Clinical trial NCT04668950
Conditions: Covid19 Coronavirus
Keywords: fluvoxamine
Sponsor: Washington University School of Medicine
Start date: 2020-12-22; Completion date: 2021-09-28
Enrollment: 670 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this research study is to determine if a drug called fluvoxamine can be used early in the course of the COVID-19 infection to prevent more serious complications like shortness of breath. Fluvoxamine is an anti-depressant drug approved by the FDA for the treatment of obsessive-compulsive disorder. The use of fluvoxamine for the treatment of COVID-19 is considered investigational, which means the US Food and Drug Administration has not approved it for this use.

This study is fully-remote, which means that there is no face-to-face contact; study materials including study drug will be shipped to participants' houses. People around the United States and Canada can participate.

Detailed description:
The investigators will randomize approximately 880 participants, age 30 and older, who have tested tested positive for COVID-19 and are currently experiencing mild symptoms. People around the United States and Canada can participate. All interactions for this study will be conducted remotely by videoconferencing, email, or phone.

Screening: All participants will first complete a pre-screen to see if they may be eligible for the study. Once a participant is confirmed eligible and consented, the study team will send the study materials. These materials will consist of study medication and self-monitoring equipment, including an oxygen saturation monitor, blood pressure monitor, and thermometer.

RCT: Participants will be randomly assigned (1:1) to take either fluvoxamine or a placebo. This phase of the study will last approximately 15 days and is double-blinded. Participants will take up to 100mg of fluvoxamine or placebo by mouth twice a day for a daily total of 200mg. Participants will continue this dose for approximately 15 days. Depending on tolerability, the dose may be adjusted. Participants will also complete short 5 minute assessments daily to report the results of self-monitoring (including oxygen level, blood pressure, and temperature), a shortness of breath rating and any adverse events.

Follow-up Phase: The study team will follow participants for approximately 90 days after the end of the randomized phase. If needed, the study team will review medical records to determine the clinical course of participants.

Arms: arm 1: Start fluvoxamine 50mg capsule once, then 100mg twice daily. May reduce dose for tolerability reasons. Will be followed in the RCT for approximately 15 days. arm 2: Start placebo one capsule, twice daily. May reduce dose for tolerability reasons. Will be followed in RCT for approximately 15 days.
Interventions: intervention 1: Fluvoxamine intervention 2: Placebo
Intervention descriptions: intervention 1: Up to 200mg per day (2 capsules per day) as tolerated, for approximately 15 days intervention 2: Will take 2 capsules per day as tolerated for approximately 15 days

Protocol documents:
Prot_000.pdf: 
FLUVOXAMINE FOR EARLY TREATMENT OF COVID-19: A FULLY-REMOTE, RANDOMIZED PLACEBO 
CONTROLLED TRIAL 
 
Principal Investigator: Eric Lenze, MD and Angela Reiersen, MD 
Sponsor: Washington University School of Medicine 
Funded by: COVID-19 Early Treatment Fund 
Version Number:  v. 5 
April 14, 2021 


FLUVOXAMINE FOR EARLY TREATMENT OF COVID-19: A FULLY-REMOTE, RANDOMIZED PLACEBO CONTROLLED TRIAL 
 
 
 
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1 
 
PROTOCOL SUMMARY 
1.1 
SYNOPSIS  
Title: 
FLUVOXAMINE FOR EARLY TREATMENT OF COVID-19: A FULLY-REMOTE, 
RANDOMIZED PLACEBO CONTROLLED TRIAL  
Study Description: 
This clinical trial will test a promising drug for early treatment of COVID-19 
in 880 adults who are SARS-CoV-2 positive and recently infected.  The trial 
will determine whether fluvoxamine (1) prevents clinical deterioration 
(defined as the combination of shortness of breath and hypoxia), and (2) 
improves short- and long-term functional outcome. Clinical deterioration is 
the primary endpoint. Fluvoxamine is an SSRI (FDA approved for OCD and 
Social Anxiety Disorder) that also activates the sigma-1 receptor (an 
immunomodulatory receptor). It prevented clinical deterioration in a 
preliminary RCT (called STOP COVID).  Fluvoxamine (or placebo) will be 
given for approximately 15 days post-randomization, during which 
participants will self-report on shortness of breath and oxygen saturation 
via a twice-daily survey.  At the end of approximately 15 days, fluvoxamine 
(or placebo) will be stopped.  An additional survey at approximately day 15 
and approximately day 90 will assess function.  
Objectives: 
 
The primary objective of this clinical trial is to test whether fluvoxamine 
prevents clinical deterioration in early COVID-19 illness.   
 
The primary outcome will be clinical deterioration, defined as both of the 
following: (1) presence of dyspnea and/or hospitalization for shortness of 
breath or pneumonia, plus (2) decrease in O2 saturation (<92% on room air 
and/or supplemental oxygen requirement to keep O2 saturation ≥92%).   
The hypotheses are: 
Participants randomized to fluvoxamine will have a lower rate of clinical 
deterioration, compared to placebo.  
A secondary objective of this clinical trial is to test whether fluvoxamine 
improves 15-day and 90-day functional outcome in early COVID-19 
illness.   
 
Secondary outcome will be post-COVID functioning at approximately  15 
days and at approximately 90 days post-randomization using the PROMIS 
10-item Global Health Scale.  This secondary outcome reflects the 
increasing concern regarding persistence of COVID-19 illness and 
functional impairment in a substantial percentage of individuals with 
initially “mild” symptoms. We will also explore persistent symptoms of 
COVID-19 at these timepoints.   
The hypotheses are:  


FLUVOXAMINE FOR EARLY TREATMENT OF COVID-19: A FULLY-REMOTE, RANDOMIZED PLACEBO CONTROLLED TRIAL 
 
 
 
2 
Participants randomized to fluvoxamine will have higher post-COVID 
functional status at day 15 and day 90, compared to placebo. 
Another secondary objective is to test whether baseline oxygen saturation 
moderates (modulates the drug-placebo difference) fluvoxamine’s effect 
on clinical deterioration.   
The hypothesis is:  
Participants with baseline O2 saturation ≤96% will have a larger treatment 
effect size (i.e., larger fluvoxamine-placebo difference in rate of clinical 
deterioration) than those with O2 saturation ≥97%.   
The basis for this hypothesis is an exploratory analysis of the preliminary 
RCT which found that all cases of clinical deterioration (26% of the placebo 
group) occurred in participants whose baseline oxygen saturation was 96% 
or less. 
Endpoints: 
Primary Endpoint: Clinical Deterioration 
Secondary Endpoints: PROMIS Global Health Scale 
Study Population: 
Not currently hospitalized, participants age 30 and older who are SARS-
CoV-2 positive and symptomatic with onset <7 days. 
Phase: 
Phase 3 
Description of 
Sites/Facilities Enrolling 
Participants: 
Washington University School of Medicine in St. Louis 
Northwestern University 
University of Utah 
Fred Hutchinson Center Clinical Research Center 
Icahn School of Medicine at Mount Sinai 
Description of Study 
Intervention: 
Fluvoxamine Maleate, 100mg twice daily x 15 days 
 
Study Duration: 
Up to 3 months 
Participant Duration: 
Up to 3 months 
 
 
1.2 
SCHEMA 
 
 
 
Diagram 1: Randomized Clinical Trial 


FLUVOXAMINE FOR EARLY TREATMENT OF COVID-19: A FULLY-REMOTE, RANDOMIZED PLACEBO CONTROLLED TRIAL 
 
 
 
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Prior to  
Enrollment 
 
 
 
 
 
 
 
 
 
Time Point  
 
 
Baseline 
Time Point  
 
 
 
 
Day 0-15 
Treatment 
 
 
 
 
Day 15 
 
 
 
 
 
Day 90 
 
 
 
 
 
Total 1100:  Pre-Screen, Obtain informed consent. Screen potential participants by 
inclusion and exclusion criteria. 
Study Supplies (including pulse oximeter) and medication (fluvoxamine vs placebo, for 15 
days) is delivered to participants  
Participants report via REDCap: (1) twice-daily O2 sat, temperature and shortness of breath. (2) once 
daily pulse, blood pressure. Research staff collect data on any hospital/ER/urgent care visits. 
Participants take fluvoxamine 100mg (or placebo), twice daily.   
PLACEBO 
FLUVOXAMINE 
 
Participants record self-collected baseline measurements.  Participant then takes first 
(day 0) dose of fluvoxamine 50mg (or placebo) and records this, whereupon they are in 
the modified intention to treat group (n=880 anticipated*). 
Randomize 
*Note this number (n=880) refers to the modified intent to treat sample: all participants for whom study eligibility is 
met at baseline and who take at least one dose of study medication.  All data analyses will be conducted using this 
sample.  The larger number n=1100 refers to the estimated number who will receive study medication (and therefore 
are considered randomized) in order to achieve n=880 in the modified intent to treat sample. 
Last day of study medication. 
Participants complete PROMIS Global Health survey and make a treatment guess (fluvoxamine/placebo) 
Participants fill out survey about their COVID-19 symptoms 
Research staff continues to collect details on hospital/ER/urgent care that occurred during days 1-15 
Last day of study. 
Participants complete PROMIS Global Health survey  
Participants fill out survey about their COVID-19 symptoms 
Research staff continues to collect details on hospital/ER/urgent care that occurred up to day 90. 


FLUVOXAMINE FOR EARLY TREATMENT OF COVID-19: A FULLY-REMOTE, RANDOMIZED PLACEBO CONTROLLED TRIAL 
 
 
 
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1.3 
SCHEDULE OF ACTIVITIES (SOA) 
 
 
Procedures 
Screening 
Day -5 to 0 
Enrollment/Bas
eline 
 
Treatment days 
0-15  
Day 15  
Treatment 
Day 90 Post 
Treatment 
Informed consent 
X 
 
 
 
 
Demographics 
X 
 
 
 
 
Medical history 
X 
 
 
 
 
Randomization 
X 
 
 
 
 
Administer study intervention 
 
X 
 
 
X 
Twice-daily REDCap survey to assess oxygen 
saturation, self-reported dyspnea, vital 
signs, and treatment adherence 
X--------------------------------------------X 
 
 
Assessment of details of COVID-19 care 
received (e.g.. hospitalization, ER, or urgent 
care visit; length of stay; requirement for 
supplemental oxygen, ventilator, or other 
organ support; mortality) 
X---------------------------------------------X 
 
X 
Adverse event review and evaluation 
X----------------------------------------------X 
X 
Treatment guess (patient guesses whether 
they took fluvoxamine vs placebo) 
 
 
 
X 
 
 
 
2 
 
INTRODUCTION 
 
2.1 
STUDY RATIONALE  
 
2.2 
BACKGROUND  
Coronavirus disease 2019 (COVID-19), caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-
2), can cause serious illness including lung damage, hypoxia, and cardiac damage, which can lead to hospitalization, 
intensive care unit (ICU) admission, and death.1   
Clinical deterioration often occurs during the second week of illness. Early investigations of COVID-19 found that serious 
illness leading to hospital admission occurred a median of 8-10 days after initially mild to moderate symptoms.2-4 
Evidence that many patients with COVID-19 develop lung damage from an excessive inflammatory response led to 
recommendations to repurpose immunomodulatory drugs to counter this hyperinflammation.5,6  More recent evidence 
supports the assertion that the inflammatory reaction, including elevations in cytokines such as IL-6, predicts clinical 
deterioration.7,8 
Many patients have debilitating persistent symptoms and loss of function, even three or more months after the initial 
stage of illness.  The causes of this persistent illness are unclear and likely heterogeneous; they include persistence of 
the viral infection, immunological changes, and exacerbation of underlying medical conditions.9 As a result, both anti-
viral and immunomodulatory drugs could potentially prevent or reduce this post-COVID functional impairment. 
 


FLUVOXAMINE FOR EARLY TREATMENT OF COVID-19: A FULLY-REMOTE, RANDOMIZED PLACEBO CONTROLLED TRIAL 
 
 
 
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Fluvoxamine, an SSRI, repurposed for early treatment of COVID-19 
Fluvoxamine is unique among the SSRIs in that it strongly activates the sigma-1 receptor (S1R), and preclinical studies 
have suggested that by this mechanism fluvoxamine could prevent the immunopathology seen in serious COVID-19.  In 
2019, it was shown that fluvoxamine given early in treatment, reduced deterioration and mortality in two animal models 
of sepsis (bacterial peritonitis and lipopolysaccharide stimulation).10 The same study demonstrated that fluvoxamine was 
anti-inflammatory in human cells, reducing IL-6 and other cytokines in lipopolysaccharide-induced inflammation.  This 
study is part of an increasing body of research supporting the S1R in protection from deleterious consequences of 
inflammation.11-13  
Fluvoxamine has one of the strongest S1R agonist effects of any existing medication.14,15  It is also highly lipophilic and 
has rapid, substantial intracellular uptake.16  Fluvoxamine also has many pragmatic advantages for repurposing, 
including ease of use, high safety margin, good tolerability, wide availability, and low cost.  We determined that, if it 
could be shown that fluvoxamine had a beneficial effect in reducing clinical deterioration of COVID-19, the drug (and 
other S1R agonists) could be an important addition to the armamentarium vs. this pandemic. 
Therefore, we conducted a double-blind, placebo-controlled RCT to test whether fluvoxamine, given as early treatment 
in individuals with mild COVID-19 illness, might prevent clinical deterioration. 49  
From April 10-Sept 19, 2020, we conducted the 
STOP COVID trial (ClinicalTrials.gov Identifier: 
NCT04342663), a preliminary single-site trial 
conducted in Missouri and Illinois, to test whether 
a course of fluvoxamine given early in COVID-19 
illness could prevent clinical deterioration.  
Participants were recruited mainly from review of 
electronic medical records to identify individuals 
with a recent positive SARS-CoV-2 PCR test. Based 
on review of the medical record, potentially eligible 
individuals were contacted to confirm eligibility 
criteria and offer participation in the study. The 
study was fully-remote, with no in-person contact 
with participants.  
The STOP COVID participant flow diagram is shown along with participant baseline characteristics (see Figure and Tables 
on next page). Participants were randomized to receive fluvoxamine 100 mg vs. placebo up to three times daily. Study 
medication and monitoring equipment (fingertip pulse oximeter, blood pressure cuff, thermometer) were delivered 
directly to participant homes. Participants entered their own O2 saturation, vital signs, and symptom rating data twice 
daily for 15 days online or via phone into REDCap surveys, which were monitored daily by study staff. Participants were 
contacted as needed to clarify symptom and vitals/ O2 saturation (e.g., when participants reported an out-of-bounds 
value or one indicating hypoxia). This monitoring included study staff, under study physician supervision, advising 
participants to contact their physician or visit an emergency room when appropriate. The primary study endpoint was 
time to clinical worsening, which was defined as 1) dyspnea or hospitalization for shortness of breath or pneumonia and 
2) O2 saturation <92% or requirement for supplemental O2 to keep saturation ≥92%.   


FLUVOXAMINE FOR EARLY TREATMENT OF COVID-19: A FULLY-REMOTE, RANDOMIZED PLACEBO CONTROLLED TRIAL 
 
 
 
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FLUVOXAMINE FOR EARLY TREATMENT OF COVID-19: A FULLY-REMOTE, RANDOMIZED PLACEBO CONTROLLED TRIAL 
 
 
 
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The key finding from STOP COVID was that 0% (0/80) 
of fluvoxamine-treated individuals suffered clinical 
deterioration, vs. 8.3% (6/72) of those who received 
placebo (Figure, right).  In this study, fluvoxamine was 
generally well-tolerated.  The fluvoxamine group had 
1 serious adverse event and 11 other adverse events, 
while the placebo group had 6 serious and 12 other 
adverse events. Further, we collected 30-day follow-
up data (after the 15-day RCT phase): 1 individual in 
each group received ER or hospital care (1 placebo for 
chest pain, 1 fluvoxamine for headache) and no 
individuals clinically deteriorated.  This demonstrated 
that fluvoxamine prevented, rather than merely 
delayed, deterioration. 
 
This preliminary study demonstrates the feasibility of conducting a fully-remote COVID-19 early treatment trial, with 
first dose of medication an average of 4 days after onset of symptoms.  A fully-remote design has been demonstrated to 
be an efficient, pragmatic technique for conducting COVID-19 early treatment trials, as demonstrated by this study as 
well as the hydroxychloroquine studies led by University of Minnesota. 
Baseline O2 may be a moderator of 
fluvoxamine’s treatment effect size.  As the 
figure to the right shows, we found that low-
normal baseline O2 saturation may be a risk 
factor for clinical deterioration and a 
moderator of fluvoxamine’s treatment effect 
size.  In post-hoc analyses, we examined 
baseline (pre-treatment) O2 saturations in the 
152 participants.  All of the clinical 
deterioration occurred in individuals with 
baseline O2 saturation of ≤96%: 6/23 (26%), 
compared to 0/49 (0%) in those with baseline 
O2 saturation ≥97%.  This is important 
because it suggests that fluvoxamine could be 
given to individuals with early COVID-19 only 
if and when their O2 saturation falls to 96% or 
less.  
Anti-inflammatory (cytokine reduction) actions resulting from S1R activation would fit with recent findings of benefits of 
other anti-inflammatory drugs for COVID-19, including colchicine and corticosteroids.17,18  However, a recent study found 
lower levels of cytokines in severe COVID-19 compared to bacterial sepsis.19  If fluvoxamine’s benefit is a S1R-mediated 
effect, this drug could be utilized not only to reduce morbidity and mortality in COVID-19, but also in other medical 
conditions in which treatments to dampen immunopathology are relevant – including future pandemics. 
There were, however, several limitations to this study.  First, this was a single-site study with a small sample size; the 
small sample size also results in wide confidence intervals (i.e., fluvoxamine appeared 100% effective at preventing 
clinical deterioration, but true effect size may be much lower than this).  Second, we did not enrich the sample for risk 
factors for deterioration (such as older age); as a result, the rate of deterioration was low (8.3%) in the placebo group; 
this led to a fragile study finding.    


FLUVOXAMINE FOR EARLY TREATMENT OF COVID-19: A FULLY-REMOTE, RANDOMIZED PLACEBO CONTROLLED TRIAL 
 
 
 
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Third, we attempted to measure symptoms of COVID-19 as a treatment outcome, by asking about most severe symptom 
at baseline and then measuring change in that symptom.  This method proved to be invalid for several reasons.  First, 
the presenting symptoms were highly heterogeneous as demonstrated in the Table above. Second, we conducted 
several advanced data analytic techniques focusing on latent trajectory modelling, and we found that the temporal 
dynamics of COVID-19 symptoms were highly heterogeneous.  In other words, while symptoms overall decelerated 
(declined non-linearly over time), the trajectories of symptoms varied greatly between participants.  This great 
heterogeneity of symptoms and their time course presents a challenge for the assessment of symptom change in clinical 
trials.20  A validated measure of functional status may be more robust for assessing COVID-19 persistence; however, we 
did not include such a measure in STOP COVID.  Additionally, a longer-term outcome is needed (beyond 15 days) to 
assess persistence of COVID-19.   
Fluvoxamine Possible Mechanisms of Action 
Fluvoxamine is a selective serotonin reuptake inhibitor (SSRI) and a S1R agonist.21 The preliminary study was motivated 
by a hypothesis that S1R agonists could dampen excessive inflammation in COVID-19.  This and other potential 
mechanisms by which fluvoxamine might improve outcomes in COVID-19 are summarized below.  
1) Anti-inflammatory effects though the S1R-IRE pathway.  The S1R is an endoplasmic reticulum (ER) chaperone protein 
involved in many cellular functions, including regulation of the ER stress response/unfolded protein response (UPR) and 
inflammation.22 S1R has been shown to inhibit ER stress sensor inositol-requiring enzyme 1α (IRE1) mediated splicing of 
XBP123, a master regulator of cytokine production. These anti-inflammatory effects may be the most likely explanation 
for fluvoxamine’s beneficial effects. In COVID-19, an excessive inflammatory process known as “cytokine storm” may 
contribute to worsening of symptoms and cardiopulmonary complications, which can sometimes occur around the 
second week of illness. Fluvoxamine may dampen this excessive inflammatory response.   
In a 2019 study by Rosen and colleagues, fluvoxamine showed benefit in preclinical models of inflammation and sepsis.10 
In one model, mice were exposed to the Toll-like receptor 4 (TLR4) ligand lipopolysaccharide (LPS), which can trigger an 
inflammatory response.  In another model, a fecal slurry was injected, which triggers a usually sub-lethal infection and 
an inflammatory response. Mice lacking the S1R showed excessive increases in cytokine levels and greatly reduced 
survival under either of these conditions, suggesting the S1R inhibits excessive inflammatory responses.  Wildtype mice 
exposed to the same inflammatory triggers showed reduced cytokine levels and increased survival when treated with 
fluvoxamine (a S1R agonist). When investigating the underlying mechanism of this effect, the authors demonstrated that 
S1R inhibits activity of IRE1, which in turn prevents the excessive cytokine production. In an experiment using human 
peripheral blood, they also showed that fluvoxamine can reduce LPS-induced cytokine production by human cells. In the 
case of COVID-19, fluvoxamine’s S1R agonist action may have a similar ability to reduce the excessive inflammatory 
response induced by the viral infection, thus reducing inflammation-mediated organ damage. 
2) Anti-viral action through effects on lysosomes, autophagy and/or endocytosis.  Coronaviruses utilize cathepsin 
proteases present in the late endosome to facilitate cell entry24 and re-model ER and phagosomal membranes into sites 
of viral replication.25 Both of these processes require stimulating the endocytosis and phagosome arms of autophagy 
and then terminating autophagy before lysosomal fusion. SARS-CoV-2 proteins Nsp6, Nsp2, Orf7b, and Orf9b have been 
shown to localize with and modulate components of the autophagy pathway.26,27 Further Nsp6 has been shown to 
physically associate with S1R.28 Critically, S1R not only drives early stage autophagy through the IRE1/UPR pathway, but 
is also essential for lysosomal fusion to complete autophagy, likely by chaperoning components of the SNARE complex.29 
We hypothesize activation of S1R with fluvoxamine may overcome Nsp6 inhibition of S1R to allow autophagy to clear 
SARS-CoV-2. Others have also recognized targeting the autophagy pathway as a promising strategy to treat SARS-CoV-
2.30,31 
Chemically, fluvoxamine is a cationic amphiphilic drug (CAD) with a log P 3.1 and a pKa 9.4 and, along with a range of 
antipsychotic and antihistamine drugs, preferentially accumulates in the lysosome. Perhaps due to this, fluvoxamine 
achieves higher concentrations in the lungs (which are lysosome-rich) than in the brain.32 In the case of COVID-19, this 
may enhance treatment effects in the airway epithelium.33 At high doses (10 uM), CADs including fluvoxamine, have 


FLUVOXAMINE FOR EARLY TREATMENT OF COVID-19: A FULLY-REMOTE, RANDOMIZED PLACEBO CONTROLLED TRIAL 
 
 
 
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been shown to inhibit lysosomal acid sphingomyelinase34 to cause drug-induced phospholipidosis. This non-specific 
activity can globally dysregulate lipid homeostasis, which in turn modulates autophagy through the mTOR nutrient 
sensing pathway.35  
3) Antiviral effects and prevention of organ damage through regulation of the ER stress response/UPR. Some viruses 
hijack the ER stress response/UPR to achieve viral functions36,37, and a number of studies have suggested drugs targeting 
the ER stress response/UPR may be beneficial in treating COVID-19.28,38  S1R agonists (such as fluvoxamine) regulate ER 
stress.  S1R ligand effects on ER stress and other ER functions may reduce organ dysfunction/damage.39,40 
4) Antiplatelet Effects (common to all SSRIs). Hyperactivity of platelets may contribute to pathophysiological processes 
leading to thrombotic complications in COVID-19.41 SSRIs can inhibit platelet activation, which may reduce the risk of 
thrombosis, and these anti-platelet effects may be cardioprotective.42  
5) Elevation of melatonin levels in the body. The SARS-CoV-2 virus may activate the NLRP3 inflammasome43, which may 
contribute to cytokine storm.44 Melatonin may act on this NLRP3 pathway to reduce inflammation.45,46 Fluvoxamine 
inhibits the metabolism of melatonin, so can increase the melatonin level in the body47, which may be beneficial in 
COVID-19. 
 
In summary: We need to replicate (or refute) these preliminary findings in a larger confirmatory trial.  We need to find 
out: (1) can fluvoxamine prevent clinical deterioration in early COVID-19? (2) Can fluvoxamine mitigate the long-term 
impact of COVID-19? (4) Do the benefits of fluvoxamine for preventing deterioration vary as a function of baseline 
oxygen saturation? 
 
2.3 
RISK/BENEFIT ASSESSMENT   
 
2.3.1 KNOWN POTENTIAL RISKS  
Potential risks associated with study assessments 
There are no risks associated with any of the assessments. 
POTENTIAL RISKS ASSOCIATED WITH STUDY MEDICATION 
Fluvoxamine:  
General comments: Fluvoxamine is an antidepressant drug that functions as a selective serotonin reuptake inhibitor 
(e.g., similar to escitalopram (Lexapro), fluoxetine (Prozac), sertraline (Zoloft), etc – among the most commonly 
prescribed drugs in the US). Its risk profile below is for chronic use in a psychiatrically ill population; the risks for short-
term use in a non-psychiatric population are likely lower, as our initial STOP COVID trial demonstrated (18 total AEs in 80 
fluvoxamine-randomized participants, compared to 19 AEs in 72 placebo participants).  The research team will carefully 
evaluate co-prescribed drugs as well as OTC medications and will instruct participants to minimize caffeine (which has its 
metabolism inhibited by fluvoxamine), to mitigate drug-drug interactions.   
Likely risks: none. 
Less likely (1-10%): Nausea, Vomiting, Weight loss, Yawning, Loss of appetite, Agitation/Nervousness/Anxiety, Insomnia, 
Somnolence, Tremor, Headache, Dizziness, Palpitations, Tachycardia (high heart rate), Abdominal pain, 


FLUVOXAMINE FOR EARLY TREATMENT OF COVID-19: A FULLY-REMOTE, RANDOMIZED PLACEBO CONTROLLED TRIAL 
 
 
 
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Dyspepsia (indigestion), Diarrhea, Constipation, Hyperhidrosis (excess sweating), Asthenia (weakness), Malaise, Sexual 
dysfunction (including delayed ejaculation, erectile dysfunction, decreased libido, etc.), Xerostomia (dry mouth). 
Rare (<1%): Arthralgia, Hallucination, Confusional state, Extrapyramidal side effects (e.g. dystonia, parkinsonism, tremor, 
etc.), Orthostatic hypotension, Cutaneous hypersensitivity reactions (e.g. edema [buildup of fluid in the tissues], rash, 
pruritus), Mania (elevated mood together with reduced need for sleep and increased energy), seizures, Abnormal 
hepatic (liver) function, Photosensitivity (being abnormally sensitive to light), Galactorrhea (expulsion of breast milk 
unrelated to pregnancy or breastfeeding). 
Minimizing risk of fluvoxamine in this study: 
Fluvoxamine has been used for the treatment of depression and anxiety disorders worldwide since the 1990s.  Its safety 
profile is well-known from millions of patient-years of use.  It is not fatal even in overdose48 and it does not prolong the 
QTc interval unlike other SSRIs (especially citalopram).  It requires no therapeutic drug level monitoring or safety labs for 
its use. Its use in this study is within FDA-approved dosing; and it is only used for approximately 15 days.  As well, all 
participants receive an initial dose of 50mg, and based on tolerability with this initial dose and in the first day(s) of 
intervention, the dose can be adjusted as needed to minimize side effects.  Further, monitoring will include oversight by 
physicians with expertise in this drug class.  Study exclusions will minimize the risk of clinically significant drug:drug 
interactions or other problems. 
Other risks 
There may also be unknown risks.  We will adjust the informed consent process if new risks are identified.   
2.3.2 KNOWN POTENTIAL BENEFITS  
Although the study hopes to prevent serious symptoms of COVID-19, there is no guarantee that the study participants 
will receive any clinical benefits by participating in the study. All participants regardless of study randomization, will 
receive increased monitoring of their COVID-19 illness, potentially leading to management (e.g., being told to contact 
their provider or go to the ER) that would not have occurred otherwise or as promptly without this monitoring.  
Importance of the Knowledge to be Gained 
COVID-19 is a US-wide and worldwide public health emergency. This study may result in effective treatment that 
reduces its morbidity. 
 
2.3.3 ASSESSMENT OF POTENTIAL RISKS AND BENEFITS  
RECRUITMENT AND CONSENT 
All personnel involved in the design and conduct of the research involving human participants will receive the required 
education on the protection of human research participants prior to the start of this project. Procedures to recruit 
participants for the protocol and obtain their informed consent or assent are conducted and supervised by the PI. 
Trained study staff will discuss the study, including the risks and benefits of participation, with potential participants and 
relevant members of their treatment team as needed to provide informed consent for interested individuals. Informed 
consent will be obtained from all participants before any study procedures are initiated. The consent form, which 
incorporates HIPAA authorization, contains a description of the purpose and procedures, risks, procedures to minimize 
them, and possible benefits. Participants will be assured that participation in the study in completely voluntary, and that 
they are free to withdraw consent at any time and discontinue participation without prejudice to their current or future 


FLUVOXAMINE FOR EARLY TREATMENT OF COVID-19: A FULLY-REMOTE, RANDOMIZED PLACEBO CONTROLLED TRIAL 
 
 
 
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medical care. The objectives of the project, all of the requirements for participation, and any possible discomforts and 
risks will be clearly explained to the participants orally and in writing.  All participants must sign a consent document (e-
consent or paper), indicating their consent, approved by the Washington University School of Medicine Institutional 
Review Board, before they can participate in the study. 
PREVENTING BREACH OF CONFIDENTIALITY 
 
Electronic records (computer files, electronic databases, etc.): The risks of breaching confidentiality will be strictly 
limited by the use of locked and restricted access to data, as well as the use of participant ID numbers rather than names 
in the survey database. All other data will be collected/entered in the secured, centralized REDCap database.  
Paper/hard copy records (hard copy surveys, questionnaires, consent, etc.): The majority of data for this study will be 
collected and maintained electronically.  For participants without access to internet, we will collect consent and data 
using paper documents. The risks of breaching confidentiality for paper documents will be strictly limited by the use of 
locked and restricted access to data, as well as the use of participant ID numbers rather than names whenever possible. 
Medical records containing PHI and research records are stored using the two-lock rule.  
Data and Safety Monitoring Plan:  
Serious adverse events (SAE) and adverse evets will be monitored continuously throughout the study and will be 
reported to the DSMB and IRB according to pre-specified requirements. SAE/AE rates and interim study results will be 
reviewed and discussed by the DSMB at the DSMB meetings. 
 
3 
OBJECTIVES AND ENDPOINTS 
 
OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR ENDPOINTS 
Primary 
 
 
(a) Participants randomized to 
fluvoxamine will have a lower rate 
of clinical deterioration, compared 
to their respective placebos. (b) 
Participants with baseline O2 
saturation ≤96% will have a larger 
treatment effect size with 
fluvoxamine (i.e., larger 
fluvoxamine-placebo difference in 
rate of clinical deterioration) than 
those with O2 saturation ≥97%. 
 
The primary outcome will be clinical 
deterioration, defined as both of the 
following: (1) presence of dyspnea 
(SOB rating of 4+ on the twice daily 0-
10 scale, and/or hospitalization for 
shortness of breath or pneumonia, 
plus (2) decrease in O2 saturation 
(<92% on room air via the twice-daily 
at-home self-monitoring or via 
monitoring at a hospital/ER/urgent 
care center, and/or supplemental 
oxygen requirement to keep O2 
saturation ≥92%).   
Two blinded research staff will 
adjudicate all potential cases of 
clinical deterioration to confirm these 
criteria are (or are not) met. 
 
The goal of the study is to test 
prevention of clinical 
deterioration.  We chose a clinical 
outcome including a laboratory-
confirmed (ie SpO2) endpoint, 
consistent with World Health 
Organization clinical trial 
recommendations 
(https://www.who.int/blueprint/15-
01-2020-nfr-bp-wg-clinical-trials-
ncov.pdf?ua=1).   In our previous 
trial (STOP COVID), 6 participants 
met this endpoint; 5/6 went to the 
hospital and 4/6 were hospitalized 
for an average of 10 days, 
demonstrating the clinical relevance 
of this endpoint. Although we saw 
no mortality and only 1 ventilator, 
mortality from COVID-19 is largely 


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OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR ENDPOINTS 
due to a generalized inflammatory 
response with a deterioration in the 
respiratory status being the largest 
contributor to death. A focus on 
clinical deterioration from a 
respiratory standpoint, commonly 
observed in COVID-19 patients early 
on prior to ventilator need, would 
be in line with WHO’s scale and 
would be consistent with an early 
deterioration observed in the 
clinical course of COVID-19 as 
described in the symptomatology 
literature   
 
Regarding baseline O2 saturation 
potential moderator of treatment 
effect on outcome, this is based on 
observations made in our 
preliminary study: all 6 cases of 
clinical deterioration (in the placebo 
group) were among those with 
baseline O2 saturation 96% or 
below. 
Secondary 
 
 
Participants randomized to 
fluvoxamine will have higher post-
COVID functional status at day 15 
and day 90, compared to placebo. 
 
Secondary outcome will be post-
COVID functioning at 15 days and at 
90 days using the PROMIS Global 
Health Scale.  This secondary 
outcome reflects the increasing 
concern regarding persistence of 
COVID-19 illness and functional 
impairment in a substantial 
percentage of individuals with 
initially “mild” symptoms. We will 
also explore persistent symptoms of 
COVID-19 at these timepoints.   
 
It is increasingly clear that COVID-19 
is a persistent illness for some.  
Measuring this persistence is 
challenging because the symptoms 
are highly heterogeneous and 
temporally dynamic.  An alternative 
is to use a validated measure of 
functional status to assess whether 
fluvoxamine results in an increased 
level of function and quality of life.  
The 10-item PROMIS Global Health 
Scale is a validated measure of 
function and quality of life. 
Tertiary/Exploratory  
 
 
We will also explore symptoms of 
COVID-19 at approximately day 15 
and day 90. 
We will ask each participant about 
symptoms of COVID-19 on a 0-10 
scale for greatest severity ever of the 
symptom, and a 1-10 scale for 
current severity of the symptom.  
 
The long-term course of symptoms 
of COVID-19 is still poorly 
understood.  These data will 
provide additional information 
about COVID-19 symptoms and 
whether their persistence is 
influenced by the study 
medications. 
 


FLUVOXAMINE FOR EARLY TREATMENT OF COVID-19: A FULLY-REMOTE, RANDOMIZED PLACEBO CONTROLLED TRIAL 
 
 
 
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4 
STUDY DESIGN  
 
4.1 
OVERALL DESIGN 
Summary: We propose a fully-remote US study: we will screen, consent, deliver fluvoxamine/placebo and other supplies 
to (self-quarantined) patients, including thermometers, blood pressure cuffs, and O2 saturation monitors.  We will 
collect data via participants’ phones/computers and via medical records.  We will carry out national recruitment, similar 
to the University of Minnesota COVID-19 hydroxychloroquine trials carried out in early 2020.   
Hypotheses: 
Primary: 
Participants randomized to fluvoxamine will have a lower rate of clinical deterioration, compared to placebo.  
Secondary: 
Participants randomized to fluvoxamine will have higher post-COVID functional status at day 15 and day 90, compared 
to placebo. 
Participants with baseline O2 saturation ≤96% will have a larger treatment effect size (i.e., larger fluvoxamine-placebo 
difference in rate of clinical deterioration) than those with O2 saturation ≥97%.   
Phase: 3 
Design: randomized, placebo-controlled, double-blinded, parallel design, nationally-recruiting, fully-remote, multi-site. 
Methods to minimize bias: placebo control, blinding, randomization. 
 
Interim analyses planned: none. 
Stratification planned: sex, age. 
Study team: The complementary expertise of our group will assure the success of this clinical trial, as already evidenced 
by the successful conduct of the preliminary trial supporting this application. 
Eric Lenze, M.D., is a clinical trialist and geriatric psychiatrist.  He has successfully conducted numerous clinical trials, 
including large-scale trials.  He and his research team led the STOP COVID trial that randomized 152 individuals to 
fluvoxamine or placebo for early treatment of COVID-19 and demonstrated fluvoxamine’s efficacy at preventing clinical 
deterioration. He will lead this clinical trial along with his study team, overseeing all aspects of the research. 
Angela Reiersen, M.D., M.P.E., is a child psychiatrist and epidemiologist with experience conducting studies of 
comorbidities, longitudinal course, and genetics (including pharmacogenetics) of various childhood-onset psychiatric 
disorders and a rare genetic disorder of endoplasmic reticulum (ER) stress (Wolfram Syndrome).  She developed the 
hypothesis regarding fluvoxamine’s potential anti-inflammatory benefits in the treatment of COVID-19. Dr. Reiersen 
hypothesized the potential anti-inflammatory effect may occur through fluvoxamine’s known actions on the S1R-
Inositol-requireing enzyme 1α (IRE1) pathway, which is a component of the ER stress response. She initially became 
interested in S1R ligands years ago due to observed differences in anxiety/depression treatment response to SSRIs with 
varying S1R actions, which she saw among study participants with Wolfram Syndrome. Along with Dr. Lenze, she 
developed and oversaw the STOP COVID trial.  Her role in the proposed trial will include study design (with emphasis on 
development of appropriate symptom questionnaires and other outcome measures), supervision of study staff, 
interpretation of findings based on knowledge of drug mechanisms, supervision of data analysis, and publication of 
results.  


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Caline Mattar, M.D., is an infectious disease physician and global health researcher.  She helped design and oversee the 
STOP COVID trial.  She will continue to advise the conduct of this new study and will help interpret, publish, and 
disseminate the results. 
William Powderly, M.D., is an infectious disease physician. He is the Director of the Institute for Public Health at 
Washington University in St. Louis. He also directs the Institute for Clinical and Translational Sciences (ICTS) and is co-
director of the Division of Infectious Diseases at the Washington University School of Medicine.   He is an expert on the 
immune pathologies present in severe COVID-19.  He will provide advice on the conduct of this study, and will help 
interpret, publish, and disseminate the results. 
Phil Miller, biostatistician, has directed data management and analysis for numerous clinical trials, including many large-
scale efforts, and has worked with Dr. Lenze for the past 5 years on several successful clinical trials, including STOP 
COVID. 
Michael Avidan, M.D., is a critical care and anesthesiology specialist.  He has successfully conducted several large 
pragmatic clinical trials in critical care populations, including the use of intra-operative ketamine to prevent post-
operative delirium. He will provide advice on the conduct of this study, and will help interpret, publish, and disseminate 
the results. 
John W. Newcomer M.D., is a psychiatrist and the President and CEO of South Florida Behavioral Health Network in 
Miami, Florida. He has previously a professor in psychiatry at Washington University in St. Louis. He will act as a 
consultant on this project. 
Mike Rich, M.D., is a cardiologist at Washington University.  He is known for his work on clinical trials, including studies of 
antidepressant medication in medically ill populations.  He is also the PI of a new study on long-term post-COVID-19 
functioning. 
Jeffrey Rado, M.D., is a psychiatrist and internist at Northwestern University. He is a clinical trialist who will lead the study 
at the Northwestern site. 
Rachel Hess, M.D., is an internist and PI of the CTSA at University of Utah.  She is an experienced clinical trialist who has 
carried out COVID-19 trials. 
Adam Spivak, M.D., is an infectious disease specialist at University of Utah.  He and Dr. Hess will lead the University of 
Utah site for this trial. 
Joshua Schiffer, M.D., is an infectious disease specialist at Fred Hutchinson Cancer Research Center in Seattle, 
Washington.  He is an experienced COVID-19 clinical trialist. 
Rachel Bender Ignacio, M.D., is an infectious disease specialist at Fred Hutchinson Cancer Research Center in Seattle, 
Washington.  She is an experienced COVID-19 clinical trialist. She and Dr. Schiffer will lead the Fred Hutch site for this 
trial. 
Sean Liu, M.D., Ph.D., is an infectious disease specialist at Icahn School of Medicine at Mount Sinai Hospital in New 
York, New York. 
Internal consultant Charles Zorumski, M.D., is a neuroscientist and is chair of Psychiatry at Washington University.  He 
has been a member of the STOP COVID team and has provided scientific direction and will continue to do so. 
Consultant David Boulware, M.D., is an infectious disease specialist.  He has successfully conducted fully-remote clinical 
trials with national (and Canada) recruitment, including the hydroxychloroquine early treatment trial which randomized 491 
patients with early COVID-19 in approximately 6 weeks.  Dr. Boulware and his team has been advising the investigators 
on the development of this new trial and will continue to do so, to ensure successful recruitment, screening and remote 
assessment and treatment of a large national sample. 


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Consultant Matthew Pullen, M.D., is an infectious disease specialist.  He worked with Dr. Boulware as a key team 
member in the hydroxychloroquine study.  He will work with this team to ensure successful recruitment, screening and 
remote assessment and treatment of a large national sample. 
 
 
 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN 
Rationale for study design: placebo control provides the highest level of rigor for efficacy and safety analyses.  A placebo 
control is both necessary and safe/ethical because of the lack of a widely-available standard of care treatment for early 
COVID-19 illness. 
 
 
4.3 
JUSTIFICATION FOR DOSE 
Fluvoxamine: Participants receive a day zero dose of 50mg fluvoxamine (or matching placebo) in the evening 
immediately after the baseline assessment and confirmation of eligibility, and 100mg twice daily as tolerated, on days 1-
15.  This dose range was determined based on fluvoxamine’s binding affinity for the S1R.  After 15 days, this study drug 
is stopped; there is no need to taper fluvoxamine (i.e., to prevent SSRI withdrawal) after only a brief course. 
The dosing target of 200mg (100mg twice daily) in the proposed study is also justified by experience from the STOP 
COVID trial. That preliminary study used a target of 100mg three times daily based on the FDA maximum dose of 
300mg/day, and based on a review of the S1R agonist activity at various doses of fluvoxamine 
(https://pubmed.ncbi.nlm.nih.gov/17662961/).  However, in STOP COVID almost all participants (86/90; 96%) in the 
fluvoxamine group achieved a dose of 200mg/day, but only 50% increased up to 300mg/day and of those that did, this 
was only after 5-6 days’ treatment, which may have already been outside the period of greatest risk for clinical 
deterioration.  In other words, it did not appear necessary to reach 300mg/d.  We also reviewed fluvoxamine’s 
pharmacokinetics and binding affinity at the S1R with several experts in pharmacology, who agreed that a maximum of 
200mg/d was sufficient for adequate binding of the S1R.   
 
4.4 
END OF STUDY DEFINITION 
The end of the study is day 90, when the participant has completed the day 90 survey; or when the participant has 
withdrawn consent or was withdrawn by the PI. 
 
5 
STUDY POPULATION 
 
5.1 
INCLUSION CRITERIA 
Inclusion criteria:  
1) Men and woman age 30 and older;  
2) Not currently hospitalized  
3) Proven SARS-CoV-2 positive (per lab or physician report).  Positive test is within 3 days prior to or during the current 
symptomatic episode. 


FLUVOXAMINE FOR EARLY TREATMENT OF COVID-19: A FULLY-REMOTE, RANDOMIZED PLACEBO CONTROLLED TRIAL 
 
 
 
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Note: Test positivity can be via participant self-report initially; however, staff will also attempt to get confirmation (eg 
forwarded text from lab, photo of positive report, etc).  For randomized participants for who there is no confirmation, a 
pre-planned secondary analysis of outcome will be conducted without them. 
4) Currently symptomatic with one or more of the following symptoms: fever, cough, myalgia, mild dyspnea, chest pain, 
diarrhea, nausea, vomiting, anosmia (inability to smell), ageusia (inability to taste), sore throat, nasal congestion. 
5) Expectation, on screening, that the participant will start study medication within 7 days of symptom onset.   
Note: participants who are randomized and then fail to start study medication by day 7 of symptoms will (or 
may) remain in the study and be managed and assessed just as other randomized participants.  They will not be 
included in the modified intention to treat sample during data analysis. 
5) Able to provide informed consent.  
6) Upon initial screening, participant reports one of the following risk factors for clinical deterioration: age≥40, 
racial/ethnic group African-American, Hispanic, South Asian, or Native American (including more than one race), or 1+ of 
the following medical conditions which increase risk for developing moderate-severe COVID illness: obesity, 
hypertension, diabetes, heart disease (coronary artery disease, history of myocardial infarction, or heart failure), lung 
disease (eg asthma, COPD), immune disorder (eg rheumatoid arthritis, lupus). 
 
5.2 
EXCLUSION CRITERIA 
Note: exclusions are same as in previous STOP COVID trial, but with additional exclusions for Coumadin and several 
other medications, based on recommendations of DSMB and co-investigators. 
1) Illness severe enough to require hospitalization or already meeting study’s primary endpoint for clinical worsening (eg 
current O2 saturation <92% on room air, current use of supplemental oxygen to maintain O2 saturation ≥92%). 
Note: participants who are randomized and then found to meet clinical deterioration criteria at baseline – or 
meet deterioration criteria prior to starting study medication - will (or may) remain in the study and be managed 
and assessed just as other randomized participants.  They will not be included in the modified intention to treat 
sample during data analysis. 
2) Unstable medical comorbidities (eg decompensated cirrhosis), per patient report and/or medical records. 
3) Immunocompromised from the following: solid organ transplant, BMT,  high dose steroids (>20mg prednisone per 
day), or tocilizumab 
4) Already enrolled in another COVID 19 medication trial (not including vaccination or prophylaxis trials) 
5) Unable to provide informed consent  
6) Unable to perform the study procedures 
7) Taking donepezil (rationale: donepezil is a S1R agonist), or sertraline (rationale: sertraline is a strong sigma-1 
antagonist). 
8) Taking warfarin-also known as Coumadin (rationale: increased risk of bleeding), phenytoin (rationale: fluvoxamine 
inhibits its metabolism), clopidogrel (rationale: fluvoxamine inhibits its metabolism from pro-drug to active drug which 
raises risk of cardiovascular events), and St John's wort (rationale: fluvoxamine + St John’s wort are considered 
contraindicated because of the risk of serotonin syndrome) 


FLUVOXAMINE FOR EARLY TREATMENT OF COVID-19: A FULLY-REMOTE, RANDOMIZED PLACEBO CONTROLLED TRIAL 
 
 
 
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9)  Taking SSRIs, SNRIs, or tricyclic antidepressants, unless these are at a low dose such that a study investigator 
concludes that a clinically significant interaction with fluvoxamine (ie either serotonin syndrome or TCA overdose) is 
unlikely (examples: participant takes escitalopram but only at 5-10mg daily; that dose plus 200mg fluvoxamine would be 
insufficient to cause serotonin syndrome; or, participant takes amitriptyline but only at 25mg nightly; even if 
fluvoxamine inhibits its metabolism, it would be an insufficient dose to cause QTc prolongation or problematic side 
effects). 
10) Individuals who report they have bipolar disorder or are taking medication for bipolar disorder (lithium, valproate, 
high-dose antipsychotic), unless the investigator concludes that the risk for mania is unlikely (ie it is doubtful that the 
patient actually has bipolar disorder). 
11) Individuals who take alprazolam or diazepam and are unwilling to cut the medication by 25% (rationale: fluvoxamine 
modestly inhibits the metabolism of these drugs). 
12) Participants taking theophylline, tizanidine, clozapine, or olanzapine (drugs with a narrow therapeutic index that are 
primarily metabolized by CYP 1A2, which is inhibited by fluvoxamine) will be reviewed with a study investigator and 
excluded unless the investigator concludes that the risk to the participant is low (this would be unlikely; example: 
participant takes tizanidine only as needed and is willing to avoid it for the 15 days of the study). 
13) Received vaccine for COVID-19.  Rationale: COVID-19 vaccines may prevent serious illness.  Note that participants in 
vaccine trials are eligible, unless they know that they received the active vaccine. 
14) Individuals who are already taking an approved or investigational COVID-19 treatment, or have already 
received monoclonal antibody treatment or convalescent plasma. (rationale: these individuals are unlikely to 
develop serious COVID-19). 
 
 
5.3 
SCREEN FAILURES 
 
Screen failures are defined as participants who consent to participate in the clinical trial and subsequently randomly 
assigned to the study intervention but do not meet inclusion criteria prior to taking their first dose of study medication.  
Individuals who do not meet the criteria for participation in this trial (screen failure) will be rescreened if they 
subsequently meet inclusion criteria.  The same subject number will be used.  
 
5.4 
STRATEGIES FOR RECRUITMENT AND RETENTION 
This proposed remote clinical study will be conducted both locally through Washington University in St Louis, and 
nationally. The catchment reflects a diversity of settings including urban and rural settings, creating a diverse sample.  
Study patients will be identified via a number of strategies, chiefly those shown effective in the fully-remote 
hydroxychloroquine studies: advertisements, media, and social media.  As well, we will use strategies that were 
successful in the STOP COVID trial: using EHR, self-referral or through referrals from individual physicians.  The research 
team, using interview with the potential participant and medical records review or discussion with the patient’s 
physician, will then screen for eligibility as per the inclusion/exclusion criteria below.  
Pre-screening and consent are conducted via REDCap surveys and telephone.  No in person visits are required. 


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6 
STUDY INTERVENTION 
 
6.1 
STUDY INTERVENTION(S) ADMINISTRATION 
 
6.1.1 STUDY INTERVENTION DESCRIPTION 
 
Participants are randomized to approximately 15 days of fluvoxamine or placebo. Study medications are matching oral 
capsules (taken twice daily).  The study medication is stopped after approximately 15 days.  The observation period for 
measuring the primary endpoint (clinical deterioration) is days 1-15 (beginning as soon as the first dose of the study 
medication and ending on day 15).   
Sample size: We propose to enroll approximately n=1,100 participants, in order to have 880 in the modified intention to 
treat sample or analyzed sample.  This sample will include all enrolled participants who were confirmed eligible at the 
baseline assessment and reporting taking at least one dose of study medication.  A modified intention-to-treat strategy 
is required because participants are shipped supplies and study medication (whereupon they are randomized) prior to 
their measuring oxygen saturation to confirm study eligibility.  In the preliminary study (STOP COVID), approximately 
20% of individuals who received study supplies were not in the intention to treat sample, mainly because study eligibility 
could not be confirmed. 
Randomization: Patients are randomized 1:1 to fluvoxamine or matching placebo capsules.  A study statistician will 
generate randomization schedules stratified by age and sex.  Treatments will be randomly allocated using alternating 
blocks of sizes 2 and 4.  Randomization allocation is conducted via REDCap which displays randomization assignment to 
research team members who prepare study materials including drug or placebo but otherwise have no contact with 
participants.  All individuals who are in contact with participants are blinded, including outcome assessors and 
investigators, as are participants themselves. 
6.1.2 DOSING AND ADMINISTRATION 
Participants receive a day zero dose of 50mg fluvoxamine (or matching placebo) in the evening immediately after the 
baseline assessment and confirmation of eligibility (as is feasible; sometimes this dose is not taken until the next day), 
and fluvoxamine 100mg (or placebo) twice daily as tolerated, on days 1-15.  Fluvoxamine will be self-administered. 
 
6.2 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING 
Participants and all study staff (except for the study statistician running the randomization, and the study staff putting 
study medication into the package to deliver to participant) are blinded.  This blinding is kept throughout the study until 
analyses of the primary endpoint are preliminarily conducted.   
 
Blocked randomization will also reduce the chance of bias.  Another strategy to reduce bias is that the primary endpoint, 
clinical deterioration, includes an objective component, oxygen saturation, which may be less prone to an expectancy 
effect (vs. self-reported measures).  Blinded study staff will not have access to randomization assignment for 
participants. Study investigators will also be blinded. 
Treatment guess: Participants will make a treatment guess at the end of the 15-day double-blind RCT phase, as is 
standard for double-blinded trials to test the adequacy of the blind.   
 
6.3 
STUDY INTERVENTION COMPLIANCE 


FLUVOXAMINE FOR EARLY TREATMENT OF COVID-19: A FULLY-REMOTE, RANDOMIZED PLACEBO CONTROLLED TRIAL 
 
 
 
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Participant data, including IP compliance, will be collected via REDCap daily surveys.    Each day the survey will ask the 
participant how many fluvoxamine (vs placebo) capsules they took. 
 
 
 
7 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT DISCONTINUATION/WITHDRAWAL 
 
7.1 
DISCONTINUATION OF STUDY INTERVENTION 
Management of participants who clinically deteriorate and/or are hospitalized or visit an emergency room or urgent 
care: We will make every effort to continue the study intervention throughout the 15-day period if patients are not 
hospitalized, or if they are hospitalized but do not meet criteria for clinical deterioration.  However, we will not exclude 
hospitalized participants from other physician-directed treatments (e.g., remdesivir, dexamethasone, convalescent 
plasma).  For patients who are hospitalized and show deterioration, such patients will discontinue fluvoxamine/placebo, 
with the rationale that this study’s main goal is test whether fluvoxamine prevents deterioration, and in such cases, the 
participant will have met this study’s primary endpoint (i.e., the prevention has “failed”).  They would be eligible for any 
studies of treatments for serious COVID.  We will continue to collect data including day-15 and day-90 data under the 
intention-to-treat principle, as well as the rationale that fluvoxamine may improve longer-term outcomes even in cases 
that it fails to prevent hospitalization.56  
 
Discontinuation from fluvoxamine or placebo does not mean discontinuation from the study, and remaining study 
procedures should be completed as indicated by the study protocol whenever possible.  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 adverse event (AE). 
 
The data that we will attempt to collect at the time of study intervention discontinuation will include the following: 
• 
Vital signs, including O2 saturation, pulse, blood pressure and temperature.  
• 
Hospitalization and supplemental oxygen status. 
 
 
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY 
Participants are free to withdraw from participation in the study at any time upon request. 
The PI may discontinue or withdraw a participant from the study for the following reasons: 
 
• 
Participant is not contributing data and/or appears to be lost to follow-up. 
• 
If any clinical adverse event (AE), laboratory abnormality, or other medical condition or situation occurs such 
that continued participation in the study would not be in the best interest of the participant or interferes with 
the integrity of the study data.  
• 
Disease progression which requires discontinuation of the study intervention 
• 
If the participant meets an exclusion criterion (either newly developed or not previously recognized) that 
precludes further study participation 
 
 
8 
STUDY ASSESSMENTS AND PROCEDURES 
 
8.1 
EFFICACY ASSESSMENTS  


FLUVOXAMINE FOR EARLY TREATMENT OF COVID-19: A FULLY-REMOTE, RANDOMIZED PLACEBO CONTROLLED TRIAL 
 
 
 
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Outcome Assessments: The primary endpoint will be clinical deterioration of COVID-19 illness. The secondary endpoint 
will be day 15 and day 90 functioning. 
Clinical deterioration is defined meeting both of the following: (1) presence of dyspnea and/or hospitalization for 
shortness of breath or pneumonia, plus (2) decrease in O2 saturation (<92%) on room air and/or supplemental oxygen 
requirement in order to keep O2 saturation ≥92%.  
The primary method of assessment for these outcomes is participants’ reports on twice-daily surveys throughout the 15-
day randomized period, corroborated by research staff (e.g., calling participants when low oxygen saturation was 
reported).  For participants who stop answering the surveys prior to day 15, as well as those who appear to be meeting 
the primary endpoint, we will use, as is feasible, medical records and subsequent calls to these participants and their 
family to determine whether they sought medical care for shortness of breath or hypoxia.  We will also confirm medical 
care needed (e.g., supplemental oxygen, length of stay, ventilator support) as is feasible.    
We will collect sufficient data on all participants to also measure the clinical deterioration on the World Health 
Administration COVID-19 clinical trial outcome scale: 0-1: ambulatory (no clinical deterioration during RCT phase), 2: 
limitation of activities but no hospitalization; 3: hospitalization but no O2 needed; 4: hospitalization, O2 needed; 5: non-
invasive ventilation or high-flow oxygen; 6: ventilator needed; 7: ventilator plus organ support needed; 8: death.  Scale 
can be found on p6 of: https://www.who.int/blueprint/priority-diseases/key-action/COVID-
19_Treatment_Trial_Design_Master_Protocol_synopsis_Final_18022020.pdf. Since ordinal scales have proved useful in 
studies of hospitalized patients with respiratory illnesses, this measure will be particularly helpful as an outcome 
measure for the subset of study participants who require hospitalization. This cross-walk with the WHO scale is also 
useful given that our primary outcome is a study-specific scale. 
The secondary endpoint will be functioning at day 15 and day 90, measured by the 10-item PROMIS Global Health Scale 
(“Global-10”).    This scale’s items assess general domains of health and functioning including overall physical health, 
mental health, social health, pain, fatigue, and overall perceived quality of life. The 10 questions of the Global-10 have 
largely been adapted from older measures such as the SF-36 and EQ-5D, with modifications that resulted in greater 
sensitivity and precision than the questions as originally worded. 
We will also measure persistence of COVID-19 symptoms as an exploratory measure, asking about all symptoms that 
have been reported in the literature to date on a 0-10 scale (0= absent; 10=severe).  
Data collection and participant interaction specifics: All interactions with participants will be fully-remote via 
phone/text/email/videoconference.  Data collection is done by twice-daily REDCap surveys sent to patients via email, 
with telephone-based data collection as a back-up to ensure that individuals without internet access are able to 
participate.  The surveys record oxygen saturation, vital signs, medication adherence, and COVID-19 symptoms.  Fixed 
race and ethnicity categories are collected by interviewers as part of the demographic information to characterize the 
sample.  The surveys measure dyspnea (shortness of breath) using a continuous 0-10 scale (0= symptom not present, 
10= symptom is very severe) via the technique of Ecological Momentary Assessment (i.e., “how bad is your symptom 
right now?”).  Phone contact is attempted daily during the first three days of the trial to address participants’ questions 
and concerns such as medication-related issues, and throughout the trial to remind them to complete assessments as 
necessary.  Additional phone calls are conducted on a case-by-case basis when participants’ survey data indicate out of 
range values (e.g., low O2 saturation) and to recheck and confirm these as necessary. This messaging will also be 
displayed when participants enter out of range values online for the baseline and daily surveys. Also, for participants 
who appear to be having worsening COVID-19 illness, study staff recommend that they seek medical attention from 
their primary care provider or via a local emergency room. 
 
8.2 
SAFETY AND OTHER ASSESSMENTS 
The first assessment of safety will be conducted at screening.  Research staff will, via telephone, determine whether 
participants meet eligibility criteria and what are their medical conditions and medications.  This information will be 


FLUVOXAMINE FOR EARLY TREATMENT OF COVID-19: A FULLY-REMOTE, RANDOMIZED PLACEBO CONTROLLED TRIAL 
 
 
 
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provided to the study physician investigator to concur with enrollment, prior to starting any study medication.  For 
example, if participants are taking an SSRI or a medication of concern for interaction with fluvoxamine (e.g., olanzapine), 
this will need to be reviewed by the physician to determine whether the participant could safely participate in the study.   
 
The second assessment of safety is conducted when study materials (including pulse oximeter, blood pressure cuff, and 
thermometer).  Participants will report on their O2 saturation, vital signs, and current symptoms, via electronic survey, 
prior to starting study medication. 
 
The third assessment of safety is throughout days 1-15 of the study.  Participants will report on their O2 saturation, vital 
signs, symptoms, and any adverse events, via the twice-daily survey, with telephone corroboration with study staff as 
necessary.  
 
All participants will, as is feasible, have a phone visit with study staff daily on days 1-3.  Additional phone calls will be as 
needed (e.g., to confirm out of bounds values on O2 saturation or vitals, and to advise participants whether to call their 
provider or go to an emergency room). 
 
Medical records, if available, will be used to supplement each of these assessments. 
   
9 
STATISTICAL CONSIDERATIONS  
 
 
9.1 
STATISTICAL HYPOTHESES 
A formal Statistical Analysis Plan (SAP) will be completed prior to database lock and unblinding of the study data.  It will 
include any additional details regarding the strategies described in this section.  
The primary hypotheses (superiority hypotheses) are: 
Participants randomized to fluvoxamine will have a lower rate of clinical deterioration, compared to placebo. (Null: 
participants randomized to fluvoxamine will not have a lower rate of clinical deterioration, compared to placebo) 
• 
Primary Efficacy Endpoint:  
 
Participants will meet the primary endpoint of clinical deterioration at the point that they meet both of the following: 
(1) presence of dyspnea and/or hospitalization for shortness of breath or pneumonia, plus (2) decrease in O2 saturation 
(<92% on room air and/or supplemental oxygen requirement to keep O2 saturation ≥92%).  This will be measured during 
study days 1-15. The primary source of information to ascertain this endpoint is the twice-daily survey which is carried 
out on study days 1-15; this survey includes participant self-report of their shortness of breath (dyspnea) rating on a 0-
10 scale (where a score of 4 or greater, indicating at least moderate dyspnea, meeting the first part of this endpoint) and 
of their pulse oximeter reading (where a reading of <92% meets the second part of this endpoint).  Study staff will 
confirm the pulse oximeter readings with participants via phone when possible, asking them to re-check, and will call 
participants to collect these data via telephone if surveys have been skipped.   Other data sources for this endpoint 
include participant and/or family report, or medical records data, regarding medical care received, during study days 1-
15, in a hospital/ER/urgent care center. 
 
The secondary hypotheses (also superiority hypotheses) are:  
Participants randomized to fluvoxamine will have higher post-COVID functional status at day 15 and day 90, compared 
to placebo. 
• 
Secondary Efficacy Endpoint(s): 


FLUVOXAMINE FOR EARLY TREATMENT OF COVID-19: A FULLY-REMOTE, RANDOMIZED PLACEBO CONTROLLED TRIAL 
 
 
 
22 
Secondary outcome will be post-COVID functioning measured at 15 days and at 90 days post-randomization using the 
PROMIS 10-item Global Health Scale.  The source of this data will be a survey sent to participants on these days, with 
data collection via telephone if the survey is skipped. 
 
An exploratory analysis will examine outcomes of participants who are randomized but discovered to meet the study 
endpoint of clinical deterioration at baseline.  We will examine whether those randomized to fluvoxamine have lower 
rates of hospitalization, ventilator care, and mortality, and we will gather the same outcomes at day 15 and day 90 post-
randomization. 
 
 
9.2 
SAMPLE SIZE DETERMINATION 
Software used for power calculations was power.prop.test in R. 
With a sample size of 880 in the modified intention to treat sample, we will have 80% power to detect a treatment 
effect of 35% reduction (20% in placebo vs. 13% in fluvoxamine).  Two-tailed alpha=0.05 for this power analysis, as time 
to clinical deterioration is the primary analysis and endpoint.   
The basis for the assumption of 20% meeting the clinical deterioration endpoint (in the placebo group) is the enrichment 
strategy for this trial, in which participants must indicate, on screening, at least one risk factor for clinical deterioration 
(e.g., age, medical condition).  
The basis for the assumption of 35% reduction: (1) 35% would be a clinically meaningful relative risk reduction in a high-
risk group; (2) a 35% relative risk reduction is what has been reported with corticosteroids such as dexamethasone when 
given in more serious COVID-19. 
To achieve n=880 in the modified intention to treat sample, we anticipate enrolling 1100 individuals, because we expect 
20% dropout/ineligible from the time of shipping/couriering study supplies to the first dose of medication, as in the 
preliminary clinical trial.  The main reason for dropout/ineligibility in the preliminary study was that we were unable to 
confirm study entry criteria, which included a baseline O2 saturation of 92% or greater.  This level of dropout/withdrawal 
after consent and shipping supplies is also consistent with the hydroxychloroquine early treatment trial conducted by 
University of Minnesota. 
This sample size has suitable power for the secondary endpoint analysis (function at day 15 and day 90).  For a simple t-
test between two groups, n=400 each (allowing for dropout), we can detect a difference of 0.2 standard deviations 
(Fleiss’ d) with a power of 80%; i.e., a small effect size. 
The examination of persistent symptoms at day 15 and day 90 will be exploratory only; the analytic plan will depend on 
the structure of the data collected.  Therefore no power analysis was conducted for this exploratory examination. 
The moderator hypothesis is: Participants with baseline O2 saturation ≤96% will have a larger treatment effect size (i.e., 
larger fluvoxamine-placebo difference in rate of clinical deterioration) than those with O2 saturation ≥97%. 
This moderator hypothesis is consistent with the strategy of prognostic enrichment, and our methodology and analytic 
strategy follows the FDA guidance on prognostic enrichment, found in https://www.fda.gov/regulatory-
information/search-fda-guidance-documents/enrichment-strategies-clinical-trials-support-approval-human-drugs-and-
biological-products. 
The test for moderation is a test of the interaction between treatment and baseline O2 saturation (dichotomized as 
≤96% vs. ≥97%).  
Power for this moderator hypothesis: We have at least 80% power at p=0.016 to find an effect size modulation such that 
in the low-risk group (baseline O2 saturation ≥97%) there was a treatment odds ratio of 1 (e.g., equal proportions of 


FLUVOXAMINE FOR EARLY TREATMENT OF COVID-19: A FULLY-REMOTE, RANDOMIZED PLACEBO CONTROLLED TRIAL 
 
 
 
23 
deterioration in both fluvoxamine and placebo groups), while in the high-risk group (baseline O2 saturation≤96%) there 
was a treatment odds ratio of 0.4 (i.e., 12% deterioration in the fluvoxamine group vs. 26% in the placebo group). 
This is not a power calculation for the moderation per se, but is an example of a moderation effect which could be 
detected. The odds ratios and the standard error of the log odds ratio are based on the usual formulas, e.g.   
OR = *x11*x22)/(x21*x12)  
SE(log(OR)) = sqrt(1/x11 + 1/x22 + 1/x21 + 1/x12)  
as is a simple Z test of the difference between the odds ratios and its P value.  
 
 
 
9.3 
STATISTICAL ANALYSES 
. 
 
9.3.1 GENERAL APPROACH 
• 
For descriptive statistics, categorical data will be presented as n (percentage), and continuous data will be 
presented as means with standard deviations, or median with interquartile range.  
• 
For all inferential tests, p-value will be 0.05 with 95% confidence intervals reported, all two-tailed. 
• 
Any covariates will be specified at the time of conducting analyses, but prior to unblinding. 
• 
The primary analysis requires no checks for normality; the secondary endpoint analysis will require a check of 
normality and corrective procedures will be applied (e.g., transformation or nonparametric tests). 
• 
We will use SAS 9.4 for analyses. 
 
 
9.3.2 ANALYSIS OF THE PRIMARY EFFICACY ENDPOINT(S) 
 
The primary analysis is survival analysis of the primary outcome (clinical deterioration).  This analysis treats participants 
as censored on the day that they meet the primary outcome, or on the last day that they fill out an outcome 
assessment. It is superior to an exact test of proportions because of the ability to handle missing data (due to dropout or 
meeting endpoint). 
 
Findings will be reported as the rates of clinical deterioration in groups (i.e., fluvoxamine vs. placebo), the absolute 
difference in the endpoint, the logrank chi square, and the respective p-value. 
 
No imputation for missing data will be used.  However, for all participants who do not complete surveys through day 15, 
we will use follow-up phone calls and medical records to ascertain whether they met the endpoint (e.g., were 
hospitalized and received supplemental oxygen). 
 
 
9.3.3 ANALYSIS OF THE SECONDARY ENDPOINT(S) 
 
Because of the potential for type 1 error due to multiple comparisons, findings for analyses of secondary endpoint 
(global function at day 15 and 90) should be interpreted as exploratory. The analyses will proceed regardless of findings 
of primary endpoint. 
 
The measurement is the summary of the 10-item scale which is expected to have a normal distribution.  It will be 
examined separately at days 15 and 90 rather than as a repeated measure.  The scale is not measured at baseline, so the 


FLUVOXAMINE FOR EARLY TREATMENT OF COVID-19: A FULLY-REMOTE, RANDOMIZED PLACEBO CONTROLLED TRIAL 
 
 
 
24 
comparison is a t-test or ANCOVA (if covariates are used) between intervention and placebo at these time points (day 
15, day 90). 
 
No imputation for missing data will be used. 
 
 
10 SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS 
 
10.1 REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS 
 
 
 
10.1.1 FUTURE USE OF STORED SPECIMENS AND DATA  
Data collected for this study will be analyzed and stored at Washington University.   After the study is completed, the de-
identified, archived data will be stored at Washington University for use by other researchers including those outside of 
the study. Permission to transmit data to other researchers will be included in the informed consent.  
 
10.1.2 SAFETY OVERSIGHT 
We will appoint DSMB members who are not involved in the study (i.e., as investigators). The board will include 
individuals with expertise important to this trial who will be responsible for overseeing the safety of participants and 
overseeing that the trial’s conduct. 
The DSMB will meet, at intervals determined by the DSMB, during the study (e.g., prior to start of recruitment, various 
times during recruitment phase, and as needed).  They will review study processes such as screening rate, enrollment 
rate, follow-up rate, dropout rate, demographics of enrolled sample, baseline clinical data, and participant safety. The 
primary safety measure will be AE reports.  
 
10.1.3 QUALITY ASSURANCE AND QUALITY CONTROL 
Each clinical site will perform internal quality management of study conduct, data collection, documentation and 
completion.   
 
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 the site(s) for 
clarification/resolution. 
 
The investigational site will provide direct access to all trial related sites, source data/documents, and reports for the 
purpose of monitoring and auditing by the sponsor, and inspection by local and regulatory authorities. 
 
 
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pentazocine through sigma1-receptor in cardiomyocytes. Am J Physiol Heart Circ Physiol. 
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Manne BK, Denorme F, Middleton EA, et al. Platelet gene expression and function in patients with 
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they prevent acute myocardial infarction? Am J Cardiovasc Drugs. 2003;3(3):149-162. 
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van den Berg DF, Te Velde AA. Severe COVID-19: NLRP3 Inflammasome Dysregulated. Front 
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Ratajczak MZ, Kucia M. SARS-CoV-2 infection and overactivation of Nlrp3 inflammasome as a trigger 
of cytokine "storm" and risk factor for damage of hematopoietic stem cells. Leukemia. 2020;34(7):1726-
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Garcia JA, Volt H, Venegas C, et al. Disruption of the NF-kappaB/NLRP3 connection by melatonin 
requires retinoid-related orphan receptor-alpha and blocks the septic response in mice. FASEB J. 
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46. 
Volt H, Garcia JA, Doerrier C, et al. Same molecule but different expression: aging and sepsis trigger 
NLRP3 inflammasome activation, a target of melatonin. J Pineal Res. 2016;60(2):193-205. 
47. 
Hartter S, Wang X, Weigmann H, et al. Differential effects of fluvoxamine and other antidepressants on 
the biotransformation of melatonin. J Clin Psychopharmacol. 2001;21(2):167-174. 
48. 
Henry JA. Overdose and safety with fluvoxamine. Int Clin Psychopharmacol. 1991;6 Suppl 3:41-45; 
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49. 
Lenze EJ, Mattar C, Zorumski CF, et al. Fluvoxamine vs Placebo and Clinical Deterioration in 
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SAP_001.pdf: 
Statistical Analysis Plan 
 
STOP COVID 2 
1 
 
Statistical Analysis Plan 
 
1. Administrative information 
1.1. Title and Trial Registration 
Full study title: Fluvoxamine for early treatment of COVID-19: A fully-remote, randomized placebo 
controlled trial 
Acronym: STOP COVID Trial 2 
ClinicalTrials.gov identifier: NCT04668950 
Washington University in St. Louis IRB ID number: 202011101 
Funding: COVID-19 Early Treatment Fund ("CETF") 
SAP version: 5.0 (11/15/2021) 
Study protocol version: 5.0 (4/14/2021) 
SAP version history: 1.0 (7/13/2021), 2.0 (9/16/2021), 3.0(9/29/2021), 4.0(10/20/2021) 
SAP version justification: Each version is modified and edited after being reviewed by PIs and 
biostatistician. 
SAP Revision timing: Revision will be conducted after reviewing by PIs and biostatistician. This 
version is the final version of the SAP. 
1.2. Roles and Responsibility 
Author: Lei Yang, Statistical Data Analyst 
Biostatistician: J. Philip Miller 
Principal investigator: Eric Lenze, MD 
 
 
          Angela Reiersen, MD 
SAP contributors and roles: Angela Stevens, Study Coordinator 
Affiliations: 1. Washington University in St. Louis, Missouri, USA 
 
       2. Northwestern University, Illinois, USA 
 
       3. University of Utah, Utah, USA 
 
       4. Fred Hutchinson Center Clinical Research Center, Washington, USA  
 
       5. McGill University Health Center, Qc, Canada  
 
       6. University of Toronto, Ont., Canada 
 
 


Statistical Analysis Plan 
 
STOP COVID 2 
2 
 
Table of contents 
1. Administrative information ................................................................................................................... 1 
1.1. Title and Trial Registration ............................................................................................................ 1 
1.2. Roles and Responsibility .................................................................................................................. 1 
Table of contents ......................................................................................................................................... 2 
Abbreviation ................................................................................................................................................ 4 
2. Introduction ............................................................................................................................................. 5 
2.1. Background and Rationale: ............................................................................................................ 5 
2.2. Objectives.......................................................................................................................................... 6 
2.2.1. Objectives and study aims ........................................................................................................ 6 
2.2.2. Hypothesis .................................................................................................................................. 6 
2.2.3. Scope ........................................................................................................................................... 6 
3. Study Methods ......................................................................................................................................... 7 
3.1. General Study Design and Plan: ..................................................................................................... 7 
3.2. Randomization ................................................................................................................................. 7 
3.3. Sample Size ....................................................................................................................................... 7 
3.4. Framework ....................................................................................................................................... 7 
3.5. Statistical interim analyses and stopping guidance ....................................................................... 7 
3.6. Timing of final analysis ................................................................................................................... 8 
3.7. Timing of outcome assessment ........................................................................................................ 8 
4. Statistical principles ................................................................................................................................ 8 
4.1. Confidence intervals and p values .................................................................................................. 8 
4.2. Adherence and protocol deviations ................................................................................................ 8 
4.2.1. Definitions of protocol deviations ............................................................................................ 8 
4.2.2. Adherence and protocol deviations ......................................................................................... 8 
4.2.3. Electronic data capture ............................................................................................................ 8 
4.3. Analysis populations ........................................................................................................................ 9 
5. Trial Population ...................................................................................................................................... 9 
5.1. Screening data .................................................................................................................................. 9 
5.2. Eligibility ........................................................................................................................................... 9 
5.2.1. Inclusion Criteria ...................................................................................................................... 9 
5.2.2. Exclusion Criteria ................................................................................................................... 10 
5.3. Recruitment .................................................................................................................................... 10 


Statistical Analysis Plan 
 
STOP COVID 2 
3 
 
5.4. Withdrawal/follow-up .................................................................................................................... 11 
5.4.1. General withdrawal rules ....................................................................................................... 11 
5.5. Baseline participant characteristics ............................................................................................. 11 
5.5.1. List of baseline characteristics ............................................................................................... 11 
5.5.2. Descriptive summarization of baseline participant characteristics .................................... 12 
6.  Analysis ................................................................................................................................................. 12 
6.1. Outcome definitions ....................................................................................................................... 12 
6.1.1. Primary and secondary outcomes ......................................................................................... 12 
6.1.2. Outcome measurements ......................................................................................................... 12 
6.2. Analysis methods ............................................................................................................................ 13 
6.3. Missing data .................................................................................................................................... 13 
6.4. Harms .............................................................................................................................................. 13 
6.5. Statistical software ......................................................................................................................... 13 
 
 
 
 


Statistical Analysis Plan 
 
STOP COVID 2 
4 
 
Abbreviation 
AE 
 
 
Adverse Event 
AIDS  
 
Acquired Immunodeficiency Syndrome 
ANOVA 
 
Analysis of Variance 
BMI 
 
 
Body Mass Index 
BMT 
 
 
Bone Marrow Transplantation 
COPD  
 
Chronic Obstructive Pulmonary Disease 
COVID -19 
 
2019 Novel Coronavirus Disease 
DSMB  
 
Data Safety and Monitoring Board 
e-CRF  
 
Electronic Case Report Form 
GCP 
 
 
Good Clinical Practice 
ICU 
 
 
Intensive Care Unit 
IRB 
 
 
Institutional Review board 
mITT  
 
Modified Intention-to-treat 
PI 
 
 
Principal Investigator 
PROMIS 
 
Patient Reported Outcome Measurement Information System 
QC 
 
 
Quality Control 
RCT 
 
 
Randomized Controlled Trial 
REDCap 
 
Research Electronic Data Capture 
S1R 
 
 
Sigma-1 Receptor 
SAE 
 
 
Serious Adverse Event 
SD 
 
 
Standard Deviation 
SNRIs  
 
Serotonin and Norepinephrine Reuptake Inhibitors 
SOB 
 
 
Shortness of Breath 
SSRIs  
 
Selective Serotonin Reuptake Inhibitors 
TCA 
 
 
Tricyclic Antidepressant 
 
 
 
 


Statistical Analysis Plan 
 
STOP COVID 2 
5 
 
2. Introduction 
2.1. Background and Rationale:  
Coronavirus disease 2019 (COVID-19), caused by the novel severe acute respiratory syndrome 
coronavirus 2 (SARS-CoV-2), can cause serious illness including lung damage, hypoxia, and cardiac 
damage, which can lead to hospitalization, intensive care unit (ICU) admission, and death. 
Clinical deterioration often occurs during the second week of illness. Early investigations of COVID-19 
found that serious illness leading to hospital admission occurred a median of 8-10 days after initially mild 
to moderate symptoms. Evidence that many patients with COVID-19 develop lung damage from an 
excessive inflammatory response led to recommendations to repurpose immunomodulatory drugs to 
counter this hyperinflammation. More recent evidence supports the assertion that the inflammatory 
reaction, including elevations in cytokines such as IL-6, predicts clinical deterioration. 
Many patients have debilitating persistent symptoms and loss of function, even three or more months 
after the initial stage of illness.  The causes of this persistent illness are unclear and likely heterogeneous; 
they include persistence of the viral infection, immunological changes, and exacerbation of underlying 
medical conditions. As a result, both anti-viral and immunomodulatory drugs could potentially prevent or 
reduce this post-COVID functional impairment. 
Fluvoxamine is unique among the SSRIs in that it strongly activates the sigma-1 receptor (S1R), and 
preclinical studies have suggested that by this mechanism, fluvoxamine could prevent the 
immunopathology seen in serious COVID-19.  In 2019, it was shown that fluvoxamine, given early in 
treatment, reduced deterioration and mortality in two animal models of sepsis (bacterial peritonitis and 
lipopolysaccharide stimulation). The same study demonstrated that fluvoxamine was anti-inflammatory in 
human cells, reducing IL-6 and other cytokines in lipopolysaccharide-induced inflammation.  This study 
is part of an increasing body of research supporting the S1R in protection from deleterious consequences 
of inflammation. 
Fluvoxamine has one of the strongest S1R agonist effects of any existing medication. It is also highly 
lipophilic and has rapid, substantial intracellular uptake.16  Fluvoxamine also has many pragmatic 
advantages for repurposing, including ease of use, high safety margin, good tolerability, wide availability, 
and low cost. Therefore, we determined that if it could be shown that fluvoxamine had a beneficial effect 
in reducing clinical deterioration of COVID-19, the drug (and other S1R agonists) could be an important 
addition to the armamentarium vs. this pandemic. 
A preliminary single-site STOP COVID Trial (ClinicalTrials.gov Identifier: NCT04342663) aimed to test 
whether a course of fluvoxamine given early in COVID-19 illness could prevent clinical deterioration was 
conducted in Missouri and Illinois from April 10th to September 19th, 2020. The key finding from the 
preliminary study, 0% (0/80) of fluvoxamine-treated individuals vs. 8.3% (6/72) of those who received 
placebo suffered clinical deterioration, demonstrated that fluvoxamine prevented, rather than merely 
delayed, deterioration.  
Therefore, we conducted a multi-site, double-blind, placebo-controlled RCT to test whether fluvoxamine, 
given as early treatment in individuals with mild COVID-19 illness, might prevent clinical deterioration. 
 


Statistical Analysis Plan 
 
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2.2. Objectives 
2.2.1. Objectives and study aims 
The study aims to replicate the preliminary findings from the previous single-site trial in a larger 
confirmatory multi-site trial. First, we will examine whether fluvoxamine prevents clinical deterioration 
in early COVID-19. Next, we will use the presence of dyspnea and decrease in O2 saturation to determine 
clinical deterioration.  We will also use a modified version of the World Health Organization (WHO) 
COVID-19 Therapeutic Trial Synopsis 9-point scale as a measure of clinical severity at its worst. The 
modified scale is defined as: 
• 
0 = no clinical or virological evidence of infection (none in our study should have this rating);  
• 
1= no limitation of activities (re-defined for this study as no hospitalization and no clinical 
deterioration by our study definition),  
• 
2=  limitation of activities (re-defined for this study as no hospitalization but did have clinical 
deterioration by our study definition),  
• 
3= hospitalized but did not require supplemental oxygen;  
• 
4= hospitalized and required supplemental oxygen;  
• 
5= hospitalized and required non-invasive ventilation;  
• 
6= required intubation & ventilation;  
• 
7= Ventilator plus organ support needed;  
• 
8=death 
Second, we will find out whether fluvoxamine mitigates the long-term impact of COVID-19 by 
comparing their post-COVID functional status and symptoms at day 15 and day 90 between the 
fluvoxamine group and placebo group. Third, we will explore ① study medication adherence between 
the fluvoxamine and placebo group; ② whether participants' co-prescribed medications vary between the 
fluvoxamine and placebo groups; ③ difference of persistent clinical symptoms at day 15 and day 90 
between fluvoxamine and placebo group; and ④ difference of symptom onset days (from symptom onset 
to start of medication) between fluvoxamine and placebo group, and between deteriorated and non-
deteriorated group. 
2.2.2. Hypothesis 
H1a: Participants randomized to fluvoxamine will have a lower rate of clinical deterioration and a higher 
level of clinical severity as compared to placebo.  
H1b: Participants with lower baseline O2 saturation will have a larger treatment effect size (i.e., a larger 
fluvoxamine-placebo difference in the rate of clinical deterioration) than those with higher O2 saturation. 
We will use a median split on baseline O2 saturation for a test of this hypothesis. 
H2: Participants randomized to fluvoxamine will have higher post-COVID functional status at day 15 and 
day 90, compared to participants randomized to placebo. 
2.2.3. Scope 
This Statistical Analysis Plan will be the guiding document for the quantitative analyses conducted in the 
STOP COVID Trial 2.  


Statistical Analysis Plan 
 
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3. Study Methods 
3.1. General Study Design and Plan: 
A fully-remote study in the US and Canada will be adopted for our trial. Participants will be screened and 
consented over the phone. Study drug fluvoxamine/placebo and other supplies will be delivered to (self-
quarantined) participants, including thermometers, blood pressure cuffs, and O2 saturation monitors. Data 
will be collected via participants' phones/computers and medical records. National recruitment in the US 
and regional recruitment in Canada will be carried out, similar to the University of Minnesota COVID-19 
hydroxychloroquine trials conducted in early 2020.  
Participants will be recruited nationally in the US and regions in Canada by cooperating with 6 
universities/centers. The six universities/centers are Washington University in St. Louis; Northwestern 
University; University of Utah; Fred Hutchinson Cancer Research Center; McGill University Health 
Center in Canada; and the University of Toronto in Canada.  
3.2. Randomization 
Participants in the US and Canada are randomized 1:1 to fluvoxamine or matching placebo capsules. A 
study statistician will generate randomization schedules stratified by age and sex. Separate randomization 
tables were prepared for the US and Canadian sites. Treatments will be randomly allocated using 
randomly alternating blocks of sizes 2 and 4. Randomization allocation is conducted via REDCap, which 
displays randomization assignments to research team members who prepare study materials including 
drug or placebo but otherwise have no contact with participants. All individuals in contact with 
participants are blinded, including outcome assessors and investigators, as are participants themselves. 
3.3. Sample Size 
Our original proposal was to recruit 1100 participants in order to have 880 participants in the modified 
intention-to-treat sample. This sample will include all enrolled participants who were confirmed eligible 
at the baseline assessment and reporting taking at least one dose of study medication. A modified 
intention-to-treat strategy is required because participants will be shipped supplies and study medication 
(whereupon they are randomized) prior to their measuring oxygen saturation to confirm study eligibility.1   
The planned recruitment number was adjusted to approximately 1100 participants in the mITT group mid-
study due to the slow recruitment rate and low event rate in the mITT sample. This was probably because 
many at-risk adults in the US and Canada were vaccinated. Not only did the case rate drop considerably, 
but also the cases were mostly occurring among those either at low risk (who would not be eligible) or 
who were vaccine-hesitant (who may less likely be willing to participate in medical research). The DSMB 
recommended stopping the study on May 19th, 2021. The last enrollment date was May 21st, 2021, with a 
total of 669 participants randomized and 551 participants included in the mITT sample. 
3.4. Framework 
Hypothesis testing framework: H0 and H1 with confidence intervals for differences. 
3.5. Statistical interim analyses and stopping guidance 
A pre-planned interim analysis was conducted once the trial had recruited >50% of the originally planned 
number of participants for the planned main analysis. On the 4th DSMB meeting on May 10th, 2021, there 
had been 657 participants randomized, with 527 of the 1100 participants in the mITT sample (data 
 
1 In the preliminary study (STOP COVID Trial), approximately 20% of individuals who received study supplies were not in the 
intention-to-treat sample, mainly because study eligibility could not be confirmed. 


Statistical Analysis Plan 
 
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presented as of May 5th, 2021). No safety signals were noted after reviewing adverse events and serious 
adverse events. While the study was initially designed under the assumption of an overall 16.5% event 
rate (20% in the placebo arm and 13% in the fluvoxamine arm), the overall event rate based on the data 
presented as of May 5th, 2021, was 5%. Conditional power under the original design was presented as 
22%. The team proposed updated assumptions of 8% for the placebo group and 4% for the fluvoxamine 
group. With those updated assumptions, the necessary mITT sample size would be approximately 550 
participants per arm, a more than 20% increase. The conditional power under the updated assumptions 
would be approximately 5%. The DSMB recommended the early stop, and a decision was made on May 
19th, 2021.  
3.6. Timing of final analysis 
H1a and H1b analyses have ensued after we decided to early stop recruitment on May 21st, 2021, and 
after all the active enrolled participants reach day 15 in the RCT phase. H2 analysis will ensue after all 
enrolled participants complete day 90 follow-up surveys in the follow-up phase.  
This statistical analysis plan was added to the study protocol at clinicaltrials.gov, before the closure of the 
database and before any analyses had been conducted. Independent study monitoring was conducted in 
adherence to the Good Clinical Practice (GCP) guidelines. The statistician will be blind to treatment 
assignments during the H1a and H1b analysis and unblind during H2 and exploratory analysis. 
3.7. Timing of outcome assessment 
Outcome assessments will be conducted at the end of the RCT phase on day 15. During the follow-up 
phase, assessments will be conducted on day 90.  
4. Statistical principles 
4.1. Confidence intervals and p values 
To test our primary hypothesis (H1) and secondary hypothesis (H2), a significance level of .05 will be 
considered statistically significant. Results will be presented with their values (e.g., coefficients, standard 
deviation, etc.) with 95% confidence intervals. 
4.2. Adherence and protocol deviations 
4.2.1. Definitions of protocol deviations 
Any alteration or modification to the IRB-approved research will not be conducted without prospective 
IRB approval. The term research encompasses all IRB-approved materials and documents, including the 
detailed protocol, IRB application, consent form, recruitment materials, questionnaires/data collection 
forms, and any other information relating to the research study. 
4.2.2. Adherence and protocol deviations 
As a pragmatic study, all levels of adherence are allowed. Compliance with the study-recommended 
medication and dosing will be followed during the trial. Reasons for non-compliance and protocol 
deviations will be documented. 
4.2.3. Electronic data capture 
This study will utilize REDCap-based electronic Case Report Forms (e-CRF's) for data capture and 
storage. All study-related materials will be stored electronically in REDCap or a secured university 
server. No physical source documents are anticipated. 


Statistical Analysis Plan 
 
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4.3. Analysis populations 
We will follow the modified intention-to-treat (mITT) principle. In other words, participants who stop 
randomized medication will continue to be followed.  Participants who meet the modified intent-to-treat 
principle will be included in the analysis. A per-protocol analysis will be performed for participants 
taking ≥80% doses of study medication until the time of deterioration or end of RCT phase.  
5. Trial Population 
5.1. Screening data 
Potential participants identified through the IRB-approved recruitment plan will be screened for 
eligibility. Staff and PI's at each site are responsible for verifying that participants meet all eligibility 
criteria before being randomized to acute treatment. All sites in the US and Canada follow the same 
screening requirements.  
5.2. Eligibility 
All participants will meet the following eligibility criteria:  
5.2.1. Inclusion Criteria 
a) Men and women aged 30 and older.2 
b) Not currently hospitalized. 
c) Proven SARS-CoV-2 positive (per lab or physician report). A positive test3 is within 3 days prior to or 
during the current symptomatic episode. 
d) Currently symptomatic with one or more of the following symptoms: fever, cough, myalgia, mild 
dyspnea, chest pain, diarrhea, nausea, vomiting, anosmia (inability to smell), ageusia (inability to taste), 
sore throat, nasal congestion. 
e) Expectation, on screening, that the participant will start study medication within 7 days of symptom 
onset.  
f) Able to provide informed consent. 
g) Upon initial screening, participant reports one of the following risk factors for clinical deterioration: 
age≥40, racial/ethnic group African-American, Hispanic, South Asian, or Native American (including 
more than one race), or 1+ of the following medical conditions which increase the risk for developing 
moderate-severe COVID illness: obesity, hypertension, diabetes, heart disease (coronary artery disease, 
history of myocardial infarction, or heart failure), lung disease (e.g., Asthma, COPD), immune disorder 
(e.g., rheumatoid arthritis, lupus). 
 
2 Inclusion criteria was: Men and Women aged 18 and older. Adjusted after first DSMB call on Feb 8th,2021 
3 Due to the study nature, it is not possible to acquire a positive test confirmation from every participant at the time of the 
recruitment.  


Statistical Analysis Plan 
 
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5.2.2. Exclusion Criteria  
a) Illness severe enough to require hospitalization or already meeting study's primary endpoint for clinical 
deterioration4 (e.g., current O2 saturation <92% on room air, current use of supplemental oxygen to 
maintain O2 saturation ≥92%). 
b) Unstable medical comorbidities (e.g., decompensated cirrhosis), per patient report and/or medical 
records. 
c) Immunocompromised from the following: solid organ transplant, BMT, high dose steroids (>20mg 
prednisone per day), or tocilizumab.5 
d) Already enrolled in another COVID 19 medication trial (not including vaccination or prophylaxis 
trials) 
e) Unable to provide informed consent. 
f) Unable to perform the study procedures. 
g) Taking donepezil, or sertraline. 
h) Taking warfarin-also known as Coumadin, phenytoin, clopidogrel, and St John's wort. 
i)  Taking SSRIs, SNRIs, or tricyclic antidepressants, unless these are at a low dose such that a study 
investigator concludes that a clinically significant interaction with fluvoxamine (i.e., either serotonin 
syndrome or TCA overdose) is unlikely. 
j) Individuals who report they have bipolar disorder or are taking medication for bipolar disorder (lithium, 
valproate, high-dose antipsychotic) unless the investigator concludes that the risk for mania is unlikely. 
k) Individuals who take alprazolam or diazepam and are unwilling to cut the medication by 25%. 
l) Participants taking theophylline, tizanidine, clozapine, or olanzapine will be reviewed with a study 
investigator and excluded unless the investigator concludes that the risk to the participant is low. 
m) Received vaccine for COVID-19. 
n) Individuals who are already taking an approved or investigational COVID-19 treatment or have already 
received monoclonal antibody treatment or convalescent plasma. 
5.3. Recruitment  
A consort diagram will be used to visualize the flow of participants. We will report the number of eligible 
participants and the number of screened participants. The reasons for lack of eligibility will be 
enumerated. The number randomized to the mITT group will be reported as well as the reasons for non-
randomized to mITT group. The number randomized into either arm (fluvoxamine vs. placebo) will be 
reported.  
 
4 participants who are randomized and then found to meet clinical deterioration criteria at baseline – or meet deterioration criteria 
prior to starting study medication - will (or may) remain in the study and be managed and assessed just as other randomized 
participants.  They will not be included in the modified intention to treat sample during data analysis. 
5 Older version: Immunocompromised (solid organ transplant, BMT, AIDS, on high dose steroids (>20mg prednisone per day). 


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5.4. Withdrawal/follow-up 
5.4.1. General withdrawal rules 
Participants are free to withdraw from participation in the study at any time upon request. 
The PI may discontinue or withdraw a participant from the study for the following reasons: 
o The participant is not contributing data and/or appears to be lost to follow-up. 
o If any clinical adverse event (AE), laboratory abnormality, or other medical condition or situation 
occurs such that continued participation in the study would not be in the best interest of the 
participant or interfere with the integrity of the study data.  
o Disease progression which requires discontinuation of the study intervention 
o If the participant meets an exclusion criterion (either newly developed or not previously 
recognized) that precludes further study participation 
After completing day 15 in the RCT phase, participants will enter the follow-up phase till day 90.  
5.5. Baseline participant characteristics 
5.5.1. List of baseline characteristics 
Participants will sign informed consent forms at baseline. Local research team assessments elements 
collected during baseline: 
o Temperature 
o Oxygen level 
o Blood pressure 
o Pulse 
o Self-assessed symptoms 
▪ 
Fever 
▪ 
Cough 
▪ 
Shortness of breath 
▪ 
Fatigue/Weakness 
▪ 
Chills 
▪ 
Sore throat 
▪ 
Nasal congestion 
▪ 
Nausea 
▪ 
Body aches 
▪ 
Diarrhea 
▪ 
Loss of appetite 
▪ 
Loss of smell 
▪ 
Loss of taste 
o Medical history 
 
The key variables being used in the study include: 
o Age 
o Gender 
o Race 
o Sites 
o Days from symptom onset to start trial medication 
o BMI 
o Coexisting conditions(medical history) 
o Self-assessed symptoms 


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o Oxygen level 
o Randomization  
o Endpoint for clinical worsening 
o Days in RCT phase free of clinical deterioration 
o WHO COVID-19 Therapeutic Trial Synopsis 9-point scale 
5.5.2. Descriptive summarization of baseline participant characteristics 
We will list general patient characteristics in a baseline characteristics table. Continuous data will be 
presented as the mean with standard deviation (SD), median with interquartile range, and range(min-
max). Dichotomous and categorical data will be presented in proportions.  
6.  Analysis 
6.1. Outcome definitions 
6.1.1. Primary and secondary outcomes 
Primary: Participants who have a ① presence of dyspnea and/or hospitalization for shortness of breath or 
pneumonia, and ② O2 saturation decrease (<92% on room air via the twice-daily at-home self-
monitoring or via monitoring at a hospital/ER/urgent care center, and/or supplemental oxygen 
requirement to keep O2 saturation ≥92%) will be clinically deteriorated.  The numerical score of the 
Modified WHO COVID-19 Therapeutic Trial Synopsis 9-point scale will be used for analysis. 
Secondary: Secondary outcome will compare post-COVID functioning at day 15 and day 90 using the 
PROMIS 10-item Global Health Scale. It reflects the increasing concern regarding the persistence of 
COVID-19 illness and functional impairment in a substantial percentage of individuals with initially 
"mild" symptoms. We will also explore persistent symptoms of COVID-19 at these time points.   
6.1.2. Outcome measurements 
Primary outcome (clinical deterioration) will be measured by ① an SOB rating of 4+ on the twice-daily 
0-10 scale and/or hospitalization for shortness of breath or pneumonia during study day 1- day 15 and ② 
O2 readings <92% on room air via the twice-daily at-home self-monitoring or monitoring at a 
hospital/ER/urgent care center, and/or supplemental oxygen requirement to keep O2 saturation ≥92% 
during study day 1- day 15. 
The secondary outcome will be measured by a PROMIS 10-item Global Health Scale on study day 15 and 
day 90. 
Four exploratory analyses will be performed. First, we will examine the difference between the 
fluvoxamine group vs. placebo group and the deterioration group vs. non-deterioration group in study 
medication adherence. Second, we will explore co-prescribed medications to look for patterns of 
difference between the fluvoxamine and placebo groups. Third, we will examine whether the persistent 
symptoms reported on day 15 and day 90 vary between the fluvoxamine and placebo groups. Fourth, we 
will examine the difference of symptom onset days (from symptom onset to start of medication) between 
the fluvoxamine and placebo group, as well as between deteriorated and non-deteriorated groups. 
In addition, we will examine the outcomes of randomized participants discovered to meet the study 
endpoint of clinical deterioration at baseline. We will examine whether those randomized to fluvoxamine 
have lower hospitalization rates, ventilator care, and mortality, and we will gather the same outcomes at 
day 15 and day 90 post-randomization.  


Statistical Analysis Plan 
 
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6.2. Analysis methods 
To test hypothesis H1a (clinical deterioration), survival analysis with the log-rank statistic stratified by 
the US vs. Canada, gender, and age group will be performed testing between the two treatment groups.  
Participants who meet the primary outcome will represent an event.  The WHO COVID-19 Therapeutic 
Trial Synopsis 9-point scale will be compared between the two groups with a t-test. We will also 
summarize the distribution of subjects at each level of the scale. 
To test hypothesis H1b (treatment effect size), a Cox proportional hazard model will fit the data using 
strata as in H1a with factors as the US vs. Canada, gender, and age group, baseline O2 saturation, and 
their interaction. The test for moderation would be a test of the interaction between treatment and baseline 
O2 saturation (dichotomized with a median split).  
To test hypothesis H2 (post-COVID functioning), an ANOVA test stratified by the US vs. Canada, 
gender, and age will be performed for day 15 and day 90. Differences between treatment groups will be 
tested. 
In terms of the exploratory outcomes, descriptive statistics with 95% confidence intervals will be 
computed. If the prevalence of persistent symptoms is adequate, we will explore post-hoc regression 
models which predict persistent symptoms based on the duration and severity of the particular symptom 
during the acute phase and other clinical features during the acute phase. If we find co-prescribed 
medication differences between two groups, a further examination on medication interaction effect will be 
performed.  We will also conduct per-protocol analysis, using only those participants who took ≥80% of 
study drug up until the time of deterioration or the end of 15-day trial. 
6.3. Missing data 
Missing data can occur from participant dropout/withdrawal (unit non-response), meeting study endpoint, 
failure to provide data (item non-response), or administrative issues. We will minimize missing data by 
closely monitoring accumulating data for missingness and implementing data quality control (QC) checks 
to reduce it when identified. Any missing data or anomalies will be communicated to the site(s) for 
clarification/resolution. When a participant drops out of the study, we will document the reason for 
dropout and who made the dropout decision. No imputation for missing data will be used for H1a and 
H1b analysis. We will use a multiple imputation analysis to estimate potential bias from missing data.  
6.4. Harms 
During the study, serious adverse events (SAE) and adverse events (AE) will be monitored continuously 
throughout the study and will be reported to the DSMB and IRB according to pre-specified requirements. 
SAE/AE rates and interim study results will be reviewed and discussed by the DSMB at the DSMB 
meetings.  
6.5. Statistical software 
Data cleaning and statistical analyses will be performed using SAS (SAS Institute, Cary NC) and R (The 
R Foundation for Statistical Computing; Vienna, Austria).