after 
enrollment 
 
Mean number of oxygenation-free days within 15 days after enrollment 
To evaluate time to resolution 
of the WHO Ordinal Scale for 
Clinical Improvement 
 
Proportion of participants who achieve a score of 1 in the WHO Ordinal 
Scale for Clinical Improvement (Appendix 1) on Day 8 and Day 15 
 
Median time (in hours) to a 2-point improvement in the WHO Ordinal Scale 
for Clinical Improvement 
 
Incidence and severity of thromboembolic events within 15 days after 
enrollment 
To evaluate the effect of 
ANA001 on thromboembolic 
events 
 
Incidence and severity of thromboembolic events within 15 days after 
enrollment 
To evaluate the relationship of 
ANA001 and markers of 
inflammation associated with 
 
Incidence of abnormal markers of inflammation to (CRP, IL-6, TF, MCP-
1, and IP-10) on Day 8 


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acute respiratory distress 
syndrome (ARDS) 
To evaluate the relationship 
between ANA001 plasma 
concentrations and viral 
dynamics 
 
Mean change in viral load from baseline (BL) on Days 1, 4, 8, 15, and 28 
 
Mean time (in days) to viral load undetectable by nasopharyngeal (NP) 
swab 


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Table 3 
Objectives and Endpoints of Study Part 2 
Objectives 
Endpoints/Parameters 
Primary 
To evaluate efficacy of 
ANA001 as therapy for 
COVID-19 patients, AND 
To evaluate the safety and 
tolerability of ANA001 as 
therapy for COVID-19 patients 
 
Time to clinical improvement measured as median time (in hours) to 
hospital discharge (where discharge is defined as a score of 1 or 2 in the 
WHO Ordinal Scale for Clinical Improvement) 
 
TEAEs, treatment-emergent SAEs, deaths and discontinuations due to a
TEAE 
 
Vital signs and laboratory (hematology, chemistry, and coagulation) 
parameters 
Secondary 
To evaluate clinical 
improvement using NEWS2 
 
Mean change from baseline (BL) in NEWS2 on Day 15 
To evaluate the need and 
duration of rescue therapy 
 
Mean number of days on rescue treatment (COVID-19 treatments that are 
FDA approved or have emergency-use authorization) within 15 days after 
enrollment 
Exploratory 
To evaluate the effect on 
subjective symptoms of 
COVID-19 
 
Median time (in days) to resolution of subjective symptoms assessed by the 
Investigator to be potentially due to COVID-19 including: fever, cough 
(productive or non-productive), sore throat, malaise, headache, muscle 
pain, gastrointestinal symptoms (i.e., nausea, vomiting, or diarrhea), 
shortness of breath (with or without exertion), and respiratory distress 
To evaluate progression of 
COVID-19 from moderate or 
severe to more severe (i.e., 
moderate to severe, moderate to 
critical, or severe to critical) 
 
-19 progresses to Severe or 
Critical (Appendix 4) within 15 days after enrollment 
 
Proportion of participants requiring ICU admission within 15 days after 
enrollment 
 
Mean change from baseline (BL) in SOFA score on Day 8 and Day 15 
To evaluate the effect of 
ANA001 on requirement for 
oxygen and/or assisted 
ventilation 
 
Proportion of participants requiring supplemental O2, high-flow nasal 
cannula (HFNC) oxygen, noninvasive positive pressure ventilation 
(NIPPV) or mechanical ventilation on Day 8 and Day 15 
 
Mean number of days on mechanical ventilation within 15 days after 
enrollment 
 
Mean number of oxygenation-free days within 15 days after enrollment 
To evaluate time to resolution 
of the WHO Ordinal Scale for 
Clinical Improvement 
 
Proportion of participants with an improvement in the WHO Ordinal Scale 
for Clinical Improvement (Appendix 1) on Day 8 and Day 15 
 
Median time (in hours) to 2-point improvement in the WHO Ordinal Scale 
for Clinical Improvement 
To evaluate the effect of 
ANA001 on thromboembolic 
events  
 
Incidence and severity of thromboembolic events within 15 days after 
enrollment 
To evaluate the relationship of 
ANA001 and markers of 
inflammation associated with 
acute respiratory distress 
syndrome (ARDS) 
 
Incidence of abnormal markers of inflammation (CRP, IL-6, TF, MCP-1, 
and IP-10) on Day 8 
To evaluate the relationship 
between ANA001 and viral 
dynamics 
 
Mean change in viral load from baseline (BL) on Days 1, 4, 8, 15, and 28 
 
Mean time (in days) to viral load undetectable by nasopharyngeal (NP) 
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4 
STUDY PLAN 
4.1 
Study Design 
This is a 2-part, multicenter, randomized, placebo-controlled clinical study of ANA001 in 
patients with moderate and severe COVID-19. The study duration for each participant will be 
approximately 62 days, including a 36-hour screening window. Screening and Day 1 may occur 
on the same day if screening criteria is met to confirm subject eligibility. Randomization of 
subjects will be stratified by oxygenation (SpO2 >93 and <98% on room air versus SpO2 93% 
on room air), diarrhea (presence versus absence), and age (<65 and 
 
The Sponsor will review blinded safety data on an ongoing basis, and an independent Data 
Monitoring Committee (DMC) will review available unblinded safety and efficacy data in 
accordance with the DMC Charter. 
Part 1 will primarily evaluate safety and tolerability of ANA001 compared with matching 
placebo and explore PK parameters. Blood samples (Primary and Back-Up) for PK are to be 
collected on Day 1, 2, 3 or Day 4 at pre-dose (i.e. within 30 minutes), 1 hour (+/-30 minutes), 
4 hour (+/- 30 minutes), 8 hour (+/- 30 minutes) and pre-dose to next study drug (i.e. within 30 
minutes) administration.  
Part 2 will evaluate safety, tolerability, and efficacy of the proposed clinical dosing regimen of 
ANA001 as compared with matching placebo. 
After provision of informed consent, participants who satisfy all inclusion and no exclusion 
criteria will be dosed within 36 hours of screening and as soon as possible following hospital 
presentation. 
 
Part 1 
Participants in Part 1 will be randomly assigned to either ANA001 or matching placebo in a 
1:1 ratio. Participants will receive capsules of ANA001 or matching placebo for 7 consecutive 
days (defined as 14 doses administered BID) according to the assignment made by the 
randomization and trial supply management (RTSM) system. Additionally, participants will 
receive continued standard-of-care (SOC) therapy (per study site policies or guidelines). 
Dosing will continue until the treatment course is completed. If the participant requires 
mechanical ventilation or for any other reason is unable to swallow oral medication over the 
course of the study, ANA001 should be administered via nasogastric (NG), orogastric (OG), 
or percutaneous endoscopic gastrostomy (PEG) tube in accordance with the appropriate section 
in the study Pharmacy Manual. If the participant is discharged prior to completing the treatment 
course, the remaining study drug will be dispensed for at-home administration. Every effort 
should be made to complete the remaining study assessments for participants who are not able 
to complete the 7-day course of study drug.  
An emergency DMC meeting will convene if 3 or more blinded participants in Part 1 or 10 or 
more blinded participants in Part 2 experience AEs leading to premature discontinuation of 
study drug.  
DMC assessments: After enrollment into Part 1 is completed, the independent DMC will 
conduct an unblinded review of safety, tolerability, and efficacy. If safety issues are identified 
or no potential for benefit is seen when compared with the placebo group, the DMC may 
recommend that the study be terminated for safety concerns or for futility. Further discussion 
of the terms for termination of the study are provided in Section 6.4.2.  


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Upon successful completion of Part 1, the safety and efficacy of ANA001 1,000 mg PO BID 
for 7 consecutive days will be evaluated in a larger population of patients in Part 2. 
 
Part 2 
Participants in Part 2 will be randomly assigned to either ANA001 or matching placebo in a 
1:1 ratio according to the assignment made by the randomization and trial supply management 
(RTSM) system. Participants will receive ANA001 or matching placebo for 7 consecutive days 
(defined as 14 doses administered BID). Additionally, participants will continue to receive 
SOC therapy (per study site policies or guidelines).  
Dosing will continue until the treatment course is completed. If the participant requires 
mechanical ventilation over the course of the study, ANA001 may be administered via 
nasogastric, orogastric, or percutaneous endoscopic gastrostomy (NG, OG, or PEG) tube in 
accordance with the appropriate section in the study Pharmacy Manual. If the participant is 
discharged from the hospital prior to completing the treatment course, remaining study drug 
will be dispensed for at-home administration. Every effort should be made to complete the all 
remaining study assessments for all participants including those who are not able to complete 
the 7-day course of study drug. 
For both Part 1 and Part 2, following discharge from the hospital, follow-up visits that do not 
require laboratory evaluations may be performed via the study approved telemedicine platform 
on Days 2, 3, 5, 6, 7, and the EOS/Day 60 visit. Assessments at the follow-up visits for Part 1 
and Part 2 will be performed according to Table 1. 
4.2 
Design Rationale 
Niclosamide has been established as a well-tolerated and effective anthelmintic agent at doses 
of up to 2,000 mg daily. Recently, several groups have demonstrated in vitro potency of 
niclosamide against SARS-CoV-2 at IC50 values ranging from 0.15 to 0.28 µM (49 to 92 
ng/mL) (Shi 2020, unpublished results, Jeon et al., 2020, Gassen et al., 2020). Cmax values 
reported in humans ranged from 149 to 182 ng/mL (0.46 to 0.56 µM) after a single oral dose 
of 1,000 mg (Schweizer et al., 2018). In humans that received oral doses of 2,000 mg, Cmax 
Andrews et al., 1982) and 0.43-0.85 
 
(1.31-2.60 M) (Burock et al., 2020). It is therefore highly likely that the proposed dosing 
regimen (1,000 mg BID daily for 7 days) will achieve concentrations of niclosamide in infected 
tissues with effective antiviral and anti-inflammatory activity. Pharmacokinetic models suggest 
that partitioning of niclosamide to lung and GI parenchyma may provide adequate therapeutic 
coverage. 
This study will explore ANA001 to evaluate its safety, tolerability, and efficacy as an oral 
therapy for the treatment of patients with moderate and severe COVID-19. It is anticipated that 
60 patients in Study Part 1 will provide sufficient information on safety, tolerability, and 
potential for efficacy to proceed to a statistically powered test of the efficacy and further 
assessment of safety and tolerability in a larger patient cohort in Study Part 2. 
 


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5 
POPULATION 
5.1 
Recruitment 
Approximately 436 participants will be enrolled from approximately 20 study sites in the US. 
5.2 
Definitions 
Participants officially enter the screening period following provision of written informed 
consent either directly or via a legally authorized representative. 
A screen failure is a consented participant who has been deemed ineligible on the basis of 1 or 
more eligibility criteria or who has withdrawn consent prior to treatment assignment. Screen 
failures may be rescreened if COVID-19 is suspected based on worsening clinical criteria (e.g., 
worsening oxygenation status or development of bilateral lower lobe pneumonia or fever 
>38.3°C) and dosing should be initiated within 36 hours of re-screening. 
An enrolled participant is one who has been deemed eligible and has been randomized to a 
treatment group.  
5.3 
Inclusion Criteria  
To be included in this study, an individual must satisfy all the following criteria: 
1. Willing and able to provide written informed consent (or their legally 
authorized representative) prior to performing study procedures. If necessary, 
emergency consent may be obtained per local procedures. 
2. Hospitalized. 
3. Understands and agrees to comply with planned study procedures, including 
ability and willingness to swallow multiple small capsules. 
4. 
18 years of age at the time of informed consent. 
5. Positive for SARS-CoV-2 by a standard RT-PCR assay or alternative Sponsor 
approved assay within 7 days of randomization and no more than 36 hours after 
hospitalization. 
6. Presence of symptoms of lower respiratory tract infection (LRTI) including at 
least 1 of the following: fever, cough, sore throat, malaise, headache, muscle 
pain, or more significant lower respiratory tract symptoms, including shortness 
of breath (at rest or with exertion). 
7. At least 1 of the following: respi
20 breaths per minute, room 
air SpO2 <98%, requirement for supplemental oxygen, heart rat
 
beats per minute, or temperature >38.3°C. 
8. Access to a telemedicine platform for outpatient visits in cases where visits to 
the study site are not possible (e.g., telephone, smartphone, tablet, or 
computer). 
9. Women of childbearing potential must agree to abstinence from heterosexual 
intercourse or use at least 1 form of contraception not including hormonal 
contraception from the day of screening through Day 30. 
5.4 
Exclusion Criteria 
If an individual meets any of the following criteria at screening, he or she is ineligible for this 
study: 
1. Hospitalized, but no longer requires ongoing inpatient medical care (i.e. 
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2. Per the clinical judgment of the Investigator, the patient is not anticipated to 
survive >48 hours OR is under palliative care. 
3. Evidence of critical illness, defined by at least 1 of the following: 
 Respiratory failure requiring at least 1 of the following:  
a. Endotracheal intubation and mechanical ventilation, oxygen delivered 
by high flow nasal cannula (heated, humidified, oxygen delivered via 
reinforced nasal cannula at flow rates >20 L/min with fraction of 
0.5) 
b. Noninvasive positive pressure ventilation (NIPVV), OR 
c. Extracorporeal membrane oxygenation (ECMO) or clinical diagnosis of 
respiratory failure (i.e., clinical need for 1 of the preceding therapies, but 
preceding therapies not able to be administered in setting of resource 
limitation) 
 Shock (defined by systolic blood pressure (BP) <90 mm Hg, or diastolic 
BP <60 mm Hg or requiring vasopressors), OR 
 Multi-organ dysfunction/failure 
4. Severe CNS conditions, e.g., acute stroke, severe confusion, or other acute 
mental status changes that may significantly determine duration of 
hospitalization and patient outcomes. 
5. Chronic kidney disease requiring dialysis. 
6. Anticipated transfer to another site, which is not a study site, within 72 hours. 
7. Known allergy to the study drug or salicylate containing medications. 
8. Suspected and/or confirmed pregnancy or breastfeeding. 
9. Current or planned participation in any other interventional clinical trial under 
a US IND or EUA. 
10. Patients receiving chemotherapeutic agents and/or immunomodulators 
(including glucocorticoids, monoclonal antibodies (Mabs), or plasma 
transfusions) for chronic disease conditions (e.g., malignancies, rheumatoid 
arthritis or other autoimmune diseases). 
5.5 
Exceptions to Eligibility Criteria 
Prospective approval of a protocol deviation of an enrollment criterion, also known as a 
protocol waiver or exemption, is not permitted. 
The Medical Monitor should be consulted if there are questions about interpretation of 
eligibility criteria.  
 


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6 
STUDY CONDUCT 
The study duration for each participant will be approximately 62 days including a 36-hour 
window allowed for screening assessments prior to randomization. Study procedures for Study 
Part 1 and Study Part 2 are presented in the schedule of events, Table 1. 
6.1 
Screening Period Assessments 
The screening procedures and evaluations are to be carried out prior to the start of treatment. 
Screening assessments are to be performed and completed no more than 36 hours before 
randomization, and as soon as possible following hospital presentation. Randomization and 
initiation of treatment should occur as soon as possible following confirmation that all inclusion 
and no exclusion criteria have been met. Screening and Day 1 may occur on the same day if 
eligibility criteria are met. Assessments to be performed and information to be collected for the 
Screening period include: 
 
 Obtain informed consent.  No study specific assessments will be conducted until after 
provision of written informed consent. 
 Demographics. 
 Eligibility assessment. 
 Medical history or current presence of signs and symptoms associated with COVID-19 
within 14 days prior to screening, including fever, cough (productive or non-
productive), sore throat, malaise, headache, muscle pain, gastrointestinal symptoms 
(i.e., nausea, vomiting, or diarrhea), shortness of breath (with or without exertion), and 
respiratory distress. Other medical history within 14 days prior to enrollment and the 
presence of comorbidities, especially cardiovascular disease, pulmonary disease (e.g., 
COPD, asthma), hypertension, diabetes, and obesity, is to be recorded as well. 
 NEWS2 (Appendix 2), vital signs, 
-19 (Appendix 
4), and assessment for presence of subjective clinical signs and symptoms of COVID-
19 will be assessed and include presence or absence of: fever, cough (productive or 
non-productive), sore throat, malaise, headache, muscle pain, gastrointestinal 
symptoms (i.e., nausea, vomiting, or diarrhea), shortness of breath (with or without 
exertion), and respiratory distress. 
 Record SpO2 on room air and need for supplemental nasal cannula oxygen (including 
flow rate) if applicable. If clinically possible, SpO2 should be recorded on room air for 
all patients and if applicable a value should be recorded on supplemental oxygen (with 
at least 30 continuous minutes of oxygen administration). 
 Targeted physical examination. 
 Nasopharyngeal (NP) swab for confirmation of SARS-CoV-2 with RT-PCR or Sponsor 
approved alternative test (e.g., local laboratory analysis used for screening). 
 WHO Ordinal Scale for Clinical Improvement score (Appendix 1) assessment. 
 Chest X-ray per local standard-of-care. 
 AE assessment (AEs are to be recorded from the time of signing of informed consent 
to the end of the study participation). 
 All systemic prior medications within 14 days prior to screening (Section 7.4). 
 Serum pregnancy test for females of childbearing potential. 
6.2 
Randomization (Day 1-Baseline) 
Participants who have provided written informed consent, completed all screening procedures 
and assessments, and who meet all of the inclusion and none of the exclusion criteria will be 
randomized. Randomization should occur as soon as possible following confirmation that all 


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inclusion and no exclusion criteria have been met and within no more than 36 hours following 
initiation of screening. 
6.3 
Dosing Period (Day 1 through Day 8) 
After provision of informed consent, participants who satisfy all necessary eligibility criteria 
will receive doses of ANA001 or matching placebo to begin within approximately 36 hours of 
site screening and as soon as possible following hospital presentation. 
6.3.1 Day 1 Assessments 
Procedures to be performed and information to be collected on Day 1: 
 Height and weight for body mass index (BMI). If a participant is unable to be measured 
for height and weight, stated height and weight is acceptable.  
 NEWS2 (Appendix 2), vital signs, 
-19 (Appendix 
4), and assessment for presence of subjective clinical signs and symptoms of COVID-
19 will be assessed and include presence or absence of: fever, cough (productive or 
non-productive), sore throat, malaise, headache, muscle pain, gastrointestinal 
symptoms (i.e., nausea, vomiting, or diarrhea), shortness of breath (with or without 
exertion), and respiratory distress. Day 1 assessments should be done before the first 
dose of study drug. 
 Record SpO2 on room air and need for supplemental nasal cannula oxygen (including 
flow rate) if applicable. For patients on supplemental oxygen, SpO2 should be recorded 
with at least 30 continuous minutes of oxygen. 
 A complete physical examination, excluding a genitourinary (GU) examination. 
 Administration of study drug (ANA001 or matching placebo). Study drug should be 
taken with a meal (or NG/OG/PEG tube feeding if applicable).  
 Serum chemistry (to be collected before initial dosing), including blood urea nitrogen 
(BUN), creatinine, sodium, potassium, chloride, carbon dioxide, glucose, direct 
bilirubin, total bilirubin, alkaline phosphatase (ALP), aspartate aminotransferase 
(AST), alanine aminotransferase (ALT). 
 Hematology and coagulation tests (to be collected before initial dosing) including a 
complete blood count (CBC), which consists of hemoglobin, hematocrit, total WBC 
count with a 5-part differential, platelet count, plus a partial thromboplastin time 
(aPTT), prothrombin time (PT), and an international normalized ratio (INR). 
 D-dimer, CRP, cardiac troponin, LDH, and ferritin samples collected for central 
laboratory testing (to be collected before initial dosing). 
 NP swab for confirmation of SARS-CoV-2 with RT-PCR (local site laboratory) per site 
SOC (to be collected before initial dosing) if part of standard-of-care. 
 NP swab for confirmation of SARS-CoV-2 with RT-PCR (central laboratory) (to be 
collected before initial dosing). 
 PK sample collection: Study Part 1 Only: See Appendix 6 for PK sample collection 
schedule. Refer to the Central Laboratory Manual for additional sample collection and 
processing instructions. PK samples should be collected in relation to the morning dose 
of study drug administration. 
 WHO Ordinal Scale for Clinical Improvement score (Appendix 1) assessment should 
be collected/recorded daily and any time the WHO Ordinal Scale for Clinical 
Improvement score changes. The WHO Ordinal Scale for Clinical Improvement should 
be recorded with the corresponding date and time of assessment (if unchanged) or with 
the date and time reflecting the numerical change in the score (if changed). 


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 Chest X-ray per local standard-of-care. 
 AE assessment. 
 All systemic concomitant medications (Section 7.4). 
 Sequential Organ Failure Assessment (SOFA) score (to be performed at baseline for all 
participants; Appendix 3). 
 Blood for exploratory tests (e.g., IL-6, tissue factor, MCP-1 and IP-10). Blood sample 
is to be collected before initial dosing. 
 
6.3.2 Daily Assessments (Day 2 through Day 8) 
It may not be possible to conduct all study visits in-person due to quarantine and other infection 
control measures. In case where in-person visits are not possible, telemedicine appointments 
should be conducted. If the participant is discharged home with study drug for self-
administration, visits appropriate for the telemedicine platform are Days 2, 3, 5, 6, 7, and the 
EOS/Day 60 visit. 
 
For telemedicine appointments, all data should be collected, and the following should be 
reviewed/discussed in detail with the participant: AEs, concomitant medication, clinical status, 
and hospital re-admission. Due to the blood and NP swab collection requirements for central 
laboratory testing on Days 4, 8, 15, and 28, these visits should be conducted in person, either 
at the stie or with a home visit. If neither is possible, then a telemedicine appointment combined 
with a home nursing appointment for blood and NP sample collection could be arranged. 
 
Procedures to be performed and information to be collected on Day 2 through Day 8 include: 
 
 NEWS2 (Appendix 2), vital signs, 
-19 (Appendix 
4), and assessment for presence of subjective clinical signs and symptoms of COVID-
19 will be assessed daily and include presence or absence of: fever, cough (productive 
or non-productive), sore throat, malaise, headache, muscle pain, gastrointestinal 
symptoms (i.e., nausea, vomiting, or diarrhea), shortness of breath (with or without 
exertion), and respiratory distress. This should be performed between 2-6 hours after 
first dose of the day with study drug. Assessments should be collected daily while 
hospitalized including any day after Day 8 that the participant remains in the hospital. 
 Record daily SpO2 on room air and need for supplemental nasal cannula oxygen 
(including flow rate) if applicable. For patients on supplemental oxygen, SpO2 should 
be recorded with at least 30 continuous minutes oxygen. Also record any noninvasive 
ventilation (i.e., No/Yes; if yes designate type). For intubated patients record PaO2 and 
FiO2 values of the worst P-F ratio of the calendar day. Assessments should be collected 
daily while hospitalized including any day after Day 8 that the participant remains in 
the hospital. 
 Daily administration of study drug (ANA001 or matching placebo). Study drug should 
be taken with a meal (or NG/OG/PEG tube feeding if applicable). Total duration of 
study drug administration is a 7-day course of treatment (i.e., 14 scheduled doses 
comprised of 56 capsules in total). Participants may be discharged before completing 
14 doses and are to be given dosing instructions, the remainder of their therapy, and a 
diary to record all study drug doses taken. 
 Daily serum chemistry (pre-dose), including blood urea nitrogen (BUN), creatinine, 
sodium, potassium, chloride, carbon dioxide, glucose, direct bilirubin, total bilirubin, 
alkaline 
phosphatase 
(ALP), 
aspartate 
aminotransferase 
(AST), 
alanine 
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 Daily hematology and coagulation tests (pre-dose) including a complete blood count 
(CBC), which consists of hematocrit, hemoglobin, total WBC count with a 5-part 
differential, platelet count, plus a partial thromboplastin time (aPTT), prothrombin time 
(PT), and an international normalized ratio (INR). 
 D-dimer, CRP, and ferritin (to be collected pre-dose on Day 4 and Day 8 only) for 
central laboratory testing. Cardiac troponin and LDH (to be collected Day 8 or EOT) 
for central laboratory testing. 
 NP swab for confirmation of SARS-CoV-2 with RT-PCR (local site laboratory) per site 
SOC if part of standard-of-care. 
 NP swab for SARS-CoV-2 testing with RT-PCR (to be collected on Day 4 and 8) for 
central laboratory testing. 
 PK sample collection: Study Part 1 Only: See Appendix 6 for PK sample collection 
schedule. Refer to the Central Laboratory Manual for additional sample collection and 
processing instructions (Day 1, 2, 3 or Day 4). PK samples should be collected in 
relation to the morning dose of study drug. 
 Daily WHO Ordinal Scale for Clinical Improvement score (Appendix 1) assessment 
should be collected/recorded daily and any time the WHO Ordinal Scale for Clinical 
Improvement score changes. The WHO Ordinal Scale for Clinical Improvement should 
be recorded with the corresponding date and time of assessment (if unchanged) or with 
the date and time reflecting the numerical change in the score (if changed). 
 Chest X-ray per local standard-of-care. 
 Daily AE assessment. 
 All systemic concomitant medications (Section 7.4). 
 SOFA score (to be performed daily only for participants who are admitted in the ICU; 
Appendix 3). 
 Blood for exploratory tests (e.g., IL-6, tissue factor, MCP-1 and IP-10) on Day 8. 
 
6.4 Day 15 (±3 days), and Day 28 (+2 days) Assessments 
Procedures to be performed and information to be collected on Day 15 and Day 28: 
 NEWS2 (Appendix 2)
-19 (Appendix 4), and 
assessment for presence of subjective clinical signs and symptoms of COVID-19 
including presence or absence of: fever, cough (productive or non-productive), sore 
throat, malaise, headache, muscle pain, gastrointestinal symptoms (i.e., nausea, 
vomiting, or diarrhea), shortness of breath (with or without exertion), and respiratory 
distress. Assessments should be collected daily while hospitalized including any day 
after Day 8 that the participant remains in the hospital. 
 Record SpO2 on room air and need for supplemental nasal cannula oxygen (including 
flow rate) if applicable. For patients on supplemental oxygen, SpO2 should be recorded 
with at least 30 continuous minutes of oxygen Also record any noninvasive ventilation 
(i.e., No/Yes; if yes designate type). For intubated patients record PaO2 and FiO2 values 
of the worst P-F ratio of the calendar day. 
 NP swab confirmation of SARS-CoV-2 with RT-PCR (local site laboratory) per site 
SOC.  
 NP swab for confirmation of SARS-CoV-2 with RT-PCR on Day 15 (±3 days), and 
Day 28 (+2 days) for central laboratory testing. 
 WHO Ordinal Scale for Clinical Improvement score (Appendix 1) assessment should 
be collected/recorded daily and any time the WHO Ordinal Scale for Clinical 
Improvement score changes. The WHO Ordinal Scale for Clinical Improvement should 


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be recorded with the corresponding date and time of assessment (if unchanged) or with 
the date and time reflecting the numerical change in the score (if changed). 
 Chest X-ray per local standard-of-care. 
 AE assessment. 
 All systemic concomitant medications (Section 7.4). 
 SOFA score (to be performed only for participants who are admitted in the ICU; 
Appendix 3). 
 
6.5 Day 60 (+2 days)/End of Study (EOS)Assessments 
Procedures to be performed and information to be collected on Day60/EOS include: 
 
 NEWS2 (Appendix 2), vital signs, 
-19 (Appendix 
4), and assessment for presence of subjective clinical signs and symptoms of COVID-
19 including presence or absence of: fever, cough (productive or non-productive), sore 
throat, malaise, headache, muscle pain, gastrointestinal symptoms (i.e., nausea, 
vomiting, or diarrhea), shortness of breath (with or without exertion), and respiratory 
distress. Assessments should be collected daily while hospitalized including any day 
after Day 8 that the participant remains in the hospital. 
 Record SpO2 on room air and need for supplemental nasal cannula oxygen (including 
flow rate) if applicable. For patients on supplemental oxygen, SpO2 should be recorded 
with at least 30 continuous minutes of oxygen Also record any noninvasive ventilation 
(i.e., No/Yes; if yes designate type). For intubated patients record PaO2 and FiO2 values 
of the worst P-F ratio of the calendar day. 
 NP swab confirmation of SARS-CoV-2 with RT-PCR (local site laboratory) per site 
SOC.  
 NP swab for confirmation of SARS-CoV-2 with RT-PCR for central laboratory testing. 
 WHO Ordinal Scale for Clinical Improvement score (Appendix 1) assessment should 
be collected/recorded daily and any time the WHO Ordinal Scale for Clinical 
Improvement score changes. The WHO Ordinal Scale for Clinical Improvement should 
be recorded with the corresponding date and time of assessment (if unchanged) or with 
the date and time reflecting the numerical change in the score (if changed). 
 Chest X-ray per local standard-of-care. 
 AE assessment. 
 SOFA score (to be performed only for participants who are admitted in the ICU; 
Appendix 3). 
6.6 
Discontinuation or Withdrawal 
6.6.1 Individual Participants 
6.6.1.1 Withdrawal from Study and Lost to Follow-up 
An individual participant may withdraw from the study at any time at his/her own request 
(withdrawal of consent) or may be withdrawn at any time for the following reasons: 
 At the request of the primary care provider if he/she thinks the study is no longer in 
the best interest of the participant. 


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 The participant is judged by the Investigator or Sponsor to be at significant risk of 
failing to comply with the provisions of the protocol so as to cause harm to self or 
seriously interfere with the validity of the study results. 
 At the discretion of the Institutional Review Board (IRB)/ Ethics Committee (EC)/ or 
government agencies as part of their duties. 
If the participant withdraws consent for disclosure of future information, the Sponsor may 
retain and continue to use any data/samples collected before such withdrawal of consent. 
 
At the time of withdrawal from study all procedures scheduled for that study day plus additional 
assessments (not already planned for that study day) which are scheduled for the end of study 
drug administration (Study Day 8) or the End of Study (EOS/Day 60) visit should be completed 
if possible AND if the participant is agreeable. See SOE (Table 1) for data to be collected at 
the time of withdrawal from study. 
 
A participant will be considered lost to follow-up if unable to be contacted by the study site. 
The following actions must be taken if a participant fails to present for a study required 
assessment: 
 The site must attempt to contact the participant as soon as possible and counsel the 
participant on the importance of maintaining the assigned procedure schedule and 
ascertain whether or not the participant wishes to and/or should continue in the study. 
 Before a participant is deemed lost to follow-up, the Investigator or designee must make 
every effort to regain contact with the participant (where possible, 3 telephone calls 
address or local equivalent methods). These contact attempts should be documented in 
 record. 
 Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up. 
 
6.6.1.2 
Discontinuation of Study Drug 
Participants may be prematurely discontinued from study drug prior to completing a full 7 
consecutive days of study drug (i.e., 14 doses administered BID) for any of the following 
reasons: 
 Withdrawal from study or Lost to follow-up (due to reasons listed in Section 6.6.1.1) 
 Participant decision (i.e., to be used as reason if participant desires to stop study drug 
but not withdrawal consent of the study). A participant is free to discontinue study drug 
therapy at any time without prejudice to further treatment. The Investigator must verify 
on the eCRF that the participant decision was not based on an adverse event (AE). In 
such cases, the reason must be recorded as premature discontinuation from study drug 
due to an AE. 
 AE (e.g., continuation of study drug poses a risk to the participant as judged by the 
Investigator) 
 Positive pregnancy test at any time during study drug treatment, OR 
 Early discontinuation/termination of the study by Sponsor 
 
In the event that a participant prematurely discontinues study drug, all study procedures and 
assessments should continue to be performed and collected until the participant completes the 
EOS/Day 60 visit to the extent possible. 


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6.6.1.3 
Replacement of Participants 
Randomized participants may not be replaced. 
6.6.2 
Discontinuation or Termination of the Study 
An independent Data Monitoring Committee (DMC) will be formed and constituted according 
to appropriate regulatory agency guidelines. Detailed information regarding the composition 
of the committee and detailed procedures will be provided in a separate DMC charter. The 
independent DMC will review the safety, tolerability, and efficacy data of Study Part 1 and 
Study Part 2 as described in the DMC charter. 
An emergency DMC meeting will convene if 3 or more blinded participants in Study Part 1 or 
10 or more blinded participants in Study Part 2 experience AEs leading to premature 
discontinuation of study drug. 
The Sponsor may discontinue further enrollment of the study at any time (including after 
unblinding of Study Part 1 study data and before enrollment of Study Part 2). 
Additionally, the Sponsor may (before beginning enrollment of Study Part 2): 
 Exclude a specific patient subgroup due to potential safety concerns 
 Modify allowed concomitant medication due to potential safety concerns, OR 
 Modify other protocol criteria due to potential safety concerns (e.g., safety laboratory 
monitoring or PK sampling) 
 Modify the sample size and/or endpoints of Study Part 2 if Study Part 1 efficacy data 
suggests that such changes may be necessary to adequately power Study Part 2 
The DMC may also recommend interruption of recruitment at ANY time during Study Part 1 
or Study Part 2 for further analysis. The DMC may also recommend termination of the study 
if any one of the following are observed and not associated with the natural course of 
COVID-19 (based on CTCAE v5: 
https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/CTCAE_v5_Quick
_Reference_5x7.pdf): 
 Grade 4 or greater nausea, vomiting, diarrhea, or abdominal pain lasting >72 hours in 
participants who have received maximal medical care 
 Grade 4 or greater anemia, neutropenia, or thrombocytopenia without an alternative 
etiology 
 
The DMC will review the study on a regular basis as outlined in the DMC charter and evaluate 
the study for safety, futility or lack of efficacy. The DMC may recommend interruption of 
recruitment or termination of the study at any time. Any recommendations for safety review, 
as summarized in section 6.4. are non-binding. The DMC is fully independent and is at liberty 
to use additional or modified criteria as a basis for determination of the safety, tolerability and 
potential futility in Study Part 1 or Study Part 2. 


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7 
STUDY INTERVENTIONS 
7.1 
Description of Products 
The investigational product is a capsule containing 250 mg of active pharmaceutical ingredient 
(API) or matching placebo. 
7.1.1 
Active Intervention  ANA001 
7.1.1.1 
Formulation, Storage, Preparation, and Handling 
For Study Part 1 and Study Part 2 ANA001 (proprietary niclosamide formulation) 250 mg 
capsules will be provided in bottles containing a sufficient number of capsules (56 per patient) 
to cover the 7-day treatment period and should be stored at room temperature out of direct 
sunlight. 
7.1.1.2 
Dosing and Administration 
ANA001 will be administered as 1,000 mg (4 capsules; 250 mg each) PO BID for 7 consecutive 
days and should be given with a meal. If the participant requires mechanical ventilation over 
the course of the study, niclosamide may be administered via NG, OG, or PEG tube and, if 
possible, should be administered with a scheduled NG, OG, or PEG feeding. Please refer to the 
study Pharmacy Manual for additional dosing and study drug administration information.  
7.1.2 
Control - Placebo 
7.1.2.1 
Formulation, Storage, Preparation, and Handling 
For Study Part 1 and Study Part 2, matching placebo (size 0, hydroxypropylmethylcellulose 
[HPMC]) will be provided in bottles containing a sufficient number of capsules (56 per patient) 
to provide for dosing for the 7-day treatment duration. Placebo should be stored at room 
temperature out of direct sunlight. 
Placebo formulation is comprised of generally recognized as safe (GRAS) excipients and 
contains fillers (microcrystalline cellulose and mannitol), a binder (hydroxypropyl cellulose), 
a disintegrant (sodium starch glycolate), a wetting agent (sodium lauryl sulfate), a glidant 
(colloidal silica), and a lubricant (sodium stearyl fumarate). No biologically active or 
potentially immunogenic compounds are included in the placebo formulation. 
7.1.2.2 
Dosing and Administration 
Placebo will be administered as 4 HPMC capsules PO BID for 7 consecutive days and should 
be given with a meal. If the participant requires mechanical ventilation over the course of the 
study, placebo may be administered via NG, OG, or PEG tube and, if possible, should be 
administered with a scheduled NG, OG, or PEG feeding. Please refer to the study Pharmacy 
Manual for additional dosing and study drug administration information. 
7.2 
Dosing Assignment and Bias Minimization 
Both Study Part 1 and Study Part 2 are randomized and double-blinded to reduce bias. 
7.2.1 
Dosing Allocation 
During Study Parts 1 and 2, participants will receive either ANA001 as a 1,000 mg PO BID 
dose or matching placebo dose for 7 days. 


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7.2.2 
Randomization Strategy and Procedure 
During Study Part 1 and Study Part 2 participants will be randomized in a 1:1 ratio to ANA001 
or matching placebo.  
The randomization plan will be overseen by the study statistician. The randomization code and 
resulting allocation list will be generated and overseen by the study statistician. The list will be 
blocked and stratified by oxygenation (SpO2 <93 and <98% on room air versus SpO2 93% on 
room air)
. 
7.2.3 
Extent and Maintenance of Blinding 
Both Study Part 1 and Study Part 2 will be blinded. The containers of study drug product 
allocated to each participant will not identify treatment allocation. Treating Investigators will 
be blinded. The DMC statistician and the DMC itself will be unblinded for analysis purposes 
as described in the DMC charter. The Sponsor may also be unblinded at any time if the Sponsor 
deems this necessary to adequately evaluate potential safety issues. The Sponsor may also be 
unblinded in accordance with procedures outlined in the statistical analysis plan (SAP). 
7.2.4 
Unblinding Procedures 
7.2.4.1 
Planned Unblinding 
The Sponsor and/or principal investigator may decide to unblind the study drug for a given 
participant if medically necessary. The investigator may request being unblinded to treatment 
assignment of a participant, in accordance with procedures outlined in the Randomization and 
Trial Supply Management (RTSM) Manual 
7.2.4.2 
Unplanned or Unintentional Unblinding 
The Sponsor or designated representative must be notified immediately if an Investigator 
and/or blinded site study team member becomes unblinded unintentionally. 
7.3 
Assessment and Verification of Compliance 
ANA001 or matching placebo will be administered to the participants by clinical staff. For 
participants who are discharged prior to completing the 7-day course of treatment, the 
remainder of the 7-day course of study drug will be provided for at-home administration in a 
bottle along with a diary card on which they are to record the dates/times/amount of study drug 
self-administered. Participants are to return the bottle and the diary card at the time of their 
follow-up visit to the Investigator. In the event that telemedicine follow-up is necessary 
arrangements to obtain the bottle and the diary card must be made as outlined in the 
Randomization and Trial Supply Management (RTSM) Manual. 
Participants should be advised not to consume alcohol or alcohol containing products while 
on study drug due to the potential for ANA001 to potential increased impairment (Yomesan 
[PI] 2008: https://www.bayer.co.za/static/documents/MSDS/PIs/YOMESAN_EN_PI.pdf). 
7.4 
Prior and Concomitant Therapies 
All prescription and over-the-counter systemic (i.e. oral, intravenous, intramuscular, inhaled, 
subcutaneous, or systemically absorbed transdermal) medications being administered or being 
taken by the participant from prior to randomization (considered prior medications) and from 
randomization through the Day 60 visit (considered concomitant medications). For the purpose 
of this study, all enteral nutrition and administration of blood products will also be considered 
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The medication, dose, route of administration, duration (e.g., start date and time and stop date 
and time), and reason for the medication (including if the medication was given as a primary 
or supportive therapy for COVID-19) must be documented on the appropriate eCRF(s). 
 
At each assessment timepoint post-hospitalization, the participant will be asked about any 
medications taken and these will be recorded in the participant s record and documented on the 
appropriate eCRF(s). 
 
given at the discretion of the Investigator and must be recorded in the appropriate sections of 
 
 
The Sponsor recognizes that new therapies for COVID-19 may become available during the 
time this study is being conducted. Therapeutics approved by the FDA and listed in CDC 
guidelines, or FDA authorized medications (i.e., under the emergency-use authorization 
program) to prevent or treat COVID-19 and offered by the respective study site as standard-of-
care may be administered and must be meticulously documented as outlined above. 
7.4.1 
Prohibited Therapies 
Patients receiving chemotherapeutic agents and/or immunomodulators (e.g., systemic 
glucocorticoids, Mabs or plasma transfusions) for chronic disease conditions (e.g., 
malignancies, rheumatoid arthritis or other autoimmune diseases) at screening will not be 
eligible for enrollment into this study. Such agents may be administered as standard-of-care 
after enrollment and should be captured on the appropriate eCRF(s) as outlined above. 
Participants should be advised not to consume alcohol or alcohol containing products while on 
study drug due to the potential for ANA001 to potential increased impairment (Yomesan [PI] 
2008: https://www.bayer.co.za/static/documents/MSDS/PIs/YOMESAN_EN_PI.pdf). 
7.4.2 
Permitted Therapies 
Therapeutics approved by the FDA and listed in CDC guidelines, or FDA authorized 
medications (i.e., under emergency-use authorization program) to prevent or treat COVID-19 
and offered by the respective study site as standard-of-care may be administered and must be 
meticulously documented as outlined above. 
Specifically, patients who deteriorate such that they fulfill criteria for more severe COVID-19 
(e.g., require mechanical ventilation or increased oxygen support) may receive all treatments 
and FDA approved or FDA authorized medications determined by the respective investigative 
site to constitute standard-of-care for the treatment of severe or critical COVID-19 and should 
remain in the study. 
7.4.3 
Rescue Therapies 
Rescue therapy is defined as any therapy that is either FDA approved (or has FDA emergency-
use authorization) for COVID-19 or is administered to a participant to treat COVID-19 based 
on the potential for clinical efficacy against SARS-CoV-2. As the available FDA approved or 
authorized therapies are likely to evolve during enrollment of this study, a complete list of such 
therapies identified in the course of this study will be generated prior to unblinding. 


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8 
SAFETY MONITORING 
8.1 
Definitions 
Adverse event (AE) - An AE is any untoward medical occurrence associated with the use of 
a drug in humans whether or not it is considered drug-related. An AE can be any unfavorable 
and unintended sign (e.g., a clinically significant abnormal laboratory finding), symptom, or 
disease temporally associated with the use of the drug and does not imply any judgement about 
causality. An AE can arise with any use of the drug (e.g., off-label use, use in combination with 
another drug and with any route of administration, formulation, or dose including an overdose). 
Events that are related to the disease under study, COVID-19, should not be considered or 
recorded as AEs unless the event fits the definition for a serious adverse event (SAE), in which 
case the SAE must be reported to the electronic data capture (EDC) system for safety reporting 
purposes in the appropriate time frame. 
Laboratory abnormalities should not be recorded as AEs or SAEs unless they are associated 
with clinical signs or symptoms or require medical intervention. However, each laboratory 
abnormality (e.g., clinically significant changes detected on hematology, chemistry, or 
coagulation test) independent from any underlying medical condition that requires medical or 
surgical intervention, or that leads to interruption of study drug administration or 
discontinuation, must be recorded as an AE or SAE, if applicable. If the laboratory abnormality 
is part of a clinical condition or syndrome, it should be recorded as the syndrome or diagnosis 
rather than as the individual laboratory abnormality. In addition, laboratory abnormalities or 
other abnormal test assessments that are associated with signs or symptoms that are not part of 
a clinical condition or syndrome must be recorded as AEs or SAEs if they meet the definition 
of an AE or SAE. 
Serious adverse event (SAE) - 
investigator or Sponsor, it results in any of the following outcomes:  
 Death 
 A life-
-
the investigator or Sponsor, its occurrence places the patient or participant at immediate 
risk of death. It does not include an AE or suspected adverse reaction (AR) that, had it 
occurred in a more severe form, might have caused death.) 
 Inpatient hospitalization or prolongation of existing hospitalization 
 A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions 
 A congenital anomaly/birth defect 
 Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical 
judgment, they may jeopardize the patient or participant and may require medical or 
surgical intervention to prevent one of the outcomes listed in this definition. Examples 
of such medical events include allergic bronchospasm requiring intensive treatment in 
an emergency room or at home, blood dyscrasias or convulsions that do not result in 
inpatient hospitalization, or the development of drug dependency or drug abuse. 
Treatment-emergent  All AEs will be collected from the signing of informed consent until 
the EOS visit/Day 60. Non-treatment-emergent AEs are defined from the signing of informed 
consent to randomization. Treatment-emergent AEs (TEAEs) are defined from randomization 
through Day 28. 


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Causality or relatedness - A treatment-related AE (TEAE) is defined as any new AE that 
begins or any preexisting condition that worsens in severity, after informed consent until the 
EOS visit (i.e., Day 60+2) and is considered by the investigator to be related to ANA001. All 
AEs and SAEs should have attribution recorded as treatment- or not treatment-related, in the 
judgment of the site investigator. 
 Related: There is a temporal relationship between the study drug and event, and the AE 
is known to occur with the study drug or there is a reasonable possibility that the study 
drug caused the AR. Reasonable possibility means that there is evidence to suggest a 
causal relationship between the study drug and the AE. 
 Not related: There is not a reasonable possibility that the administration of the study 
drug caused the event, there is no temporal relationship between the study drug and 
event onset, or an alternate etiology has been established. 
Adverse reaction - An AR is any AE caused by a drug. 
Suspected adverse reaction (SAR) - An SAR is any AE for which there is a reasonable 
possibility that the drug caused the AE. For the purposes of the IND safety reporting, 
ship between the 
drug and the AE. SAR implies a lesser degree of certainty about causality than AR. 
Unexpected event- 
Brochure (IB), is not listed at the specificity or severity that has been observed, or, if an IB is 
not required or available, is not consistent with the risk information described in the General 
Investigational Plan or elsewhere in the IND. Unexpected also refers to events that are 
mentioned in the IB as occurring with a class of drugs or as anticipated from the 
pharmacological properties of the drug but are not specifically mentioned as occurring with the 
particular drug under investigation. 
Severity or intensity - All AEs that are recorded must have their severity graded. To grade 
AEs, study sites should refer to the Common Terminology Criteria for Adverse Events 
(CTCAE v5) criteria (USDHHS 2017: 
https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/CTCAE_v5_Quick
_Reference_5x7.pdf). 
8.2 
Documenting Adverse Events 
AEs will be recorded in the appropriate electronic case report form (eCRF). 
8.2.1 
Time Frame for Collection 
AEs will be collected from the signing of informed consent through study completion (EOS 
visit; Day 60+2) or study withdrawal. 
8.3 
Recording Adverse Events 
Whenever possible, diagnoses should be given when signs and symptoms are due to a 
common etiology (e.g., dizziness, light-
the study drug and record a severity grade (using the criteria defined in the CTCAE v5 
[USDHHS 2017: 
https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/CTCAE_v5_Quick
_Reference_5x7.pdf])  on the appropriate eCRF. All measures required for (S)AE 
management must be recorded in the source documents and reported according to the 
 


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All (S)AEs occurring at any time during the study (including the follow-up period) must be 
followed by the Investigator until resolution, return to baseline, or until the event is deemed 
stable or irreversible. 
8.4 
Communicating an SAE/SUSAR to the Sponsor and/or CRO 
As soon as a clinical site investigator or other staff member becomes aware of a possible SAE 
in a study participant, regardless of attributability to study treatment, he/she should enter the 
AE/SAE information into the EDC system and reported on the SAE report within 24 hours of 
awareness for reporting to the Sponsor/CRO. The Medical Monitor will review and assess the 
SAE for regulatory reporting and potential impact on study participant safety and protocol 
conduct. 
8.5 
Expedited Reporting of SAE/SUSAR to IEC/IRB and Regulatory Authorities 
With documentation support from the CRO and Sponsor, US Investigators must promptly 
submit all expedited safety reports to their IRB/EC within 7 days for fatal and life-threatening 
events and 15 days for other reportable events. The Sponsor or designee will be responsible for 
reporting an SAE/suspected unexpected serious adverse reaction (SUSAR) to regulatory 
authorities. 
The FDA will be notified for any subject who is withdrawn from the study for safety reasons 
and for any DMC decision to pause enrollment or terminate the study. 
8.6 
Adverse Events of Special Interest  
There are no identified AEs of special interest for ANA001. 
8.7 
Clinical Laboratory Findings 
An AE can include any unfavorable and unintended abnormal laboratory findings temporally 
associated with the use of an investigational product whether or not considered related to the 
product. 
Safety laboratory testing will be conducted as outlined in Section 9.3.6.2 and Appendix 5 
8.8 
Pregnancy 
Pregnancies occurring in participants enrolled in this study must be reported and followed to 
outcome on the Pregnancy Notification Form. Pregnancy alone is not regarded as an AE unless 
there is a possibility that ANA001 may have interfered with the effectiveness of a contraceptive 
medication. Elective abortions without complications should not be considered AEs unless they 
were therapeutic abortions. Hospitalization for normal delivery of a healthy newborn should 
not be considered an SAE. Pregnancy is not considered an SAE unless there is an associated 
serious outcome. Spontaneous abortions should always be reported as SAEs. 
8.9 
Overdose or Misuse 
ANA001 overdose, including misuse or abuse of the product and medication errors, must be 
reported in the 
 notes and captured on the appropriate eCRF(s). 
 


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9 
DATA ANALYSIS AND STATISTICAL METHODS 
In this section, key details of the statistical analyses to be performed using data captured 
according to this protocol will be provided. This study consists of 2 main parts: 
Study Part 1 is designed to primarily assess the safety and tolerability of ANA001 1,000 
mg PO BID and  
Study Part 2 is designed to primarily assess efficacy of ANA001 1,000 mg PO BID. 
A complete statistical analysis plan (SAP) describing all planned analyses for each part will be 
finalized prior to unblinding of Study Part 1 (database freeze) and database lock after 
completion of Study Part 2. A DMC charter and DMC SAP will be finalized prior to initiation 
of Study Part 1. 
9.1 
Determination of Sample Size 
9.1.1 Study Part 1 
60 participants (30 randomized to ANA001 and 30 to placebo) are anticipated to provide 
sufficient data to assess safety and tolerability of ANA001 in patients with moderate and severe 
COVID-19. The sample size is based on clinical consideration and is consistent with the size 
of other studies with similar objectives. 
9.1.2 Study Part 2 
One study reported that subjects treated with placebo will have a median time to clinical 
improvement around 15 days (Beigel et al., 2020). Treatment with ANA001 is expected to 
reduce median time to clinical improvement to 11 days. At least 374 recoveries must be 
achieved for a log rank test to have 85% power at a two-sided significance level of 0.05. 
Assuming a 6 months accrual period and the last enrolled subject will be followed for 30 days, 
at least 376 subjects must be randomized in 1:1 ratio. That is, at least 188 subjects must be 
randomized to be treated with ANA001 and 188 subjects to be treated with placebo.  
9.2 
Analysis Populations 
The following populations will be considered for analysis of various endpoints: 
Randomized Set: It includes all randomized subjects who satisfied the inclusion and exclusion 
criteria described in this protocol 
Full Analysis (or Intent-to-Treat [ITT]) Set: It is the analysis population for the primary 
efficacy analysis. It includes all randomized subjects classified according to the treatment arm 
into which they were randomized regardless of the actual treatment received. 
Per Protocol Set: It includes all subjects in the Full Analysis (or ITT) Set who satisfy COVID-
19 disease criteria at baseline without any major protocol deviations which may affect the 
evaluation of the primary efficacy endpoints 
Safety Set: It includes all randomized subjects, classified according to the actual treatment 
received regardless of randomization assignment, who received any amount of study drug and 
have at least one post-baseline safety evaluation. This is the analysis population for all planned 
safety analyses. 


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Pharmacokinetic (PK)-Evaluable Set: It consists of all randomized subjects, classified 
according to the actual treatment received regardless of randomization assignment, who receive 
at least one dose of study drug. A baseline and at least one pharmacokinetic blood sample 
following a dose of study treatment is required for inclusion in this analysis set. This is the 
analysis population for all planned pharmacokinetic analyses. 
9.3 
Planned Analyses 
The analyses described in this section will be performed for data captured in Study Part 1 and 
Study Part 2 separately. No formal statistical inference is planned for data captured in Study 
Part 1. 
As a general strategy, continuous efficacy and safety endpoints will be summarized using the 
five-number summary (mean, standard deviation, median, minimum, and maximum). 
Frequency distributions (counts and percentages) will be used to summarize categorical 
endpoints. 
9.3.1 Disposition of the Study Participants 
The disposition of subjects will be described with summaries by treatment group of the number 
of subjects in each analysis set described above, the number of subjects who completed the 
study (including the reasons for withdrawal), and the number of subjects for whom study drug 
was permanently discontinued (including the reasons for discontinuation). The ITT set will be 
used to produce this analysis. 
9.3.2 Demographic and Baseline Disease Characteristics 
Demographic and baseline disease characteristics will be summarized and compared by 
treatment group. Results will be reported using subjects in the ITT Analysis Set. 
Medical history will be coded and reported by system organ class and body system. 
Prior medications will be classified according to the anatomical therapeutic chemical (ATC) 
codes in the World Health Organization Drug (WHODRUG) dictionary. The incidence rate of 
each classified medication will be tabulated by treatment group. Tables will be sorted by the 
incidence use of the entire sample. 
9.3.3 Exposure to Study Treatment and Compliance 
Frequency distributions of the number of doses received will be presented by treatment group. 
Treatment duration and treatment compliance for all randomized subjects will also be described 
by treatment group. 
Concomitant medications will be classified and reported in a manner similar to prior 
medications. 
9.3.4 Analysis of Primary Efficacy Endpoints of Study Part 2 
The primary efficacy endpoint in Study Part 2 is median time (in hours) to hospital discharge 
where discharge is defined as a score of 1 or 2 in the 8-point WHO Ordinal Scale for Clinical 
Improvement score. It is defined as the number of days from randomization to the first 
occurrence of discharge from the hospital (e.g., clinical recovery). 


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Median time (in hours) to hospital discharge and corresponding 95% confidence intervals will 
be estimated using the Kaplan-Meier method. Additionally, Cox proportional hazards model, 
with randomization factors as covariates, will be used to estimate the hospital discharge rate 
and corresponding 95% confidence interval. P-value will also be reported. 
9.3.5 Analysis of Secondary Efficacy Endpoints 
Mean change from baseline in continuous secondary efficacy endpoints will be compared using 
an analysis of variance model with baseline values and stratification factors as covariates. 
Difference in least-squares means and associated 95% confidence intervals will be reported. 
Sample size permitting, P-values will also be reported. 
Logistic regression models, with stratification factors as covariates, will be used to compare 
categorical secondary endpoints.  Odds ratio and corresponding 95% confidence intervals will 
be reported. P-values will also be reported. 
9.3.6 Safety Analysis 
All safety endpoints will be summarized using data from the safety set. Safety analyses will 
involve examination by treatment group of the incidence, relatedness, severity and type of 
treatment-emergent adverse events reported, changes from baseline (the assessment prior to first 
dose) in laboratory test results and in vital signs to specified timepoints throughout the study. 
Concomitant medications use will also be summarized by treatment group. 
9.3.6.1 Treatment-Emergent Adverse Events 
All adverse events reported during the study will be coded using a MedDRA (v21.1) dictionary. 
Non-treatment-emergent AEs will be captured on the appropriate eCRF and a listing will be 
generated for the randomized set. Only treatment-emergent AEs (TEAEs) will be summarized 
in the planned safety analyses. The incidence of treatment-emergent adverse events will be 
summarized by treatment group and the following: 
Preferred term 
System organ class and preferred term 
System organ class, preferred term and severity 
These summaries will be presented for the following subsets: 
All adverse events 
Serious adverse events 
Drug-related adverse events 
Adverse events leading to study treatment discontinuation. 
For tables reporting adverse events by severity, if a subject has multiple occurrences of an 
adverse event with the same organ class and preferred term, the most severe event will be 
presented. 
9.3.6.2 Clinical Laboratory Evaluation 
Safety laboratory parameters will be summarized by treatment group at each visit. Each 
summary will include the values of the laboratory parameters and their change from baseline. 


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Shift tables from baseline will be presented for laboratory values in the hematology, chemistry, 
and coagulation tests. Parameters will be classified according to the laboratory reference 
normal ranges. A listing will be provided for out of normal range as well as potentially 
clinically significant abnormal laboratory values. 
9.3.6.3 Vital Signs 
Vital signs, including pulse, respiratory rate, blood pressure (i.e., systolic and diastolic), and 
temperature will be summarized by treatment group and timepoint. For each assessment of 
vital signs, change and percent change in vital signs from baseline will be summarized by 
treatment group. 
9.4 
Interim Analysis 
Upon completion of Study Part 1, the independent DMC will conduct a review of safety and 
efficacy data to provide potential recommendations for early termination or possible study 
adaptations as outlined in the DMC charter. Additional details regarding interim analyses are 
outlined in the DMC statistical analysis plan (SAP) and the study SAP. 
9.5 
Independent Data Monitoring Committee 
An independent Data Monitoring Committee (DMC) will be formed and constituted according 
to appropriate regulatory agency guidelines. Detailed information regarding the composition 
of the committee and detailed procedures will be provided in a separate DMC charter. The 
independent DMC will review the safety, tolerability, and efficacy data of Study Part 1 and 
Study Part 2 as described in the DMC charter. 
9.6 
Handling of Missing Data 
Missing efficacy assessments will be imputed using a multiple imputation method appropriate 
to the pattern of missingness. Details of the considered patterns and associated sensitivity 
analyses will be described in the Statistical Analysis Plan. 
9.7 
Multiplicity Adjustment 
A hierarchical testing scheme is planned to preserve the familywise type I error of the study. If 
statistical significance of the primary efficacy endpoint is established, secondary efficacy 
endpoints will be tested in the following order: 
1. Mean change from baseline (BL) in National Early Warning Score (NEWS2) 
2. Mean number of days on rescue treatment (COVID-19 treatments that are approved 
under NDA or EUA) within 15 days after enrollment 
The testing scheme will be halted at the first secondary endpoint that fails to establish 
statistical significance. 
9.8 
Pharmacokinetic Analysis 
Descriptive statistics of individual plasma concentrations for ANA001 will be summarized 
and listed according to the sampling schedule outlined in Appendix 6 for Study Day 1, 2, 3, 
or 4 for the PK-Evaluable set and will be reported in the CSR. 
Derived PK parameters, population PK analyses, and potential 
pharmacokinetic/pharmacodynamic (PK/PD) relationships will be reported separately. 


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10 
ETHICAL CONSIDERATIONS 
10.1 
Good Clinical Practice 
This study will be conducted in compliance with Good Clinical Practices (GCP), i.e., 
International Council for Harmonization (ICH) of Technical Requirements for Pharmaceuticals 
for Human Use guideline E6 (R2) on Good Clinical Practice, other ICH guidelines, and 
relevant national guidelines on GCP. 
10.2 
Ethics Review  
The study protocol, site-specific informed consent forms (ICFs), participant education and 
recruitment materials, and other requested documents, including any subsequent modifications, 
will be reviewed and approved by the Independent Ethics Committee (IEC)/IRB. 
10.3 
Informed Consent 
The principles of informed consent in the ICH GCP guideline E6 (R2) will be implemented 
before any protocol-specified procedures or interventions are carried out. The consent form 
will describe the purpose of the study, the procedures to be followed, and the risks and benefits 
of participation. A copy of the consent form will be given to the participant, and this fact will 
 
10.4 
Data Privacy 
necessary for oversight by: 
 The principal investigators or designees 
 IRB/IEC 
 Sponsor or designees, AND/OR 
 Regulatory authorities 
10.5 
Disclosure 
Each study site will establish a standard operating procedure for confidentiality protection. 
Each site will ensure that study records including administrative documentation and regulatory 
documentation, as well as documentation related to each participant enrolled in the study, 
including ICFs, locator forms, CRFs, notations of all contacts with the participant, and all other 
source documents are stored in a secure manner. 
10.6 
Biological Specimens and Data 
All laboratory specimens, evaluation forms, reports, and other records that leave the site will 
be identified by coded number only to maintain participant confidentiality, unless otherwise 
required by local or state authorities, e.g., SARS-CoV-2 testing results, which are participant 
to local and state reporting that is name-based. Local public health agencies may contact 
participants diagnosed with SARS-CoV-2 for the purpose of surveillance and contact 
notification. Participants will be informed prior to SARS-CoV-2 testing that results are 
reportable and may lead to contact by local public health officials if results are positive for 
infection. 
All records will be kept in a secure location. All computer entry and networking programs will 
be done with coded information. Clinical information will not be released without written 
permission of the participant, except as necessary for monitoring by the principal investigators 


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or designees, IRB/IEC, Office for Human Research Protections (or other local, US, and 
international regulatory entities as part of their duties), and/or the Sponsor or designees. 
 


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11 
OVERSIGHT 
11.1 
Data Monitoring Committee 
An independent DMC will be convened for this study consisting of at least 3 medical doctors, 
with expertise in infectious diseases, pulmonary/critical care, investigational drug 
development, and/or experienced in the management of hospitalized COVID-19 patients. The 
DMC will also include a biostatistician experienced in clinical trial design and analyses. The 
purpose of the DMC is to monitor the study for operational safety, and efficacy (including 
futility). The DMC will provide recommendations to the Sponsor as described in the DMC 
charter. 
The DMC will conduct interim reviews when adequate data have been accrued. Open reports 
containing accrual and retention rates, participant characteristics, and SAEs will be sent to the 
DMC members prior to each scheduled or unscheduled DMC meeting. Only the DMC 
members (including the unblinded biostatistician) will receive password-protected closed 
reports containing unblinded study data. The DMC members will also have access to unblinded 
data at their request. Further details are contained in the DMC charter. 
11.2 
Quality Control and Assurance 
11.2.1 
Monitoring 
Study conduct will be monitored by site-independent monitors. Monitors will visit participating 
clinical research sites to review the individual participant records, including consent forms, 
eCRFs, supporting data, laboratory specimen records, and endpoints through laboratory and 
and 
ensure protection of study participants, compliance with the protocol, and accuracy and 
completeness of records. The monitors also wi
and management. When on-site visits to the participating clinical research sites are not feasible 
due to COVID-19 control measures and/or other institutional restrictions, remote monitoring 
visits will be performed per the study clinical monitoring plan. 
11.2.2 
Protocol Deviations 
Prospective approval of a protocol deviation of an enrollment criterion, also known as a 
protocol waiver or exemption, is not permitted. 
Protocol deviations will be listed by treatment group for all randomized participants. Protocol 
deviations are defined as any variation from the protocol, including enrollment of a subject 
who did not meet all inclusion criteria or who met an exclusion criterion, or the failure to 
perform the assessments and procedures as specified in the protocol within the required time 
frames. 
11.2.3 
Records 
11.2.3.1 
Data Capture and Management 
Participant information will be captured and managed by study sites on eCRFs by a web-based 
EDC tool. 


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11.2.3.2 
Records Retention 
Investigator shall retain all study records until at least 2 years after the last approval of a 
marketing application in an ICH region and until there are no pending or contemplated 
marketing applications in an ICH region or at least 2 years have elapsed since the formal 
discontinuation of clinical development of the study drug. In the event that study records are 
relocated to a different location from the site location during this study retention period, the 
Investigator must notify the Sponsor and/or its designees. 
 
11.3 
Study Completion/Termination 
The Sponsor will register the study and post study results upon study completion or 
termination, regardless of outcome, on a publicly accessible website in accordance with the 
applicable laws and regulations. 
The Sponsor also will notify, when required, the regulatory authorities and IECs/IRBs about 
the completion or termination of this study and send a copy of the study report synopsis in 
accordance with necessary timelines. 
 


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12 
PUBLICATION POLICY 
The Sponsor retains the rights to publish the results of this study. Details are included in the 
clinical trial agreement. 
 


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FUNDING 
NeuroBo Pharmaceuticals, Inc.  is the Sponsor of this study.  
 


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15 
APPENDICES 
APPENDIX 1 
WHO ORDINAL SCALE FOR CLINICAL IMPROVEMENT 
Score 
Status 
1 
Not hospitalized, no limitations on activities 
2 
Not hospitalized, limitation on activities and/or requiring home oxygen 
3 
Hospitalized, not requiring supplemental oxygen - no longer requires ongoing 
medical care 
4 
Hospitalized, not requiring supplemental oxygen - requiring ongoing medical 
care (COVID-19 related or otherwise) 
5 
Hospitalized, requiring supplemental oxygen 
6 
Hospitalized, on non-invasive ventilation or high flow oxygen devices 
7 
Hospitalized, on invasive mechanical ventilation or extracorporeal membrane 
oxygenation (ECMO) 
8 
Death 
Reference: WHO R&D Blueprint: novel Coronavirus; COVID-19 Therapeutic Trial 
Synopsis. Geneva, Switzerland. 18 Feb 2020 
 


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APPENDIX 2 
NATIONAL EARLY WARNING SCORE 2 (NEWS2) 
The resulting observations are compared with a normal range to generate a single composite 
score, for instance based on the following diagram (an early modified NEWS): 
 
Table 4 
NEWS2 
 
 
A summary of this scoring system can be accessed at 
https://www.rcplondon.ac.uk/projects/outputs/national-early-warning-score-news-2 
For patients confirmed to have hypercapnic respiratory failure on blood gas analysis on either 
a prior or their current hospital admission and requiring supplemental oxygen should be noted. 
Scale 2 on the NEWS2 chart will be used to record and score the oxygen saturation for the 
NEWS. 
The vital signs of the participant (including: pulse, respiratory rate, SpO2 (including room air 
or oxygen [with oxygen delivery and rate]), blood pressure (systolic and diastolic), and 
temperature will be entered into an eCRF. The individual parameters of the NEWS2 scoring 
system will be populated using these values. 
Concurrently with determination of NEWS2, 
-19 (Appendix 
4) and subjective signs and symptoms of COVID-19 will be assessed and include presence or 
absence of: fever, cough (productive or non-productive), sore throat, malaise, headache, muscle 
pain, gastrointestinal symptoms (i.e., nausea, vomiting, or diarrhea), shortness of breath (with 
or without exertion), and respiratory distress. 
This chart collected variable and scoring system is not intended to guide or modify standard-
of-care at the respective investigative sites. 
 
 
 


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APPENDIX 3 
SEQUENTIAL ORGAN FAILURE ASSESSMENT (SOFA) 
SCORE 
 
Source: de Mendonça et al., 2000 
FIO2=fraction of inspired oxygen; PaO2=partial pressure of oxygen. 
 
 


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APPENDIX 4 
CRITERIA FOR MODERATE, SEVERE, AND CRITICAL 
COVID-19 
Severity 
Criteria 
Moderate 
Development of one of the following: 
1. Symptoms suggestive of moderate illness 
(fever, cough, sore throat, malaise, headache, 
muscle pain, gastrointestinal symptoms, AND 
shortness of breath with exertion, OR 
2. Clinical signs indicative of moderate systemic 
illness with COVID-19, such as respiratory rate 
min, SpO2 >93% on room air, AND 
No criteria for Severe or Critical Severity 
Severe 
Development of one of the following: 
1. Symptoms suggestive of severe illness, which 
could include any symptom of moderate illness 
PLUS shortness of breath at rest or respiratory 
distress, OR 
2. Clinical signs indicative of severe systemic 
illness with COVID-19, such as respiratory rate 
breaths per minute
per min, SpO2 
% on room air, AND 
No criteria for Critical Severity 
Critical 
Evidence of critical illness, defined by at least 1 of the 
following: 
1. Respiratory failure requiring at least 1 of the 
following:  
a. Endotracheal intubation and mechanical 
ventilation, oxygen delivered by high 
flow nasal cannula (heated, humidified, 
oxygen delivered via reinforced nasal 
cannula at flow rates >20 L/min with 
 
b. Noninvasive positive pressure 
ventilation (NIPPV), OR 
c. Extracorporeal membrane oxygenation 
(ECMO) or clinical diagnosis of 
respiratory failure (i.e., clinical need for 
1 of the preceding therapies, but 
preceding therapies not able to be 
administered in setting of resource 
limitation) 
2. Shock (defined by systolic blood pressure (BP) 
<90 mm Hg, or diastolic BP <60 mm Hg or 
requiring vasopressors), OR 
3. Multi-organ dysfunction/failure 


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Reference: FDA. COVID-19: Developing Drugs and Biological Products for Treatment or 
Prevention: Guidance for Industry. May 2020. 
 
 
 


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APPENDIX 5 
LABORATORY ASSESSMENTS  
 Hematology (Local Laboratory Tests)* 
Serum Chemistry (Local Laboratory Tests)* 
Hemoglobin 
Blood urea nitrogen (BUN) 
Hematocrit 
Creatinine 
Total WBC count with 5-part differential 
Sodium 
Platelet count 
Potassium 
 
Chloride 
 
Carbon dioxide 
 
Glucose 
Coagulation (Local Laboratory Tests)* 
Total bilirubin 
Partial thromboplastin time (aPTT) 
Direct Bilirubin 
Prothrombin time (PT) 
Alkaline phosphatase (ALP) 
International normalized ratio (INR) 
Aspartate aminotransferase (AST) 
 
Alanine aminotransferase (ALT) 
 
Additional Tests (Central Laboratory Tests) 
 
D-dimer 
 
Cardiac troponin 
 
Ferritin 
 
LDH 
 
CRP 
 
Exploratory tests (e.g., IL-6, TF, MCP-1, IP-10) 
* 
Denotes laboratory assessment used primarily to generate safety summaries 
 
 
 


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APPENDIX 6 PK SAMPLE COLLECTION SCHEDULE (STUDY PART 1 ONLY) 
 
SAMPLING 
SCHEDULE 
Day 1, 2, 3, or Day 4 
Pre-Dose (i.e., 
within 30 
minutes) 
 
1 hour  
(+/- 30 minutes)
4 hour 
(+/- 30 minutes)
8 hour 
(+/- 30 minutes)
Pre-Dose to 
next study drug 
(i.e., within 30 
minutes) 
administration 
  
Please refer to the Central Laboratory Manual for primary and back-up sample collection and 
processing instructions. Remaining blood plasma volume may be used for central laboratory 
and/or exploratory analyses (e.g., IL-6, tissue factor, MCP-1 and IP-10). 
 

SAP_001.pdf: 
 
STATISTICAL ANALYSIS PLAN 
for Part 1 for ANA001-001 Study  
Protocol Number 
ANA001-001 
Protocol Title: 
A Phase 2/3 Randomized and Placebo-Controlled Study of 
ANA001 in Moderate and Severe COVID-19 Patients 
Product: 
Niclosamide (ANA001) 
Indication: 
Moderate and Severe COVID-19 Infection 
Development Phase: 
2/3 
Version: 
1.0 
Date: 
30 August 2022 
 
Prepared by: 
 
 
Hany Zayed, PhD 
 
Biostatistician 
Consultant 
Reviewed by:
 
 
Doug Rank, MD 
 
Director, Clinical Development 
NeuroBo Pharmaceuticals Inc. 
 
 
 
Gil Price, MD 
President and CEO 
 
NeuroBo Pharmaceuticals Inc. 
 
 


Protocol ANA001-001 
 
Statistical Analysis Plan v1.0 
2 
Table of Contents 
1. 
INTRODUCTION 
4 
2. 
STUDY OBJECTIVES 
4 
2.1 
Primary Objectives 
4 
2.2 
Secondary Objectives 
4 
2.3 
Exploratory Objectives 
4 
3. 
STUDY DESIGN 
5 
4. 
STUDY ENDPOINTS AND COVARIATES 
6 
4.1 
Demographic and Baseline Disease Characteristics 
6 
4.2 
Efficacy Endpoints 
7 
4.2.1 
Secondary Efficacy Endpoints 
7 
4.2.2 
Exploratory Efficacy Endpoints 
7 
4.3 
Safety Endpoints 
8 
4.4 
Covariates 
8 
5. 
ANALYSIS POPULATIONS AND SUBGROUPS 
8 
5.1 
Analysis Populations 
8 
5.2 
Subgroups 
9 
6. 
ANALYTIC DEFINITIONS 
9 
7. 
STATISTICAL ANALYSIS AND METHODOLOGY 
10 
7.1 
Participant Disposition and Protocol Deviations 
10 
7.2 
Demographics and Baseline Disease Characteristics 
10 
7.3 
Treatment Exposure and Compliance 
12 
7.4. 
Efficacy Analysis for Secondary Endpoint 
12 
7.5 
Efficacy Analysis for Exploratory Endpoints 
13 
7.5.1 
Change from Baseline in NEWS-2 
13 
7.5.2 
Number of Days on COVID-19 Rescue Therapy 
13 
7.5.3 
Duration of COVID-19 Symptoms 
14 
7.5.4 
Progression of COVID-19 
14 
7.5.5 
ICU Admission 
15 
7.5.6 
Sequential Organ Failure Assessment (SOFA) Score 
15 
7.5.7 
Oxygen and Assisted Ventilation 
16 


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7.5.8 
WHO Ordinal Scale for Clinical Improvement 
16 
7.5.9 
Thromboembolic Events 
17 
7.5.10 Inflammation Markers Associated with Acute Respiratory Distress Syndrome 
(ARDS) 17 
7.5.11 Viral Dynamics 
17 
7.6 
Safety Endpoints 
18 
7.6.1 
Adverse Events 
18 
7.6.2 
Clinical Laboratory Evaluation 
18 
7.6.3 
Vital Signs 
19 
8. 
VISIT WINDOW 
19 
9. 
MULTIPLICITY ADJUSTMENT 
19 
10. 
HANDLING OF MISSING DATA 
19 
10.1 Missing Efficacy Data 
19 
10.2 Adverse Events Missing Data 
19 
10.3 Concomitant Medications Missing Dates 
19 
APPENDIX A. 
SCHEDULE OF EVENTS (STUDY PART 1 AND STUDY PART 2) 
21 
APPENDIX B. 
QUESTIONNAIRE SCORING 
24 
B.1 
NATIONAL EARLY WARNING SCORE 2 (NEWS2) 
24 
B.2 
SEQUENTIAL ORGAN FAILURE ASSESSMENT (SOFA) SCORE 
25 
APPENDIX C. 
POTENTIALLY CLINICALLY SIGNIFICANT LABORATORY CRITERIA
 
26 
 
 
 
 


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1. 
INTRODUCTION 
The purpose of this document is to outline the planned statistical analyses at the end of Part 1 of 
data captured according to NeuroBo Pharmaceuticals protocol ANA001-
A Phase 2/3 
Randomized and Placebo-Controlled Study of ANA001 in Moderate and Severe COVID-19 
Patients  Version 4.0 (Amendment 3) dated 25 February 2021.  This trial was registered on 
ClinicalTrials.gov Identifier NCT04603924 by ANA Therapeutics, which was acquired by 
NeuroBo Pharmaceuticals. 
Tables, listings, and figures planned for the final analyses of Part 1 will be provided in a separate 
document. 
2. 
STUDY OBJECTIVES 
2.1 
Primary Objectives 
Part 1 of the study has one primary objective: 
 Evaluate the safety and tolerability of ANA001 as therapy for moderate and severe 
COVID-19 patients 
2.2 
Secondary Objectives 
The following is the secondary objective of Part 1 of the study: 
 Evaluate the efficacy of ANA001 as therapy in moderate and severe COVID-19 patients 
 Evaluate pharmacokinetics (PK) of ANA001 
2.3 
Exploratory Objectives 
The exploratory objectives of Part 1 of the study: 
 Evaluate clinical improvement using National Early Warning Score 2 (NEWS2) 
 Evaluate the need and duration of rescue therapy 
 Evaluate the effect on subjective symptoms of COVID-19 
 Evaluate progression of COVID-19 from moderate or severe to more severe (i.e., 
moderate to severe, moderate to critical, or severe to critical) 
 Evaluate the effect of ANA001 on requirement for oxygen and/or assisted ventilation 
 Evaluate time to resolution of the WHO Ordinal Scale for Clinical Improvement 
 Evaluate the effect of ANA001 on thromboembolic events 
 Evaluate the relationship of ANA001 and markers of inflammation associated with acute 
respiratory distress syndrome (ARDS) 


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Evaluate the relationship between ANA001 plasma concentrations and viral dynamics
3.
STUDY DESIGN
This is a 2-part, multicenter, randomized, placebo-controlled clinical study of ANA001 in 
patients with moderate and severe COVID-19.  The study duration for each participant will be 
approximately 62 days, including a 36-hour screening window. Screening and Day 1 may occur 
on the same day if screening criteria are met to confirm participant eligibility.  After provision of 
informed consent, participants who satisfy all inclusion and no exclusion criteria will be 
randomized in a 1:1 ratio to be treated with ANA001 1000 mg BID or matching placebo.  
Randomization of participants will be stratified by oxygenation (SpO2 > 93 and < 98% on room 
air versus
93% on room air
Participants will be dosed within 36 hours of screening and as soon as possible following 
hospital presentation.
Participants will receive capsules of ANA001 or matching placebo for 7 consecutive days 
(defined as 14 doses administered BID) according to the assignment made by the randomization 
and trial supply management (RTSM) system.  Additionally, participants will receive continued 
standard of care therapy (per study site policies or guidelines).  Dosing will continue until the 
treatment course is completed.  If the participant requires mechanical ventilation or for any other 
reason is unable to swallow oral medication over the course of the study, ANA001 will be 
administered via nasogastric (NG) or orogastric (OG) tube in accordance with the appropriate 
section in the study Pharmacy Manual.  If the participant is discharged prior to completing the 


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treatment course, the remaining study drug will be dispensed for at-home administration.  Every 
effort will be made to complete the remaining study assessments for participants who are not 
able to complete the 7-day consecutive course of study drug.  
Upon successful completion of Part 1, the safety and efficacy of ANA001 1,000 mg PO BID for 
7 consecutive days will be evaluated in a larger population of patients in Part 2. 
4. 
STUDY ENDPOINTS AND COVARIATES 
The following endpoints will be considered for Part 1. 
4.1 
Demographic and Baseline Disease Characteristics 
Demographics characteristics include: 
 Age at baseline (including number of participants 18  <40, 40  < 
 65 years) 
 Sex at birth 
 Ethnicity 
 Race 
 Height (m) 
 Weight at Baseline (kg) 
 Body mass index at Baseline (kg/m2) (including number of participants > 30 kg/m2). 
Baseline disease characteristics include:  
 WHO Ordinal Scale for Clinical Improvement score 
 Number of days from first symptom to randomization 
 Number of COVID-19 symptoms 
 Number of co-existing conditions (0, 1, 2, 3, 4) as determined by medical history and 
other screening data, including 
o Age at screening >60 years 
o Obesity, which is defined BMI at screening >30 kg/m2 
o Hypertension 
o Cardiovascular disease 
o Chronic lung disease 
o Chronic kidney disease 
o Chronic liver disease 
o Chronic immunosuppression, and 
o Diabetes 
 Respiration rate (
 20 to <25,  25 to <30, and  30 breaths per minutes) 
 Pulse rate (
 
 
 125 beats per minute) 
 Temperature 
 38.3 versus > 38.3C) 


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 Peripheral capillary oxygen saturation (SpO2) (>93% and <98% on room air versus <93% 
on room air) 
 Fraction of Inspired Oxygen (SpO2/FiO2
 
4.2 
Efficacy Endpoints 
The primary endpoints for Part 1 of the study are safety endpoints including treatment-emergent 
adverse events (TEAEs), vital signs and laboratory (hematology, chemistry, and coagulation) 
parameters and are described in Section 4.3. The secondary and exploratory efficacy endpoints 
for Part 1 are described in the following sections. 
4.2.1 Secondary Efficacy Endpoints 
The secondary efficacy endpoint of Part 1 of this study is the median time (in hours) to hospital 
discharge (where discharge is defined as a score of 1 or 2 in the WHO Ordinal Scale for Clinical 
Improvement).  For the purpose of deriving this efficacy endpoint, hospital discharge is defined 
as achieving WHO Ordinal Scale for Clinical Improvement score of: 
 1: Not hospitalized, no limitations on activities or  
 2: Not hospitalized, limitation on activities and/or requiring home oxygen. 
4.2.2 Exploratory Efficacy Endpoints 
The following are the exploratory efficacy endpoints of Part 1 of this study: 
 Mean change from baseline in the NEWS-2 total score on Day 15 
 Mean number of days on rescue treatment (COVID-19 therapies that are FDA approved 
or have emergency-use authorization) within 15 days after enrollment. 
 Median time (in days) to resolution of subjective symptoms assessed by the Investigator 
to be potentially due to COVID-19 including: fever, cough (productive or non-
productive), sore throat, malaise, headache, muscle pain, gastrointestinal symptoms (i.e., 
nausea, vomiting, or diarrhea), shortness of breath (with or without exertion), and 
respiratory distress 
 
-19 progresses to Severe or Critical within 15 
days after enrollment 
 Proportion of participants requiring ICU admission within 15 days after enrollment 
 Mean change from baseline in SOFA score on Days 8 and 15 
 Proportion of participants on Days 8 and 15 requiring:  
o Supplemental oxygen 
o High flow nasal cannula (HFNC) oxygen 
o Non-invasive positive pressure ventilation (NIPPV) 
o Mechanical ventilation 
 Mean number of days on mechanical ventilation within 15 days after enrollment 
 Mean number of oxygenation-free days within 15 days after enrollment 


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 Proportion of participants who achieve a score of 1 on the WHO Ordinal Scale for 
Clinical Improvement on Days 8 and 15 
 Median time (in hours) to a 2-point improvement in the WHO Ordinal Scale for Clinical 
Improvement 
 Incidence and severity of thromboembolic events within 15 days after enrollment 
 Incidence of abnormal markers of inflammation to include CRP, IL-6, TF, MCP-1, and 
IP-10 on Day 8 
 Mean change in viral load from baseline on Days 1, 4, 8, 15, and 28 
 Median number of days to viral load undetectable by nasopharyngeal (NP) swab 
4.3 
Safety Endpoints 
The following endpoints will be used to assess the safety and tolerability of ANA001: 
 Incidence of treatment-emergent adverse events, serious adverse events, adverse events 
leading to study treatment discontinuation and adverse events leading to death 
 Incidence of treatment-emergent potentially clinically significant laboratory 
abnormalities, including test results in the hematology, blood chemistry, and coagulation 
panels 
 Incidence of vital signs abnormality, including temperature ( C), systolic and diastolic 
blood pressure (mmHg), pulse (beats/min), and respiratory rate (breaths/min). 
4.4 
Covariates 
Sample size permitting, the following randomization factors will be considered as covariates: 
 Oxygenation (SpO2 > 93 and < 98% on room air,  93% on room air) 
 Diarrhea (presence, absence), and  
 
 
Additionally, baseline score of the WHO Clinical Improvement Scale and the number of co-
existing conditions will be used as covariates. 
5. 
ANALYSIS POPULATIONS AND SUBGROUPS 
5.1 
Analysis Populations 
The following populations will be considered for analysis: 
Randomized Set: It includes all randomized participants who satisfied the inclusion and 
exclusion criteria described in this protocol. 
Full Analysis (or Intent-to-Treat [ITT]) Set: It is the analysis population for the primary efficacy 
analysis.  It includes all randomized participants classified according to the treatment arm into 
which they were randomized regardless of the actual treatment received. 


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Safety Analysis Set: It includes all randomized participants, classified according to the actual 
treatment received regardless of randomization assignment, who received any amount of study 
drug and have at least one post-baseline safety evaluation.  This is the analysis population for all 
planned safety analyses. 
5.2 
Subgroups 
Sample size permitting, the following subgroups will be considered: 
 Age at baseline: 18  40, 40  <
 65 years 
 Sex: Male, Female 
 Ethnicity: Hispanic or Latino, Not Hispanic or Latino 
 Race: While, African American/Black, Asian, Other 
 Symptoms duration: < 
 7 days 
 Baseline score of the WHO Clinical Improvement Scale: 3, 4 
 Co-existing conditions: chronic lung disease, cardiovascular or cerebrovascular disease, 
hypertension, diabetes, obesity, an immunocompromised state 
 Peripheral Capillary Oxygen Saturation (SpO2): > 93% and < 98% on room air versus 
 93% on room air. 
6. 
ANALYTIC DEFINITIONS 
Baseline Measurements will be the last measurement for the corresponding endpoint prior to the 
first dose of study drug. 
Age at Baseline is the last non-missing age collected before the first dose of study drug. 
Body Mass Index is calculated as (Weight in kg / (Height in meter)2).  The last non-missing 
weight and height collected before the first dose of study treatment will be used to calculate the 
baseline body mass index. 
Study Drug Exposure is calculated as number of days from first dose day to last.  That is: 
Study Drug Exposure = Last Study Drug Date  First Study Drug Date + 1. 
Study Drug Compliance (%) for a participant is calculated as: 100*total number of doses 
taken/total number of doses the participant was supposed to have taken during the treatment 
period. That is, 100*total number of doses taken ÷ (8* Study Drug Exposure [in Days]). 
A Treatment-Emergent Adverse Event (TEAE) is any adverse event that occurs on or after first 
dosing and up through Day 28. 
COVID-19 Rescue Treatments that are defined as any treatment approved under NDA or 
Emergency Use Authorization (EUA) for COVID-19 or off label medications given as direct 
treatment of COVID-19. 


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Concomitant Medication will be defined as the medications used on/after the first dose of study 
drug or started before first dose of study drug and continued during the study. 
7. 
STATISTICAL ANALYSIS AND METHODOLOGY 
The statistical analysis of the data of this protocol will be performed using SAS® version 9.4 or 
higher. 
Unless otherwise specified, continuous endpoints will be summarized with number of non-
missing observations (n), mean, standard deviation (SD), median, 25th quartile (Q1) and 75th 
quartile (Q3), minimum and maximum.  In general, the same number of decimal places as in the 
raw data will be presented when reporting minimum and maximum, one more decimal place than 
in the raw data will be presented when reporting mean and median, and two more decimal places 
than in the raw data will be presented when reporting SD.  If the raw data have 3 decimals or 
more, 3 decimals will be presented for mean, median, minimum, maximum, and standard 
deviation. 
Categorical endpoints will be described using the number and percentage of participants in the 
various categories of the endpoint.  One decimal will be presented for percentages.  Percentages 
equal to 100 will be presented as 100%. 
All two-sided inference tests will be performed at the 0.05 significance level and all one-sided 
inference tests will be performed at the 0.025 significance level.  
7.1 
Participant Disposition and Protocol Deviations 
participants, 
the number and percentage of participants randomized but not treated, number and percentage of 
participants in each of the stratification factors, the number and percentage of participants in 
each analysis set by treatment group.  Additionally, the number and percentage of participants 
who completed treatment and those who discontinued treatment early along with the reason for 
early treatment discontinuation as well as the number and percentage of participants who 
completed the study or withdrew early from the study along with the reason for early withdrawal 
from the study will be presented by treatment group. 
Number and percentage of participants randomized by site number and investigator name will 
also be reported by treatment group. 
Incidence of major protocol deviation will be tabulated by protocol deviation category and 
deviation for all participants in the Full Analysis Set. 
7.2 
Demographics and Baseline Disease Characteristics 


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Demographics characteristics listed in Section 4.1 will be summarized by treatment group for 
participants in the Full Analysis Set. 
For baseline height, weight, and BMI, 24 hours window will be added for baseline values. To be 
more specific, the baseline value is defined as last non-missing value prior to first dose date + 1 
day. For participants who are randomized but not dosed, baseline will be the last non-missing 
value prior to date of randomization. 
Baseline disease characteristics listed in Section 4.1 will be summarized by treatment group for 
participants in the Full Analysis Set.  It should be noted that: 
 Co-existing medical conditions of interests include the following: 
o Age at screening >60 
o Obesity, which is defined BMI at screening >30 kg/m2 
o Hypertension 
o Cardiovascular disease 
o Chronic lung disease 
o Chronic kidney disease 
o Chronic liver disease 
o Chronic immunosuppression, and 
o Diabetes 
Participants in immunocompromised will be identified during the blinded medical review 
 
 
 In calculating baseline SOFA score assume the following: 
 
o SOFA score for respiratory system could be calculated as follows: 
SOFA Respiratory System 
Score 
PaO2/FiO2 
(mmHg) 
SpO2 
(%) 
0 
> 400 
> 96 on Room Air 
1 
301  400 
> 93 and < 97 on Room Air 
 
 
> 93 on 1 L/min 
 
 
> 96 on 2 L/min 
2 
201  300 
94  96 on 2 L/min 
For participants do not have SOFA score collected at baseline, the last non-
missing SpO2 respiration score prior to the first dose will be used for the baseline 
value. 
o For participants not admitted to ICU, assume Glasgow Coma Score of 16 


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 Fraction of Inspired Oxygen (SpO2/FiO2) can be calculated as follows: 
Oxygen Tank Flow Rate 
FiO2 
Room Air 
0.21 
1 L/min Nasal Cannula 
0.24 
2 L/min Nasal Cannula 
0.28 
7.3 
Treatment Exposure and Compliance 
Number of doses received, treatment duration (in days) and percent of treatment compliance and 
compliance category (<80%, 80%-120%, >120%) will be summarized by treatment group for all 
participants in the Full Analysis Set. 
COVID-19 rescue medications will be classified according to the anatomical therapeutic 
chemical (ATC) codes in the World Health Organization Drug (WHODRUG) dictionary; version 
B3 WHO Drug DDE  March 2020.  The incidence rate of each classified medication will be 
tabulated by treatment group for all participants in the intent-to-treat population. 
Concomitant medications will be classified and tabulated in a manner similar to rescue 
medications. 
7.4. 
Efficacy Analysis for Secondary Endpoint 
The secondary efficacy endpoint for Part 1 of this study is the median time (in hours) from 
randomization to hospital discharge (where discharge is defined as a score of 1 or 2 in the WHO 
Ordinal Scale for Clinical Improvement).  
Kaplan-Meier curves will be constructed to display time-to- hospital discharge.  Participants who 
are lost to follow-up or ended study early prior to achieving clinical improvement will be 
censored at the day of the last obtained assessment of their WHO Ordinal Scale for Clinical 
Improvement.  Participants who complete follow-up without hospital discharge will be censored 
at the day of their Day 60 visit.  Participants who die for any reason during the study will be 
right-censored at Day 60 or date of death, whichever is earlier.  For the analysis of this efficacy 
endpoint, missing scores of the WHO Ordinal Scale for Clinical Improvement will be assumed to 
be > 2 (i.e., no hospital discharge).  Median time-to-clinical improvement and corresponding 
95% confidence interval will be estimated from the Kaplan-Meier curves and tabulated for each 
treatment group. 
The Cox proportional hazard method will be used to calculate the hospital discharge rate ratio of 
ANA001 relative to placebo while controlling for the stratification factors, baseline WHO 
Ordinal Scale for Clinical Improvement, and number of co-existing conditions.  Hospital 
discharge rate ratio is akin to a hazard ratio but for the beneficial outcome of hospital discharge.  


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A hospital discharge rate ratio > 1 indicates a benefit for ANA001.  Treatment groups will be 
compared using a stratified log-rank test. 
The above analyses will be produced for all participants in the Full Analysis Set and by baseline 
WHO Ordinal Scale for Clinical Improvement scores.  Additionally, the same analysis will be 
produced for participants in the Per-Protocol Analysis Set and Safety Analysis Set. 
If WHO Ordinal Scale are missing at baseline, 6 hours window after first dose will be added for 
baseline values. 
7.5 
Efficacy Analysis for Exploratory Endpoints 
As a general strategy, analyses of the exploratory efficacy endpoints will be presented for all 
participants in the Full Analysis Set. 
7.5.1 Change from Baseline in NEWS-2 
NEWS-2 will be administered daily for hospitalized participants.  NEWS-2 total score will be 
tions (Appendix B.1).  For participants who get 
discharged from the hospital before Day 15, their last available NEWS-2 total score will be 
carried forward to Day 15. 
Mean observed and mean change from baseline in NEWS-2 total score at Day 15 will be 
tabulated by treatment group.  Additionally, the difference in the least-squares means and their 
standard errors adjusted for baseline NEWS-2 score, stratification factors, baseline WHO 
Ordinal Scale for Clinical Improvement score, and number of co-existing conditions will be 
tabulated.  Corresponding 95% confidence interval of the difference between two least-squares 
means and p-value will also be reported. 
7.5.2 Number of Days on COVID-19 Rescue Therapy 
According to the protocol, participants are allowed to receive concomitant treatments during the 
course of the study per the standard-of-care at the investigational site.  Some concomitant 
treatments (e.g., treatments granted US FDA approval, Emergency Use Authorization or 
glucocorticoid therapy) may aid the cure of COVID-19.  For the purpose of this analysis, 
medications that may have direct anti-viral effects or systemic effects on the acute inflammatory 
processes of the virus/COVID and are given more than 24 hours after study drug started and no 
more than 240 hours (10 days) after enrollment will be considered COVID-19 rescue therapy.  
All concomitant medications will be reviewed in a blinded fashion prior to the database lock by 
team members with appropriate background and training to identify concomitant treatment that 
may be considered COVID-19 rescue therapy. 


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Mean number of days on COVID-19 rescue treatment within 15 days after enrollment will be 
tabulated by treatment group.  The difference in the least-squares mean and their standard errors 
adjusted for stratification factors, baseline WHO Ordinal Scale for Clinical Improvement score, 
and number of co-existing conditions will be tabulated.  Corresponding 95% confidence interval 
of the difference between two least-squares means and p-value will also be reported. 
Participants who do not require any COVID-19 rescue treatment during the study will be 
excluded from the analysis of this endpoint. 
7.5.3 Duration of COVID-19 Symptoms 
Subjective symptoms assessed by the investigators to be potentially due to COVID-19, including 
fever, cough (productive or non-productive), sore throat, malaise, headache, muscle pain, 
gastrointestinal symptoms (i.e., nausea, vomiting, or diarrhea), shortness of breath (with or 
without exertion), and respiratory distress will be captured and followed up until resolution. 
Duration (in days) to resolution of subjective COVID-19 symptoms will be defined as:  
End date of last COVID-19 symptom  Start date of first COVID-19 symptom+1. 
Participants who did not have resolution of COVID-19 symptoms are censored at date of 
completion/withdrawal. Kaplan-Meier curves will be constructed to duration of COVID-19 
symptoms for participants in each treatment group.  The curves will be constructed in a manner 
similar to the primary efficacy endpoint (Section 7.4).  Median duration of COVID-19 symptoms 
and corresponding 95% confidence interval will be presented for each treatment group. 
7.5.4 Progression of COVID-19 
The table below describes the criteria FDA adapted for severe and critical COVID-19: 
Severity 
Criteria 
Severe 
Development of one of the following: 
1. Symptoms suggestive of severe illness, which could include any 
symptom of moderate illness PLUS shortness of breath at rest or 
respiratory distress, OR 
2. Clinical signs indicative of severe systemic illness with COVID-19, 
per min, SpO2 
 
No criteria for Critical Severity 
Critical 
Evidence of critical illness, defined by at least 1 of the following: 
1. Respiratory failure requiring at least 1 of the following:  


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a.
Endotracheal intubation and mechanical ventilation, oxygen 
delivered by high flow nasal cannula (heated, humidified, 
oxygen delivered via reinforced nasal cannula at flow rates >20 
 
b. Noninvasive positive pressure ventilation (NIPPV), OR 
c. Extracorporeal membrane oxygenation (ECMO) or clinical 
diagnosis of respiratory failure (i.e., clinical need for 1 of the 
preceding therapies, but preceding therapies not able to be 
administered in setting of resource limitation) 
2. Shock (defined by systolic blood pressure (BP) <90 mm Hg, or diastolic 
BP <60 mm Hg or requiring vasopressors), OR 
3. Multi-organ dysfunction/failure 
The proportion of participants whose COVID-19 infection progresses to Severe or Critical at 
Day 15 along with the corresponding 95% binomial confidence interval will be reported by 
treatment group.  Sample size permitting, reported binomial confidence intervals will be based 
number of 
Severe or Critical COVID-19 infection be small, the exact distribution will be used instead of the 
normal approximation to derive the confidence intervals. 
7.5.5 ICU Admission 
The number and proportion of participants requiring ICU admission at any time within the first 
15 days after enrollment will be tabulated by treatment group and Baseline WHO Ordinal Scale 
for Clinical Improvement score.  The corresponding 95% binomial confidence interval will also 
be reported.  Sample size permitting, Wilson
intervals.  The difference in proportions will also be reported with the corresponding 95% 
small, the exact distribution will be used instead of the normal approximation to derive the 
confidence intervals. 
Participants who did not get admitted to ICU will not contribute to this analysis 
7.5.6 Sequential Organ Failure Assessment (SOFA) Score 
The Sequential Organ Failure Assessment (SOFA) will be administered for all participants who 
Appendix 
B.2).  For participants who get discharged from ICU before Day 8 or Day 15, their last available 
SOFA score will be carried forward to Day 8 or Day 15, respectively. 


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Mean observed and mean change from baseline in SOFA score at Days 8 and 15 will be 
tabulated by treatment group.  Additionally, the difference in the least-squares means and their 
standard errors adjusted for baseline SOFA score, stratification factors, WHO Ordinal Scale for 
Clinical Improvement score, and number of co-existing conditions will be tabulated.  
Corresponding 95% confidence interval of the difference between two least-squares means will 
also be reported. 
Participants who did not get admitted to ICU will not contribute to this analysis. 
7.5.7 Oxygen and Assisted Ventilation 
Number and proportion of participants requiring each of the following on Days 8 and 15 will be 
tabulated by treatment group: 
 Supplemental oxygen only: This is defined as nasal cannula and oxygen level 1-15 L/min 
or 
, or simple facemask, or non-rebreather 
 High-flow nasal cannula (HFNC) oxygen: This is defined as nasal cannula and oxygen 
level>15L/min or FiO2>40% and up to 100%. 
 Noninvasive positive pressure ventilation (NIPPV): This is defined as non-invasive 
CPAP or non-invasive - BIPAP 
Mechanical ventilation: This is defined as invasive  mechanical PPV, invasive  
negative pressure, or invasive ECMO 
Each proportion will be analyzed in a way similar to the analysis of proportion of participants 
requiring ICU Admission in Section 7.5.5.  Additionally, the proportion of subjects requiring any 
of the above will also be analyzed. 
Mean number of days on mechanical ventilation within 15 days after enrollment and mean 
number of oxygenation-free days within 15 days after enrollment will be tabulated by treatment 
group.  Participants who are not off mechanical ventilation are censored at date of 
completion/withdrawal. Participants without requiring oxygenation within 15 days after 
enrollment are censored at Day 15 or date of completion/withdrawal, whichever is earlier. 
Sample size permitting, these endpoints will be compared in a way similar to the analysis of the 
Duration of COVID-19 Symptoms in Section 7.5.3. 
7.5.8 WHO Ordinal Scale for Clinical Improvement 
Number and proportion of participants who achieve a score of 1 on the WHO Ordinal Scale for 
Clinical Improvement on Days 8 and 15 will be tabulated by treatment group and Baseline WHO 
Ordinal Scale and compared in a way similar to the analysis of ICU Admissions in Section 7.5.5. 


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The corresponding 95% binomial confidence interval will also be reported. Sample size 
e these confidence intervals. The difference in 
proportions will also be reported with the corresponding 95% confidence interval using 
will be used instead of the normal approximation to derive the confidence intervals. 
Similarly, the number and proportion of participants who achieve 2-point improvement from 
baseline in the WHO Ordinal Scale for Clinical Improvement on Days 8 and 15 will be analyzed 
based on Full Analysis Set.  Median number of days to a 2-point improvement will be tabulated 
by treatment group and compared in a way similar to the analysis of duration of COVID-19 
symptoms in Section 7.5.3. The same analysis will be provided in the Safety Analysis Set. 
7.5.9 Thromboembolic Events 
All adverse events will be reviewed in a blinded fashion prior to the database lock by team 
members with appropriate background and training.  The team will identify adverse events with 
an onset date within 15 days after enrollment that may be considered thromboembolic. 
Incidence and severity of thromboembolic events will be tabulated by treatment group and 
compared in a way similar to the analysis of ICU Admissions in Section 7.5.5. 
7.5.10 Inflammation Markers Associated with Acute Respiratory Distress Syndrome (ARDS) 
The following inflammation markers associated with acute respiratory distress syndrome will be 
analyzed at a central lab: CRP, IL-6, TF, MCP-1, and IP-10.  An inflammation marker is 
considered abnormal if the reported value is > ULN. 
Incidence of abnormal inflammation markers at Day 8 will be tabulated by treatment group and 
compared in a way similar to the analysis of ICU Admissions in Section 7.5.5. 
7.5.11 Viral Dynamics 
Observed mean and mean change in log-transformed viral load from baseline on Days 1, 4, 8, 15, 
and 28 will be tabulated by treatment group and compared similar to the analysis of the SOFA 
score in Section 7.5.6. 
Time-to-viral load undetectable (i.e., <LOD) by nasopharyngeal swab is defined as the number 
of days from randomization to achieving undetectable viral load.  That is: 
(Date/Time to Undetectable Nasopharyngeal Swap  Date/Time of Randomization)/24. 
Participants who are lost to follow-up or ended study early prior to achieve Undetectable 
Nasopharyngeal Swap will be censored at the day of the last obtained assessment. Median 


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number of days to undetectable will be tabulated by treatment group and compared in a way 
similar to the analysis of duration of COVID-19 symptoms in Section 7.5.3. 
7.6 
Safety Endpoints 
Safety data will be summarized descriptively.  No inferential statistics will be provided.  All 
safety analyses and summaries will be based on the Safety analysis set. 
7.6.1 Adverse Events 
Treatment-emergent adverse events reported during the study will be coded using a MedDRA 
dictionary.  Incidence of treatment-emergent adverse events will be summarized by treatment 
group and the following:  
 
Preferred term 
 
System organ class and preferred term. 
These summaries will be presented for the following subsets: 
 
All adverse events 
 
Serious adverse events 
 
Drug-related adverse events 
 
All adverse events with severity Grade 3 
 
All adverse events leading to death 
 
All adverse events leading to study treatment discontinuation. 
A participant with multiple occurrences of the same adverse event or a continuing adverse event 
will only be counted once for tables reporting adverse events by preferred term and system organ 
class. 
For tables reporting adverse events by severity, if a participant has multiple occurrences of an 
adverse event with the same organ class and preferred term, the most severe event will be 
presented.  Adverse events with missing severity will be imputed to Grade 3.  Additionally, for 
tables reporting adverse events by relationship, if a participant has multiple occurrences of an 
adverse event with the same organ class and preferred term, only the strongest relationship level 
will be presented in the relationship summary.  Adverse events with missing relationship will be 
imputed as drug-related.  Details on the treatment of missing data are provided in Section 11.2. 
7.6.2 Clinical Laboratory Evaluation  
Laboratory parameters will be summarized by treatment group at each visit.  Each summary will 
include the values of the laboratory parameters and their change from baseline.  Shift tables from 
baseline will be presented for laboratory values in the chemistry and hematology panels that are 
captured categorically.  Parameters will be classified as potentially clinically significant 
according to the criteria described in Appendix C. In addition, the laboratory results will be 


Protocol ANA001-001 
 
Statistical Analysis Plan v1.0 
19 
graded by CTCAE v5.0 and the summary of treatment-emergent laboratory results by highest 
CTCAE grade will be summarized. 
7.6.3 Vital Signs 
Vital signs, including pulse, blood pressure, temperature, respiratory rate and body weight will 
be summarized by treatment group and time point. For each assessment of vital signs, change 
and percent change in vital signs from baseline will be summarized by treatment group. 
8. 
VISIT WINDOW 
Implementation of visit windows is not planned for the analysis of this study.  Results will be 
analyzed according to reported visits. 
9. 
MULTIPLICITY ADJUSTMENT 
There are no plans to implement any adjustment to type-I error for Part 1 analyses as the primary 
endpoint is safety. 
10. 
HANDLING OF MISSING DATA 
10.1 
Missing Efficacy Data 
Missing data for the secondary efficacy endpoint is discussed in Section 7.4.  Limited imputation 
of missing data is planned for exploratory efficacy endpoints. 
10.2 
Adverse Events Missing Data 
Treatment-emergent adverse events (TEAEs) with missing severity will be considered Grade 3 
and TEAEs with missing relationship will be counted as drug-related. 
In cases where the start date is not complete, the assumption will be made that the adverse event 
is a treatment-emergent event unless there is evidence to the contrary.  The first treatment start 
date will be used as the AE start date if the start date is missing.  Missing adverse event end dates 
will not be imputed.  The adverse event will be assumed to be ongoing if end date is missing. 
10.3 
Concomitant Medications Missing Dates 
In cases where the start or stop dates are not complete, the assumption will be made that the 
medication is a concomitant medication unless there is evidence to the contrary.  
If the year and month are available (and only day is missing) the first day of the month will be 
used to impute the start date, and the last day of the month will be used to impute the stop date.  
If only the year is available and it is before the year of first study treatment date, January will be 
used to impute the start date and December will be used to impute the stop date. If the year is 
equal to the year of the first study treatment date, month and day of the first study treatment date 


Protocol ANA001-001 
 
Statistical Analysis Plan v1.0 
20 
will be used to impute the start date, and month of the last study treatment date will be used to 
impute the stop date.  
If the start or stop date is completely missing, the first study treatment date will be used to 
impute the start date, and the last study treatment date to impute the stop date.  
Imputed dates will be used for categorization of medications to concomitant or prior, but data 
listings will present the date as recorded on the Case Report Forms. 
 


Protocol ANA001-001
Statistical Analysis Plan
21 
APPENDIX A. 
SCHEDULE OF EVENTS (STUDY PART 1 AND STUDY PART 2) 
Study Day  
(All Study Days are calendar days) 
Screeninga 
Day 1 
Day 2b 
Day 3b 
Day 4 
Day 5b 
Day 6b 
Day 7b 
Day 8/ETs 
Day 15 
Day 28 
Day 60/ESb 
Window 
36 hoursa 
 
 
 
 
 
 
 
 
±3 days 
+2 days 
+2 days 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
Eligibility assessment 
X 
 
 
 
 
 
 
 
 
 
 
 
Medical historyc 
X 
 
 
 
 
 
 
 
 
 
 
 
Height and weight for BMId 
 
X 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
NEWS2e,n, vital signs, COVID-19 
severity and subjective symptoms 
of COVID-19 n 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Record SpO2 and supplemental 
oxygen, and type of ventilation, if 
applicablee,f 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Complete physical examination 
(excluding GU) 
 
X 
 
 
 
 
 
 
X 
 
 
 
Targeted physical examination 
X 
 
 
 
 
 
 
 
 
 
 
 
Study drug administrationg 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Serum chemistryh, p 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Hematology and coagulationi, p 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
D-dimers (central lab) j 
 
X 
 
 
X 
 
 
 
X 
 
 
 
CRP (central lab) j 
 
X 
 
 
X 
 
 
 
X 
 
 
 
Cardiac troponin (central lab) j 
 
X 
 
 
X 
 
 
 
X 
 
 
 
LDH (central lab) j 
 
X 
 
 
X 
 
 
 
X 
 
 
 
Ferritin (central lab) j 
 
X 
 
 
X 
 
 
 
X 
 
 
 
NP swab for confirmation of 
SARS-CoV-2 with RT-PCRk 
(local site lab) 
X 
Per local SOC 


Protocol ANA001-001
Statistical Analysis Plan
22 
Window 
36 hoursa 
 
 
 
 
 
 
 
 
±3 days 
+2 days 
+2 days 
NP swab for confirmation of 
SARS-CoV-2 with qRT-PCR k 
(central lab) 
 
X 
 
 
X 
 
 
 
X 
X 
X 
 
PK sampling l (Part 1 Only) 
 
X 
 
 
 
 
 
 
 
WHO Ordinal Scale for Clinical 
Improvemente,m 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Chest X-ray 
Per local SOC 
AE assessmente 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medicationse,r 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
SOFAe,o 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Blood for exploratory tests j (e.g., 
IL-6, Tissue Factor, MCP-1 and 
IP-10) 
 
X 
 
 
 
 
 
 
X 
 
 
 
Serum pregnancy test for females 
of childbearing potential 
X 
 
 
 
 
 
 
 
 
 
 
 
a 
Screening assessment are to be completed within 36 hours of randomization. Screening and Day 1 may occur on the same day if results are available to confirm 
participant eligibility (SARS-CoV-2-positive NP swab confirmed with RT-PCR or alternative Sponsor approved assay at screening). 
b 
It may not be possible to conduct all study visits in-person due to quarantine and other infection control measures. In case where in-person visits are not possible, 
telemedicine appointments should be conducted. All visits are required to be conducted as in-person visits (due to sample collection requirements) except for Days 2, 3, 
5 ,6, and 7 (if discharged home with study drug for self-administration) and the EOS/Day 60 (+2) visit which may be conducted by a telemedicine appointment. For 
telemedicine appointments, all data should be collected, and the following should be reviewed/discussed in detail with the participant: AEs, clinical status, and hospital 
readmission. 
c 
Any history or current presence of signs and symptoms associated with COVID-19 within 14 days prior to screening, including fever, cough (productive or non-
productive), sore throat, malaise, headache, muscle pain, gastrointestinal symptoms (i.e., nausea, vomiting, or diarrhea), shortness of breath (with or without exertion), 
and respiratory distress. Other medical history within 14 days prior to enrollment and presence of comorbidities especially cardiovascular disease, pulmonary disease 
(e.g., COPD, asthma), hypertension, diabetes, and obesity, is to be recorded. 
d 
If the participant is unable to be measured for weight and height, stated weight and height is acceptable. 
e 
Assessments should be collected daily while hospitalized including any day after Day 8 that the patient remains in the hospital. NEWS2 (Appendix 2) score to be 
assessed 2 to 6 hours post-first dose per day. If first dose assessments are missed, use the same collection timepoint post-second dose of the day (2-6 hours post-dose). 
f 
If mechanically ventilated (or ECMO), document PaO2 and FiO2. SpO2 and any supplemental oxygen saturation and rate at SpO2 determination timepoint; also, any 
noninvasive ventilation (No, yes; if yes, designate type). For intubated patients, record PaO2 and FiO2 values of the worst P-F ratio of the calendar day. 
 
 


Protocol ANA001-001
Statistical Analysis Plan
23 
g 
Dosing should be performed within 36 hours of screening and continue until the treatment course is completed. Study drug is to be administered for 7 consecutive days 
(defined as 14 doses administered BID). ANA001 or matching placebo should be taken with a meal. If the participant is ventilated, study drug may be administered via 
NG or OG tube. Please refer to the Pharmacy Manual for instructions for NG or OG administration. Total duration of study drug administration is a 7-day course of 
treatment. 
h 
Chemistry labs to be collected pre-dose (prior to first study drug dose of the day) and include the following: BUN, creatinine, sodium, potassium, chloride, carbon 
dioxide, glucose, direct bilirubin, total bilirubin, ALP, AST, and ALT 
i 
Hematology and coagulation samples will be collected prior to first study drug dose of the day and include a CBC (consisting of hemoglobin, hematocrit, total WBC 
count with 5-part differential, and platelet count) plus a partial thromboplastin time (aPTT), a thrombin time (PT), and an international normalized ratio (INR). 
j 
Test sample is for central lab assessment. Additionally, a central lab blood sample for each participant and timepoint collected will be stored for possible virology testing 
(e.g., genotypic resistance testing). 
k 
NP swab for assessment of viral load is to be obtained at the indicated timepoints. Laboratory-confirmed SARS-CoV-2 infection as determined by RT-PCR, or other 
Sponsor approved assay used by the investigational site is to be obtained at Screening prior to baseline (Day 1). If a positive RT-PCR result for SARS-CoV-2 was 
collected as part of SOC during the study screening window, the result may be used to fulfill the applicable inclusion criteria. Quantitative assessment of viral load by 
qRT-PCR will be performed by an external central lab. Please refer Central Laboratory Manual for sample collection instructions. NP swab may be collected at any time 
during the day. 
l 
PK samples will be collected for Part 1 ONLY. Blood samples (Primary and Back-Up) for PK are to be collected either on Day 1, 2, 3, or Day 4 at pre-dose (i.e., within 
30 minutes), 1 hour (+/- 30 minutes) , 4 hour (+/- 30 minutes), 8 hour (+/- 30 minutes) and pre-dose to next study drug (i.e., within 30 minutes) administration. Remaining 
blood plasma volume may be used for exploratory analyses (e.g., IL-6 and TF). Please refer to the Central Laboratory Manual for additional sample collection and 
processing instructions (Appendix 6). 
m 
Appendix 1 summarizes the criteria for daily WHO Ordinal Scale for Clinical Improvement score. The WHO Ordinal Scale for Clinical Improvement score should be 
determined concomitantly with the NEWS2 variables. Assessments should be collected daily while hospitalized including any day after Day 8 that the patient remains 
in the hospital. 
n 
Appendix 2 summarizes the criteria for NEWS2. The parameters (e.g., vital signs, SpO2, oxygen requirement) used to determine the NEWS2 score will be entered into 
the eCRF. Concurrently with determination of NEWS2, vital signs (including: pulse, respiratory rate, blood pressure (systolic and diastolic), and temperature), severity 
-19 infection (based on criteria in Appendix 4), and subjective clinical signs and symptoms of COVID-19 will be assessed and include 
presence or absence of: fever, cough (productive or non-productive), sore throat, malaise, headache, muscle pain, gastrointestinal symptoms (i.e., nausea, vomiting, or 
diarrhea), shortness of breath (with or without exertion), and respiratory distress. Assessments should be collected daily while hospitalized including any day after 
Day 8 that the patient remains in the hospital. 
o 
Appendix 3 summarizes the criteria for SOFA score. SOFA score to be calculated only for participants admitted to the ICU. 
p 
Appendix 5 summarizes Laboratory Assessments. 
q 
Appendix 6 summarizes PK Sample Collection Schedule (Part 1 Only). 
r 
All prescription and over-the-counter systemic (i.e., oral, intravenous, intramuscular, inhaled, subcutaneous, or systemically absorbed transdermal) medications being 
administered or being taken by the participant from prior to randomization (considered prior medications) and from randomization through the Day 60 visit (considered 
concomitant medications). For this study, all enteral nutrition and administration of blood products will also be considered as medication. 
s 
Assessments (including NEWS2, vital signs, severity of COVID-19, subjective symptoms of COVID-19, SpO2, WHO Ordinal Scale for Clinical Improvement, AEs, 
concomitant medications, and SOFA score, should be collected daily while hospitalized including any day after Day 8 that the patient remains in the hospital. Results 
will be collected on an Unscheduled Visit eCRF. 
 
 


Protocol ANA001-001 
 
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APPENDIX B. 
QUESTIONNAIRE SCORING 
B.1 
NATIONAL EARLY WARNING SCORE 2 (NEWS2) 
The NEWS-2 is based on a simple aggregate scoring system in which a score is allocated to 
physiological measurements when participants present to, or are being monitored in hospital.  
Six simple physiological parameters form the basis of the scoring system: 
 Respiration Rate (0  3) 
 Oxygen Saturation (0  3) 
 Systolic Blood Pressure (0  3) 
 Pulse Rate (0  3) 
 Level of consciousness or new confusion (0  3) 
 Temperature (0  3) 
 
 
A score is allocated to each parameter as they are measured, with the magnitude of the score 
reflecting how extremely the parameter varies from the norm. The score is then aggregated and 
uplifted by 2 points for people requiring supplemental oxygen to maintain their recommended 
oxygen saturation.  The higher the NEWS, the more critical is the state of the participant. 
 
 


Protocol ANA001-001 
 
Statistical Analysis Plan v1.0 
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B.2 
SEQUENTIAL ORGAN FAILURE ASSESSMENT (SOFA) SCORE 
The SOFA score is based on a simple aggregate scoring system in which a score is allocated to 
the following six simple physiological parameters: 
 Respiration (0  4) 
 Coagulation (0  4) 
 Liver (0  4) 
 Cardiovascular (0  4) 
 Central Nervous System (0  4) 
 Renal (0  4) 
 
SOFA score 
0 
1 
2 
3 
4 
Respirationa 
 PaO2/FIO2 (mm Hg) 
>400 
301  400 
201  300 
101  200 
 
  
 
 
 
 
 
Coagulation 
 Platelets (×103/mm3) 
>150 
101  150 
51  100 
21  50 
 
Liver 
 Bilirubin (mg/dL) 
<1.2 
1.2  1.9 
2.0  5.9 
6.0  11.9 
 
Cardiovascularb 
 Hypotension 
None 
MAP <70 
mmHg 
or dobutamine 
(any dose) a 
Dopamine >5 
Dopamine >15
Central Nervous System
 Glasgow Coma Score 
 
13  14 
10  12 
6  9 
<6 
Renal
Creatinine (mg/dL) 
or urine output (mL/d) 
<1.2 
1.2  1.9 
2.0  3.4 
3.5  4.9 
or <500 
>5.0 
or <200 
 
FIO2, fraction of inspired oxygen; PaO2, partial pressure of oxygen; MAP, mean arterial pressure; SaO2, peripheral arterial oxygen saturation 
a 
 
A score is allocated to each parameter as they are measured, with the magnitude of the score 
reflecting how extremely the parameter varies from the norm. The score is then aggregated.  The 
higher the SOFA score, the more critical is the state of the participant. 
 
 


Protocol ANA001-001 
 
Statistical Analysis Plan v1.0 
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APPENDIX C. 
POTENTIALLY CLINICALLY SIGNIFICANT LABORATORY 
CRITERIA 
Local Laboratory 
Parameter 
SI Unit 
Lower 
Limit 
Higher 
Limit 
% Decrease 
from BSL 
% Increase 
from BSL 
CHEMISTRY 
Blood urea nitrogen (BUN) 
mmol/L 
NA 
>1.5*ULN 
NA 
>100 
Creatinine 
mg/dL 
NA 
>1.5*ULN 
NA 
>50 
Sodium 
mmol/L 
<0.85*LLN 
>1.1*ULN 
>10 
>10 
Potassium 
mol/L 
<0.8*LLN 
>1.2*ULN 
>20 
>20 
Chloride 
mmol/L 
<0.8*LLN 
>1.2*ULN 
>20 
>20 
Carbon dioxide (Bicarbonate) 
 
<0.7*LLN 
>1.3*ULN 
>40 
>40 
Glucose 
mmol/L 
<0.6*LLN 
>3.0*ULN 
>40 
>200 
Total bilirubin 
mg/dL 
NA 
>2.5*ULN 
NA 
>150 
Direct bilirubin 
mg/dL 
NA 
>1.5*ULN 
NA 
>150 
Alkaline Phosphatase 
U/L 
<0.5*LLN 
>2.0*ULN 
>80 
>100 
Aspartate Aminotransferase (AST) 
U/L 
NA 
>3.0*ULN 
NA 
>200 
Alanine Aminotransferase (ALT) 
U/L 
NA 
>3.0*ULN 
NA 
>200 
HEMATOLOGY 
Hematocrit 
Ratio 
<0.8*LLN 
>1.3*ULN 
>20 
>30 
Hemoglobin 
g/L 
<0.8*LLN 
>1.3*ULN 
>20 
>30 
Platelet Count 
109/L 
<0.65*LLN 
>1.5*ULN 
>50 
>100 
White Blood Cell Count 
109/L 
<0.65*LLN 
>1.6*ULN 
>60 
>100 
Neutrophils, absolute cell count 
109/L 
<0.65*LLN 
>1.6*ULN 
>75 
>100 
Lymphocytes, absolute count 
109/L 
<0.25*LLN 
>1.5*ULN 
>75 
>100 
Eosinophils, absolute count 
109/L 
NA 
>4.0*ULN 
NA 
>300 
Monocytes, absolute count 
109/L 
NA 
>4.0*ULN 
NA 
>300 


Protocol ANA001-001 
 
Statistical Analysis Plan v1.0 
27 
Basophils, absolute count 
109/L 
NA 
>4.0*ULN 
NA 
>300 
COAGULATION 
Partial thromboplastin time (aPTT) 
sec 
<0.5*LLN 
>2.0*ULN 
>100 
>100 
Prothrombin time (PT) 
sec 
<0.5*LLN 
>2.0*ULN 
>100 
>100 
International normalized ratio 
(INR) 
Ratio 
<0.5*LLN 
>2.0*ULN 
>100 
>100 
LLN:  Lower limit of normal value provided by the local laboratory 
ULN: Upper limit of normal value provided by the local laboratory 
BSL: Baseline 
 
 


Protocol ANA001-001 
 
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Central Laboratory Results 
Parameter 
SI Unit 
Lower 
Limit 
Higher 
Limit 
% Decrease 
from BSL 
% Increase 
from BSL 
ADDITIONAL TESTING 
D-Dimer 
ng/mL 
NA 
>1.0*ULN 
NA 
>20 
Cardiac troponin 
ng/mL 
NA 
>1.0*ULN 
NA 
>30 
Ferritin 
ng/mL 
NA 
>1.2*ULN 
NA 
>30 
LDH 
U/L 
<0.4*LLN 
>4.0*ULN 
>60 
>300 
CRP 
mg/dL 
<1.0*ULN 
>1.3*ULN 
>80 
>50 
LLN:  Lower limit of normal value provided by the local laboratory 
ULN: Upper limit of normal value provided by the local laboratory 
BSL: Baseline