A Double-blind, Placebo-controlled Clinical Trial of Fluvoxamine for Symptomatic Individuals With COVID-19 Infection
Phase: PHASE2
Conditions: COVID 19, Coronavirus
Sponsor: Washington University School of Medicine

 
 
A double-blind, placebo-controlled clinical trial of fluvoxamine 
for     symptomatic individuals with COVID-19 infection 
 
 
NCT: 04342663 
 
 
Study Protocol & Statistical Analytic Plan 
 
October 21, 2020 
 

A double-blind, placebo-controlled clinical trial of fluvoxamine for symptomatic individuals 
with COVID-19 infection 
Faculty: Eric Lenze, M.D., Caline Mattar, M.D., Angela Reiersen, M.D., Ginger Nicol, M.D., Charles 
Zorumski, M.D., J. Philip Miller   
 
Background: 
The biphasic evolution of COVID-19 infection: The clinical course of COVID-19 infection varies, 
with approximately 20% of individuals developing serious illness including lung damage, hypoxia, and 
cardiac damage.  This leads to hospitalization, ICU admission, and in some cases fatality.   
 
Many infected individuals show a biphasic evolution of the illness, in which clinical deterioration often 
develops during the second week of illness https://www.cdc.gov/coronavirus/2019-ncov/hcp/clinical-
guidance-management-patients.html. In China, one report of 41 hospitalized patients found that 55% 
developed dyspnea 8 days (median; range 5-13) after illness onset 
https://www.ncbi.nlm.nih.gov/pubmed/31986264.  Also, a data extraction of 1099 patients found the 
mean time from illness onset to hospital admission with pneumonia was 9 days. 
https://www.ncbi.nlm.nih.gov/pubmed/32109013. The first cases in Europe had the same course, with 
a deterioration leading to requirement of supplemental oxygen 10-11 days after the onset of mild 
symptoms and in spite of a decreasing viral load, and it was postulated that “the lung damage is more 
related to immunopathological lesions, resulting from an excessive pro-inflammatory host response, 
rather than to uncontrolled viral replication” https://www.thelancet.com/action/showPdf?pii=S1473-
3099%2820%2930200-0.  
 
Thus, many patients with COVID-19 develop lung damage resulting from excessive inflammatory 
responses, or “cytokine storm”.  These individuals often develop cardiac injury, further highlighting the 
short-term and long-term risks and complications from infection 
https://www.ncbi.nlm.nih.gov/pubmed/32169400. This cytokine storm led to recommendations to trial 
hydroxychloroquine which could suppress T cell activation 
https://www.ncbi.nlm.nih.gov/pubmed/32196083 as well as other immunosuppressive strategies 
https://www.ncbi.nlm.nih.gov/pubmed/32192578. Many of these drugs have significant toxicities, and 
to date most clinical trials have focused on individuals who already have serious to critical illness.   
  
Sigma-1 receptor agonism as a pathway to preventing the cytokine storm: A 2019 study 
showed that SSRI fluvoxamine reduces damaging aspects of the inflammatory response during 
sepsis, and protects mice from lethal septic shock https://www.ncbi.nlm.nih.gov/pubmed/30728287. 
Fluvoxamine binds to the sigma-1 receptor (S1R), which regulates inflammation by inhibiting cytokine 
production.  Fluvoxamine may also induce the S1R 
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4123092/. The S1R restricts the endonuclease activity 
of an Endoplasmic Reticulum (ER) stress sensor called Inositol-Requiring Enzyme1 (IRE1) and 
reduces cytokine expression, without inhibiting classical inflammatory pathways.  
 
IRE1 is also necessary for induction of autophagy during infection of cells by a coronavirus that 
causes infectious bronchitis in animals https://www.ncbi.nlm.nih.gov/pubmed/31082732.  S1R 
agonists (including fluvoxamine) also have cardioprotective effects in rodents 
https://www.ncbi.nlm.nih.gov/pubmed/23044468 and protective effects in other tissues https://www-
ncbi-nlm-nih-gov.beckerproxy.wustl.edu/pubmed/27056295. 
 
Repurposing antidepressants for COVID-19: A recent preprint entitled, “A SARS-CoV-2-Human 
Protein-Protein Interaction Map Reveals Drug Targets and Potential Drug Repurposing” argued that a 
key drug repurposing strategy was “modulation of the ER stress and the protein unfolding response 
pathway by targeting the Sigma1 and Sigma2 receptor” 
https://www.biorxiv.org/content/10.1101/2020.03.22.002386v1.full.pdf. 

  
Many antidepressants (except sertraline) are S1R agonists, and a recent article on drug repurposing 
has suggested SSRIs may have value in treating COVID-19 https://www.nature.com/articles/s41421-
020-0153-3. SSRIs in particular are excellent candidates for drug repurposing because of their ease 
of use, including high safety margin, good tolerability, widespread availability, and low cost such that 
primary care physicians and other providers could prescribe them. 
 
Fluvoxamine has biochemical properties favorable for repurposing as a S1R agonist against COVID-
19 infection.  It has the strongest S1R agonist effect of any SSRI 
https://www.ncbi.nlm.nih.gov/pubmed/24508523.  A PET study found that a single dose of 150-
200mg produced 60-63% S1R binding in brain regions 
(https://www.ncbi.nlm.nih.gov/pubmed/17662961).  This suggests that fluvoxamine would have 
clinically meaningful S1R agonist effects within its clinical dosing range (up to 300mg/day is the 
maximum per FDA). It is also highly lipophilic and has demonstrated to have rapid, substantial 
intracellular uptake (http://dmd.aspetjournals.org.beckerproxy.wustl.edu/content/35/8/1325#sec-4). 
Fluvoxamine also is an ideal drug for repurposing in outpatients with COVID-19.  It is safe, 
inexpensive, and already widely available and FDA-approved.  Our team has prescribed it across the 
age span including in older adults at maximum therapeutic doses, finding it safe and well-tolerated.  
Fluvoxamine does not promote QT prolongation unlike some SSRIs 
(https://www.ncbi.nlm.nih.gov/pubmed/30885935), and it can be rapidly initiated at high therapeutic 
doses.  It is devoid of off-target effects, having only SSRI and S1R binding at clinically approved 
doses. In our review of all of the available, FDA-approved drugs that are agonists of S1R, 
fluvoxamine appears have the desirable combination of potent S1R agonism at clinically approved 
dosing, and ease of use including safety and tolerability. 
These features of fluvoxamine also make it an ideal drug for a pragmatic trial in outpatients.  Given 
risks from face-to-face contact, pragmatic fully-remote trials are a mandate.  Fluvoxamine requires no 
therapeutic drug monitoring or baseline or follow-up laboratory testing, even in older adults.  Our 
research group has expertise with such trials, and with secondary prevention studies (eg, 
https://www.ncbi.nlm.nih.gov/pubmed/31147244, https://www.ncbi.nlm.nih.gov/pubmed/23680817, 
https://www.ncbi.nlm.nih.gov/pubmed/16540613) with SSRIs.  In fact, our ongoing antidepressant 
trial, OPTIMUM, has been minimally affected by the ongoing pandemic because of the ability to 
continue the trial fully remotely with work-from-home staff and investigators 
(https://www.ncbi.nlm.nih.gov/pubmed/32207542). 
 
Summary: In the fight against COVID-19, we need a simple, benign drug that could be provided 
widely to outpatients early in the course of mild illness, to prevent the clinical deterioration to serious 
and life-threatening cardiopulmonary problems.  Existing clinical trials have been appropriately 
focused on treating more serious cases, but with few if any focusing on this clinical space.  S1R 
agonists – of which fluvoxamine is a particularly attractive candidate - could be given early in the 
course of symptomatic illness, to outpatients with mild symptoms, to decrease the excessive 
inflammatory response with COVID-19, and potentially prevent the evolution to more serious 
disease.  A search (on March 28; repeated April 9) of clinicaltrials.gov and the WHO International 
Registry of Clinical Trials (https://www.who.int/ictrp/en/) finds no trials – yet – of fluvoxamine, or any 
S1R agonist. 
 
Human Participants Involvement, Characteristics, and Design 
 
Subject Involvement:  

The proposed study is a pragmatic trial that will rapidly deliver drug/placebo and other supplies to 
(quarantined) patients, including thermometers, blood pressure cuffs, pregnancy tests (to confirm 
pregnancy exclusion in childbearing-capable females), and O2 saturation monitors.  The risk pertaining 
to face-to-face contact is with research staff, not participants (who are already COVID-19 positive), so 
we will conduct the trial via a “no contact” method that will not require PPE.  Because of the large, well-
trained research staff in the Healthy Mind Lab, we will be able to recruit, screen, e-consent, and start 
intervention in each participant rapidly. All staff will be trained in COVID-19 precautions using the WHO 
training for health care providers (https://www.who.int/emergencies/diseases/novel-coronavirus-
2019/training/online-training) and supervised by physician faculty. The Healthy Mind Lab has extensive 
experience conducting clinical trials in adults including older adults, including pragmatic trials with 
antidepressants.  
 
Recruitment & retention: For the present study, participants will be recruited through EPIC, physician 
referrers, doctor’s hotlines, COVID-19 Testing Centers, and Emergency Rooms (microbiology lab).   
They may also be recruited, as needed, via word of mouth, referrals by colleagues, the Healthy Mind 
Lab website (www.healthymind.wustl.edu), flyers, and email notification. Participants will be considered 
eligible per the inclusion/exclusion criteria and at the PI’s determination. 
Both 
genders 
will 
be 
enrolled without regard to race, ethnicity, or religion. Potential participants undergo screens by email 
and phone/videoconference.   
 
The proposed study will require voluntary participation of individual persons and will abide by all federal 
regulations related to human subject protection, inclusion of women and minorities, and privacy of 
individually identifiable health information. As with any study that collects sensitive information, breach 
of confidentiality is a potential risk. To mitigate this risk, all study personnel will undergo training specific 
to the use of human participants in research (CITI), will be Health Insurance Portability and 
Accountability Act (HIPAA) and Good Clinical Practices (GCP) trained, and will be approved by the 
Washington University in St. Louis Institutional Review Board (IRB).  Throughout the study, we will 
confirm plans to assure: 1) accurate, complete, and verifiable data collection and 2) the rights and well-
being of human subjects will be protected, in accordance with 45 CFR 46 (Protection of Human 
Subjects) and, as applicable, 21 CFR part 50 (Protection of Human Subjects). Additionally, all data will 
be maintained strictly according to the HIPAA “two lock” policy. Only study personnel will have access 
to this data.  
 
Participation in the proposed study-supported activities will be entirely voluntary and permitted only 
following completion of all consent-related procedures. We view informed consent as an ongoing 
process, and will continue the informed consent conversation with subjects throughout their 
participation.  
 
 
Inclusion and Exclusion Criteria 
 
Inclusion criteria:  
1) men and woman age 18 and older;  
2) Outpatients (living in the community)  
3) Proven SARS-CoV-2 positive (per lab or physician report). 
4) Currently symptomatic with one or more of one or more of the following symptoms: fever, cough, 
myalgia, mild dyspnea, diarrhea, vomiting, anosmia (inability to smell), ageusia (inability to taste), 
sore throat. 
5) Able to provide informed consent.  
 
Exclusion criteria:  

1) Illness severe enough to require hospitalization or already meeting study’s primary endpoint for 
clinical worsening. 
2) Unstable medical comorbidities including, but not limited to: Severe underlying lung disease 
(COPD on home oxygen, interstitial lung disease, pulmonary hypertension), decompensated 
cirrhosis, Congestive heart failure (stage 3 or 4 per patient report and/or medical records). 
3) Immunocompromised (solid organ transplant, BMT, AIDS, on biologics and/or high dose steroids 
(>20mg prednisone per day) 
4) Already enrolled in another COVID 19 clinical trial 
5) Unable to provide informed consent (eg moderate-severe dementia diagnosis) 
6) Unable to perform the study procedures 
 
Rationale for inclusion & Exclusion Criteria:Adults 18 and older who are not already medically 
compromised (eg severe lung disease) are at risk for developing clinical deterioration late in their clinical 
course.  The Inclusion criteria will ensure that we collect as generalizable sample as possible of at-risk 
adults, while the exclusion criteria will ensure that we do not recruit individuals who are likely to need 
immediate hospitalization or are otherwise too medically unstable to participate in an outpatient study 
with remote monitoring.  Older adults will be included; exclusion criteria will exclude individuals who are 
highly frail, medically compromised, or highly cognitively impaired. 
 
 
Study Procedures, Materials, and Potential Risks  
Sources of Materials 
Research materials will be obtained by remote interviews, self-reports, medical records (when 
available), and remote self-monitoring. All materials will be obtained solely for the purposes of the 
research study. All data collected from the participants enrolled in the study will be stored and 
maintained confidentially and no identifying information, such as participant names, will be disclosed in 
any published documents.  
 
Study Procedures 
After passing an initial prescreening, potential participants will provide informed consent and be 
administered emailed, phone or videoconference-based screening assessments by trained research 
staff to assess the above inclusion and exclusion criteria. Participants who qualify after completing all 
screening assessments will then be sent or provided the study materials.  This consists of study 
medication and self-monitoring equipment, including, as needed, a pregnancy test [for females of 
childbearing age not using contraception], oxygen saturation monitor, automated blood pressure 
monitor, and thermometer. We will finalize screening (ie confirming medical stability via oxygen 
saturation monitor, and vital sign measurement) prior to instructing participants to begin taking study 
medication, after which point (after taking first dose) they are considered “randomized”, consistent 
with Intention to Treat principles.   
 
Study Design 
This study will randomize approximately n=152 participants.  This study has an initial double-blind 
phase (to test the drug’s effectiveness) followed by an open-label phase (to provide all participants 
with exposure to the drug, and allow a taper off of it for those initially taking active drug). 
 
Assignment will be 1:1; (1) Active treatment: start and maintain fluvoxamine 100mg, three times daily.  
May reduce dose (or start at reduced dose) for tolerability reasons; (2) Control: placebo, three times 
daily.  This drug vs placebo phase will last approximately 15 days and will be followed by an open-
label fluvoxamine phase that will typically last 6-7 days but could last up to 15 days: 100mg two times 
daily for 3 days, then 50mg two times daily for 3 days, then discontinue. 
 

Randomization will be stratified by age (we anticipate: 18-44, 45-54, 55-64 and >65 years, 
respectively, to reflect the age distribution of ascending risk for severe symptoms requiring 
hospitalization (https://www.cdc.gov/mmwr/volumes/69/wr/mm6912e2.htm#F2_down) and sex. Final 
determination of stratification will be made by the biostatistician (Phil Miller). Stratified randomization 
schedules will be generated by statistician Michael Yingling.  
 
After the randomized phase, all participants will be followed for approximately 30 days to collect 
clinical data (i.e., on hospitalization and other clinical outcomes). Thus, total study participation is 
approximately 45 days (15 days randomized, 30 days follow-up). 
 
All enrolled participants will also be sent a longterm follow up survey which asks about persistent 
COVID 19 symptoms, and a PROMIS scale which asks about functioning and quality of life. 
 
Management: To protect research staff, there will be no face-to-face contact with participants; all 
interactions will be fully-remote via Zoom videoconference and/or phone/text/email, as well as 
REDCap surveys pushed out to patients via their smartphones or other devices.   
 
For consented participants who start protocolized treatment we will inform their relevant medical 
providers, such as a PCP, towards the goal of an informed and collaborative management strategy. 
 
As this is a “prevention of clinical deterioration” study, it is anticipated that a minority (~10-15%) of 
participants will become hospitalized during the study, and that this will most likely occur during the 
randomized phase. Research staff under the physician investigators’ supervision will provide support 
including engagement with participants’ caregivers and physicians to ensure timely medical contact 
and emergency care (including calling 911).    
 
If a study participant develops a decrease in oxygen saturation to less than 90% on room air on >2 
readings, persistent increase in respiratory rate to >30 breaths per minute, persistent increase in Heart 
Rate to > 120 beats per minute, alteration in mentation, or severe worsening in shortness of breath, the 
research staff will direct them to seek emergency medical care at the nearest emergency department. 
If none of the above conditions are met, but the research staff still feel that the participant is unwell, 
one of the physician investigators will evaluate the participant via phone/telehealth and direct them for 
further care if needed. When a participant is directed to seek emergency medical care, they will be 
instructed to use a mask if available, and to identify themselves to EMS or to the Emergency 
Department staff as having been diagnosed with COVID-19. 
 
Safety Assessments 
We will assess for adverse events (including serious adverse events) daily via participant self-report 
during the first 15 days, and then again at the end of the study. 
 
Outcome Assessments 
As this is a prevention (of clinical deterioration) trial, the primary endpoint will be a “time to” clinical 
worsening analysis.  Following the intention to treat principle, all participants who are confirmed to 
have taken at least one dose of study medication are included in the analyses. 
 
Definition of clinical worsening: Clinical worsening 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%. A laboratory-confirmed clinical endpoint is 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). 
 

Power analysis: The below table regards the primary endpoint.  It assumes 80% power, alpha=0.05, 
and a 20% rate of progression to serious symptoms in the placebo group.  The table shows sample 
size required based on reduction in that rate in the active (fluvoxamine) group.  With total n=152 (76 
per group), we would have 80% power to find a statistically significant difference in survival curves 
(i.e,. time to clinical worsening) if the rate of progression with fluvoxamine is only 5% (i.e., a three-
quarters reduction in the risk of clinical deterioration).  This power calculation is conservative because 
it does not take into account the potentially improved power gained by stratification, or the enhanced 
power for Kaplan Meier vs. simple rates; therefore, we are likely to be sufficiently powered for a more 
modest treatment effect. 
  
Treatment 
Response 
N (each 
group) 
.05 
76 
.06 
90 
.07 
108 
.08 
131 
.09 
160 
.10 
199 
 
We will also examine the following secondary endpoints: 
1. clinical deterioration on a Likert-type scale: (1) moderate severity of illness as defined by O2 
saturation <92% but no supplemental oxygen requirement; (2) O2 saturation plus supplemental 
oxygen requirement; (3O2 saturation <92% plus hospitalization (related to dyspnea/hypoxia); (4) the 
above, plus ventilator support requirement; (5) the above, plus ventilator support for at least 3 days; 
(6) death. 
2. clinical deterioration measured by number of days: (1) requiring supplemental oxygen; (2) requiring 
hospitalization; (3) requiring ventilator support. 
These Likert-type assessments are based on our review of current COVID-19 treatment studies.  
They will be collected in retrospect via patient or family report and/or medical records. 
 
3. Total symptomatic severity during the 15 days using a continuous scale of each patient’s 
presenting symptoms on a 0-10 Likert scale (0= symptom not present, 10= symptom is very severe).  
Outcomes will be collected daily, with symptomatic data collected approximately twice daily via the 
technique of Ecological Momentary Assessment (ie “how bad is your symptom right now?”). The most 
severe symptom at baseline will be the focus.This data collection and analytic technique (with 
frequent measurement of the symptom[s] most relevant to the individual patient) should greatly 
increase precision and power (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6524455/). 
 
Data management and analysis: Data will be collected in REDCap and outcomes will be collected 
by blinded research staff.  The study statistician, Michael Yingling, will conduct blinded (ie “treatment 
1 vs treatment 2”) analysis under the supervision of Phil Miller.  We may conduct an interim “futility” 
analysis at approximately n=100 participants.  The primary analysis will be survival analysis of the 
primary outcome (clinical worsening), while secondary endpoints (symptomatic severity) will be 
examined using appropriate (descriptive, Area Under the Curve (AUC), and trajectory) comparisons. 
Sharing of de-identified data from this study will be critical because it will help characterize this patient 
population and, if positive results, would immediately lead to a potential new treatment for COVID-
19.  Therefore it is planned that a pre-print of the article along with de-identified data will be posted on 
a public repository such as arxiv (arxiv.org).  This has been standard during the pandemic in order to 
share results as rapidly as possible. 

 
Additional measurements: 
Baseline: vital signs (pulse, blood pressure, temperature), O2 saturation, weight and height, 
symptoms and symptomatic severity. 
Follow-up: daily vital signs, O2 saturation, adverse events (participant self-report). 
 
 
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 commohly 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.  The research team will carefully evaluate co-prescribed drugs as well as OTC medications 
and caffeine use, to mitigate drug-drug interactions.  We anticipate approximately 20% of participants 
will be on current SSRI/SNRI use at recruitment – will include these individuals, so long as the 
participant can be safely switched over to fluvoxamine briefly. 
 
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, 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. 
oedema [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), Galactorrhoea (expulsion of breast milk unrelated to pregnancy 
or breastfeeding). 
 
Potential risk associated with Breach of Confidentiality:  
One risk of participating in this study is that confidential information may be accidentally disclosed.  We 
will use our best efforts to keep the information about participants secure.  All private information is 
stored in secured areas and on encrypted and password-protected servers. 
 
Other risks: 
There may also be unknown risks.  We will adjust the informed consent process if new risks are 
identified.   
Adequacy of Protection Against Risks 
Recruitment and Informed 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 relevant potential participants and relevant members of their 
treatment team to provide informed consent or assent for interested individuals. Informed consent will 
be obtained from all participants before any study procedures are initiated. The e-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 medical care. The objectives of the project, all 
of the requirements for participation, and any possible discomforts and risks will be clearly explained at 
each contact to the participants orally and in writing.  All participants must sign an e-consent, 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 
This project will be conducted at Washington University School of Medicine. The risks of breaching 
confidentiality will be strictly limited by the use of locked and restricted access to data as well as study 
ID numbers rather than participants’ names in the database that will be created for this project. No 
identifiers will be included in any computer files or reports generated by this study. All personnel 
involved in the design or conduct of research involving the human participants will receive the required 
education on the protection of human research participants and will also undergo training in the 
psilocybin exposure protocol.  
 
Minimizing risk: 
Fluvoxamine is a commonly prescribed serotonin reuptake inhibitor which has been commonly 
prescribed in the US for more than 2 decades, and in this study it is provided only briefly.  Therefore, 
moderate-severe and serious treatment-attributable AEs would be uncommon, but monitoring will 
include oversight by physicians with expertise in this drug class (Drs Lenze, and Nicol).