Fluoxetine to Reduce Intubation and Death After COVID19 Infection
Phase: PHASE4
Conditions: COVID-19, Cytokine Storm
Sponsor: University of Toledo Health Science Campus

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Fluoxetine to Reduce the Risk of Morbidity and Mortality with COVID-19 Infection 
Cheryl McCullumsmith, MD PhD, Principal Investigator 
NCT04377308 
May 2, 2020  
 
 

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Fluoxetine to reduce the risk of morbidity and mortality with COVID-19 infection 
Cheryl McCullumsmith, MD PhD, Principal Investigator 
 
1. Background, Review of the Literature, Significance  
Much of the morbidity and mortality with COVID-19 infection is thought to be the result of 
multisystem organ failure after a cytokine storm (Huang et al. Lancet 2020). This cytokine storm is 
very similar if not identical to the Secondary Hemophagochytic Lymphohistiocytosis (SHLH)  seen in 
Severe Acute Respiratory Syndrom (SARS) also caused by a coronavirus, and includes increased 
levels of IL-2, IL-7, C-CSF, TNF-2, interferon-G inducible protein, MCP1 and MIP1a, all of which are 
driven by increased levels of IL-6. (Taraz 2013, Gobin, 2014) These findings have led to use of 
medications such as tocilizumab, an IL-6 receptor antagonist, to treat COVID-19 pneumonia.  
Fluoxetine and certain other selective serotonin reuptake inhibitors (SSRIs) have demonstrated in vitro 
and in vivo efficacy at reducing IL-6 and both preventing and treating hyperimmune responses 
associated with elevated levels of IL-6. Further, fluoxetine has a very safe therapeutic profile and could 
be used both prophylactically to prevent the cytokine storm with COVID-19, as well as an adjuvant 
treatment for critically ill patients.  
In vitro and in vivo data demonstrate that fluoxetine and some other selective serotonin 
reuptake inhibitors (SSRIs) effectively reduce IL-6 to prevent hyperimmune response. In addition to 
SSRI use in adjuvant treatment for critically ill patients, the established safety profiles of many SSRIs 
allow these drugs to be used prophylactically in order to prevent cytokine storm associated with 
COVID-19 infections. SSRI treatment before starting antiviral therapies reduces incidence of 
interferon-induced depression and carries minimal side effect profiles consisting of rare 
dizziness (Udina et al., 2014). The SSRI fluoxetine demonstrates a particularly pronounced ability to 
inhibit IL-6 activation (Durairaj, Steury, & Parameswaran, 2015; Hashioka et al., 2007). This effect is 
mediated by non-serotonergic pathways involving NF-kB suppression and inhibition of dendritic cell 
antigen presentation (Branco-de-Almeida et al., 2011; D. Liu et al., 2011; R. P. Liu et al., 2014; 
Vollmar, Haghikia, Dermietzel, & Faustmann, 2008; Young et al., 2014). Animal models demonstrate 
that SSRIs protect against hyperinflammatory conditions and diseases states. In fact, pretreatment with 
fluoxetine frequently outperforms pretreatment with corticosteroids  (Dong et al., 2016). Recently, 
clinical trials have demonstrated compelling relationships between SSRI treatment and cytokine 
levels (Amitai et al., 2016). A recent 2019 review and meta-analysis by Wang et al. echoes previous 
animal work and suggests that SSRI therapy indeed reduces IL-6 levels in human subjects (Wang et 
al., 2019). 

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These data are significant to COVID-19 patients at risk for pulmonary symptoms. Pretreatment 
with SSRIs results in decreased destructive immune reactions across a variety of animal models. In rat 
models of chronic obstructive pulmonary disease, fluoxetine decreases lung injury and inhibits 
cytokines such as TNF-a and IL-6 (Cai et al., 2017). Indeed, fluoxetine reduces inflammatory reaction 
in several models of human disease, providing marked decreases in reactive cytokines (Roumestan et 
al., 2007). In addition to decreasing expression of inflammatory cytokines, pretreatment with 
fluoxetine also decreases incidence of pulmonary arterial hypertension, pulmonary arterial 
muscularization, and extracellular matrix remodeling  (Li et al., 2011). Bronchial asthma models show 
therapeutic effects of fluoxetine pretreatments in rats (Sherkawy, Abo-Youssef, Salama, & Ismaiel, 
2018), and several studies suggest positive therapeutic efficacy may be concurrent with reduced levels 
of cytokines including IL-6 (Blatteau et al., 2012; Blatteau et al., 2015). 
Overall, there is significant preclinical data supporting the use of SSRI’s in the abrogation of harmful 
inflammatory side effects, such as those driving COVID19 morbidity and mortality. Furthermore, 
clinical data shows robust safety and efficacy profiles supporting the use of fluoxetine pretreatment 
interventions. At the University of Toledo Medical Campus, we are fortunate to have a leading expert 
on the relationship between antidepressant drugs and their anti-inflammatory therapeutic effects. Dr. 
Kevin Pan, who will be leading the laboratory work described in this proposal, has published 
extensively on the use of antidepressants to limit organ damage, decrease pro-inflammatory cytokine 
production, and inhibit intracellular migration of early-stage inflammatory response  (Lu, Wang, Chen, 
Jiang, & Pan, 2020). A recent Nature publication from Dr. Pan and his team explore connections 
between antidepressant drug administration and cytokine signaling, providing compelling support for 
the use of antidepressants in inflammatory disease states. Several studies from Pan et al. indicate 
antidepressant use inhibits pro-inflammatory cytokine gene expression both in vitro and in vivo. Using 
Dr. Pan’s methods, we will assay and investigate cytokine expression in our control and experimental 
patients while utilizing the expertise that Dr. Pan and his University of Toledo researcher team has 
developed on this topic. 
 
Further evidence for the efficacy of fluoxetine in decreasing the IL-6 response that stimulates 
the cytokine storm in COVID-19 infection comes from an analysis comparing the transcriptomes of 
cells lines treated with fluoxetine, dexamethasone (a steroid established to decrease IL-6), and 2 other 
antidepressants : bupropion and paroxetine to the transcriptome of the same cell line with a knock 
down in the IL-6 signal transduction molecule. This analysis was performed this week in the 
bioinformatics group in the Department of Neurosciences at University of Toledo and is illustrated 

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below. The concordance of the fluoxetine and IL-6ST knockdown cell lines is remarkably high, 
averaging over 0.7 . This concordance is greater than that seen with dexamethasone treatment, the 
standard anti-inflammatory steroid, and is higher than 2 other commonly used antidepressants, 
bupropion and paroxetine.  
 
2. Objectives/Specific Aims  
 
Aim 1: Fluoxetine treatment begun early after COVID-19 infection will reduce hospitalizations, 
intubations, and death from COVID-19 and complications more than no medication 
Aim 2:  Fluoxetine will decrease intubations and mortality in patients hospitalized with COVID-19 
infection greater than no medication. 
Aim 3 : Fluoxetine treatment of COVID-19 infected patients will not cause significant side effects or 
increase morbidity and mortality compared to no medication 
Aim 4.  Collect blood samples from 40 subjects for future cytokine analysis: both subjects taking 
fluoxetine and not taking fluoxetine samples taken at baseline and weekly after study initiation. 
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
Fluoxetine
Dexamethasone
Bupropion
Paroxetine
Transcriptome Analysis Concordance with IL-6 
Signal Transduction Knock Down in same Cell Line
A375
HEPG2
mean

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3. Methods 
 
a) Study Design : Pragmatic Clinical Trial : Experimental and Observational 
 
b) Method of treatment assignment  
Single arm patient centered clinical trial 
At study entry, participants will consent study participation via daily monitoring and will choose 
whether to participate in the activity monitoring, cytokine assessment and drug treatment portions 
of the trial. Participants who do not choose to take fluoxetine will serve as the control subjects. 
Additionally, patients will have the choice weekly to decide to start, continue, or discontinue the 
fluoxetine.  See figure below : 
 
c) Inclusion/exclusion criteria  
  
Inclusion :  
Patients aged 18 and above, able to give informed consent 

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COVID-19 test positive or presumptive positive awaiting COVID testin or  
results by following criteria: fever, cough and shortness of breath  
 
Overall Study Exclusion Criteria : 
Unable to give informed consent 
Prisoner/ institutionalized patient  
Under age 18 
Exclusion from Fluoxetine Arm:  
 
Active bleeding requiring blood products 
 
 
 
Bipolar disorder not on mood stabilizing medication* 
 
 
 
Known allergy or hypersensitivity to fluoxetine 
 
 
 
Currently taking the following medications : MAO I, pimozide, thioridine  
Currently taking hydroxychloroquine 
 
 
 
Pregnant or breastfeeding (pregnancy questionnaire attached) 
 
 
 
For hospitalized patients : QTc greater than 500 ms 
*Hospitalized patient may be on hydroxychloroquine if QTc<500 and the 
primary attending approves 
 
Exclusion from Blood Sample Provision: 
 
 
 
Pregnant 
 
 
 
Self-report of under 110 pounds 
d) Justification of the number of subjects  
All power calculations were done with the clincalc program and assume a dichotomous endpoint in 
a two independent sample study and are based on achieving the standards of a power of 0.80 and 
with an alpha of 0.05. Please note, that the assumptions of fluoxetine effect size are based on the 
absolute most conservative values in the published literature reviewed above. 
Aim 1 : Hospitalization rates  
Assumptions: 
1. 2/3 of patients who enter the trial will choose to take fluoxetine 
2. 10% of COVID-19 + patients will progress to a clinical condition requiring hospitalization 
3. Fluoxetine treatment decreases hospitalization rate by 50% 
Sample Size : 312 in the no medication group and 624 in the 2 fluoxetine groups, for a total sample 
size of 936. This sample size is very achievable given the current coronavirus pandemic. 
Prevention of Hospitalization 

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Hospitalization, no medication 
10% 
Hospitalization, Fluoxetine 
5% 
Alpha 
0.05 
Beta 
0.2 
Power 
0.8 
Sample Size 
No medication 
312 
Fluoxetine, low or high 
624 
Total 
936 
Aim 2 : Intubation in those hospitalized 
Assumptions 
1. 10% of patients requiring hospitalization for COVID-19 + will progress to intubation 
2. Fluoxetine treatment decreases intubation rate by 20% 
Aim 2:  Death in those hospitalized 
Assumptions 
1. 1% of patients requiring hospitalization for COVID-19 + will die during that hospitalization 
2. Fluoxetine treatment decreases mortality rate by 20% 
Sample Size : 3213 in the no medication group and 3213 in the fluoxetine groups, for a total sample 
size of 6426.These sample sizes will not be achievable in this pilot study. Data from Aims 3 and 4 will 
therefore be used qualitatively for the gathering of pilot data.  
Prevention of intubation, death 
Sample Size 
No medication 
3213 
Fluoxetine 
3213 
Total 
6426 
Prevention of Intubation  

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Intubation, death in no medication 
10% 
Intubation, death in fluoxetine 
8% 
Alpha 
0.05 
Beta 
0.2 
Power 
0.8 
 
e) Study setting  
Telephone, outpatient offices, emergency department, Hospital 
f) Primary and secondary outcome measures  
Primary Outcome Measures: 
Aim 1 : Rates of Hospitalization 
Aim 2 : Rates of Intubation and Death 
Aim 3 : Side effect profile 
Secondary Outcome Measures: 
Aim 1 and 2 : Depression, Anxiety, Suicidal thinking,  Days of Illness, Severity of Illness 
 
g) Variables  
Demographic information (age, gender, medical history, co-morbidities, etc.)   
Medications 
Symptom profile 
• Number of days of symptoms prior to testing 
• Epidemiologic information from CDC/Health Department surveillance interview 
• Hospital Course 
Days in Hospital, Intubation, Complications 
Outcome: Never hospitalized, Hospitalized, Intubation, Death 
 
h) Procedures, interventions, schedule  

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Week/Day 
Patient Intervention 
Setting/ 
Responsible 
Individual 
Standard 
of Care 
Research 
Purposes Only  
1/1 
Informed Consent 
Phone/ research team 
------ 
Yes 
1/1 
Baseline Study Data  
Phone/ research team 
 
Yes 
1 
Blood Sample  
Laboratory Services 
Inpatient 
outpatient 
1 
Physician Interview/ 
Medication Prescription 
Phone/Study 
physician 
---- 
Yes 
Daily 
Symptom/ Side effect 
Check In 
Phone/ research team 
 
Yes 
Weekly 
Physician Interview/ 
Medication Prescription 
Phone/Study 
physician 
---- 
Yes 
Weekly or 
Change in 
Clinical 
Status* 
Blood Sample  
Laboratory Services 
Inpatient 
outpatient 
 
*Change in Clinical Status includes outpatient to inpatient, transfer to ICU, and intubation 
Procedures: 
 
Instrument 
Duration 
Assessment Time 
Points 
Frequency 
 
 
 
 
Baseline Intake Form 
Chart Review Form  
         04/1/19-present 
Baseline Demographics and past 
medical history  
30 min 
Initial study entry 
Once 
PHQ-9 
5 min 
Initial Study Entry 
Weekly 
GAD-7 
5 min 
Initial Study Entry 
Weekly 
Columbia Screener-recent 
3 min 
Initial study Entry 
------- 
Symptom Checklist 
5 min 
(included in baseline) 
Daily assessments 
Columbia Screener – since last 
visit 
3 min 
------- 
Daily assessments 
 
 
 
 
Physician Interview/Medication 
Prescription 
40 min 
Baseline 
weekly 

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Drug Distribution 
 
Once, at entry 
monthly 
Blood Draw for future 
assessment of cytokine levels 
60 min 
Baseline 
Weekly, as possible 
Chart Review Followup 
 
At study exit, one 
month, 3 months, 6 
months and one year 
after study exit 
See notes to left 
5 data points 
From 4/1/19- 4/1/23 
Physician Interview/Medication Prescription 
Interview includes : 
1) Assessment for pregnancy, contraindicated medications and review of baseline intake 
2) Explanation of risks and benefits of medication : see patient handout information sheet 
Blood Draw for Future Assessment of Cytokine Levels : 
• Not to exceed 2 blood draws per week or a total of 50 ml total over 8 weeks time period 
• Outpatient blood draws will occur only if study participants have regular clinical care blood 
draws until adequate personal protection equipment (PPE) is available for use in research 
settings. Study outpatient blood draw will occur by appointment at UTMC Emergency 
Department in a negative pressure room. Outpatient blood draws will not be done until there is 
adequate PPE available for research study purposes.  
o Study participant and phlebotomist will be equipped in full PPE.  
• Inpatient blood draws will occur during normal clinical care blood draws.  
• Blood samples will be stored at -80 degrees F in the hospital laboratory freezers for future 
cytokine analysis  
 

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4) Planned data analysis  
Aim 1, 2, 3 : Descriptive statistics, 
Compare rates of primary and secondary outcome measures in subjects receiving fluoxetine with 
those not receiving fluoxetine by Student t-test and Chi-square test as appropriate. 
 
Data Safety Monitoring Board 
Interim data analyses will be performed every 3 months and will be presented to a 4 member data 
safety monitoring board who will prepare a report on the ongoing safety of the clinical trial and 
consideration of  early termination of the study for either benefit or harm per the guidelines of 
Tyson et al. 2016.  
 
 
 

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