Conditions: COVID 19 Coronavirus
Keywords: COVID 19 fluvoxamine
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 152
Healthy volunteers: no

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. Only residents of Missouri and Illinois may participate.

Detailed description:
We will consent approximately 152 participants, age 18 and older, who have tested tested positive for COVID-19 and are currently experiencing mild symptoms. 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 a pregnancy test (for females of childbearing age not using contraception), an oxygen saturation monitor, blood pressure monitor, and thermometer. Once the study team has finalized the screening process, the participant will begin taking the study medication.

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 100mg of fluvoxamine or placebo by mouth three times a day for a daily total of 300mg. They will continue this dose for approximately 15 days. Depending on tolerability, the dose may be adjusted. Participants will also complete short 10-15 minute assessments daily to assess symptoms, results of self-monitoring (including oxygen level, blood pressure, and temperature) and any adverse events.

Open-label Phase: After completing the randomization phase, participants will then participate in an open-label phase (participant will definitely receive fluvoxamine) that will last up to 15 days. Those randomized to placebo will have the opportunity to try fluvoxamine during this time. Those randomized to fluvoxamine will continue this medication while slowly decreasing the drug. The participant may opt out of this phase. The dosage during this time will be 50-100mg two times daily until discontinuing the drug.

Follow-up Phase: We will follow participants for approximately 30 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 100mg capsules, three times daily. May reduce dose (or start at reduced dose) for tolerability reasons. Will be followed in the RCT for approximately 15 days. arm 2: Start placebo one capsule, three times daily. May reduce dose (or start at reduced dose) for tolerability reasons. Will be followed in RCT for approximately 15 days.

Interventions: intervention 1: Fluvoxamine intervention 2: Placebo
Intervention descriptions: intervention 1: Randomized to either fluvoxamine or placebo for approximately 15 days. Will take up to 300mg per day (3 capsules per day) as tolerated. intervention 2: Randomized to either fluvoxamine or placebo for approximately 15 days. Will take up to 3 capsules per day as tolerated.

Protocol document:
Prot_SAP_000.pdf: 
 
 
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).    
 
 
 

ICF_001.pdf: 
FOR IRB USE ONLY 
IRB ID #: 202004023 
APPROVAL DATE: 04/20/20 
RELEASED DATE: 04/20/20 
EXPIRATION DATE: 04/07/21 
 
 
 
 
 
INFORMED CONSENT DOCUMENT 
 
Project Title:    The STOP-COVID trial: a double-blind, placebo-controlled clinical trial of 
fluvoxamine for symptomatic individuals with COVID-19 infection 
 
Principal Investigator:         Eric Lenze, M.D. 
 
Research Team Contact:     Angela Stevens    (314)362-6291 
Marissa Rhea      (314)362-3797 
 
 
 
This consent form describes the research study and helps you decide if you want to participate.  It 
provides important information about what you will be asked to do during the study, about the risks and 
benefits of the study, and about your rights and responsibilities as a research participant. 
• You should read and understand the information in this document including the procedures, 
risks and potential benefits. 
• If you have questions about anything in this form, you should ask the research team for more 
information before you agree to participate. 
•   You may also wish to talk to your family or friends about your participation in this study. 
• Do not agree to participate in this study unless the research team has answered your 
questions and you decide that you want to be part of this study. 
 
WHAT IS THE PURPOSE OF THIS STUDY? 
 
This is a research study.  We invite you to participate in this research study because you are 18 or older, 
have tested positive for the COVID-19 infection, and are currently exhibiting symptoms of the infection. 
 
The purpose of this research study is to determine if a widely used 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 U.S. Food and Drug Administration 
(FDA) for the treatment of obsessive-compulsive disorder.  The use of fluvoxamine for the treatment of 
COVID-19 is considered investigational, which means the U.S. Food and Drug Administration has not 
approved it for this use. 
 
WHAT WILL HAPPEN DURING THIS STUDY? 
 
Screening 
For your safety and the safety of others, all interactions for this study will be conducted remotely with 
you by videoconferencing, phone, and email. Once we have determined from a short pre-screen that you 
may be eligible, study staff will contact you to go over this informed consent.  You will then be asked to 
complete brief screening assessments to determine if you meet criteria for the study.  If you qualify after 
completing the screening assessments, the study team send you the study medication.  You will also use 
self-monitoring equipment to record your oxygen level (a monitor goes on your fingertip), blood


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pressure and pulse, and temperature.  If you are a female of childbearing age and are not using 
contraception, you will also take a pregnancy test.  If you do not have the equipment needed to measure 
your blood pressure and pulse, temperature, or oxygen levels daily, we can help you obtain the proper 
equipment. Once the study team has finalized the screening process, you will begin taking the study 
medication. 
 
Randomized Controlled Trial (Fluvoxamine vs. Placebo) 
You will be randomly assigned (like flipping a coin) to take either fluvoxamine or a placebo (a sugar pill 
without active medication).  Your assignment is completely random; therefore, you will not have a 
choice in this study decision. This phase of the study will last approximately 15 days and is double- 
blinded, meaning neither you nor the investigators will know if you are receiving fluvoxamine or 
placebo.  You will take up to 100mg of fluvoxamine or placebo by mouth three times a day for a daily 
total of 300mg.  You will continue this dose for approximately 15 days.  Depending on how you tolerate 
the medication, we may adjust the dose.  You will also complete short 10-15 minute assessments daily 
to assess your symptoms, results of self-monitoring your illness (including your oxygen level, blood 
pressure and pulse, and temperature) and any adverse events. Daily surveys are for data collection 
purposes only and are not monitored in real time. If you experience a worsening of symptoms, please 
contact your physician or go to the nearest emergency room. 
 
Open-label Fluvoxamine Phase 
After completing the randomization phase, you will then participate in an open-label phase (meaning 
you will definitely receive fluvoxamine) that will last up to 15 days.  If you were randomized to placebo, 
you will have the opportunity to try fluvoxamine during this time.  If you were randomized to 
fluvoxamine, you will continue this medication while slowly decreasing the drug.  You may opt out of 
this phase per your preference. 
 
Follow-up Phase (approximately 30 days after the randomized phase) 
Once you have discontinued the study drug, we will follow you for approximately 30 days. You will 
complete one short survey at the end.  If needed, we will review your medical records to determine your 
clinical course (for example, what happened if you were hospitalized). 
 
Will you save my research information to use in future research studies? 
Identifiers may be removed from your private information and used for future research or shared with 
others. If this occurs, we will not ask you for additional consent. 
 
HOW MANY PEOPLE WILL PARTICIPATE? 
 
Approximately 152 people from the community will take part in this study conducted by investigators at 
Washington University. 
 
HOW LONG WILL I BE IN THIS STUDY? 
 
If you agree to take part in this study, your involvement will last for approximately 45 days.  This 
includes: 
•   Randomized phase, lasting approximately 15 days 
•   Open-label phase, lasting up to 15 days


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•   Follow-up, lasting approximately 30 days after the randomized phase 
 
Your involvement will also include 10-15 minute daily assessments, which will be conducted either by 
videoconferencing, email, or phone. 
 
WHAT ARE THE RISKS OF THIS STUDY? 
 
You may experience one or more of the risks indicated below from being in this study. In addition to 
these, there may be other unknown risks, or risks that we did not anticipate, associated with being in this 
study. 
 
Risks of stopping SSRI: 
If you are currently taking a selective serotonin reuptake inhibitor, you will need to stop this medication 
for participation in this trial. There is a 50% chance that you will be randomized to placebo or 
fluvoxamine. Your mood could change as a result of stopping your prescribed SSRI. 
 
Study Assessments 
There are no risks associated with any of the assessments. 
 
Fluvoxamine 
Likely/common 
>10% 
Less likely/less common (1-10%) 
Rare (<1%) 
none 
Dizziness 
Painful joints 
Weight loss or loss of appetite 
Hallucinations or confusion 
Agitation, nervousness, or anxiety 
Stiff muscles 
Yawning 
Drop in blood pressure while standing 
Trouble sleeping or excessive sleepiness 
Rash or itchy skin 
Tremor 
Mania (elevated mood) 
Headache 
Seizures 
Palpitations (feeling your heart beating) 
Abnormal liver function 
High heart rate 
Becoming sensitive to light 
Diarrhea or constipation 
Breast milk unrelated to pregnancy or 
breast feeding 
Sweating 
Weakness or feeling of malaise 
Dry mouth 
Sexual dysfunction (delayed orgasm or 
reduced libido) 
 
If you are a woman capable of becoming pregnant, we will ask you to have a pregnancy test before 
beginning this study.  You must use effective birth control methods and try not to become pregnant 
while participating in this study.  If you become pregnant, there may be unknown risks to your unborn 
child, or risks to your unborn child that we did not anticipate.  Although there are no known risks of 
fluvoxamine to an unborn child, here may be long-term effects of this medication that could increase the 
risk of harm to an unborn child.  You must tell the doctor if your birth control method fails while you are


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on the study medication. If you believe or know you have become pregnant while participating in this 
research study, please contact the research team member identified at the top of this document as soon as 
possible.  You do not need to wait before becoming pregnant after completing the medication in this 
study. 
 
Potential risk associated with Breach of Confidentiality 
One risk of participating in this study is that confidential information about you may be accidentally 
disclosed.  We will use our best efforts to keep the information about you secure.  Please see the section 
in this consent form titled “How will you keep my information confidential?” for more information. 
 
WHAT ARE THE BENEFITS OF THIS STUDY? 
 
You may or may not benefit from being in this study. 
 
However, we hope that, in the future, other people might benefit from this study because the results will 
provide more knowledge on the effectiveness of fluvoxamine in the treatment for COVID-19. 
 
WHAT OTHER TREATMENT OPTIONS ARE THERE? 
 
Before you decide whether to be in this study, you may discuss with your doctor the other options that 
are available to you.  Instead of being in this study, you could take a different experimental treatment for 
COVID-19.  However, at this time there is no known effective treatment for COVID-19. 
 
If your condition worsens, you may or may not be able to participate in other COVID trials. 
 
WILL IT COST ME ANYTHING TO BE IN THIS STUDY? 
 
You will not have any additional costs for being in this research study. 
 
WILL I BE PAID FOR PARTICIPATING? 
 
You will not be paid for being in this research study. 
 
WHO IS FUNDING THIS STUDY? 
 
The University and the research team are not receiving payment from other agencies, organizations, or 
companies to conduct this research study. 
 
WHAT IF I AM INJURED AS A RESULT OF THIS STUDY? 
 
Washington University investigators and staff will try to reduce, control, and treat any complications 
from this research. If you feel you are injured because of the study, please contact the investigator at 
314-362-1671 and/or the Human Research Protection Office at 1-(800)-438-0445. 
 
Decisions about whether payment for medical treatment for injuries relating to your participation in 
research will be made by Washington University. If you need to seek medical care for a research-related


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injury, please notify the investigator as soon as possible. 
 
The federal government has issued a declaration under a law known as the Public Readiness and 
Emergency Preparedness (PREP) Act to address the coronavirus (COVID-19) public health emergency. 
If you are injured or harmed as a result of participating in this study, that federal government declaration 
may limit your ability to obtain damages by filing a lawsuit against the study’s researchers, health care 
providers, study site, study sponsor, and/or manufacturer or distributer of the drug.  However, if you are 
injured or harmed as a result of participating in this study, the federal government has established a 
program that may provide compensation to you or your family. To find out more about this program, 
known as the “Countermeasures Injury Compensation Program” (CICP), go to 
https://www.hrsa.gov/cicp/about/index.html or call 1-855-266-2427.  The CICP is the payer of last 
resort, meaning that the CICP would generally only reimburse or pay for items or services to the extent 
such items or services are not covered by other third-party payers, such as your health insurance or 
workers’ compensation you receive. 
 
HOW WILL YOU KEEP MY INFORMATION CONFIDENTIAL? 
 
Other people such as those indicated below may become aware of your participation in this study and 
may inspect and copy records pertaining to this research.  Some of these records could contain 
information that personally identifies you. We will keep your participation in this research study 
confidential to the extent permitted by law. 
• Government representatives (including the Office for Human Research Protections) to complete 
federal or state responsibilities 
•   The U.S. Food and Drug Administration 
•   Your primary care physician if a medical condition that needs urgent attention is discovered 
•   Hospital or University representatives to complete Hospital or University responsibilities 
• Information about your participation in this study may be documented in your health care records 
and will be available to anyone with access to your health care record, including your health 
insurance company.  This information may also be released as part of a release of information 
request. 
• Washington University’s Institutional Review Board (a committee that oversees the conduct of 
research involving human participants) and the Human Research Protection Office. The 
Institutional Review Board has reviewed and approved this study. 
•   Any report or article that we write will not include information that can directly identify you. 
The journals that publish these reports or articles require that we share your information that was 
collected for this study with others to make sure the results of this study are correct and help 
develop new ideas for research. Your information will be shared in a way that cannot directly 
identify you. 
 
To help protect your confidentiality, all electronic records will be password-protected. 
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by U.S. 
Law. This Web site will not include information that can identify you. At most, the Web site will 
include a summary of the results. You can search this Web site at any time.


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Are there additional protections for my health information? 
Protected Health Information (PHI) is health information that identifies you. PHI is protected by federal 
law under HIPAA (the Health Insurance Portability and Accountability Act). To take part in this 
research, you must give the research team permission to use and disclose (share) your PHI for the study 
as explained in this consent form.  The research team will follow state and federal laws and may share 
your health information with the agencies and people listed under the previous section titled, “How will 
you keep my information confidential?” 
 
Once your health information is shared with someone outside of the research team, it may no longer be 
protected by HIPAA. 
 
The research team will only use and share your information as talked about in this form or as permitted or 
required by law.  When possible, the research team will make sure information cannot be linked to you 
(de-identified).  Once information is de-identified, it may be used and shared for other purposes not 
discussed in this consent form. If you have questions or concerns about your privacy and the use of your 
PHI, please contact the University’s Privacy Officer at 866-747-4975. 
 
Although you will not be allowed to see the study information, you may be given access to your health 
care records by contacting your health care provider. 
 
If you decide not to sign this form, it will not affect 
•   your treatment or the care given by your health provider. 
•   your insurance payment or enrollment in any health plans. 
•   any benefits to which you are entitled. 
However, it will not be possible for you to take part in the study. 
 
If you sign this form: 
•   You authorize the use of your PHI for this research 
•   This authorization does not expire. 
•   You may later change your mind and not let the research team use or share your information 
(you may revoke your authorization). 
• To revoke your authorization, complete the withdrawal letter, found in the Participant section 
of the Human Research Protection Office website at 
https://hrpo.wustl.edu/participants/withdrawing-from-a-study/ or you may request that the 
investigator send you a copy of the letter. 
o If you revoke your authorization: 
!  The research team may only use and share information already collected for 
the study. 
!  Your information may still be used and shared as necessary to maintain the 
integrity of the research, for example, to account for a participant’s 
withdrawal from the research study or for safety reasons. 
!  You will not be allowed to continue to participate in the study. 
 
 
 
Can we contact you by email?


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We would like to contact you by email for the purposes listed below.  Some of these emails may contain 
health information that identifies you. 
• We may use emails to schedule remote visits, communicate about your medications, follow- 
up to your questions or to an adverse event, send links to surveys and/or assessments, and 
patient education. 
 
Only the research team will have access to your email communications.  We will only communicate by 
email to send you the information listed above.  If you have any questions or need to contact us for an 
urgent or emergent situation, please contact the research team member identified at the top of this 
document. 
 
You should be aware that there are risks associated with sending your health information via email. 
• There is always a risk that the message could be intercepted or sent to the wrong email 
address.  To avoid sending messages to the wrong email address, the first email we send you 
will be a test message to ensure we have the correct email address. 
•   When using any computer you should be careful to protect your username and password. 
Make sure you log-out before getting up from the computer. 
• If you share a home computer with other family members, and do not want them to know you 
are participating in this study make sure you provide an email address that only you can 
access. 
• Your employer will have access to any email communications sent or received on any 
electronic devices used for work or through a work server. 
 
Do you agree to allow us to send your health information via email? 
 
           Yes                  No 
Initials                 Initials 
 
IS BEING IN THIS STUDY VOLUNTARY? 
 
Taking part in this research study is completely voluntary.  You may choose not to take part at all.  If 
you decide to be in this study, you may stop participating at any time. Any data that was collected as 
part of your participation in the study will remain as part of the study records and cannot be removed. 
 
If you decide not to be in this study, or if you stop participating at any time, you won’t be penalized or 
lose any benefits for which you otherwise qualify. 
 
What if I decide to withdraw from the study? 
 
You may withdraw by telling the study team you are no longer interested in participating in the study or 
you may send in a withdrawal letter. A sample withdrawal letter can be found at 
https://hrpo.wustl.edu/participants/withdrawing-from-a-study/ under Withdrawing from a Research 
Study. 
 
Will I receive new information about the study while participating?


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If we obtain any new information during this study that might affect your willingness to continue 
participating in the study, we’ll promptly provide you with that information. 
 
Can someone else end my participation in this study? 
 
Under certain circumstances, the investigator might decide to end your participation in this research 
study earlier than planned. This might happen for no reason or because in our judgment it would not be 
safe for you to continue. 
 
WHAT IF I HAVE QUESTIONS? 
 
We encourage you to ask questions.  If you have any questions about the research study itself, please 
contact: Angela Stevens, 314-324-6291 or Marissa Rhea, 314-362-3797. If you experience a research- 
related injury, please contact: Eric Lenze at the 24/7 exchange number at 314-388-5205 (local)/800-909- 
4903 (toll free) and tell the operator you are a participant in Eric Lenze’s research study. 
 
If you have questions, concerns, or complaints about your rights as a research participant, please contact 
the Human Research Protection Office 1-(800)-438-0445, or email hrpo@wustl.edu.   General 
information about being a research participant can be found on the Human Research Protection Office 
web site, http://hrpo.wustl.edu.  To offer input about your experiences as a research participant or to 
speak to someone other than the research staff, call the Human Research Protection Office at the number 
above.


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This consent form is not a contract. It is a written explanation of what will happen during the study if 
you decide to participate. You are not waiving any legal rights by agreeing to participate in this study. 
As a participant you have rights and responsibilities as described in this document and including: 
•  To be given enough time before signing below to weigh the risks and potential benefits and 
decide if you want to participate without any pressure from the research team or others. 
•  To understand all of the information included in the document, have your questions answered, 
and receive an explanation of anything you do not understand. 
•  To follow the procedures described in this document and the instructions of the research team to 
the best of your ability unless you choose to stop your participation in the research study. 
•  To give the research team accurate and complete information. 
•  To tell the research team promptly about any problems you have related to your participation, or 
if you are unable to continue and wish to stop participating in the research study. 
 
Your signature indicates that this research study has been explained to you, that your questions have 
been answered, and that you agree to take part in this study.  You will receive a signed and dated copy 
of this form. 
 
 
 
Do not sign this form if today’s date is after EXPIRATION DATE: 04/07/21. 
 
 
 
 
(Signature of Participant)                                                       (Date) 
 
 
 
 
(Participant's name – printed) 
 
Statement of Person Who Obtained Consent 
 
The information in this document has been discussed with the participant or, where appropriate, with the 
participant’s legally authorized representative.  The participant has indicated that they understand the 
risks, benefits, and procedures involved with participation in this research study. 
 
 
 
 
(Signature of Person who Obtained Consent)                        (Date) 
 
 
 
 
(Name of Person who Obtained Consent - printed)