Clinical trial NCT04399356
Conditions: COVID-19
Keywords: SARS-CoV-2 Coronavirus Treatment Pill Telehealth Viral shedding
Sponsor: Tufts Medical Center
Start date: 2020-10-01; Completion date: 2021-08-19
Enrollment: 73 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study will evaluate the antihelmintic drug, Niclosamide, as a potential treatment for mild to moderate coronavirus disease 2019 (COVID-19).

Detailed description:
Niclosamide, which has potent antiviral activity against single-stranded RNA viruses including coronaviruses, was proposed as an antiviral during the Severe Acute Respiratory Syndrome (SARS) outbreak in 2002 and has activity including Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) where it was found to inhibit SARS coronavirus, SARS-CoV, in in vitro studies and similarly structured RNA viruses (both in vitro and in vivo). The investigators hypothesize that the antiviral activity of Niclosamide may be extended to COVID-19.

Arms: arm 1: Participants in the treatment arm will receive Niclosamide 2 grams orally on day 1 and daily for 6 more days (total 7 days of treatment) arm 2: Participants in the control group will receive identical-appearing placebo by mouth in the same numbers of pills on day 1 and daily for 6 more days (total 7 days of treatment)
Interventions: intervention 1: Niclosamide intervention 2: Placebo intervention 3: Telehealth monitoring
Intervention descriptions: intervention 1: Participants in the treatment arm will receive Niclosamide 2 grams orally once daily for 7 days in addition to current standard of care treatment. Oropharyngeal swab samples will be collected for viral shedding as measured by PCR on days 3, 7, 10, 14. Fecal samples will be collected for viral shedding as measured by PCR on days 3, 7, 10, 14, 21. A baseline fecal and oropharyngeal sample will be obtained on Day 1 prior to starting dosing of Niclosamide/ placebo. intervention 2: The collection of oropharyngeal samples will be observed by a Study Team member via the telehealth platform. intervention 3: In addition to Niclosamide or placebo treatments, all enrolled patients will be provided a home thermometer as well as a fingertip probe pulse oximeter, with the specific instructions to monitor both temperature at oxygen saturation at the time of daily oral administration of drug. The collection of oropharyngeal samples will be directly observed by a Study Team member via the telehealth platform.

Protocol documents:
SAP_002.pdf: 
1 
 
Statistical analysis plan -- Niclosamide for Patients with Mild to Moderate Disease 
from Novel Coronavirus (COVID-19) 
Clinicaltrials.gov NCT04399356 
SAP version 1, August 10, 2021 based on protocol version 8.0, February 2021 
SAP contributors 
Ludovic Trinquart 
Lori Lyn Price 
 


2 
 
Background and rationale 
 
Therapeutic approaches are needed to improve outcomes in patients with COVID-19. Niclosamide is an 
oral anthelminthic drug primarily used to treat parasitic infections. However niclosamide may have 
broad clinical applications to treat diseases other than those caused by parasites. Niclosamide has 
potent antiviral activity against single-stranded RNA viruses including coronaviruses. It was proposed as 
an antiviral during the SARS outbreak in 2002. It was found to inhibit SARS coronavirus, SARS-CoV, in in 
vitro studies and similarly structured RNA viruses (both in vitro and in vivo). Niclosamide has antiviral 
properties for similarly structured pathogenic viruses, including Zika virus, adenovirus, dengue, and 
chikungunya virus.  
Because the drug is inexpensive and has few if any side effects, taking Niclosamide prophylactically 
might help to prevent COVID-19 spreading. Even if this treatment does not completely eradicate 
infection, niclosamide treatment may help to decrease viral load, thereby allowing the host immune 
system to better combat the disease. 
Objectives 
 
Primary Objective: To evaluate the efficacy of niclosamide in shortening contagious period as 
determined by time to viral clearance. 
Secondary Objectives: To evaluate the efficacy of niclosamide on symptoms and progression to severe 
COVID-19.  
Study Methods 
Trial design 
The trial is a single-center, randomized, parallel-group, placebo-controlled trial. Treatment allocation 
was a 1:1 ratio. Patients were randomized to either niclosamide (2 grams orally once daily for 7 days) or 
matched placebo control. 
Randomization 
The random allocation sequence was computer-generated by a biostatistician. Randomization was 
stratified into three strata: Tufts lab and non-Tufts lab. We used blocking (block size 4). The random 
allocation sequence was implemented into the Redcap Electronic Data Capture (EDC) system which 
guaranteed concealment of the sequence until treatments were assigned. 
Sample size 
For the primary efficacy endpoint of respiratory virologic clearance at Day 3 measured by oropharyngeal 
viral shedding, 40 participants in each group achieve 89.1% power to detect a difference between the 
group proportions of 35%. We assumed that 50% and 15% of participants in the niclosamide and 
placebo groups would have a negative test on Day 3. The calculation was under a two-sided Fisher's 
Exact Test and a significance level of 0.05. 
Framework 
For all objectives, we test for superiority of niclosamide against placebo. 
Statistical interim analyses and stopping guidance 
We did not plan or perform any interim analyses. 
The trial was closed to recruitment on June 22, 2021 due to the effective ending of the COVID-19 
epidemic in Massachusetts resulting in lack of available candidates.   


3 
 
Timing of final analysis 
Final analysis will take place in one stage, when every patient has reached 30-day follow-up and data for 
the primary and secondary endpoints have been received and cleaned. 
Timing of outcome assessments, including visit windows 
Primary efficacy endpoint: respiratory viral clearance at Day 3. 
Secondary efficacy endpoints 
• Fecal viral clearance at Day 14. 
• Reduction in viral shedding as measured by oropharyngeal swab on days, 3, 7, 10, 14. 
• Reduction in fecal viral shedding as measured by fecal PCR on days, 3, 7, 10, 14 and 21.  
• Progression to severe COVID. 
• Resolution of symptoms (including but not limited to fever, cough, fatigue). 
Statistical principles 
Confidence intervals and P values 
All statistical tests will be 2-sided and will be performed using a 5% significance level. We will derive 95% 
two-sided confidence intervals. 
Adherence and protocol deviations 
In this study, four pills are to be taken daily for 7 days. Compliance is assessed by the percentage of 
subjects who have taken the scheduled number of pills:  
% compliance = 100x (number of pills taken / 28 pills supposed to have been taken). 
We will summarize compliance by randomization group: mean % compliance as well as number and 
percentage of participants with more than 80% compliance (24 pills out of 28). 
Similarly, we will assess compliance with oropharyngeal and fecal sampling. 
Protocol deviations will be classified into: 
• PCR > 3 days before randomization   
• taking the first dose before the first telehealth visit 
• missing at least 1 telehealth visit 
• collecting at least one oropharyngeal sample outside of window (day 1, 3, 7, 10, 14 ±1 day) 
• collecting at least one fecal sample outside of window (day, 1, 3, 7, 10, 14, 21 ±1 day) 
• collecting less than 5 oropharyngeal samples 
• collecting less than 6 fecal samples 
• taking the wrong dose at least once 
• taking the wrong dose at least once 
• missing a dose at least once 
• expected assessments not completed during at least one telehealth visit (e.g., physician disconnected) 
Protocol deviations were classified prior to unblinding of treatment assignment. We will report detailed 
protocol deviations per participant. We will summarize the number and percentage of participants with 
protocol deviations by treatment group with details of type of deviation.   
Analysis populations 
We will exclude participants who withdrew consent after randomization but before taking any sample or 
pill. 
The intention-to-treat (ITT) population will include all randomized patients according to the treatment 
they were randomized to receive.  


4 
 
The per-protocol population will a subset of the participants in the full analysis (ITT) set who took at 
least 80% of study intervention. 
The modified ITT population will include participants who took at least one pill, have a positive 
oropharyngeal test result on Day 1 and have Day 3 oropharyngeal sample results available for analysis.  
The safety population will include participants who took at least one pill.  
Trial population 
Screening, eligibility, recruitment, and withdrawal/follow-up 
We will use a CONSORT flow diagram to summarize the number of participants who were: 
• assessed for eligibility at screening 
• eligible at screening 
• eligible and randomized 
• withdrew prior to received first dose 
• randomized and included in the primary analysis 
The flow diagram will also show the numbers who were eligible but not randomized, who did not 
receive the randomized allocation, who were lost to follow-up, who discontinued the intervention, and 
we will describe the reasons. 
Baseline patient characteristics 
Participants will be described at the time of randomization with respect to age, sex, race/ethnicity, 
COVID-19 symptoms, smoking, obesity/overweight, asthma, COPD, cancer, cerebrovascular disease, 
CKD, cystic fibrosis, heart conditions, hypertension, immunocompromised state, liver disease, neurologic 
conditions, pulmonary fibrosis, sickle cell disease, thalassemia, diabetes, both overall and separately for 
the two randomization groups. We will summarize categorical data by numbers and percentages. We 
will summarize continuous data by mean, SD (or median, Q1-Q3 if data are skewed). We will not 
undertake tests of statistical significance. We will note the clinical importance of any imbalance. 
Analysis 
Outcome definitions 
Viral clearance 
Respiratory viral clearance is defined as the first day a participant’s oropharyngeal sample result is 
negative, provided that none of the subsequent oropharyngeal sample results are positive. In primary 
analyses, we will use sample results (positive or negative) as returned by Diagnostic Solutions 
Laboratory. We will use a similar definition for fecal viral clearance. We will calculate the time to 
clearance since Day 1. 
If a participant has several samples on the same day, we will consider the result to be positive if at least 
one of the sample results is positive, and negative otherwise. 
In table 1, we illustrate possible patterns of time to viral clearance and time post-viral clearance. We 
illustrate samples available on days per protocol. But, according to our definition of clearance, time to 
clearance and time post-clearance are identifiable even if samples taken on different days. 
Table 1: Patterns of sample results and time to viral clearance 
Day 1 
Day 3 
Day 7 
Day 10 
Day 14 
Clearance 
vs. 
censored 
Time to 
clearance 
Time post-
clearance 


5 
 
+ 
+ 
+ 
- 
- 
1 
10 
4 
- 
- 
- 
- 
- 
1 
1 
13 
- 
+ 
- 
+ 
+ 
0 
14 
0 
- 
+ 
- 
- 
- 
1 
7 
7 
 
In absence of deviations from protocol, we expect oropharyngeal sample results on 5 distinct days (day 
1, 3, 7, 10, 14) and fecal sample on 6 distinct days (day 1, 3, 7, 10, 14, 21). Some participants may have 
samples on less than 5 or 6 distinct days. We will identify the occurrence of viral clearance as defined 
above based on available samples. If clearance is not observed, we will censor participants at their last 
available sample.  In Table 2, we illustrate possible patterns of non-available sample results. 
Table 2: Patterns of days without sample result available and time to viral clearance 
Day 1 
Day 3 
Day 7 
Day 10 
Day 14 
Clearance 
vs. 
censored 
Time to 
clearance 
Time post-
clearance 
+ 
+ 
NA 
- 
- 
1 
10 
4 
- 
- 
- 
NA 
NA 
1 
1 
6 
- 
+ 
- 
+ 
NA 
0 
10 
0 
- 
+ 
NA 
- 
- 
1 
10 
4 
NA: not available. 
Analysis methods 
Primary analysis 
The primary endpoint is viral clearance in respiratory samples at day 3. The primary analysis will be 
based on the ITT population (i.e., all randomized participants). We will estimate the cumulative 
probability of being in clearance in each randomization group by using the Kaplan-Meier estimator. We 
will compare the cumulative probability of clearance at day 3 between the two groups by using a chi-
square test based on a log(− log(·)) transformation for the survival function.[Klein et al. Statist. Med. 
2007; 26:4505-4519]. 
𝜒2 =
{log (−log (Ŝ1(t))) −log (−log (Ŝ0(t)))}
2
𝜎̂1(𝑡)2
log (Ŝ1(t))
2 +
𝜎̂0(𝑡)2
log (Ŝ0(t))
2
 
Under the null hypothesis of no difference in probability of being in clearance between the two groups, 
the statistic of test is asymptotically χ12-distributed. We will provide the between-group difference in 
probability of viral clearance at day 3 and the associated 95% confidence interval based on the cloglog 
transformation of the survival function. 
Secondary analyses 
In secondary analyses,  


6 
 
1) We will compare the respiratory clearance probability functions from day 1 to 14 between the 
two groups by using a log-rank test.  
2) We will calculate the area under each respiratory clearance-free probability curve which gives 
the mean time to viral clearance up to day 14. We will estimate the mean difference in time 
post-viral clearance between groups and the associated 95% confidence interval. 
3) We will compare how the proportion of negative oropharyngeal sample results evolved over 
time between treatment groups by using random-intercepts logistic regression models for 
longitudinal binary outcome data. 
4) We will repeat the primary analysis for fecal viral clearance at day 14. 
5) We will repeat the secondary analyses 1)-3) above for fecal viral clearance. 
6) We will repeat the primary and secondary analysis by considering the combined oropharyngeal 
and/or fecal sample results. If both types of samples are available on a given day, we will 
consider the result to be positive if at least one of the sample results is positive, and negative 
otherwise. If only one type of sample is available on a given day and it is positive (respectively 
negative), the result will be positive (negative) for that day. 
7) We will compare the proportion of participants who progressed to severe COVID disease 
between groups.  
8) We will compare the proportions of participants free of symptoms. We will include participants 
who reported symptoms on Day 1 and we will assess the time to symptom resolution (symptom 
no longer reported). We will analyze 8 symptom categories described in Table 3. 
9) We will repeat the primary and secondary analyses for viral clearance in the mITT population. 
10) We will repeat the primary and secondary analyses for viral clearance in the per protocol 
population. 
 
Subgroup analyses  
We pre-specified subgroup analyses of viral clearance and symptom resolution according to BMI (<25 
kg/m2 vs. ≥25 kg/m2) and according to diabetes. 
Exploratory analyses 
In exploratory analyses, we will repeat the primary and secondary analyses of viral clearance by 
calculating the time to viral clearance from the confirmatory PCR before randomization. 
Moreover, in an analysis blinded to random allocation, we will analyze the trajectories of oropharyngeal 
and fecal sample results. In particular, we will identify participants with a negative test result followed 
by at least one positive test result (as defined by the DSL COVID-19 Assay); we will examine the Ct values 
of the positive test results following a negative test result. We will repeat the primary and secondary 
analyses by considering alternative thresholds to define a positive result, based on the blinded review of 
data. 
We also will perform longitudinal analyses to assess the between-group difference in gene expression 
over time. For each participant and each sample, we will calculate the difference in expression (in terms 
of quantification cycle) between the target gene (SARS-CoV-2 specific nucleocapsid N1; panspecific CoV 
nucleocapsid N3; or SARS-CoV-2 spike) and a reference gene (RNase P): ΔCq= Cq(target 
gene)−Cq(reference gene). We will create spaghetti plots in each randomization group with lowess 
smoother curve superimposed. We will create heatmaps of ΔCq values scaled to the mean and standard 
deviation within each participant. We will use linear mixed models, including a term for the group, a 
term for time, and group x time interaction term and a subject-level random intercept, to compare the 
trajectories in normalized expression between groups over time.  


7 
 
Data will include a number of non-detects, i.e. reactions lacking a Cq value. Missing Cq value can 
correspond to a true Cq value above the Cq threshold. Alternatively it can correspond to zero expression 
(no amplification above the Cq threshold). Or it can correspond to a failure to detect a true Cq value 
below the Cq threshold. We will account for non-detects by setting undetermined Cq values at 40. In 
sensitivity analyses, we will account for non-detects by using hot deck imputation. 
We will also consider the following modified ITT analyses of viral clearance: 
- for the analysis based on oropharyngeal samples, fecal samples, and both types, we will include 
participants who took at least one pill, have a positive test result at any time during the trial and have 
Day 3 sample results available for analysis. 
- for the analysis based on fecal samples, we will include participants who took at least one pill, have a 
positive oropharyngeal test result and have Day 3 fecal sample results available for analysis. 
Missing data 
For the longitudinal analyses, we will perform sensitivity analyses by imputing data according to 
sequential multiple imputation 
Harms 
The number (and percentage) of patients experiencing each adverse event will be presented, both for 
the overall safety population and in each randomization group. We will not perform statistical testing. 
We will assess the clinical significance of the differences. Adverse events will include abdominal pain, 
congestion or runny nose, cough, diarrhea, dizziness, dyspnea, fatigue, fever or chills, headaches, 
hypoxia, loss of appetite, muscle or body aches, nausea, new loss of taste or smell, pruritus, shortness of 
breath/difficulty breathing, skin rash, sore throat, vomiting, and other. 
Statistical software 
The analysis will be carried out by using SAS and R. 
 


8 
 
Table 3: Classification of symptoms into 8 categories 
1.Central nervous system 
Dizziness 
Fatigue 
Headache 
2.Upper gastrointestinal 
Appetite change 
Nausea  
Vomiting 
3.Lower gastrointestinal 
Abdominal pain 
Diarrhea 
4.Ear, nose, throat 
Sore throat 
Congestion 
Loss of taste/smell 
5.Respiratory/Pulmonary 
Cough 
Dyspnea/Shortness of breath 
Hypoxia 
6.Musculoskeletal 
Muscle aches 
Dermatologic 
Rash 
Pruritus 
7.Systemic 
Fever/Chills 
8.Other 
 

Prot_000.pdf: 
 
 
 
 
 
 
 
 
 
 
 
Niclosamide for Patients with Mild to Moderate Disease  
from Novel Coronavirus (COVID-19) 
Principal Investigator: Harry Selker, MD 
 01202021  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
Summary of Changes from Previous Version: 
 
Affected 
Section(s) 
Summary of Revisions Made 
Rationale 
Protocol Title  
Addition of asymptomatic patients  
1. FDA 
recommendation 
Study Synopsis  
Addition of Day 21 fecal specimen, 
addition of asymptomatic 
participants, addition of Wellforce 
and Clinical Research Network 
(CRN) sites for recruitment. 
Study duration 2 months, study 
completion 4 months  
1. FDA 
recommendation 
2. Recruitment 
optimization 
3. Decreased 
numbers of daily 
COVD positive 
patients 
Section 3.0 
Objectives and 
endpoints  
The primary objective of this study 
is to determine if a course of 
treatment with niclosamide 
improves respiratory viral clearance 
compared to treatment with 
placebo. 
1. Viral shedding 
endpoint 
Section 4.0 
Study design  
Reduction in fecal viral shedding as 
measured by fecal PCR on days, 3, 
7, 10, 14. Day 21 fecal specimen 
added. 
1. FDA 
recommendation  
Section 4.3  
Justification of 
Dose  
Additional literature and 
background added  
1. FDA 
recommendation  
Section 5.1 
Inclusion 
Criteria 
Physical assessment data removed.  
No need for oxygen 
supplementation added. 
 
1.  Virtual 
recruitment  
5.2 Exclusion 
Criteria  
 
Systemic treatments removed as 
exclusion.   
1. FDA 
recommendation 
5.3 Lifestyle 
considerations  
 
Advisement to avoid alcohol added  
 
1. FDA 
recommendation 
5.5 Strategies 
for recruitment 
and retention 
 
1. Updates to include Wellforce 
and CRN sites  
2. Twenty-dollar ($20) ClinCard 
payment at each specimen 
collection timepoint 
3. Update to recruitment with 
community outreach, study 
information distribution and 
nurses script 
 
1. Recruitment 
enhancement  
2. Time and effort of 
participants for 
specimen 
collection 


 
 
 
6.1.1. Study 
Intervention 
 
Day 21 fecal specimen added 
Additional data on oropharyngeal 
specimen collection added  
 
1. FDA 
recommendation 
6.2.2 
Formulation, 
Appearance, 
Packaging and 
Labeling 
 
Study drug specific information 
added as provided by Bayer 
Pharmaceuticals  
 
1. Updated as per 
IND 
6.2.3 and 6.2.4 
Product storage 
and preparation 
 
Changed to blister packaging  
 
1. Updated as per 
IND 
7.2 Participant 
discontinuation/ 
withdrawal 
from study 
 
Revised  
 
1. FDA 
recommendation 
8.1 Efficacy 
assessments 
 
Baseline and screening (Day 0) 
Record COVID symptoms, if 
symptomatic 
Record number of days since onset 
of symptoms, if symptomatic  
Follow-up Evaluation  
• Collect temperature and oximetry 
data daily, with the caveat that if 
O2 goes below 92%, an addition 
oximeter reading should be taken 2 
hours later.  ADDED:  If the follow-
up O2 saturation remains below 
92%, the participant will be referred 
to their Primary Care Physician 
(PCP) or to the local Emergency 
Department  
•Collect fecal samples for viral 
shedding Day 21 added  
Early Termination/Hospitalization    
1. FDA 
recommendation 


 
A 30-day follow-up call and AE 
assessment for those patients who 
are hospitalized will be performed. 
 
 
8.3.7 Reporting 
of pregnancy 
 
Additional information added re: 
pregnancy and breast feeding  
 
1. FDA 
recommendation 
10.1.6  Safety 
Oversight  
 
Independent Safety Monitor and 
stopping rules added  
 
1. FDA 
recommendation 
4.1 Overall 
Study Design 
 
Addition of affiliate site recruitment 
detail 
1. Reliance 
affiliate 
1.1 Study 
Synopsis 
Primary endpoint change 
1. Primary Efficacy 
Endpoint: 
Respiratory viral 
clearance at Day 
3.  
 
1.2 Schedule of 
activities 
Addition of +/1 1-day windows 
1. Increase options for 
participant study 
visits  
 
4.1 Overall 
study design 
 
Increase sample size to n=200 
 
1. The current 
positivity rate on 
Day 1 of ~40% 
results in ITT 
sample size of 200.   
 
5.1 Exclusion 
Criteria 
Add:  History of receipt of COVID-19 
vaccine  
1. Potential effect of 
vaccine on viral 
shedding 
5.2 Strategies 
for Recruitment 
Added: Newton Wellesley Hospital, 
Maine Medical Center and New 
1. Agreed to 
distribute study 
brochures and 
posters 


 
 
England Quality Care Alliance 
(NEQCA) 
6.1 Study 
Intervention  
Removed: Transport by courier 
service to the Tufts Medical Center  
Telemedicine Platform 
Removed: Amwell 
Added: A HIPPA compliant 
telehealth platform; e.g., Doximity, 
will be used to conduct remote 
study visits. 
Added: COVID positive list 
generated twice daily 
1. No contact FedEx 
pickup/  delivery 
to CLIA certified 
lab  
2. Doximity platform 
used  
 
9.1 Statistical 
Hypothesis 
Sample size calculation revision 
1. Sample size 
increase 
9.2 Sample Size 
Determination  
Revised  
1. Increase d 
sample size 
9.3 Populations 
for analysis 
Modified Intention-to-Treat 
Analysis Dataset modified 
1. Sample size 
increase 
9.4 Statistical 
Analysis 
Revised analysis of the primary 
endpoint 
1. Sample size 
increase 


  
Table of Contents 
STATEMENT OF COMPLIANCE ............................................................................................................................. 1 
1 
PROTOCOL SUMMARY ............................................................................................................................... 1 
1.1 
Synopsis ................................................................................................................................................ 1 
SchemA 
3 
1.2 
Schedule of Activities (SoA) ............................................................................................................... 4 
2 
INTRODUCTION ............................................................................................................................................ 5 
2.1 
Study Rationale .................................................................................................................................... 5 
2.2 
Background........................................................................................................................................... 6 
2.3 
Risk/Benefit Assessment .................................................................................................................... 7 
2.3.1 
Known Potential Risks ..................................................................................................... 7 
2.3.2 
Known Potential Benefits ................................................................................................ 7 
2.3.3 
Assessment of Potential Risks and Benefits ................................................................ 8 
3 
OBJECTIVES AND ENDPOINTS ................................................................................................................ 8 
4 
STUDY DESIGN ............................................................................................................................................. 9 
4.1 
Overall Design ...................................................................................................................................... 9 
4.2 
Scientific Rationale for Study Design.............................................................................................. 10 
4.3 
Justification for Dose ......................................................................................................................... 10 
4.4 
End of Study Definition ..................................................................................................................... 11 
5 
STUDY POPULATIOn ................................................................................................................................. 12 
5.1 
Inclusion Criteria ................................................................................................................................ 12 
5.2 
Exclusion Criteria ............................................................................................................................... 12 
5.3 
Lifestyle Considerations .................................................................................................................... 12 
5.4 
Screen Failures .................................................................................................................................. 12 
5.5 
Strategies for Recruitment and Retention ...................................................................................... 13 
6 
STUDY INTERVENTION ............................................................................................................................ 13 
6.1 
Study Intervention(s) Administration ............................................................................................... 13 
6.1.1 
Study Intervention Description ..................................................................................... 13 
6.1.2 
Dosing and Administration ............................................................................................ 15 
6.2 
Preparation/Handling/Storage/Accountability ................................................................................ 15 
6.2.1 
Acquisition and accountability ...................................................................................... 15 
6.2.2 
Formulation, Appearance, Packaging, and Labeling ................................................ 16 
6.2.3 
Product Storage and Stability ....................................................................................... 16 
6.2.4 
Preparation ...................................................................................................................... 16 
6.3 
Measures to Minimize Bias: Randomization and Blinding ........................................................... 16 
6.4 
Study Intervention Compliance ........................................................................................................ 17 
6.5 
Concomitant Therapy ........................................................................................................................ 17 
6.5.1 
Rescue Medicine ............................................................................................................ 17 
7 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAl. .................................................................................................................... 18 
7.1 
Discontinuation of Study Intervention ............................................................................................. 18 
7.2 
Participant Discontinuation/Withdrawal from the Study ............................................................... 18 
7.3 
Lost to Follow-Up ............................................................................................................................... 19 
8 
STUDY ASSESSMENTS AND PROCEDURES ..................................................................................... 19 
8.1 
Efficacy Assessments ....................................................................................................................... 19 
8.2 
Safety and Other Assessments ....................................................................................................... 21 
8.3 
Adverse Events and Serious Adverse Events ............................................................................... 21 


  
8.3.1 
Classification of an Adverse Event. ............................................................................. 22 
8.3.2 
Time Period and Frequency for Event Assessment and Follow-Up ....................... 23 
8.3.3 
Adverse Event Reporting .............................................................................................. 23 
8.3.4 
Serious Adverse Event Reporting ............................................................................... 24 
8.3.5 
Reporting Events to Participants ................................................................................. 24 
8.3.6 
Events of Special Interest ............................................................................................. 24 
8.3.7 
Reporting of Pregnancy ................................................................................................ 24 
8.4 
Unanticipated Problems .................................................................................................................... 24 
8.4.1 
Definition of Unanticipated Problems (UP):................................................................ 24 
8.4.2 
Unanticipated Problem Reporting ................................................................................ 25 
8.4.3 
Reporting Unanticipated Problems to Participants ................................................... 25 
9 
STATISTICAL CONSIDERATIONS .......................................................................................................... 25 
9.1 
Statistical Hypotheses ....................................................................................................................... 25 
9.2 
Sample Size Determination .............................................................................................................. 25 
9.3 
Populations for Analyses .................................................................................................................. 26 
9.4 
Statistical Analyses............................................................................................................................ 26 
9.4.1 
General Approach .......................................................................................................... 26 
9.4.2 
Analysis of the Secondary Endpoint(s) ....................................................................... 27 
9.4.3 
Safety Analyses .............................................................................................................. 27 
9.4.4 
Baseline Descriptive Statistics ..................................................................................... 27 
9.4.5 
Planned Interim Analyses ............................................................................................. 28 
9.4.6 
Sub-Group Analyses ..................................................................................................... 28 
9.4.7 
Tabulation of Individual participant Data .................................................................... 28 
9.4.8 
Exploratory Analyses ..................................................................................................... 28 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS .............................. 28 
10.1 
Regulatory, Ethical, and Study Oversight Considerations. .......................................................... 28 
10.1.1 
Informed Consent Process ........................................................................................... 28 
10.1.2 
Study Discontinuation and Closure ............................................................................. 30 
10.1.3 
Confidentiality and Privacy ........................................................................................... 30 
10.1.4 
Future Use of Data ......................................................................................................... 31 
10.1.5 
Key Roles and Study Governance .............................................................................. 31 
10.1.6 
Safety Oversight ............................................................................................................. 32 
10.1.7 
Clinical Monitoring .......................................................................................................... 33 
10.1.8 
Quality Assurance and Quality Control ....................................................................... 34 
10.1.9 
Data Handling and Record Keeping. ........................................................................... 34 
10.1.10 
Protocol Deviations ........................................................................................................ 35 
10.1.11 
Publication and Data Sharing Policy ........................................................................... 35 
10.1.12 
Conflict of Interest Policy .............................................................................................. 35 
10.2 
Additional Considerations ................................................................................................................. 36 
10.3 
Abbreviations ...................................................................................................................................... 37 
10.4 
Protocol Amendment History ........................................................................................................... 39 
11 
REFERENCES ............................................................................................................................................. 40 
 


NIC for COVID  
Version 7.0  
Protocol 00000605 
Selker PI 
01022021 
NIH-FDA Clinical Trial Protocol Template – v1.0 7 Apr 2017 
 
1 
STATEMENT OF COMPLIANCE 
The trial will be carried out in accordance with International Conference on Harmonisation Good Clinical 
Practice (ICH GCP) and the following:  
• 
United States (US) Code of Federal Regulations (CFR) applicable to clinical studies (45 CFR 
Part 46, 21 CFR Part 50, 21 CFR Part 56, 21 CFR Part 312, and/or 21 CFR Part 812)  
 
National Institutes of Health (NIH)-funded investigators and clinical trial site staff who are responsible 
for the conduct, management, or oversight of NIH-funded clinical trials have completed Human Subjects 
Protection and ICH GCP Training. 
 
The protocol, informed consent form(s), recruitment materials, and all participant materials will be 
submitted to the Institutional Review Board (IRB) for review and approval.  Approval of both the 
protocol and the consent form must be obtained before any participant is enrolled.  Any amendment to 
the protocol will require review and approval by the IRB before the changes are implemented to the 
study.  In addition, all changes to the consent form will be IRB-approved; a determination will be made 
regarding whether a new consent needs to be obtained from participants who provided consent, using a 
previously approved consent form. 
1 
 
PROTOCOL SUMMARY 
1.1 
SYNOPSIS  
Title: 
Niclosamide for Patients with Mild to Moderate Disease from Novel 
Coronavirus (COVID-19) 
 
Study 
Description: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
This study will evaluate the antihelmintic drug, niclosamide, as a potential 
treatment for mild to moderate coronavirus disease 2019 (COVID-19).  
Niclosamide, which has potent antiviral activity against single-stranded RNA 
viruses including coronaviruses, was proposed as an antiviral during the SARS 
outbreak in 2002 and has activity including SARS-CoV-2 where it was found to 
inhibit SARS coronavirus, SARS-CoV, in in vitro studies and similarly structured 
RNA viruses (both in vitro and in vivo).  We hypothesize that the antiviral activity 
of Niclosamide may be extended to COVID-19. 
Objectives:   
 
 
Primary Objective: To evaluate the efficacy of niclosamide in shortening 
contagious period as determined by time to viral clearance. 


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 
Secondary Objectives:  To evaluate the efficacy of niclosamide in mitigating 
clinical outcomes and shortening duration of symptoms resulting from 
COVID-19 infection. 
 
 
Endpoints:                 
Primary Efficacy Endpoint: Respiratory viral clearance at Day 3.  
 
Secondary Efficacy Endpoints:   
 
Fecal viral clearance at Day 14. 
 
Reduction in viral shedding as measured by oropharyngeal swab on days 
1, 3, 7, 10, 14 
 
Reduction in fecal viral shedding as measured by fecal PCR on days 1, 3, 
7, 10, 14, 21  
 
Progression to severe COVID, as a composite endpoint defined as O2 
saturation <92% on room air in two consecutive measurements at least 2 
hours apart OR requirement of hospitalization OR need for artificial 
ventilation OR death. 
 
Time to resolution of fever 
Safety endpoint: incidence of Adverse Events (AEs)  
Study Population: 
 
Patients 18 years of age or older who are COVID-19 (SARS-CoV-2) positive by PCR 
who are asymptomatic or have mild to moderate symptoms of COVID infection. 
 
 
Phase: 
Phase II 
Description of 
Sites/Facilities  
 
Enrolling 
Participants: 
 
Study participants will be recruited for participation from Tufts Medical Center, 
Wellforce and Clinical Research Network (CRN) sites.   
 
Participants will be identified as those reporting to Tufts Medical Center, 
Wellforce and CRN sites for outpatient COVID-19 testing.  Patients with SARS-
CoV-2 positive test results will be provided the option to participate in our study. 
The Study Team will enroll and randomize patients into the study after the 
patient has a confirmed positive test result and meets all the inclusion and none 
of the exclusion criteria.   
 
Additional sites and/or social media may be used to enhance recruitment. The 
study will be listed at www.clinicaltrials.gov. 
 
 
Description of 
Study 
Intervention: 
Participants in the treatment arm will receive niclosamide 2 grams orally once 
daily for 7 days in addition to current standard of care treatment.  Those in the 
control group will receive placebo by mouth in the same numbers of pills on day 
1 and daily for 6 more days (total 7 days of treatment) in addition to current 
standard of care treatment.  Fecal samples and oropharyngeal swab samples will 
be collected for viral shedding as measured by PCR on days 3, 7, 10, 14 and 21 
(fecal sample only).  A baseline fecal and oropharyngeal sample will be obtained 
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Study Duration: 
The study is estimated to complete enrollment within 2-months of initiation of 
enrollment; however, enrollment will remain open until the study goal is met. 
The duration of the entire project is anticipated to be a maximum of 4 months. 
 
 
Participant 
Duration: 
Individual participant will complete all participant visits within 30 days.  Adverse 
events will be monitored and collected by the Study Team from the point of 
signed consent until 7 (for non-serious adverse events) or 30 days (for serious 
adverse events) after the last day of study participation.   
SCHEMA 
 
 
 


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1.2 
SCHEDULE OF ACTIVITIES (SOA) 
 
 
Screen 
& 
Baseline 
Day 0 
Treat 
Day 1 
 
+/- 1 day 
Treat 
Day 2 
 
+/- 1 day 
Treat 
Day 3 
 
+/- 1 
day 
Treat 
Days 4-6 
 
+/- 1 day 
Post-
Treatment 
Day 7 
 
+/- 1 day 
Post-
Treatment 
Day 10 
 
+/- 1 day 
Post-
Treatment 
Day 14 * 
 
+/- 1 day 
30-day 
Safety Call 
 
+/ - 1 Day  
 
 
Confirmed 
COVID-19 + test 
X 
 
 
 
 
 
 
 
 
Medical/ 
Social 
History 
(Demographics) 
 
X 
 
 
 
 
 
 
 
 
Inclusion/ 
Exclusion 
Criteria 
X 
 
 
 
 
 
 
 
 
Informed 
Consent 
X 
 
 
 
 
 
 
 
 
Assign Subject 
ID 
X 
 
 
 
 
 
 
 
 
Randomize 
X 
 
 
 
 
 
 
 
 
 
Initiation of Study 
Dose treatment 
group with 2g 
niclosamide or 
placebo 
 
X 
X 
X 
X 
 
 
 
 
Provide sample 
collection 
packet, 
thermometer, 
and finger-tip 
pulse oximetry  
 
X 
 
 
 
 
 
 
 
 
Participant reporting and sample collection 
AE reporting  
 
X 
X 
X 
X 
X 
X 
X 
X 
O2 & Temp 
reporting  
 
X 
X 
X 
X 
X 
X 
X 
X 


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* An additional AE assessment and fecal specimen will be collected at day 21 
 
 
2 
 
INTRODUCTION 
 
2.1 
STUDY RATIONALE  
The ongoing COVID-19 pandemic is an urgent public health crisis with few if any rapid and practical 
solutions.  The outbreak of COVID-19 has been declared to be a public health emergency of international 
concern by the World Health Organization (WHO), and the development of effective therapies for fast-
spreading fatal COVID-19 is in an urgent need. Given the seriousness and time-sensitive nature of this 
highly contagious virus, the medical and scientific communities must work quickly and efficiently to find 
a feasible way to address this global emergency.   
Niclosamide is an anthelminthic drug that has been widely used in humans to treat tapeworm infections 
for several decades and is currently listed on the WHO List of Essential Medicines, the safest and most 
effective medicines needed in a health system. There are no current proven treatments for COVID-19, 
and significant efforts are going toward developing novel therapeutics that have not been assessed for 
safety in humans.  There are a number of existing drugs prescribed for other indications that have 
demonstrated potent antiviral activity [1-3].  In a recent study, Niclosamide exhibited antiviral activity 
against SARS-CoV-2, the strain responsible for the current COVID-19 pandemic [3]. That niclosamide has 
already demonstrated efficacy in specifically inhibiting SARS-CoV-2 replication in vitro is incredibly 
promising.   
A recent study evaluated clinical samples from 73 hospitalized patients with SARS-CoV-2 infection. In 39 
of those patients, their fecal samples tested positive for SARS-CoV-2 RNA, with 17 of those patients 
remaining SARS-CoV-2-positive in feces after becoming negative in respiratory samples [29].  Taken 
together, this suggests that both the commonly accepted route of infection through the respiratory 
system as well as the GI tract are implicated in the pathogenesis of COVID-19-related disease 
manifestations.  
While severe acute respiratory syndrome (SARS) coronavirus 2, SARS-CoV-2-infected patients most 
commonly present with fever, tiredness and dry cough; a subset of these patients present with 
gastrointestinal (GI) issues [2]. Importantly, a recent study found that fecal viral shedding continues 
nearly 5 weeks after the last detection of SARS-CoV-2 RNA in respiratory samples, suggesting that the GI 
tract serves as a viral reservoir and allows for prolonged COVID-19 infection and transmission [4]. Given 
that SARS-CoV-2 is so highly contagious and can be easily spread by both respiratory droplets and fecal-
oral route [5], limiting its transmission is paramount to public health. These data suggest that there is a 
Oropharyngeal 
& fecal sample 
collection 
 
X 
(prior to 
dosing) 
 
X 
 
X 
X 
X 
 


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critical need to develop practical COVID-19 intervention strategies to treat SARS-CoV-2 infection and to 
prevent person-to-person transmission. 
Repurposing reliable and effective drugs for COVID-19 therapy is not only a safer strategy but will also 
allow for more rapid introduction into clinical practice.  For this reason, we propose to use the widely 
used antihelmintic drug, Niclosamide for treatment of COVID-19.  
2.2 
BACKGROUND  
SARS-CoV-2 has been shown to invade human tissues via the angiotensin converting enzyme II receptor 
(ACE2), which is highly expressed on cell types found in various tissues [30]. In a study to identify 
potential routes of infection for the SARS-CoV virus corresponding to the outbreak in China in 2002, a 
remarkable finding was the high surface expression of ACE2 protein on human lung alveolar epithelial 
cells and enterocytes, the simple columnar epithelial cells lining the inner surface of the small and large 
intestines[30].   
This is not the first time that this small molecule (niclosamide) has been proposed as a therapeutic for 
this specific application.  Shortly after the SARS outbreak in China in 2002-2003, niclosamide was tested 
for its potential use as an antiviral medication. Perhaps somewhat surprisingly, niclosamide was found 
to inhibit SARS coronavirus, SARS-CoV, in in vitro studies [14]. Later studies went on to evaluate its 
potential in combating coronavirus in vivo [31]. Fortunately, the SARS outbreak subsided rather quickly, 
and as a result, no future interventions were necessary.  
Multiple studies have studied the antiviral capacity of niclosamide in treating other similarly structured 
pathogenic viruses.  During the outbreak of the Zika virus (ZIKV), another positive-sense RNA-based virus 
similar to the coronavirus family, Niclosamide was again identified as a potential antiviral therapeutic, 
with ZIKV-inhibiting effects both in vitro [13] as well as in a humanized in vivo model of ZIKV-induced 
microcephaly [5]. Upon reviewing the literature, we found that niclosamide was also able to inhibit 
production of a variety of viral strains [4, 7, 8, 10-12, 15, 32], including adenovirus [10], dengue [4] and 
chikungunya virus [11]. Its mechanism of action in this capacity is to increase the pH within acidic 
endosomes of host cells, thereby inhibiting virus entry and release.  
In addition to its antihelmintic and antiviral properties, niclosamide has also demonstrated anti-bacterial 
[8, 33, 34], anti-inflammatory [16, 17] and anti-cancer activity [18, 19, 23, 33, 35-40]. Moreover, 
niclosamide has also shown promise for treating respiratory illness [14, 18, 20-22] even functioning as a 
bronchodilator in an in vivo mouse model of asthma [21, 22]. 
Niclosamide has demonstrated efficacy as a cancer therapeutic in both animal models [19, 36] as well as 
human clinical trials [23, 35] which suggests that in addition to potentially being efficacious in this anti-
COVID-19 capacity, Niclosamide is also likely to induce few complications as it is tolerated well even in 
immunocompromised cancer patients.   
In the current pandemic crisis, medical professionals are understandably focused more on stabilizing the 
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even in the uninfected), it would be monumental in terms of returning to normal life.  Because the drug 
is inexpensive and has few if any side effects, taking Niclosamide prophylactically might help to prevent 
COVID-19 spreading.  Even if this treatment does not completely eradicate infection, niclosamide 
treatment may help to decrease viral load, thereby allowing the host immune system to better combat 
the disease. 
2.3 
RISK/BENEFIT ASSESSMENT   
2.3.1 KNOWN POTENTIAL RISKS  
Niclosamide has been used since mid of the 1960s as an antihelmintic drug which inhibits glucose 
uptake, oxidative phosphorylation and anaerobic metabolism.  Niclosamide has few side effects and is 
known to be well tolerated even when applied over a long period [19]. Reported adverse effects of 
Niclosamide are mild and infrequent. This may include GI disturbances, lightheadedness, malaise, and 
pruritus. Alcohol may enhance the absorption of niclosamide, increasing the risk of side effects and 
therefore should be avoided when taking this drug.   
Pregnancy and breastfeeding are not exclusion criteria.  The FDA categorizes medications based on 
safety for use during pregnancy. Five categories - A, B, C, D, and X, are used to classify the possible risks 
to an unborn baby when a medication is taken during pregnancy. 
 
Niclosamide falls into category B: 
• There are no well-done studies that have been done in humans with Niclosamide. But in animal 
studies, pregnant animals were given this medication, and the babies did not show any medical issues 
related to this medication. 
• Studies in women suggest that this medication poses minimal risk to the infant when used during 
breastfeeding. 
2.3.2 KNOWN POTENTIAL BENEFITS  
 
Niclosamide is an oral medication that has been used to treat tapeworm infestations since 1960[6]. It is 
on the World Health Organization (WHO) List of Essential Medicines, the safest and most effective 
medicines needed in a health system [6]. In addition to its originally prescribed use, Niclosamide has 
been repurposed for a variety of clinical applications.  Niclosamide has demonstrated antiviral activity 
both in vitro and in vivo on a variety of single stranded RNA-based viral strains [4, 5, 7-13] and even 
SARS-CoV, a previous strain of coronavirus associated with the SARS outbreak in China in 2002[14]. Even 
more recently, Niclosamide was shown to inhibit SARS-CoV-2, the strain responsible for the current 
COVID-19 pandemic [3]. Its mechanism of action in this capacity is to increase the pH within acidic 
endosomes of host cells, thereby inhibiting virus entry and release [4, 11, 15]. In addition to its 
antihelmintic and antiviral properties, Niclosamide has also demonstrated anti-inflammatory activity 
[16, 17], and has shown promise for treating respiratory illness [18-20] even functioning as a 
bronchodilator in an in vivo mouse model of asthma [21, 22]. Furthermore, that Niclosamide has been 
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25] suggests that is likely to induce few complications as it is tolerated well even in 
immunocompromised cancer patients.   
 
2.3.3 ASSESSMENT OF POTENTIAL RISKS AND BENEFITS  
The primary goal is to maximize patient safety. To fulfill this goal, Tufts and the study team will take 
every measure to reduce patient risk of COVID-19-related complications, which includes the following: 
• Reduction of in-patient and outpatient face- to face visits to limit amount of exposure to 
patient and related populations 
• Use of a courier service to provide study materials and no pickup and delivery FedEx to obtain 
patient samples required for this study 
• Extensive patient screening prior to enrollment to ensure that all enrolled patients meet 
inclusion/exclusion criteria; more specifically to avoid enrollment of COVID-19 patients already 
severely ill due to this disease.  A screening and enrollment log will be maintained. 
There is no expectation of severe adverse outcomes or reactions due to a patient being treated with 
niclosamide.  Niclosamide is generally well tolerated and has been prescribed clinically for over 30 years.  
Reported AEs in current use are mild and include nausea and diarrhea. All participants will be given 
access to contact information of the Study Team, and any adverse reactions will be reported as required 
by the protocol.  
 
3 
OBJECTIVES AND ENDPOINTS 
 
The primary objective of this study is to determine if a course of treatment with niclosamide improves 
respiratory viral clearance compared to treatment with placebo. 
 
Secondary objectives include comparing the viral shedding from fecal samples and severity of clinical 
outcomes between treatment groups. 
 
Primary Efficacy Endpoint:  
 
Respiratory viral clearance at Day 3.  
 
Secondary Efficacy Endpoints:  
 
Fecal viral clearance at Day 14. 
 
Reduction in viral shedding as measured by oropharyngeal swab on days, 3, 7, 10, 14 
 
Reduction in fecal viral shedding as measured by fecal PCR on days, 3, 7, 10, 14 and 21  
 
Progression to severe COVID, as a composite endpoint defined as O2 saturation <92% on room 
air in two consecutive measurements at least 2 hours apart OR requirement of hospitalization 
OR need for artificial ventilation OR death. 
 
Time to resolution of fever 
Safety endpoint: incidence of AEs 
 


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4 
STUDY DESIGN  
4.1 
OVERALL DESIGN 
 
This is a double-blinded randomized controlled trial of 200  adult outpatients with mild to moderate 
symptoms of COVID-19 not requiring hospitalization.  Participants will be identified as those reporting to 
Tufts Medical Center seeking COVID-19 testing.  All patients will be provided the option to participate in 
our study pending a positive SARS-CoV-2 test result. The Study Team will enroll and randomize patients 
into the study after the patient has a confirmed positive test result and meets all the inclusion and none 
of the exclusion criteria.   
Participants in the treatment arm (n= 100) will receive niclosamide 2g orally daily for 7 days in addition 
to current standard of care treatment.  Those in the control group (n=100) will receive placebo by 
mouth in the same numbers of pills on day 1 and daily for 6 more days (total 7 days of treatment) in 
addition to current standard of care treatment.  
Laboratory PCR testing will be performed at Tufts Medical Center laboratory or other CLIA certified lab. 
Study participants will be recruited for participation from Tufts Medical Center. Associated sites at 
Newton-Wellesley Hospital, Melrose Wakefield and Lowell General Hospital as well as CRN sites will be 
included in recruitment and engaged as deemed necessary by the Study Team to ensure identification 
and reporting of maximum number of positive cases and prompt patient engagement/ enrollment.   
 
A study recruitment brochure will be distributed at the associated Wellforce and CRN sites.  A study 
poster will be available for affiliated outpatient sites that perform COVID testing.  Both will include a QR 
code for ease of accessing study information.  In addition, nurses who provide results to patients (by 
phone) who have tested positive at Tufts Medical Center outpatient will provide basic, scripted study 
information to potential participants.  This information will include contact information for the Study 
Team and has been submitted to the Tufts IRB.  Participation at Wellforce and CRN sites will be limited 
to distribution of study brochures and display of posters and (on a site by site basis) provision of PHI 
(name and contact phone number of potential participants who express interest in the study).  This 
information will be provided to the Tufts Study Team via a secure, encrypted message.   Revisions to the 
study brochure or any recruitment material will be provided to the site contact by the Tufts Study Team.   
No research activities will be conducted at the associated sites (e.g., informed consent, study visits, data 
collection, data entry, data analysis, etc.).  All study activity will be conducted by the Tufts Study Team.  
The Tufts Study Team will keep record of the site of origin for each enrolled study participant.  This de-
identified, aggregated recruitment data will be provided to each site as requested by the site.  
 
A study recruitment brochure will be distributed in the community.  A study poster will be available for 
affiliated outpatient sites that perform COVID testing.  Both will include a QR code for ease of accessing 
study information.  In addition, nurses who provide results to patients (by phone) who have tested 
positive will provide basic, scripted study information to potential participants.  This information will 
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Potential participants will initially be identified as those reporting to Tufts Medical Center, Wellforce or 
CRN outpatient.  The Study Team will enroll and randomize patients into the study after the patient has 
a confirmed positive test result and meets all the inclusion and none of the exclusion criteria.  
 
Participants who provide informed consent and meet all of the inclusion and none of the exclusion 
criteria will be randomized on Treatment Day 0 in a 1:1 ratio to either the Treatment Group or the 
Control Group, in accordance with a computer-generated schedule prepared by a biostatistician.  The 
randomization schedule will be incorporated into the REDCap Electronic Data Capture (EDC) system.  
Randomization will then be performed by study personnel directly in the EDC system.  Study personnel 
will be instructed not to randomize until participant has been confirmed to meet all inclusion/exclusion 
criteria on treatment day 0.  
 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN 
 
Randomized double-blind placebo control (RDBPC) studies provide the strongest possible evidence of 
causation.  Phase II trials are used to determine the efficacy and safety of an intervention in participants 
with the disease for which a new intervention is proposed.  Randomization in combination with blinding 
helps to avoid possible bias in the selection of participants, their assignment to an intervention or 
control, and the analysis of their response to the intervention.   
 
4.3 
JUSTIFICATION FOR DOSE 
The standard oral dosage of Niclosamide prescribed for Hymenolepis nana tapeworm infestation (e.g. 
adults—maximum of 2 grams/day for seven days) is clinically efficacious in this antiviral capacity. Based 
on previous antiviral studies of Niclosamide both in vitro and in vivo [5, 13, 14], the average required 
dosage to achieve antiviral activity is 1 uM, which corresponds to ~0.327 µg/ml. In a recent clinical trial 
to test efficacy of Niclosamide as an antimetastatic therapy [23, 24], clinicians found that upon oral 
intake, Niclosamide Cmax plasma level peaked to a median of 0.665 µg/ml ( ranging from 0.429 to 0.848 
µg/ml ), suggesting that traditional oral drug delivery should be sufficient to inhibit SARS-CoV-2 
production.  Repeated dosing is commonly used when treating an infection where viruses may (at the 
time of ingestion) be at various stages of attachment, invasion, and replication.   
Importantly, human infections with SARS-CoV-2 have demonstrated two known reservoirs of the virus.  
Viremia tends to be relatively uncommon, with viral replication largely occurring in the respiratory and 
gastrointestinal systems [37, 38]. The few cases in which SAR-CoV-2 titers are detectable in plasma have 
been reported in those patients already progressed to severe disease requiring hospitalization [39]. 
Plasma levels are limited both by oral absorption, but also by high plasma protein binding.  In Bayer 
simulations Cmax levels reaching almost 1200 nmol/l, or 1.2 uM is predicted.  There is 99% plasma 
protein binding.  Though free drug concentrations may not exceed the IC50 in plasma, we do not 
anticipate viral burden in the plasma to be a significant contributor to disease or spread of virus. 
While we firmly believe that standard oral delivery of Niclosamide will be sufficient to achieve anti-
COVID-19 activity, it is important to address certain issues previously posed with regard to the 


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pharmacokinetics of this drug. The inaugural publication describing studies of Niclosamide in human 
subjects reported that upon a single oral dose of 2g carbonyl-14C-labeled Niclosamide, up to 25% of 14C-
activity was detected in urine while the remainder was eliminated in feces[31] suggesting that 
Niclosamide may be preferentially sequestered in the GI tract. Other studies have also suggested a 
similar biodistribution of Niclosamide in the colon[34]. Oral delivery of Niclosamide in mice infected with 
an epidemic strain of Clostridium difficile, inhibited disease pathogenesis by targeting host mechanisms 
to prevent pathogen entry into intestinal epithelia without disrupting the endogenous gut 
microbiota[34]. With increasing insights emerging into the critical role of GI involvement in COVID-19 
severity and transmission, this potential sequestration of Niclosamide in the gut could likely be 
beneficial for both treatment strategies as well as prevention of transmission.   
The second major viral reservoir, the respiratory tract, may be a key site of activity for the niclosamide. 
Though lung tissue and epithelial lining fluid concentrations are not available, there is measurable 
activity in the respiratory tract.  In a transgenic mouse model of asthma, niclosamide treatment (13 
mg/kg/day) reduced mucus production, bronchoconstriction, and inflammation of airway tissues. 
Assuming the average human weighs approximately 62kg, our dosing strategy of 2g/day, is the 
equivalent of approximately 32mg/kg/day, which is significantly higher and likely to have similar effects. 
In addition, systemic delivery of niclosamide (20mg/kg) significantly enhanced efficacy of 
chemotherapeutic drugs in an in vivo mouse model of non-small cell lung cancer [40], further 
demonstrating that niclosamide can specifically target the lung in vivo. 
4.4 
END OF STUDY DEFINITION 
 
A participant is considered to have completed the study if he or she has completed all phases of the 
study including the last visit or the last scheduled procedure shown in the Schedule of Activities, Section 
1.2. 
 
Early Termination/Hospitalization 
All participants have the right to withdraw from study participation at any time during the study. If, for 
whatever reason, a participant withdraws from the study or is hospitalized for increased severity of 
COVID symptoms or other cause, an Early Termination Visit will be performed as deemed feasible by 
the PI or physician Investigator.   
 
Any AE, SAE or other medical condition or situation that occurs such that continued participation in the 
study would not be in the best interest of the participant will result in early termination.  
 
The following procedures will be performed at the Early Termination Visit: 
 
Assess for AEs 
 
Assess for complications following treatments 
 
Document all current medications, including medications over the counter and herbal 
medications 
 
Perform clinical assessment (as deemed feasible if hospitalized) 
 
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If clinical evaluation is deemed not feasible due to patient condition, the Study Team will collect as much 
of the Early Termination Visit data via the Electronic Medical Record as is available. 
 
5 
STUDY POPULATION 
5.1 
INCLUSION CRITERIA 
 
In order to be eligible to participate in this study, an individual must meet all the following criteria: 
• 
SARS-CoV-2 infection confirmed by PCR ≤ 3 days before randomization 
• 
Provision of informed consent 
• 
Stated willingness to comply with all study procedures and availability for the duration of the 
study  
• 
Male or female, over 18 years of age 
• 
No need for oxygen supplementation 
• 
No requirement for hospitalization at the time of enrollment 
• 
Ability to take oral medication and be willing to adhere to the Niclosamide/placebo regimen 
 
5.2 
EXCLUSION CRITERIA 
 
An individual who meets any of the following criteria will be excluded from participation in this study: 
• 
Known allergic reactions to components of the niclosamide 
• 
Participation in another trial or use of any experimental treatment for COVID-19, including 
chloroquine, hydroxychloroquine, remdesivir, and lopinapir/ritonavir  
• 
History of receipt of COVID-19 vaccine*  
• 
Current hospitalization or requiring hospital admission at screening 
 
* If a participant is enrolled in the study and then subsequently has an appointment for the COVID-19 
vaccine, they will remain on study and will be advised that they can keep their vaccine appointment. 
Vaccine administration will be noted and considered in the final data analysis. 
 
5.3 
LIFESTYLE CONSIDERATIONS 
 
No special preparations or additional steps (for example, special diets, fasting, other medicines, 
laxatives, or enemas) are necessary before, during, or immediately after taking niclosamide. Participants 
are advised to avoid alcohol consumption during the study treatment period. 
 
5.4 
SCREEN FAILURES 
 
Screen failures are defined as participants who consent to participate in the clinical trial but are not 
subsequently randomly assigned to the study intervention or entered in the study. A minimal set of 
screen failure information is required to ensure transparent reporting of screen failure participants, to 


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meet the Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities. Minimal information includes demography, screen 
failure details, eligibility criteria, and any SAE. 
 
5.5 
STRATEGIES FOR RECRUITMENT AND RETENTION 
 
Participants will be identified as those outpatients reporting to Tufts Medical Center, Wellforce or our 
CRN sites seeking COVID-19 testing. Any asymptomatic patient and those with mild to moderate COVID-
19 symptoms not requiring hospital admission or supplemental oxygen, will be provided the option to 
participate in our study once they have a reported positive SARS-CoV-2 test result.  Lowell General, St. 
Elizabeth’s, Newton Wellesley Hospital, Maine Medical Center and New England Quality Care Alliance 
(NEQCA) have agreed to distribute our study brochure at the time of testing at their drive thru testing 
and ambulatory locations. These sites will also be displaying our study poster (with QR code) in the ED, 
Primary Care clinics.  Additional Wellforce and CRN sites may be used to enhance recruitment.  Study 
brochures and promotional material will be given to potential participants at each of the testing sites 
including study team contact information.  The study brochure will be given to the patient at the time of 
COVID- 19 testing, by the testing site personnel. The participant will proactively contact the study team 
if interested in participation following a positive COVID-19 test.   
 
The Study Team will enroll and randomize patients meeting the above criteria into the study after the 
patient has a confirmed positive test result and meets all of the inclusion and none of the exclusion 
criteria.   
 
Tufts Community Health Improvement Program will incorporate the distribution of study material 
(brochure) with their general COVID-19 materials within the Chinatown community and residential 
towers.  The Tufts Medical Center (TMC) Symptom Clinic, staffed by TC registered nurses (RNs), will be 
contacting patients who test positive by phone. The RN will give a brief (scripted) overview of the study 
and contact information for the study team at the time of call to provide testing result.  
 
Social media will be used to enhance recruitment.  This study will be listed at www.clinicaltrials.gov. 
 
Participants will be offered twenty dollars ($20) for time and effort (via ClinCard) at each specimen 
collection timepoint (Days 1, 3, 7, 10, 14 and 21). 
 
All research activity including Informed Consent will be performed by Tufts Medical Center employees.   
 
6 
STUDY INTERVENTION 
6.1 
STUDY INTERVENTION(S) ADMINISTRATION 
 
6.1.1 STUDY INTERVENTION DESCRIPTION 
 


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Informed Consent will be obtained, all the inclusion and none of the exclusion criteria are met.   
 
In addition to niclosamide or placebo treatments, all enrolled patients will be provided a home 
thermometer as well as a fingertip probe pulse oximeter, with the specific instructions to monitor both 
temperature at oxygen saturation at the time of daily oral administration of drug.  The relatively low 
reported percentage of error for the finger probe supports that the finger probe is the modality of 
choice to measure intermittent oxygen saturation in the outpatient setting.   
 
Oropharyngeal and fecal swabs will be collected at days 1 (baseline), 3, 7, 10, and 14 of the study. An 
additional fecal specimen will be collected at day 21. In the case of oropharyngeal samples, care will be 
taken to ensure that sampling methods are consistent for each individual patient across all included 
timepoints, to limit any bias due to potential differences in viral load.   
 
Oropharyngeal collection is minimally invasive and can reliably be self-administered.  Recent research 
testing SARS-CoV-2 detection, nasopharyngeal and oropharyngeal (saliva) samples from confirmed                    
SARS-CoV-2 found that oropharyngeal yielded greater detection sensitivity and consistency throughout 
the course of infection. Less variability in self-sample collection was also found. This research 
demonstrated that oropharyngeal samples are a viable and more sensitive alternative to 
nasopharyngeal swabs and can enable at-home self-administered sample collection for accurate SARS-
CoV-2 testing [41, 42].  
 
The collection of oropharyngeal samples will be directly observed by a Study Team member via the 
telehealth platform.  The participant will open the viral transport kit and swab the back of the throat and 
tonsil area (avoiding mouth, teeth, and gums) and place to swab back into the vial.  For fecal specimen, 
the participant will swab feces from a plastic container (or wrap) placed on the toilet seat.  Printed 
instructions will be provided to each participant with detail on how to collect both the oropharyngeal 
and fecal specimens. These instructions will also be reviewed with the participant by a member of the 
Study Team. 
 
Once obtained, samples will be transported by no contact pickup and delivery FedEx  service to the Tufts 
Medical Center or CLIA- certified lab to prevent unnecessary hospital visits and to encourage compliance 
given the self-quarantine status of enrolled patients.    
 
Telemedicine Platform 
 
A HIPPA compliant telehealth platform; e.g., Doximity, will be used to conduct remote study visits. 
 
Twice daily a list of COVID-19 positive patients will be generated by the Tufts Medical Center lab and 
provided to the Study Team via a secure Tufts email account.  Upon receiving the COVID-19 positive test 
notification, COVID-19 positive participants will be approached remotely by a study Investigator for 
remote (telephone) Informed Consent.  Once consent is obtained, all the inclusion and none of the 
exclusion criteria are met, the study CRC will engage with the participant to enroll them in the telehealth 
platform and schedule the follow-up telehealth study appointments.   


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If the participant does not have a Smartphone, one will be provided to them along with the other study 
materials.   A prepaid USPS envelope with additional instructions will be provided to send the package 
through the USPS for return.  Participants will be guided thru the step-by-step telemedicine setup on 
their Smartphone by the study CRC.  Scripted guidance will be provided to the study CRCs to ensure that 
instructions provided to participants are consistent.  For example, included in the script, the study CRC 
will provide instruction in simple, easy to understand language such as, “I am going to take a minute and 
walk you through signing up for the app so you are ready on your visit date. “I’ve have actually gone 
ahead and scheduled the visit for you in the app”.  The app is navy blue, has a picture of a doctor with a 
stethoscope and lighter blue heart”.   Once set up, a reminder of the upcoming appointment will be sent 
to the participant via email and text message.   
 
Once the participant “checks- in” for their study visit, the CRC, investigator, or Study Team member will 
receive a notice that the participant is in the Waiting Room.  A family member or other support person 
of the participant’s choice can be included in any/all visits via Facetime.  More than one study team 
member can also join the appointment as needed or desired with the “Add Person” Facetime 
number/address.  Once the study team enters the Waiting Room, a split screen clearly displays the 
patient, support person and the study team member(s).    
6.1.2 DOSING AND ADMINISTRATION 
 
Participants eligible for the study will review and undergo informed consent at the time they receive 
confirmation of positive SARS-CoV-2 test result.  After obtaining consent, participants will be randomly 
assigned on a 1:1 basis to receive:   
 
 
Treatment Group blinded: Will receive niclosamide 2g orally daily for 7 days in addition to 
current standard of care  
 
Control Group blinded: Will receive placebo by mouth daily for 7 days in addition to current 
standard of care   
 
Niclosamide may be taken on an empty stomach (either 1 hour before or 2 hours after a meal). 
However, to prevent stomach upset, it is best taken after a light meal (for example, breakfast). 
Participants will be advised to avoid alcohol consumption during study treatment period. 
 
6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY    
6.2.1 ACQUISITION AND ACCOUNTABILITY 
 
In accordance with recent COVID-19 FDA Guidance, if scheduled visits at clinical sites are significantly 
impacted, certain IP, such as those that are typically distributed for self-administration, may be 
amenable to alternative secure delivery methods.   As such: 
 
Niclosamide and placebo (Investigational Product, IP) will be stored in the Tufts Medical Center 
Investigational Pharmacy.  Upon enrollment, the investigational pharmacy will package and dispense the 


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IP to the patient, along with the sampling kit.  The entire supply of study medication will be dispensed at 
one time.  It will be delivered to the subject via courier service.  Subjects will be asked to document 
compliance with study protocol in a subject diary.  If a subject does not use all the IP, the remainder 
shall be returned to the study investigators with the day 14 samples.  The IP will then be returned to the 
manufacturer or destroyed on site.  
 
Investigational new drug application (IND) submitted under section 505(i) of the Federal Food, Drug, and 
Cosmetic Act (FDCA) for Niclosamide chewable tablets, 500 mg has been approved:  FDA IND # 151423. 
 
Placebo manufacturer KABS Laboratories Inc. See Appendix A for manufacturing detail. 
 
 
6.2.2 FORMULATION, APPEARANCE, PACKAGING, AND LABELING 
 
Niclosamide will be provided as 500 mg chewable tablets.  They are gray-yellow round tablets with FE 
printed on one side and the “Bayer Cross” on the other side.  The excipients include: corn starch, talc, 
sodium lauryl sulphate, povidone, vanillin, magnesium stearate, saccharin sodium.  They will be 
provided in blister packages for ease of use and enhanced stability.  They will be labeled as “Niclosamide 
OR Placebo,” with adequate administration instructions prior to dispensing to subjects.   
 
6.2.3 PRODUCT STORAGE AND STABILITY 
 
Niclosamide and the placebo are oral tablets.  They can be stored at room temperature, 25°C (77°F) with 
excursions permitted to 15-30°C (59-86°F).  They will be dispensed in blinded blister packaging.   
 
6.2.4 PREPARATION 
There will be no significant preparation.  Both niclosamide and placebo tablets will be dispensed in 
blinded blister packages and labeled in accordance with state and federal regulation. 
6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING 
 
Participants who sign informed consent and meet all inclusion and exclusion criteria will be randomized 
on Treatment Day 0 in a 1:1 ratio to either the Treatment Group or the Control Group, in accordance 
with a computer-generated schedule prepared by a biostatistician.  The randomization schedule will be 
incorporated into the REDCap EDC system.  Randomization will then be performed by study personnel 
directly in the EDC system.  Study personnel will be instructed not to randomize until participant has 
been confirmed to meet all inclusion/exclusion criteria on treatment day 0. 
 
As all members of the Study Team will be blinded, Tufts Investigational Drug Services (IDS) will be 
unblinded and will dispense both the Niclosamide and placebo. The study intervention (niclosamide) 
and placebo will be packaged and as indistinguishable as possible.   
 


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Refer to Section 9, Statistical Considerations for sample size calculations. 
 
6.4 
STUDY INTERVENTION COMPLIANCE 
During the Baseline and Screening (Day 0), the Principal Investigator (PI) or a co-Investigator will review 
the study with the participant and obtain informed consent and Health Insurance Portability and 
Accountability Act of 1996 (HIPAA) authorization.  A second member of Study Team (e.g., the study 
Clinical research coordinator (CRC)) will serve as a witness to the informed consent.  After the informed 
consent is obtained, the participant will be assigned a unique enrollment number. The subject will then 
be randomized to treatment in EDC and provided blinded treatment (either Niclosamide or placebo) and 
other study materials via courier.  
On Treatment Day 1, a member of the Study Team or study CRC will review the dosing and schedule of 
Niclosamide/ placebo.   
• 
The patient will be instructed to record all doses in Study Drug Administration Diary 
• 
During each telehealth visit, the study CRC or other Study Team member will review the diary 
with the participant  
• 
The participant will be advised not to discard any study pill bottles 
• 
Baseline AEs, O2 saturation, temperature, oropharyngeal & fecal sample collection will be 
obtained 
 
Refer to the Section 1.2, Schedule of Activities.  
 
6.5 
CONCOMITANT THERAPY 
 
Concomitant therapies are any new or existing medications or therapy taken by the patient including:   
 
Drugs, including but not limited to, prescription, over the counter, birth control 
pills/patches/hormonal devices, and homeopathic preparations 
 
Nondrug therapies, including but not limited to, thermal/laser/radiation procedures, vitamins, 
herbal medicines/supplements. 
 
During the Screening process, information on all concomitant therapies, medications, and procedures 
will be recorded in the source documents and appropriate Case Report Form (CRF) along with the 
diagnosis or reason for use. Once the patient receives the first dose of study drug, recording of 
concomitant therapies will be limited to any new medication or modification of an existing medication 
taken for treatment of an AE. These therapies will be recorded in the source documents and appropriate 
CRF along with the diagnosis or reason for use. Those therapies used for the treatment of an adverse 
event are to be linked to an AE and documentation of the AE must also be completed 
 
6.5.1 RESCUE MEDICINE 
The study site will not supply rescue medication. 
   


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7 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL.  
7.1 
DISCONTINUATION OF STUDY INTERVENTION 
 
This study may be temporarily suspended or prematurely terminated if there is enough reasonable 
cause.  Written notification, documenting the reason for study suspension or termination, will be 
provided by the suspending or terminating party to the study team, the Sponsor and the Institutional 
Review Board (IRB), as appropriate.  If the study is prematurely terminated or suspended, the study 
team will promptly inform the IRB and will provide the reason(s) for the termination or suspension.  
 
Discontinuation from niclosamide does not mean discontinuation from the study, and remaining study 
procedures should be completed as indicated by the study protocol.  If a clinically significant finding is 
identified (including, but not limited to changes from baseline) after enrollment, the investigator or 
qualified designee will determine if any change in participant management is needed. Any new clinically 
relevant finding will be reported as an AE. 
 
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY 
All participants are free to withdraw from participation at any time, for any reason, specified or 
unspecified, and without prejudice.  Reasonable attempts will be made by the Investigator to provide a 
reason for participant withdrawals. The reason for the participant’s withdrawal from the study will be 
specified in the participant’s source documents and the CRF. The study team will make every effort to 
contact participants who are lost to follow-up. Attempts to contact such participants will be 
documented in the participant’s records (e.g., times and dates of attempted telephone contact, receipt 
for sending a registered letter, etc.). 
 
A participant will be discontinued from the study for the following reasons only: 
• 
Participant withdrawal of consent 
• 
Lost to follow-up 
• 
Participant death 
• 
Hospitalization for severe COVID- 19 symptoms  
The following procedures will be performed at the Early Termination visit: 
 
Assess for AEs 
 
Assess for complications following treatments 
 
Document all current medications, including medications over the counter and herbal 
medications 
 
Perform clinical assessment (as deemed feasible if hospitalized) 
 
Evaluate for increased severity of COVID-19-related disease  
  
If clinical evaluation is deemed not feasible due to patient condition, the Study Team will collect as much 
Early Termination Visit data as possible from the Electronic Medical Record 


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The reason for participant discontinuation or withdrawal from the study will be recorded on the CRF.   
 
7.3 
LOST TO FOLLOW-UP 
 
A participant will be considered lost to follow-up if he or she fails to complete more than (2) scheduled 
telehealth visits and is unable to be contacted by the study staff.  
 
The following actions must be taken if a participant fails to attend a required telehealth visit: 
 
The Study Team will attempt to contact the participant and reschedule the missed visit and 
counsel the participant on the importance of maintaining the assigned visit schedule and 
ascertain if the participant wishes to and/or should continue in the study. 
 
Before a participant is deemed lost to follow-up, the investigator or designee will make every 
effort to regain contact with the participant (where possible, 3 telephone calls and, if necessary, 
a certified letter to the participant’s last known mailing address or local equivalent methods). 
These contact attempts will be documented in the participant’s medical record or study file.  
 
Should the participant continue to be unreachable, he or she will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up. 
 
For participants considered lost to follow-up, the CRF will be completed up to the last contact 
with the participant. 
 
8 
STUDY ASSESSMENTS AND PROCEDURES 
8.1 
EFFICACY ASSESSMENTS  
 
The specific timing of procedures/evaluations to be done at each study visit are found in Section 1.2, 
Schedule of Activities.  All assessment will be performed by the study investigators or a qualified 
member of the study team. 
 
Baseline and Screening (Day 0) 
The following procedures will be performed at the Baseline/Screening visit: 
 
Review the study with the participant and obtain written informed consent and Health 
Insurance Portability and Accountability Act of 1996 (HIPAA) authorization 
 
Assign the participant a unique enrollment number 
 
Review and record medical history, surgical history, and medication history to determine 
eligibility based on inclusion/exclusion criteria 
 
Record smoking history  
 
Record demographics (age, race, ethnicity, gender) 
 
Document all current medications, including medications over the counter and herbal 
medications 
 
Record COVID symptoms, if symptomatic  
 
Record confirmation of positive SARS-CoV-2 test result 


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 
Record number of days since onset of symptoms, if symptomatic 
Randomization and Treatment (Day 0) 
 
Confirm patient meets all inclusion and none of the exclusion criteria 
 
Randomize subject to treatment in EDC 
 
Provide blinded treatment (either niclosamide or placebo) and other study materials via courier 
 
Follow-Up Evaluation 
Remote clinical follow-up will occur at the following time points: Days 1, 2, 3, 7, 10, 14, 21 and 30.  
The following procedures will be performed at all follow-up visits, expected to be done by tele-medical 
methods, unless otherwise noted: 
 
Assess for AEs 
 
Assess COVID signs and symptoms  
 
Document all current medications, including medications over the counter and herbal 
medications 
 
Document patient’s status as an outpatient, subsequently hospitalized, or died 
 
Perform clinical assessment by patient report and vital signs (temperature and oxygen 
saturation) 
 
Evaluate for increased severity of COVID-19-related disease 
 
Collect temperature and oximetry data daily, with the caveat that if O2 goes below 92%, an 
addition oximeter reading should be taken 2 hours later.  If the follow-up O2 saturation remains 
below 92%, the participant will be referred to their Primary Care Physician (PCP) or to the local 
Emergency Department. 
 
Collect oropharyngeal swab samples for viral shedding on days 1, (baseline), 3, 7, 10, 14 (courier 
transport of specimen) 
 
Collect fecal samples for viral shedding as measured by fecal PCR on days 1, (baseline), 3, 7, 10, 
14 and 21 (courier transport of specimen) 
 
Final Study Visit (Non-hospitalized Participants) 
The following procedures will be performed at the final post treatment visit: 
 
Assess for AEs 
 
Assess for complications following treatments 
 
Document all current medications, including medications over the counter and herbal 
medications 
 
Perform clinical assessment to evaluate for increased severity of COVID-19-related diseases 
 
Early Termination/Hospitalization    
All participants have the right to withdraw from study participation at any time during the study. If, for 
whatever reason, a participant withdraws from the study or is hospitalized, an Early Termination Visit 
will be performed. 
 
The following procedures will be performed at the Early Termination Visit: 


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 
Assess for adverse events 
 
Assess for complications following treatments 
 
Document all current medications, including medications over the counter and herbal 
medications 
 
Perform clinical assessment (as deemed feasible if hospitalized) 
 
Evaluate for increased severity of COVID-19-related disease   
 
If clinical evaluation is deemed not feasible due to patient condition, the Study Team will collect Early 
Termination Visit data via the Electronic Medical Record. 
A 30-day follow-up call and AE assessment for those patients who are hospitalized will be performed. 
8.2 
SAFETY AND OTHER ASSESSMENTS 
 
For Study procedures and evaluations to be done as part of the study to monitor safety and support the 
understanding of the study intervention’s safety refer to Section 1.2, Schedule of Activities and Section 
8.1 Study Assessments. 
   
8.3 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
 
Adverse event data will be summarized for all participants in the safety population. Site-reported serious 
adverse events and unexpected adverse drug reactions will be summarized as participant-based counts 
and percentages by AE category. MedDRA system organ class and preferred term In addition, participant 
listings will be provided for serious, unexpected, and unanticipated adverse reactions. Any adverse 
events leading to discontinuation of study drug or death will also be listed for all participants.  
 
Definition of Adverse Event (AE) 
An AE is defined as any unanticipated medical occurrence regardless to relationship of the investigative 
arm of the trial. An AE can be any unintended sign, lab abnormality, symptom, or disease associated 
with the trial. Any abnormality that presents during a medical test are to be defined as an AE if it 
produces clinical signs and/or symptoms, requires intervention, or deemed clinically significant by the 
Investigator. 
 
The Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 will be utilized for AE reporting 
the following study- specific AEs: 
 
Cough 
 
Dyspnea 
 
Hypoxia 
 
Nausea 
 
Vomiting 
 
Abdominal pain 
 
Pruritus 
 
Loss of appetite 


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 
Dizziness 
 
Skin rash 
 
Definition of Serious Adverse Event (SAE) 
 
An AE is considered serious if it results in any of the following: 
 
results in death; 
 
is life-threatening (places the subject at immediate risk of death from the event as it occurred); 
 
requires inpatient hospitalization or prolongation of existing hospitalization; 
 
results in a persistent or significant disability/incapacity; 
 
results in a congenital anomaly/birth defect; or 
 
any other adverse event that, based upon appropriate medical judgment, may jeopardize the 
subject’s health and may require medical or surgical intervention to prevent one of the other 
outcomes listed in this definition  
 
Definition of Unexpected Adverse Reaction (UAE) 
An adverse reaction, the nature or severity of which is not consistent with the applicable product 
information (e.g. Product Information/Summary of Product Characteristics). This would include any SAE 
on health or safety, any life-threatening problem or death caused by, or associated with a drug; or any 
other unanticipated serious problem associated with a drug that relates to the rights, safety, or welfare 
of subjects. 
 
8.3.1 CLASSIFICATION OF AN ADVERSE EVENT. 
8.3.1.1 SEVERITY OF EVENT 
 
All AEs will be assessed by the study clinician using the CTCAE V. 5.0 
 
Grade 1:  Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated.  
 
Grade 2:  Moderate; minimal, local or noninvasive intervention indicated 
 
Grade 3:  Severe or medically significant but not immediately life-threatening; hospitalization or 
prolongation of hospitalization indicated 
 
8.3.1.2 RELATIONSHIP TO STUDY INTERVENTION 
A Study Team physician will oversee the evaluation of patient reported severity of AEs using the 
following categories: 
Relationship to Study Products 
All AEs must have their relationship to study intervention assessed by the clinician who examines and 
evaluates the participant based on temporal relationship and his/her clinical judgment. The degree of 
certainty about causality will be graded using the categories below.  
 


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Definitely: 
 
The relationship of the AE and the drug or the study procedure can be 
established. 
 
Probably: 
 
While a clear relationship to the drug or to the study procedure cannot be 
established, the AE is associated with an expected AE or there is no other 
medical condition or intervention, which could explain the occurrence of such 
an event. 
 
Possibly: 
 
There is no clear relationship between the AE and the drug or study procedure; 
however, one cannot conclude that there is no relationship. 
 
Unrelated: 
 
There is no relationship between the AE and the drug or study procedure.  This 
may include but is not limited to the incident being an expected outcome of a 
previously existing or concurrent disease, concomitant medication or 
procedure the participant experienced. 
 
 
8.3.1.3 EXPECTEDNESS  
Study Team members who are clinically qualified (e.g., a physician co- Investigator) will be responsible 
for determining whether an AE is expected or unexpected. An AE will be considered unexpected if the 
nature, severity, or frequency of the event is not consistent with the risk information previously 
described for the study products. This information will be provided to the IRB, to the Study Sponsor, and 
to any relevant governmental agency with regulatory or public health authority.  
8.3.2 TIME PERIOD AND FREQUENCY FOR EVENT ASSESSMENT AND FOLLOW-UP 
 
The occurrence of an AE or SAE may come to the attention of study personnel during study visits and 
interviews of a study participant presenting for medical care. 
 
All AEs including local and systemic reactions not meeting the criteria for SAEs will be captured on the 
appropriate CRF. Information to be collected includes event description, time of onset, clinician’s 
assessment of severity, relationship to study product (assessed only by those with the training and 
authority to make a diagnosis), and time of resolution/stabilization of the event. All AEs occurring while 
on study must be documented appropriately regardless of relationship. All AEs will be followed to 
adequate resolution. 
 
8.3.3 ADVERSE EVENT REPORTING  
Adverse event data will be summarized for all participants in the safety population. Serious adverse 
events and unexpected adverse drug reactions will be summarized as participant-based counts and 
percentages by AE category. In addition, participant listings will be provided for serious, unexpected, 
and unanticipated adverse reactions. Any adverse events leading to discontinuation of study drug or 
death will also be listed for all participants.  


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8.3.4 SERIOUS ADVERSE EVENT REPORTING  
 
Study team members who are qualified will immediately report any serious adverse event, whether or 
not considered study intervention related, including those listed in the protocol and must include an 
assessment of whether there is a reasonable possibility that the study intervention caused the event. 
Study endpoints that are SAEs must be reported in accordance with the protocol.   
 
8.3.5 REPORTING EVENTS TO PARTICIPANTS  
 
AEs, SAEs and UPs will be reported to IRB as outlined in Sections 8.3.5, 8.3.6 and 8.4.2 
 
8.3.6 EVENTS OF SPECIAL INTEREST  
 
N/A 
 
8.3.7 REPORTING OF PREGNANCY  
 
During the Informed Consent discussion, the MD study Investigator will ask women of childbearing 
potential if they are pregnant.  That yes/ no response will be recorded.  We will not exclude women who 
are of childbearing years or pregnant.  We will collect pregnancy status information at the time of 
enrollment.  Niclosamide is a Category B (animal studies show no risks, but there are no controlled 
studies in pregnant women). Category B drugs include prenatal vitamins, acetaminophen and several 
other medications used routinely and safely during pregnancy.   
 
In addition to recording whether women of childbearing age are pregnant at the time of study 
enrollment, we will also record their breastfeeding status. For enrolled subjects who are pregnant or 
breastfeeding, we will include follow up a specific query for any adverse effects on pregnancy and/or 
breastfeeding infant during the course of the study. 
 
8.4 
UNANTICIPATED PROBLEMS 
8.4.1 DEFINITION OF UNANTICIPATED PROBLEMS (UP): 
 
The Office for Human Research Protections (OHRP) considers unanticipated problems involving risks to 
participants or others to include, in general, any incident, experience, or outcome that meets all the 
following criteria: 
 
• 
Unexpected in terms of nature, severity, or frequency given (a) the research procedures that are 
described in the protocol-related documents, such as the Institutional Review Board (IRB)-
approved research protocol and informed consent document; and (b) the characteristics of the 
participant population being studied; 
• 
Related or possibly related to participation in the research (“possibly related” means there is a 
reasonable possibility that the incident, experience, or outcome may have been caused by the 
procedures involved in the research); and 


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• 
Suggests that the research places participants or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or recognized. 
 
8.4.2  UNANTICIPATED PROBLEM REPORTING  
 
The investigator will report unanticipated problems (UPs) to the reviewing Institutional Review Board 
(IRB).  The UP report will include the following information: 
 
• 
Protocol identifying information: protocol title and number, PI’s name, and the IRB project number; 
• 
A detailed description of the event, incident, experience, or outcome;  
• 
An explanation of the basis for determining that the event, incident, experience, or outcome 
represents an UP;  
• 
A description of any changes to the protocol or other corrective actions that have been taken or 
are proposed in response to the UP. 
 
To satisfy the requirement for prompt reporting, UPs will be reported using the following timeline:   
• 
UPs that are SAEs will be reported to the IRB within 5 working days of the investigator becoming 
aware of the event.  
• 
A Study Team evaluation of an UP will be performed with a report of results of such evaluation 
will be provided to the reviewing IRB by the PI within 5 working days.  
• 
All other Reportable New Information will be reported to the IRB as per the policy. 
 
8.4.3 REPORTING UNANTICIPATED PROBLEMS TO PARTICIPANTS  
 
AEs, SAEs and UPs will be reported to IRB as outlined in Sections 8.3.5, 8.3.6 and 8.4.2 
 
9 
STATISTICAL CONSIDERATIONS  
9.1 
STATISTICAL HYPOTHESES 
 
The null hypothesis is that the proportion of participants with respiratory viral clearance at Day 3 is the 
same in both treatment groups. The alternative hypothesis is that they are different. 
  
 
9.2 
SAMPLE SIZE DETERMINATION 
 
For the primary efficacy endpoint of respiratory virologic clearance at Day 3 measured by oropharyngeal 
viral shedding we assume that on Day 3, 50% of participants in the niclosamide group who have a 
positive result on Day 1 (prior to dosing) will have a negative test results and 15% in the placebo group.    
With 40 participants  per group we have 89% power to show a statistically significant difference 
between groups at Day 3 using Fisher’s Exact test at the two-sided 0.05 significance level.  Assuming that 
40% of randomized participants have a positive respiratory test result, 200 participants will be required 
to be randomized into the study.  
 


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9.3 
POPULATIONS FOR ANALYSES 
 
 
Intention-to-Treat (ITT) Analysis Dataset (all randomized participants) 
 
Modified Intention-to-Treat Analysis Dataset (participants who took at least one dose of study 
intervention, have a positive test result on Day 1 and have Day 3 oropharyngeal sample results 
available for analysis. 
 
Safety Analysis Dataset: participants who took at least one dose of study intervention 
 
Per-Protocol Analysis Dataset: subset of the participants in the full analysis (ITT) set who took at 
least 80% of study intervention and had no protocol violations that would affect the primary 
efficacy endpoint.  
 
Other Datasets that may be used for sensitivity analyses 
 
9.4 
STATISTICAL ANALYSES 
9.4.1 GENERAL APPROACH 
 
Baseline demographic and clinical characteristics and other results will be summarized using descriptive 
summary statistics. Data collected in the trial will be summarized overall and by treatment arm. For 
continuous variables, results within each treatment arm will be summarized with the numbers of 
observations, mean, standard deviation, minimum, and maximum, as well as the 95% confidence 
interval for the mean. For treatment comparisons, the difference between the two treatment arms will 
be summarized with the difference of the two means and 95% confidence interval for the difference of 
the means. These calculations will be done under the assumption that the data for the two arms are 
independent and approximately normal in distribution. If not otherwise specified, the confidence 
interval for the difference of two means is calculated assuming unequal variance between the two 
groups. If asymptotic assumptions fail, nonparametric summary statistics (medians, 25th and 75th 
percentiles) may be displayed as an alternative. In addition, more appropriate non-parametric tests will 
be considered if the assumptions for the parametric tests are violated. For the comparison of two 
independent samples, if the data are not normally distributed, Wilcoxon rank-sum test will be 
performed instead of the parametric t-test.  
 
For categorical variables, results within each arm will be summarized with participant counts, 
percentages, and 95% confidence intervals. The differences between the two treatment arms will be 
summarized with the difference in percentages and the asymptotic 95% confidence interval for the 
difference of two percentages. 
 
Survival analysis techniques will be used to analyze the time-to-event variables. Survival curves will be 
constructed using Kaplan-Meier estimates. Log-rank test results will be computed for comparison of 
survival distributions. Summary tables for safety and efficacy endpoints will include event rates (Kaplan-
Meier estimates of event rates), relative risk, confidence interval for the relative risk, the difference in 
means/rates, the confidence interval for difference in means/rates, and the p-value. 
 


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For the primary efficacy endpoint, respiratory Clearance at Day 3 will be summarized by treatment 
group and the difference will be tested using a two-sided Fisher’s Exact Test at the 0.05 significance 
level. The corresponding confidence interval for the difference in proportions will be calculated.  
 
Every effort will be made to ensure the oropharyngeal samples are collected at all time points specified 
by the protocol even if the subject discontinues the study drug.  The primary analytic sample will be the 
mITT cohort 
 
All analyses will be repeated using the per-protocol population. 
 
9.4.2 ANALYSIS OF THE SECONDARY ENDPOINT(S) 
 
Secondary Efficacy Analysis 
• 
Fecal viral clearing at day 14 will be summarized by treatment group and the difference will 
be tested separately for each day using a two-sided Fisher’s Exact Test. 
 
• 
Respiratory viral shedding as measured on days 1, 3, 7, 10, 14 will be compared between 
treatment groups using repeated measures analysis.  
 
•            Fecal viral shedding as measured on days 1, 3, 7, 10, 14 and 21 will be compared between 
treatment groups using repeated measures analysis. 
 
We plan to consider additional analysis approaches including but not limited to: time to negative COVID-
19 test as determined by PCR using oropharyngeal and/or fecal samples; longitudinal analysis of 
continuous measures such as body temperature and O2 saturation; The proportion of participants in 
each treatment group who progress to severe COVID disease will be compared using a two-sided z test 
with continuity correction. The corresponding confidence interval for the difference in proportions will 
be calculated. 
 
All secondary endpoint analyses will be performed for the mITT and PP populations at the 0.05 
significance level.  No adjustment for multiple testing will be performed. 
 
9.4.3 SAFETY ANALYSES 
  
Adverse event data will be summarized for all participants in the safety population. Site-reported serious 
adverse events and unexpected adverse drug reactions will be summarized as participant-based counts 
and percentages by AE category.  
 
In addition, participant listings will be provided for serious, unexpected, and unanticipated adverse 
reactions. Any adverse events leading to discontinuation of study drug or death will also be listed for all 
participants. 
  
9.4.4 BASELINE DESCRIPTIVE STATISTICS 


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Demographic characteristics and medical history, adverse events, COVID disease signs and symptoms 
and treatment compliance will be summarized and compared between treatment groups. The details of 
the statistical analyses will be included in the Statistical Analysis Plan. 
 
9.4.5 PLANNED INTERIM ANALYSES  
 
N/A 
 
9.4.6 SUB-GROUP ANALYSES 
N/A 
9.4.7 TABULATION OF INDIVIDUAL PARTICIPANT DATA 
 
N/A 
 
9.4.8 EXPLORATORY ANALYSES 
 
A detailed description of all statistical analyses will be presented in the Statistical Analysis Plan. 
 
10 SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS 
10.1 REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS.   
10.1.1 INFORMED CONSENT PROCESS 
 
10.1.1.1 CONSENT/ASSENT AND OTHER INFORMATIONAL DOCUMENTS PROVIDED TO 
PARTICIPANTS 
 
Consent describing in detail the study intervention, study procedures, and risks will be provided to the 
participant and documentation of informed consent will be required prior to administering study 
interventions.  Non-English speakers will be enrolled using interpreters and IRB approved Short Forms 
per the IRB’s Short Form policy. 
 
10.1.1.2 CONSENT PROCEDURES AND DOCUMENTATION 
 
Informed consent (IC) is a process that is initiated prior to the individual’s agreeing to participate in the 
study and continues throughout the individual’s study participation. The PI or physician co-Investigator 
will explain the research study to the participant and answer any questions that may arise.  Utilizing the 
telehealth platform, an explanation will be provided in terms suited to the participant’s comprehension 
of the purposes, procedures, and potential risks of the study and of their rights as research participants.  
Potential participants will have the opportunity to ask questions. The participants will have the 
opportunity to discuss the study with their family or surrogates or think about it prior to agreeing to 
participate. They will be informed that participation is voluntary and that they may withdraw from the 
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emphasizing to them that the quality of their medical care will not be adversely affected if they decline 
to participate in this study. 
 
FDA regulations generally require that the informed consent of a trial participant be documented by the 
use of a written consent form that has been approved by the IRB and signed and dated by the subject at 
the time of consent (21 CFR 50.27(a)). Considering COVID-19 infection control measures, if the 
technology is available, current FDA guidance suggests that electronic methods of obtaining informed 
consent should be considered as follows: 
 
 
To ensure that patients are approached in a consistent fashion, a standard process should be 
used that will accomplish the following:  
 
Identification of who is on the call or telemedicine visit 
 
Review of the IC with the patient by the investigator (or their designee) and response to 
any questions the patient may have 
 
Confirmation by the witness that the patient’s questions have been answered  
 
Confirmation by the investigator that the patient is willing to participate in the trial and 
sign the informed consent document while the witness is listening on the phone  
 
Verbal confirmation by the patient that they would like to participate in the trial and 
that they have signed and dated the informed consent document that is in their 
possession. 
 
 
If the signed informed consent document cannot be collected from the patient’s location and 
included in the study records, FDA considers the following option acceptable to provide 
documentation that the patient signed the informed consent document:  
 
A dated attestation by the witness who participated in the call and by the investigator 
that the patient confirmed that they agreed to participate in the study and signed the 
informed consent. 
 
For this study involving participants with COVID-19 positivity, in accordance with FDA guidance, the 
following steps will be performed while obtaining the IC by phone or telehealth video chat from the 
Subject. 
 
1) Purpose of the study and the potential risks/benefits of the use of the Investigational Agent 
Niclosamide in the treatment of confirmed COVID-19 infection will discussed in detail by the 
principal investigator or sub-investigator (PI/Sub-I) with the subject prior to obtaining the IC.  
Opportunity to review the ICF (informed consent form) prior to or during the discussion will be 
provided.  Adequate time for discussion between the PI/Sub-I will be given to the potential 
participant.  After review of the IC, any questions that the potential participant has will be 
addressed during or after review of the IC. 
 


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2) Availability and/or possibility of other potential treatment options will be discussed with the 
participant. 
 
3) A second member of the study team will be present on the phone or video chat during the entire 
discussion. The witness will ask the potential participant if they understand the contents of the 
discussion and if they have any questions to address. The participant will be informed that they can 
ask questions at any time during the trial. 
 
4) The PI/Sub-I will sign the ICF along with the witness. Copies of the signed form will be placed in the 
patient’s medical record and provided to the participant.  
 
5) This document will be placed into the electronic medical record and electronically signed, and time 
stamped by the investigator. In de-identified form, it will be the study source document for 
documenting the process of obtaining ICF.  A copy of the electronically signed consent (signed by 
the witness and investigator) is either emailed, sent by US Mail to subject. 
10.1.2 STUDY DISCONTINUATION AND CLOSURE 
 
This study may be temporarily suspended or prematurely terminated if there is sufficient reasonable 
cause.  Written notification, documenting the reason for study suspension or termination, will be 
provided by the suspending or terminating party to study participants, investigator, funding agency, and 
regulatory authorities.  If the study is prematurely terminated or suspended, the Principal Investigator 
(PI) will promptly inform study participants and the Institutional Review Board (IRB) for the termination 
or suspension.  Study participants will be contacted, as applicable, and be informed of changes to study 
visit schedule. 
  
Circumstances that may warrant termination or suspension include, but are not limited to: 
 
Determination of unexpected, significant, or unacceptable risk to participants 
 
Insufficient compliance to protocol requirements 
 
Data that are not sufficiently complete and/or evaluable 
 
Determination that the primary endpoint has been met 
 
The study may resume once concerns about safety, protocol compliance, and data quality are addressed 
and the IRB. 
 
10.1.3 CONFIDENTIALITY AND PRIVACY  
 
Participant confidentiality and privacy is strictly held in trust by the participating investigators, their 
staff, and the sponsor(s) and their interventions. This confidentiality is extended to cover testing of 
biological samples in addition to the clinical information relating to participants. Therefore, the study 
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information concerning the study, or the data will be released to any unauthorized third party without 
prior written approval of the sponsor.  
 
All research activities will be conducted in as private a setting as possible.  The use of the telehealth 
video platform will include participant instruction on using the platform in a private setting or with a 
family member/ significant other via Facetime as described in the Study Intervention. 
 
Representatives of the Institutional Review Board (IRB), regulatory agencies or pharmaceutical company 
supplying study product may inspect all documents and records required to be maintained by the 
investigator, including but not limited to, medical and pharmacy records for the participants in this 
study.  The clinical study site will permit access to such records. 
 
The study participant’s contact information will be securely stored at each clinical site for internal use 
during the study. At the end of the study, all records will continue to be kept in a secure location for as 
long a period as dictated by the reviewing IRB, Institutional policies, or sponsor requirements. 
The Principal Investigator will be responsible to ensure the study is conducted in accordance with the 
protocol, Good Clinical Practice (GCP), applicable regulatory requirements, and that the data recorded is 
valid. To achieve this objective, the study will be continuously monitored, and the study conduct 
reviewed on a weekly basis by the Study Team. 
Monitoring will be conducted to ensure that the rights and well-being of human participants are 
protected, that the reported trial data are accurate, complete, and verifiable, and that the conduct of 
the trial follows the currently approved protocol/amendment(s), with GCP, and with applicable 
regulatory requirement(s). 
A Clinical Monitoring Plan will be created by the Study Team and will describe in detail the personnel 
who will conduct the monitoring, at what frequency monitoring will be done, at what level of detail 
monitoring will be performed, and the distribution of monitoring reports. 
 
10.1.4 FUTURE USE OF DATA  
The collection of personal patient information will be limited to the amount necessary to achieve the 
aims of the research, so that no unneeded sensitive information is being collected. 
Data from the EDC will be exported into Excel or SAS file format (password protected), which will then 
be used for data analysis.  Only de-identified, not including the participant’s contact or identifying 
information data will be used for data analysis.  
 
10.1.5 KEY ROLES AND STUDY GOVERNANCE 
Provide the name and contact information of the Principal Investigator. 
Principal Investigator 


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Harry Selker, MD 
Institute for Clinical Research and Health Policy Studies 
Tufts Clinical and Translational Science Institute (CTSI) 
Tufts University 
Tufts Medical Center 
800 Washington Street, # 63, Boston, MA 02111 
Phone: (617) 636-5009 
Fax: (617) 636-8023 
Email 
 
 
10.1.6 SAFETY OVERSIGHT 
An appropriately credentialled Independent Safety Monitor (ISM) without association to the trial or 
conflicts of related to the study will monitor the data on a weekly basis and make recommendations to 
the PI with respect to the: 
 
Safety of the trial participants including adverse events (AEs), serious adverse events (SAE's), 
and unexpected problems 
 
The Independent Safety Monitor will review and evaluate all AEs and SAEs in a blinded fashion, 
however, can be unblinded as needed. 
 
The ISM will have access to unblinded SAE rates for participants randomized to niclosamide and 
placebo. Rates of non-serious AEs will also be compared between the two study groups.  
Subjects will be monitored for adverse events (AEs) and serious adverse events (SAEs). A greater than 3x 
incidence of treatment related SAEs in the niclosamide treatment group vs placebo will be added to the 
protocol as the stopping threshold 
 
The PI is personally responsible for conducting and supervising the conduct of human subject’s research 
by protecting the rights, safety, and welfare of subjects under the investigator’s care.  The PI also must 
ensure that all the research conducted is done so in an ethical manner and in accordance with all 
federal, state, and local laws and regulations, institutional policies/procedures, the study protocol/plan, 
and the requirements of the IRB. Oversight is defined as management by overseeing the performance or 
operation of a person or group, watchful care, superintendence, general supervision. Any person serving 
as a PI has voluntarily accepted these responsibilities and is expected to fully comply with these 
requirements. To provide PI oversight and to ensure that the rights, safety, and welfare of research 
subjects is protected the PI will, at a minimum, confirm:  
 
Any individual to whom a task is delegated is qualified by education, training, and experience to 
perform the task.  
 
There is adequate training for all staff participating in the conduct of the study 
 
 The PI or another qualified individual associated with the study is available to study subjects to 
answer questions or provide care during the conduct of the research 
 
All research staff adhere to the research plan (i.e., inclusion/exclusion criteria, safety 
assessments, safety monitoring and reporting of unanticipated problems). 
 


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Expected Oversight Practices  
 
The PI will work closely with the study team to ensure oversight of the research study and the 
necessary documentation of such activities. A sub- Investigator can cover for the PI when he is 
unavailable or is on vacation. 
 
A Delegation of Authority Log will be completed prior to opening to accrual. This log will be 
maintained accurately during the life of the study. 
 
A Training Log will be completed prior to opening to accrual. This log will be maintained 
accurately during the life of the study. 
 
The PI or delegated physician Investigator will sign-off on all study-related documents (i.e., 
eligibility verification) prior to subjects beginning study treatment per protocol to ensure the 
safety of the study participants 
 
The PI or delegated physician Investigator will evaluate and ascribe attribution, sign-off on all 
AEs and SAEs. 
 
The PI and Study Team will establish the method in which they will consistently communicate. 
At a minimum, this is intended to be through a combination of electronic, audio, and face to 
face interactions. Details and specifics of these interactions will be established by the PI and 
Study Team prior to activation of each study.  
 
Communication regarding SAEs will be documented in real-time. If the PI is not available, the 
delegated physician Investigator should be notified. 
 
Regular meetings with the PI to discuss subject participation, including AEs and treatment, will 
be established to ensure adequate oversight. This is in addition to the immediate availability of 
the PI, or delegated physician Investigator, to address SAE, protocol interpretation, safety 
monitoring or other urgent clinical needs.  Involvement of the treating sub-investigator is 
recommended but not required. 
 
Timely and accurate documentation of oversight is required and will be provided by the PI 
consistent with FDA1572. The nature of oversight documentation is through written and 
electronic means.  
 
The PI or physician Investigator will complete urgent documents including initial SAE review and 
sign-off within 24 hours of notification of the event.  
 
All non-urgent regulatory documents including IRB submission/revisions, AE attribution 
assignments, AE grading will be completed by the PI or physician Investigator within 48 hours. 
 
Additional study documents including but not limited to research notes, email correspondences, 
and study logs are to be reviewed at least on a weekly basis by the PI and included with research 
documentation. 
 
 
10.1.7 CLINICAL MONITORING 
 
Clinical monitoring will be conducted to ensure that the rights and well-being of trial participants are 
protected, that the reported trial data are accurate, complete, and verifiable, and that the conduct of 
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Conference on Harmonisation Good Clinical Practice (ICH GCP), and with applicable regulatory 
requirement(s).  
 
Refer to Section 10.1.6 Safety Oversite for details. 
 
10.1.8 QUALITY ASSURANCE AND QUALITY CONTROL 
   
Quality control (QC) procedures will be implemented beginning with the data entry system and data QC 
checks that will be run on the database will be generated. Any missing data or data anomalies will be 
communicated to study PI or designee for resolution. 
 
Following written Standard Operating Procedures (SOPs), the PI and co- Investigators will verify that the 
clinical trial is conducted, and data are generated, and biological specimens are collected, documented 
(recorded), and reported in compliance with the protocol, International Conference on Harmonisation 
Good Clinical Practice (ICH GCP), and applicable regulatory requirements (e.g., Good Laboratory 
Practices (GLP), Good Manufacturing Practices (GMP)).  
 
The investigational site will provide direct access to all source data/documents, and reports for the 
purpose of monitoring, auditing and inspection by local and regulatory authorities. 
 
10.1.9 DATA HANDLING AND RECORD KEEPING.  
 
10.1.9.1 DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES  
 
Data collection is the responsibility of the Study Staff under the supervision of the Investigator. The 
Investigator is responsible for ensuring the accuracy, completeness, legibility, and timeliness of the data 
reported. 
 
All source documents will be completed in a neat, legible manner to ensure accurate interpretation of 
data.   
 
Any hardcopies of study visit worksheets will be provided for use as source document worksheets for 
recording data for each participant enrolled in the study.  Data recorded in the electronic case report 
form (eCRF) derived from study source documents will be consistent with the data recorded on the 
source documents.  
 
Clinical data, AEs, concomitant medications, and any other data collected from participants will be 
entered into a REDCap database.  The data system includes password protection and internal quality 
checks, such as automatic range checks, to identify data that appear inconsistent, incomplete, or 
inaccurate. Clinical data will be entered directly from the source documents. 
 
10.1.9.2 STUDY RECORDS RETENTION  


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We will follow the IRB’s HRP-073 - SOP - Records Retention Timeframe – Investigators (0.03) 
 
10.1.10 
PROTOCOL DEVIATIONS  
 
A protocol deviation is any noncompliance with the clinical trial protocol, International Conference on 
Harmonisation Good Clinical Practice (ICH GCP), or Manual of Procedures (MOP) requirements. The 
noncompliance may be either on the part of the participant, the Investigator, or the Study Team. As a 
result of deviations, corrective actions are to be developed by the site and implemented promptly.  
 
These practices are consistent with ICH GCP:  
• 
4.5 Compliance with Protocol, sections 4.5.1, 4.5.2, and 4.5.3  
• 
5.1 Quality Assurance and Quality Control, section 5.1.1  
• 
5.20 Noncompliance, sections 5.20.1, and 5.20.2.  
Protocol deviations will be summarized by type of deviation and treatment group. Protocol deviation 
summaries will be participant-based. 
 
10.1.11 
PUBLICATION AND DATA SHARING POLICY 
The preparation and submittal for publication of manuscripts containing the study results shall be in 
accordance with a process determined by mutual written agreement among the study Sponsor and 
participating institutions.  The publication or presentation of any study results shall comply with all 
applicable privacy laws, including, but not limited to, the Health Insurance Portability and Accountability 
Act of 1996. 
This study will comply with the NIH Data Sharing Policy and Policy on the Dissemination of NIH-Funded 
Clinical Trial Information and the Clinical Trials Registration and Results Information Submission rule. As 
such, this trial will be registered at ClinicalTrials.gov, and results information from this trial will be 
submitted to ClinicalTrials.gov. In addition, every attempt will be made to publish results in peer-
reviewed journals. 
 
10.1.12 
CONFLICT OF INTEREST POLICY 
 
The independence of this study from any actual or perceived influence, such as by the pharmaceutical 
industry, is critical.  Therefore, any actual conflict of interest of persons who have a role in the design, 
conduct, analysis, publication, or any aspect of this trial will be disclosed and managed. Furthermore, 
persons who have a perceived conflict of interest will be required to have such conflicts managed in a 
way that is appropriate to their participation in the design and conduct of this trial.  The study 
leadership in conjunction has established policies and procedures for all study group members to 
disclose all conflicts of interest and will establish a mechanism for the management of all reported 
dualities of interest. 
 


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10.2 ADDITIONAL CONSIDERATIONS 
 
 
 


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10.3 ABBREVIATIONS 
 
AE 
Adverse Event 
ANCOVA 
Analysis of Covariance 
CFR 
Code of Federal Regulations 
CLIA 
Clinical Laboratory Improvement Amendments 
CMP 
Clinical Monitoring Plan 
COC 
Certificate of Confidentiality 
CONSORT Consolidated Standards of Reporting Trials 
CRF 
Case Report Form 
DCC 
Data Coordinating Center 
DHHS 
Department of Health and Human Services 
DSMB 
Data Safety Monitoring Board 
DRE 
Disease-Related Event 
EC 
Ethics Committee 
eCRF 
Electronic Case Report Forms 
FDA 
Food and Drug Administration 
FDAAA 
Food and Drug Administration Amendments Act of 2007 
FFR 
Federal Financial Report 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practices 
GMP 
Good Manufacturing Practices 
GWAS 
Genome-Wide Association Studies 
HIPAA 
Health Insurance Portability and Accountability Act  
IB 
Investigator’s Brochure 
ICH 
International Conference on Harmonisation  
ICMJE 
International Committee of Medical Journal Editors 
IDE 
Investigational Device Exemption 
IND 
Investigational New Drug Application 
IRB 
Institutional Review Board 
ISM 
Independent Safety Monitor 
ISO 
International Organization for Standardization 
ITT 
Intention-To-Treat 
LSMEANS 
Least-squares Means 
MedDRA 
Medical Dictionary for Regulatory Activities 
MOP 
Manual of Procedures 
MSDS 
Material Safety Data Sheet 
NCT 
National Clinical Trial 
NIH  
National Institutes of Health 
NIH IC 
NIH Institute or Center 
OHRP 
Office for Human Research Protections 
PI 
Principal Investigator 
QA 
Quality Assurance 
QC 
Quality Control 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 


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SMC 
Safety Monitoring Committee 
SOA 
Schedule of Activities 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
UP 
Unanticipated Problem 
US 
United States 
 
 
 


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10.4 PROTOCOL AMENDMENT HISTORY 
The table below is intended to capture changes of IRB-approved versions of the protocol, including a 
description of the change and rationale. A Summary of Changes table for the current amendment is 
located in the Protocol Title Page.  
 
Version 
Date 
Description of Change  
Brief Rationale 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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11 REFERENCES  
1. Wu, Y., C. Guo, L. Tang, Z. Hong, J. Zhou, X. Dong, H. Yin, Q. Xiao, Y. Tang, X. Qu, L. Kuang, X. 
Fang, N. Mishra, J. Lu, H. Shan, G. Jiang, and X. Huang, Prolonged presence of SARS-CoV-2 viral 
RNA in faecal samples. Lancet Gastroenterol Hepatol, 2020. 5(5): p. 434-435. 7158584 
2. Jeon, S., M. Ko, J. Lee, I. Choi, S.Y. Byun, S. Park, D. Shum, and S. Kim, Identification of antiviral 
drug candidates against SARS-CoV-2 from FDA-approved drugs. bioRxiv, 2020: p. 
2020.03.20.999730.  
3. Jung, E., S. Nam, H. Oh, S. Jun, H.J. Ro, B. Kim, M. Kim, and Y.Y. Go, Neutralization of Acidic 
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