COVID-OUT: Early Outpatient Treatment for SARS-CoV-2 Infection (COVID-19)
Phase: PHASE3
Conditions: Covid19, SARS-CoV Infection
Sponsor: University of Minnesota

Study Title: COVID-OUT: Outpatient Treatment for SARS-CoV-2 infection, a Factorial 
Randomized Clinical Trial 
NCT04510194 
Version Date of Protocol: 08 December 2021 

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PROTOCOL COVER PAGE 
Protocol Title 
COVID-OUT: Outpatient Treatment for SARS-CoV-2 infection, a 
Factorial Randomized Clinical Trial 
Protocol Number 
MET29324 
Principal Investigator 
Carolyn Bramante, MD MPH 
Department: Medicine 
Telephone Number: 651-717-8915 
Email Address: bramante@umn.edu 
Scientific Assessment 
HRPP facilitated scientific assessment 
IND # 
152439 
IND Holder 
Carolyn Bramante, MD MPH 
University of Minnesota 
Version Number/Date 
Version: 3.4 
Date: 08 December 2021 
 
 
 
Confidentiality Statement: 
 
The information contained in this document is confidential. It is provided to you in confidence as an 
investigator, potential investigator, or consultant, for review by you, your staff, and an applicable Ethics 
Committee or Institutional Review Board. 
 
It is understood that this information will not be disclosed, duplicated, referenced, or transmitted in any 
form or by any means (electronic, mechanical, photocopy, recording, or otherwise) to others without 
written authorization from the Principal Investigator or the University of Minnesota.  
 
 

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VERSION HISTORY 
Version # 
Version Date 
Summary of Changes 
1.0 
08DEC2020 
Initial protocol 
2.0 
28 Feb 2021 
Protocol amendment submitted to allow screening online.  
3.0 
08MAR2021 
Protocol amendment: response to administrative clarification of request 
to remove Post-exposure prophylaxis and added final factorial design.  
3.1 
30APR2021 
Includes response to FDA questions on full factorial design.  
3.2 
08July2021 
Small updates, mostly around data collection 
3.3 
02 Sept 2021  
Small update around Inclusion criteria  
3.4 
08 Dec 2021 
Updated sample size.  
 
 
 

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TABLE OF CONTENTS 
 
PROTOCOL COVER PAGE ................................................................................................................... 1 
VERSION HISTORY ............................................................................................................................... 2 
TABLE OF CONTENTS ......................................................................................................................... 3 
ABBREVIATIONS/DEFINITIONS ........................................................................................................ 4 
 
1.0 
Objectives ...................................................................................................................................... 5 
2.0 
Background .................................................................................................................................... 5 
3.0 
Study Endpoints ........................................................................................................................... 11 
4.0 
Investigational Product ................................................................................................................ 12 
5.0 
Study Procedures ......................................................................................................................... 15 
6.0 
Study Population .......................................................................................................................... 24 
7.0 
Sharing of Results with Participants ............................................................................................ 28 
8.0 
Withdrawal of Participants .......................................................................................................... 28 
9.0 
Risks to Participants .................................................................................................................... 28 
10.0 Potential Benefits of Metformin .................................................................................................. 30 
11.0 Data and Specimen Banking ........................................................................................................ 31 
12.0 Statistical Considerations ............................................................................................................. 32 
13.0 Safety ........................................................................................................................................... 38 
14.0 Data Monitoring ........................................................................................................................... 41 
15.0 Provisions to Protect the Privacy Interests of Participants .......................................................... 42 
16.0 Compensation for Research-Related Injury ................................................................................. 43 
17.0 Multi-Site Research ..................................................................................................................... 43 
18.0 Appendices .................................................................................................................................. 43 
19.0 References .................................................................................................................................... 44 
 
 

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ABBREVIATIONS/DEFINITIONS 
 
ACE2 
Angiotensin-Converting Enzyme 
 
AE 
Adverse Events 
 
AHC-IE 
Academic Health Center Information Exchange 
 
ARDS 
Acute Respiratory Distress Syndrome 
 
COVID-19 
Disease caused by the virus SARS-CoV-2, or “Wuhan coronavirus” 
 
CLIA 
Clinical Laboratory Improvement Amendments 
 
CTSI 
Clinical and Translational Science Institute 
 
DM 
Type 2 Diabetes Mellitus  
 
DSMB 
Data Safety Monitoring Board 
 
ECMO 
Extracorporeal membrane oxygenation 
 
eConsent 
Electronic consent 
 
ED 
Emergency Department 
 
EGFR 
Estimated Glomerular Filtration Rate 
 
EHR 
Electronic Health Record 
 
ER 
Extended Release 
 
GDF 15 
Growth/Differentiating Factor 15 
 
ICF 
Informed Consent Form 
 
ICU 
Intensive care unit 
 
IDS 
Investigational Drug Services 
 
IL-6 
Interleukin 6 
 
IL-10 
Interleukin 10 
 
IQR 
Interquartile Range 
 
IR 
Immediate Release 
 
MHealth 
University of Minnesota Health 
 
mtDNA 
Mitochondrial DNA 
 
mTOR 
Mammalian Target of Rapamycin 
 
NDMA 
Nitrosodimethylamine 
 
NETs 
Neutrophil-Extracellular Traps 
 
RC’s 
Research Coordinators, and refers to members of the study team (includes                    
project manager, Co-I, PI).  
 
SAE 
Severe Adverse Event 
 
SARS 
Severe Acute Respiratory Syndrome 
 
SOPs 
Standard Operating Procedures 
 
SIREN 
Strategies to Innovate Clinical Trials network 
 
TLR7 
Toll-Like-Receptor 7 
 
TNF-alpha 
Tumor Necrosis Factor alpha 
 
UMMC 
 
University of Minnesota Medical Center 
 
 
 

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1.0 
Objectives 
 Title:  
COVID-OUT: Outpatient treatment of SARS-CoV-2 infection, a factorial Randomized Clinical 
Trial.  
Purpose:  
1) To understand whether metformin vs fluvoxamine vs ivermectin vs 
metformin+fluvoxamine vs metformin+ivermectin are superior to placebo in non-
hospitalized adults with SARS-CoV-2 infection for preventing COVID-19 disease 
progression. 
2) To understand if the active treatment arms are superior to placebo in improving viral load, 
serologic markers associated with Covid-19, and gut microbiome in non-hospitalized adults 
with SARS-CoV-2 infection. 
3) To understand if any of the active treatment arms prevent long-covid syndrome, PASC 
(post-acute sequelae of SARS-CoV-2 infection). 
2.0 
Background 
 Significance of Research Question/Purpose:  
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a rapidly spreading viral 
infection causing COVID-19 disease. While vaccine development for SARS-CoV-2 has been 
promising, there may be hurdles to wide distribution, reduced immunity in persons with advanced 
age or obesity (a state of thymic aging), and reduced willingness among the public to receive a 
vaccine developed so quickly.1 Additionally, new strains appear resistant to the vaccines. 
 Preliminary Data:  
Several observational studies have shown an association with decreased mortality with outpatient 
metformin use in patients who were then hospitalized with COVID-19, including a study we 
conducted.2 Two prospective studies have found efficacy of fluvoxamine in prevention 
hospitalization and death.3,4 Biophysical modeling of the SARS-CoV-2 life cycle, which 
accurately predicted the efficacy of remdesivir and the lack of efficacy of hydroxychloroquine, 
identified viral protein translation, which is inhibited by mTOR inhibitors such as metformin, as 
an especially sensitive node in the model (Castle et al., 2020). 
 Existing Literature:  
Table 1: Existing Literature 
Papers in 2020 with observational mortality findings related to metformin and COVID-19. 
Author 
Population 
Methods 
Finding 
Luo et al.1 
Am J Trop 
Med Hyg 
283 adults with 
DM hospitalized 
with COVID-19 
in Wuhan. 
Retrospective review, 
appears to be of home 
metformin us; 104 in 
metformin, 179 in no-
metformin group 
Hospital mortality 2.9% in metformin 
group vs 12.3% in no-metformin group, 
p=0.01.  OR for survival: 4.36 (1.22-
15.59, p=0.02). No difference in length of 
stay. No mortality difference based on use 
of other DM medications. 

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Cariou et 
al,2  
“Coronado 
study” 
Diabetalgia 
1,317 adults 
with DM in 
France, with or 
without home 
metformin use 
Multi-center 
observational study. 
Main outcome: 
mortality or 
intubation; Secondary 
outcome was 
mortality. 
HbA1C was not associated with main 
outcome (p=0.28) or death (p=0.91); 
home metformin was associated with 
lower mortality OR 0.59 (0.42, 0.84). 
Increased risk of death with insulin OR 
1.71, (1.20, 2.43). No association with 
other DM meds. 
Bramante 
et al. 
Lancet 
Healthy 
Longevity.  
6,256 adults 
with DM or 
obesity 
hospitalized for 
COVID-19 in 
the US. 
Retrospective review 
of USA UHG claims 
data of home 
metformin use (claims 
for >= 90 days in prior 
12 months) 
Metformin was associated with a reduced 
mortality in females: OR 0.759 (0.601, 
0.960) by propensity matching; OR 0.780 
(0.631, 0.965) by a mixed effects model; 
OR 0.785 (0.650, 0.951) by Cox 
proportional-hazards.  
Crouse et 
al. 
Metrxiv.org 
239 persons with 
diabetes and 
COVID-19   
Retrospective review 
of 25,326 subjects 
tested for COVID-19 
between 2/25 - 
6/22/20 at UAB. 
- Metformin treatment was independently 
associated with a significant mortality 
reduction in subjects with diabetes and 
COVID-19, OR 0.33 (0.13-0.84; p=0.02) 
Paper with laboratory findings suggesting lower IL-6 in metformin users with COVID-19 
Chen et al.3 
Diabetes 
Care 
904 patients with 
COVID-19, 136 
of whom had 
DM 
Retrospective review 
of patients with DM 
and COVID-19 in 
association with 
glucose lowering 
medications. 
Metformin users had lower IL-6 (4.07 vs 
11.1, p=0.02). In PCR-confirmed cases, 
IL-6 was also lower in metformin users 
than non-metformin users (4.77 vs 11.1, 
p=0.024). No differences between DDP-4 
users vs non-users. GLP-1 use not 
reported. 
Bramante 
et al, under 
review. 
2,135 patients 
with SARS Co-
V-2, subset with 
lab values 
Lab 
Bicarb 
Lactate 
IL-6 
CRP 
No Metformin 
25 (8), n=438 
1.5 (1.1), n=136 
1,702 (1,011), n=66 
111 (83), n=290 
Metformin 
26 (5), n=25 
1.3 (0.5), n=7 
54 (69), n=7 
84 (75), n=16 
P Value 
0.38 
0.78 
0.08 
0.02 
 
 
Figure 1: Pooled risk of mortality in hospitalized COVID‐19 patients with diabetes with preadmission 
metformin. (heterogeneity: I2= 29%; p = .23).5 
Prior to COVID-19, the exact mechanisms by which metformin conveyed benefit was a matter 
of debate. There are several ways by which metformin may offer protection from SARS-CoV2. 
Overall 
Study
OR (95% CI)      % Weight
0.62 (0.43, 0.89)    100.0
Kow, J M ed Virol
OR

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Existing Literature on Mechanistic Reasons for Metformin to be Effective against COVID: 
High glucose is associated with worse COVID-19 outcomes: Metformin reduces blood glucose 
levels, but not below physiologic levels, by reducing hepatic gluconeogenesis. Worse glucose 
control has also been associated with higher mortality and end-organ complications in patients 
with COVID-19.6 
 
Metformin could decrease endothelial injury and its complications: Metformin has been shown 
to improve microvascular endothelial function in women perhaps due to a significant increase in 
response to acetylcholine, decrease in insulin resistance, and non-significant decrease in tissue 
plasminogen activating factor, as was shown in a randomized control study of 8 weeks of 
metformin versus placebo in women with angina and normal coronary arteries .7 Pulmonary 
vascular endotheliatis has been observed in the lungs of patients with COVID-19.8 Endothelial 
dysfunction may be an important mechanism and therapeutic target in mitigating COVID-19 
sequelae. Metformin decreases thrombosis in long-term follow-up, possibly by inhibiting platelet 
activation factor and mitochondrial DNA (mtDNA) release,9,10 and may mediate improved 
cardiovascular outcomes via mechanisms beyond glucose control. COVID associated 
coagulopathy and thrombosis is a unique attribute to this disease, and the pathophysiology is 
poorly understood. Further, frequently widespread micro and macrovascular thrombosis has been 
reported in autopsies of patients with COVID 19.11,12  
 
Metformin decreases neutrophil-extracellular traps (NETs), and the neutrophil to lymphocyte 
ratio.13-15 NETs are microbiocidal compounds containing DNA, histones, and proteins.14,15 Sera 
from patients with COVID-19 demonstrate elevated levels of these histones and DNA 
components.15 It has been hypothesized that excessive NET formation leads to cytokine storm 
and microthrombus (possibly independent of tissue factor), and ultimately acute respiratory 
distress syndrome (ARDS) in COVID-19.16 Lymphopenia and neutrophil infiltration in 
pulmonary capillaries have been an important feature of severe COVID-19 disease.13,17-19 
Metformin’s inhibition of NET release could therefore mitigate the development of downstream 
lung injury.  
 
Metformin could decrease the viral cycle: There is evidence that metformin increases endosomal 
pH via action on vacuolar ATPase and/or endosomal Na+/H+ exchangers,20 thus reducing viral 
replication. Metformin leads indirectly to alteration of the mammalian target of rapamycin 
(mTOR)  pathway,21 which could decrease the viral lifecycle through effects on proteins 
including Orf9c and Nsp7.21  Biophysical modeling of the SARS-CoV-2 life cycle, which 
accurately predicted the efficacy of remdesivir and the lack of efficacy of hydroxychloroquine, 
identified viral protein translation, which is inhibited by mTOR inhibitors such as metformin, as 
an especially sensitive node in the model.22 Metformin has been shown to inhibit mTOR, and 
mTOR inhibition is associated with efficacy against MERS and COVID-19.23-25 

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Figure 2. Gordon et al found decreased 
SARS-CoV-2 and increased cell viability 
with metformin in vitro.21 
 
Figure 3. Biophysical modeling. 
 
Metformin may decrease entry of SARS-CoV-2 into cells: Activation of AMPK by metformin 
increases expression of angiotensin-converting enzyme 2 (ACE2). Simultaneously, increased 
phosphorylation of the ACE2 receptor leads to conformational changes26-28 that could 
theoretically decrease SARS-CoV-2 binding and entry into cells.29  
 
 
Figure 4, Karam et al, in press.  
 
Metformin has immune-modulatory effects: In patients with and without diabetes, metformin has 
been shown to favorably alter inflammatory mediators, including interleukin 6 (IL-6), TNF-
alpha, and to possibly boost interleukin 10 (IL-10), and suppress the C-C motif chemokine 
ligand.13,30-32 Metformin’s activation of the AMPK/mTor/Stat3 pathway seems to steer 
Red: viral growth
Black: cell viability

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macrophages away from the pro-inflammatory classical activation that produces TNF/IL6/IL1b, 
cytokines that contribute to morbidity in COVID-19.33-35 Possible evidence of this effect was 
seen in a retrospective study by  Chen et al of, review 904 patients with COVID-19 which showed 
that metformin users had lower IL-6 levels compared to non-metformin users (Table 2).18 
Metformin also inhibits toll-like-receptor 7 (TLR7) signaling and interferon production, which 
appears important to COVID-19 pathophysiology.36,37 Metformin also inhibits IgE- and aryl 
hydrocarbon-mediated mast cell activation.38 Mast cell activation has been implicated as an early 
indicator of inflammatory response to SARS-CoV-2. and possibly an indicator of impending 
cytokine storm.39,40 Mast cells from female rats have been found to cause a greater increase in 
tumor necrosis factor alpha (TNF-alpha) than mast cells in male rats, which may explain the 
observational findings of reduced mortality in women on metformin, but no among men on 
metformin.41  
 
Metformin has a history of anti-infectious properties: Metformin was found to have antiviral 
activity before SARS-CoV-2. In the 1940s and 1950s, metformin was used against influenza (as 
“Flunamine”), and was found to be effective against parainfluenza and cowpox.42,43 Metformin 
has also been associated with improved response to anti-infectious agents in HIV and 
tuberculosis.44 With the Zika virus, another RNA virus, activation of AMPK by metformin 
resulted in restricted viral replication by potentiating innate antiviral responses and decreasing 
glycolysis, with PKA Inhibitor PKI leading to decreased viral infection and replication.45,46 In 
patients with hepatitis C, metformin has been associated with improved virologic response to 
antivirals through decreased insulin resistance.47  
 
Metformin’s past anti-infectious benefits have been both against the infectious agent directly, as 
well as by improving the underlying health of the human host. It is unknown if the lower mortality 
observed in patients infected with COVID-19 who are on metformin is due to direct activity 
against the virus itself, improved host substrate, or both.  
 
Fluvoxamine 
In addition to metformin, fluvoxamine appears to have important anti-viral and anti-
inflammatory effects in SARS-CoV-2 infection. There is evidence that SARS-CoV-2 infection 
causes ER stress and activates pathways of unfolded protein response.48,49 This response is 
related to several signaling pathways such as autophagy, apoptosis, innate immunity, pro-
inflammatory response, and MAP kinase pathways.48 Further study has demonstrated that the 
virus can take over the ER by utilizing the stress sensor inositol requiring enzyme 1 (IRE1) 
which helps to regulate coronavirus-induced autophagy.49 This ER response provides a 
potential pathway for immunomodulatory treatment.  
 
Sigma-1 receptor (S1R) is an ER chaperone protein that regulates cytokine production through 
interaction with IRE1.4 S1R modulation has demonstrated significant changes to coronavirus 
replication, and atypical antipsychotics with S1R activity have displayed protective effects 
against clinical deterioration.50 Fluvoxamine is a selective serotonin reuptake inhibitor that is a 
powerful S1R agonist.51 Fluvoxamine has previously been shown to protect mice from septic 
shock and reduce the inflammatory response.52 There is potential for fluvoxamine as an 
immunomodulatory treatment for SARS-Cov-2. Fluvoxamine in CACO2 cells infected with 

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SARS-Cov-2 had a reduction in production of a subset of cytokines including IL-6, IL-8, 
CXCL1, and CXCL10.53 A randomized controlled clinical trial of 152 patients showed that 
patients who received fluvoxamine were less likely to experience clinical deterioration, or 
serious adverse events due to SARS-Cov-2 when compared to placebo (0% vs. 8%).4  A follow 
up real world observational cohort had similar findings of 0% (0/65) hospitalization with 
fluvoxamine vs. 12% (6/48) with observation.54  
 
 
 
Ivermectin 
Ivermectin has also shown anti-inflammatory effects that would reduce the harmful cytokine 
cascade noted in severe Covid-19 disease.55 A recent trial assessing a multi-therapy including 
12mg one-time dose of ivermectin found a 75% reduction in hospitalizations.56 Another small 
double-blinded RCT showed significant increased chance of viral clearance after a 5-day 
course of ivermectin.57 Another March 2021 RCT reported no effect on diminishing symptoms, 
but was under-powered for assessing reductions in hospitalization.58 An RCT with ivermectin 
must be done in the US, as endemic strongyloidiasis in other countries may confound results.  
 
Importance of factorial design approach: 
It is important to study all 3 of these medications in a factorial design because they all fit into 
the same implementation category: all are existing, FDA-approved, generic, inexpensive, 
currently available world-wide, and have long records of excellent safety. They each hold few 
medication or co-morbidity related contraindications, and none of them require any follow-up 
for short-term use.  
 
A factorial design approach is important for minimizing the percentage of patients who receive 
placebo in this urgent public health emergency. A factorial design allows us to efficiently 
compare the drugs directly to each other, as well as combination arms, while maintaining a 
placebo control. While EUA’s and prospective cohorts have become common in the body of 

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literature about Covid-19, we feel that randomized placebo control is necessary for best 
understanding medication effect.  
3.0 
Study Endpoints 
 Primary Endpoint:  
1) Clinical progression, defined as: Emergency department visit for any COVID-19 
related symptom (including hospitalization or death) or decrease in O2 saturation 
(≤93%*59 on room air, or need for supplemental oxygen to maintain an O2 saturation 
>93%) by 14 days.  
*COVID-19-related symptoms as defined by the CDC*, or attributed to COVID by 
treating team. *https://www.cdc.gov/coronavirus/2019-ncov/symptoms-
testing/symptoms.html. Currently those symptoms include: Fever or chills, cough, 
shortness of breath or difficulty breathing, fatigue, muscle or body aches, headache, 
new loss of taste or smell, sore throat, congestion or running nose, nausea or vomiting, 
or diarrhea. 
  
Secondary Endpoints:  
 Clinical deterioration on a Likert-type scale: (0) No symptoms (1) moderate severity of 
illness as defined by O2 saturation ≤93% but no supplemental oxygen requirement; (2) 
O2 saturation >93% plus supplemental oxygen requirement; (3) ED visit for any 
COVID symptoms (4) hospitalization for any COVID symptom; (5) the above, plus 
ventilator support requirement; (6) the above, plus ventilator support for at least 3 days; 
(7) death;4,60 and by number of days requiring supplemental oxygen; hospitalization; 
ventilator support), by Day 28. Hospitalized patients may be followed for maximal 
outcome.                 
 Time to meaningful recovery61 (symptoms or severity improved by one category and 
sustained for at least 36 hours) 
 Maximum symptom severity experienced by Days 14, 28 (Appendix B) 
 Incidence of all-cause study medicine discontinuation (Day 14). 
 Portion of participants with Post-Acute Sequelae of SARS-CoV-2 Infection (PASC)  
 a. PASC assessment monthly after enrollment for 6 months to 12 months with the 
“Questionnaire to characterize long COVID.” (Appendix G).62  
  
 Laboratory Endpoints:  
The first approximately 62 patients who are enrolled will be analyzed as a sub-study of 
continuous lab outcomes63 comparing those on metformin versus placebo: C-reactive protein 
(CRP) level; albumin level; viral load; as well as microbiome changes (stool sample is optional 
for participants), from baseline to days 5 and 10.64-66 (See Section 13 for more information) 

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*Patients will be asked to take a second reading if they have a reading ≤93% and to hold a hand-
warmer for 5 minutes first to obtain good blood flow; to take the reading while sitting up; and 
advised to place the oximeter on the 4th finger (where skin is thinner). 
4.0 
Investigational Products 
 Description:  
Metformin: a biguanide, administered in its immediate release (IR) formation, 1,500mg by mouth 
(typical dose for clinical use is 2,000mg per day). Patients will be instructed to take 500mg once 
on Day 1, ideally in the PM; 500mg in the AM and PM of Days 2-5; and 500mg in the AM and 
1,000mg in the PM of Days 6-14. 
Fluvoxamine: an antidepressant, administered in twice daily dosing, 50mg twice per day for 14 
days (typical dose for clinical use is 100mg to 300mg per day).  
Ivermectin: is an antiparasitic medication administered typically in ranges of 200-
800mcg/kg/day.67 In order to stay within this dose range, the following doses will be given in 
the following weight categories: 74 kg - 88 kg = 35 mg; 88kg – 106kg = 42mg; 106-124kg = 
49mg; >124kg = 56mg. See details in Section 4.2. Treatment will be given for 3 days, and the 
remaining 11 days will be placebo tablets that exactly match the ivermectin in order to protect 
the blind.  
 Rational for formulation and dose:  
Metformin: Given the current recall of Metformin Extended Release, ER, (see section on FDA 
recall below), availability of ER is limited. Additionally, it is possible that additional lots of ER 
will be recalled, further complicating supply issues and exposure to the recalled substance to 
patients. The side effect profile of immediate and extended release is similar, and we are limiting 
the dose at 1,500mg daily to balance the need to achieve a consistent dose and an effective dose 
without causing side effects, as the risk of side effects increase at a dose of 2,000mg daily.68  
Fluvoxamine: A dose of 100mg TID was recently used in a small randomized trial,4 and 50mg 
BID were recently used in a prospective cohort study.69 The higher dose elicited side effects in 
approximately 10% of participants.4 A separate ongoing phase III trial is now testing 100mg BID.  
We feel it is important to test a lower 50mg BID dose as the risks of side effects is lower and the 
public may be more willing to take an antidepressant medication if it is low dose. Additionally, 
the risk of serotonin syndrome and other drug interactions that may occur with fluvoxamine is 
lower with a lower dose, and thus persons currently on a serotonin reuptake inhibitor (SSRI) 
would not have to stop or alter their current therapy.  
Ivermectin: we are using the standard release formulation (and only formulation) of ivermectin 
tablets. Given our lower BMI limit of 25kg/m2, we do not anticipate enrolling many individuals 
weighing < 74kg. If someone weighs < 74kg or >124kg enrolls, the RC will contact the lead 
pharmacy for guidance on individual dispensing (regardless of treatment allocation, as the RC 
will be blinded to this), to keep the dose within approximately 390-470mcg/kg/day for the 
majority of patients, 350mcg/kg/day-480mcg/kg/day for all patients.   
- 
We anticipate that most individuals enrolled will weigh between 68-104kg.  
 
35mg/day: is 390-470 mcg/kg/day for body masses of 74 to <88kg  

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 
42mg/day: is 390-470 mcg/kg/day for body masses of 88 to <106kg.  
 
49mg/day: is 390-470 mcg/kg/day for body masses of 106 to <124kg 
 
56mg/day: is 390-470mcg/kg/day for body masses of >=124kg 
Acquisition:  
A sufficient quantity of the FDA-approved formulation of metformin IR, ivermectin, and 
fluvoxamine IR for the study has been acquired by the MHealth Fairview IDS pharmacy. 
 Storage and Stability:  
Store at room temperature up to 30ºC. Dispense in a tight, light-resistant container. 
 Pharmacokinetics:  
Metformin: Intravenous single-dose studies in normal subjects demonstrate that metformin is 
excreted unchanged in the urine and does not undergo hepatic metabolism (no metabolites have 
been identified in humans) nor biliary excretion. Renal clearance is approximately 3.5 times 
greater than creatinine clearance, which indicates that tubular secretion is the major route of 
metformin elimination. Following oral administration, approximately 90% of the absorbed drug 
is eliminated via the renal route within the first 24 hours, with a plasma elimination half-life of 
approximately 6.2 hours. In blood, the elimination half-life is approximately 17.6 hours, 
suggesting that the erythrocyte mass may be a compartment of distribution. 
Fluvoxamine: Onset of action: Anxiety disorders (obsessive-compulsive, panic, and posttraumatic stress 
disorder): Initial effects may be observed within 2 weeks of treatment, with continued improvements 
through 4 to 6 weeks (Issari 2016; Varigonda 2016; WFSBP [Bandelow 2012]); some experts suggest 
up to 12 weeks of treatment may be necessary for response, particularly in patients with obsessive-
compulsive disorder and posttraumatic stress disorder (BAP [Baldwin 2014]; Katzman 2014; WFSBP 
[Bandelow 2012]). Depression: Initial effects may be observed within 1-2 weeks of treatment, with 
continued improvements through 4- 6 weeks (Papakostas 2006; Posternak 2005; Szegedi 2009; Taylor 
2006). Distribution: Vd: ~25 L/kg  
Protein binding: ~80%, primarily to albumin 
Metabolism: Extensively hepatic via oxidative demethylation and deamination 
Bioavailability: Immediate release: 53%; Extended release: 84%; not affected by food. 
Half-life elimination: ~14 to 16 hours; ~17 to 26 hours in the elderly 
Time to peak, plasma: 3 to 8 hours 
Excretion: Urine (~85% as metabolites; ~2% as unchanged drug) 
 
Ivermectin: Absorption: Well absorbed in the fasting state (Baraka 1996; Edwards 1988; Okonkwo 
1993); may be increased with a high-fat meal (Duthaler 2020; Guzzo 2002; Miyajima 2013). 
Distribution: Vd: 3.1 to 3.5 L/kg in healthy volunteers; mean 9.9 L/kg (range: 6.9 to 15.3 L/kg) in 
patients with onchocerciasis; high concentration in the liver and adipose tissue; does not readily cross 
the blood-brain barrier (Gonzalez Canga 2008; Okonkwo 1993). 
Protein binding: ~93% primarily to albumin (Gonzalez Canga 2008) 
Metabolism: Hepatic via CYP3A4 (major), CYP2D6 (minor), and CYP2E1 (minor) 
Half-life elimination: 18 hours 
Time to peak, serum: ~4 hours 
Excretion: Feces; urine (<1%) 

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 Dose Modification:  
Participants will be advised to take ivermectin and its matching placebo on an empty stomach 
with water. Ivermectin and its matching placebo are provided in a small blister-packed square. 
 
Participants will be advised to take all other medications (i.e., metformin and/or fluvoxamine 
and their matching placebos) with a small amount of food (not on an empty stomach). 
 
With mild side effects, participants will be reminded to take the tablets at the end of a meal, as 
opposed to the beginning of or “with” a meal. They will also be advised to stay upright for about 
an hour after consuming the study tablet. 
With mild-moderate side effects, if the patients find them tolerable, patients will be advised the 
above, and that side effects should decrease after about 5 days of the medication. With moderate 
or moderate-substantial side effects that the patient finds intolerable, participants will be advised 
that they can break tablets in half if they feel they are having a non-tolerable medication side 
effect. Each type of active drug and placebo pill in this study can be broken in half. Dose 
modification will be recorded in the study database.  
In the event of substantial side effects, participants may discontinue the study medication and 
stay in the study to complete follow up. This treatment discontinuation (whether in the placebo 
or any active treatment group), will not be considered study withdrawal.  
 Placebo:  
The placebo will be tablet  of microcrystalline cellulose, made to exactly mimic metformin or 
fluvoxamine or ivermectin.  
 Study Drug Handling:  
Fairview IDS, part of M Health Fairview, will oversee the study and provision of bulk and pre-
packaged study drug (including placebo) to participating sites. Participants will be given a study 
number coded by site (e.g. 01-001, 02-001, etc.). The pharmacy team involved will be unblinded 
to patient randomization. All other members of the clinical care team and the participants will be 
blinded to treatment allocation. The research team statisticians will remain blinded (additional 
information in Section 13, Statistical Considerations).  
The IDS pharmacy will oversee the pre-packaging of the study drug into 2-week AM/PM pill 
packs for patients to improve compliance with the study drug regimen, improve safety (so they 
take the right number of each type of medication pill), and facilitate delivery to patients on the 
day of their consent. The research staff or pharmacy will select study drug based on the 
randomization code that preserves blinding, place the patient’s name and study ID in the drug 
accountability log and study database, and place it in the study box for that patient and arrange 
for the delivery. 
Pill packs will be labeled with the study name and PI name, contact information about the study; 
and the names and doses of all potential study drugs.   
4.7.1 Provision of study drug to patients: 

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Following randomization, study drug to participants in an expedited way (for example 
courier, overnight mail service).  
 Study Unblinding:  
Each participating pharmacy team, or the central pharmacy, will hold the blind for their site. Each 
site will have 24-hour access to the blind. Each subject will be provided information as to whom 
to contact for unblinding information in the event of an emergency. There is one unblinded 
statistician with two unblinded supporting statisticians on the study team.  
4.8.1 Multiple strategies will be developed to assure that study drug is stopped at the time of 
hospitalization (as metformin is typically stopped at hospitalization for safety reasons)  
4.8.2 Multiple strategies will be developed to inform patients and their medical providers that 
they are in study involving metformin or fluvoxamine or ivermectin, and that it should 
be stopped prior to imaging studies with contrast. 
4.8.3 Multiple strategies will be developed to inform patients’ medical providers that they are 
in a study involving metformin or fluvoxamine or ivermectin, and thus any potential 
interacting medications, or metformin itself, should not be started while the patient is in 
the study. The patient may withdraw consent at any time.     
 Biosafety:  
Patient samples will be carried in an expedited way (i.e. courier or mail services) in packaging 
that is approved for Biologic Substances Category B, UN 3373, per CDC guidelines for shipping 
SARS-CoV-2 
samples: 
https://www.cdc.gov/coronavirus/2019-ncov/lab/lab-biosafety-
guidelines.html#specimen 
5.0 
Study Procedures 
 Study Design:  
Double-blinded, factorial, placebo-controlled randomized trial comparing metformin vs 
fluvoxamine vs ivermectin vs metformin + fluvoxamine vs metformin +ivermectin vs placebo 
for outpatient treatment of COVID-19 disease. This is an outpatient study. Study drug will be 
stopped at the time of hospitalization for any reason. 
 
Overview of Study*: 

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*Updated sample size: 225 per arm, 1,350 total.  
 Recruitment 
Advertising may be done by approaching patients who are scheduled to come for PCR testing, 
prior to or after their SARS-CoV-2 screening test, and before or after they may have the results. 
Advertising to patients before their SARS-CoV-2 test result is back allows the patients to 
consider the study and read about metformin and discuss with family. Receiving a positive 
SARS-CoV-2 test result will be overwhelming and make it challenging for patients to fully 
consider whether or not they want to participate. Being informed of the study before results are 
known will facilitate enrolling soon after their result is known so that study medication can be 
started early in the course of disease or soon after exposure.  
Clinical teams may refer patients to the study in person or over the phone, including transferring 
patients to the study phone line if they are willing to be transferred. RC’s may reach out to close 
contacts of persons with positive SARS-CoV-2 infection, and/or respond to patient emails, phone 
calls, or inquiries on the study website. The study teams may receive lists of persons who reach 
out to community patient advocacy groups looking for trials to enroll into.  The central and 
participating site study teams may receive names and phone numbers of persons with a positive 
SARS-CoV-2 result from other facilities conducting testing. This information will only be in a 
secure database (Redcap or Box).  
Patients may be given a brochure or electronic message with study information for contacting 
the study team if interested in this clinical trial. RC’s may also pro-actively reach out to patients 
who are scheduled for SARS-CoV-2 testing or recently underwent SARS-CoV-2 testing either 
before or after they receive test results, as not all patients may receive or read an electronic 
message or brochure.  
Patients can also self-refer based on seeing advertisements (such as through all forms of social 
media, newspaper, local posters, and email referrals). 
Patients receiving test results by phone from the clinical care team may be alerted they may 
qualify for a research study and that study team members may contact the patient about eligibility. 
 

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Every attempt will be made to make sure the clinical team is informing patients of their SARS-
CoV-2 testing results rather than the research team.   
At times recruitment and enrollment efforts may be focused on priority populations within the 
eligibility criteria. 
 Screening: 
● Based on patient feedback, to reduce participant burden because SARS-CoV-2 symptoms 
may be present, we will offer the opportunity for patients to self-screen online to avoid 
burden and barriers to participating 
○ This will be performed via a web-based form. Eligibility criteria and medical 
history will be by self-report entries into the secure web-based form. 
○ After self-screening online, patients may elect to self-consent online, or have a 
consent discussion with an RC (section 5.4).  
● For patients who do not want to screen or consent via web-based form, screening and consent 
may be done over the phone with RC with eligibility criteria and history entered into the web-
based form by the RC. 
● Patients will be asked to submit proof of their positive SARS-CoV-2 result via secure means, 
but the receipt of the result may occur after enrollment.  
5.3.1 GFR  
GFR will be collected on persons > age 75 years or persons of any age who select or 
respond that they have chronic kidney disease, heart failure, or liver disease if a GFR is 
not available within 2 weeks in the EHR. It may be collected from patients by either self-
collection kits sent to patients’ homes with return arranged by the study team; or by local 
in-person collection.  
Participants will receive the study drug at the same time as the GFR testing kit in the mail 
(or GFR drawn in person), as well as a return envelope for the study drug. They will start 
the study drug before their GFR result is returned. If the GFR result returns and is < 
45ml/min, they will be asked to stop taking the study drug and return the remainder of 
the study drug. This will count as a screen failure.  
We are taking this approach for 3 reasons: a) this is consistent with clinical practice in 
which metformin us often started while a GFR result is pending, because the use of 
metformin for two weeks at a dose of 1,500mg does not significantly increase risk of 
lactic acidosis in someone who has no known history of severe heart, liver or kidney 
injury, including in persons with COVID-19;70 b) to start the study drug early in the 
course of the disease, as in real life an outpatient post-exposure prophylactic or treatment 
therapy would be offered at the time of SARS-CoV-2 exposure or positive infection, c) 
maintain a virtual study design so as to not create unnecessary exposure and use of PPE 
by having labs drawn in person. Metformin is FDA approved down to a GFR > 30ml/min, 
though sometimes used down to a GFR of 15.71   
For any in-person contact, all measures will be taken to mitigate risk of SARS-CoV-2 
exposure to the phlebotomy or study team members, and to the participant.  

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Optional serum samples 
Serum samples (approximately 20-30cc) will be collected on patients who are willing to 
provide these samples, via mobile phlebotomy to their home, to better understand 
treatment response and mechanism. A random sample of 95% of these samples will be 
analyzed. Labs will be processed at local eligible labs, or at the University of Minnesota 
Advanced Research and Diagnostic Laboratory, which is a CLIA-certified, CAP-
accredited clinical testing laboratory that is certified to receive, process and test samples 
from COVID-19 patients. Any antibody samples will be conducted by FDA-approved 
assays or academic institutions that have validated their assays. 
 Informed Consent 
Consent will be obtained (via self-consent (below), or a traditional consent conversation) before 
beginning any study procedures. The entire consent document will be reviewed, including all 
study procedures and expectations, risks, benefits, and what volunteering means. Participants 
will be asked questions to gauge their level of understanding. 
Potential participants will be given time to read the consent and ask questions. If needed, a 
participant may take additional time to review the consent or discuss participating in the study 
with family/friends. The consent conversation will be done remotely, using a phone or secure 
HIPAA compliant video/web conferencing or in-person.  
Based on patient feedback, we will also offer the opportunity to self-consent online, waiving the 
consent conversation. This would mean that after potential participants answer eligibility 
questions with the RC or online (section 5.3 above), they could access the online consent module. 
○ Patients will be able to read the consent form online and asked to answer 
comprehension questions about the consent. Participants will review short 
sections and need to click in order to move to the next section to increase 
engagement and comprehension of the study during the self-consent process. 
○ If their responses to the comprehension questions indicate that they are well-
informed about the study, they would be able to sign the consent form online.  
○ If their responses indicate that they lack understanding, the RC may call them 
for a traditional consent conversation and assessment of comprehension.  
 
The consent document will be presented to the participant as an electronic document (eConsent) 
through the University of Minnesota’s instance of REDCap.  The REDCap eConsent document 
will contain the full consent text and is compliant with FDA 21 CFR Part 11 for the electronic 
capture of signatures. Participants will be sent a link via email or text to the REDCap survey 
which will contain the full consent text.  After signing the consent, participants will receive an 
electronic copy of the signed document or a paper copy if in-person. Consent may also be done 
in person via hard-copy print out of the consent form if patients are in clinic for other reasons. 
5.4.1 Non-English Speaking Participants:  
Non-English speaking patients will not be specifically targeted for enrollment, but any 
non-English speaking participants will be consented using the short form consent process. 

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Before consenting, the study team will ensure that a suitable interpreter will be available 
during the consent process and throughout the study. For any non-English speakers who 
are enrolled using the short form consent process, a certified translation will then be 
obtained for the long form consent form in the participant’s preferred language. After the 
IRB approves this document, the participant will be re-consented using the translated 
form. 
 
Enrollment: 
Eligible patients will be randomized to metformin IR or fluvoxamine or fluvoxamine + 
metformin or ivermectin or ivermectin + metformin or placebo and will receive the study drug 
by courier or mail service with every effort made to deliver the drug same-day or via overnight 
delivery.  
Medication regimen:  
Metformin or Placebo: Participants will be advised to take 1 pill by mouth on Day 1, ideally in 
the evening; and 1 pill by mouth approximately every 12 hours starting Day 2; and 1 pill by 
mouth in the AM and 2 in the PM day 6 and onwards, and to take pill at the end of a balanced 
meal and to stay upright for at least an hour after taking it.  
Fluvoxamine or Placebo: Participants will be advised to take 1 pill by mouth on Day 1, ideally 
in the evening, and 1 pill by mouth approximately every 12 hours for Days 2 – 14.  
Ivermectin: Participants will be advised to take any blister-packed tablets on an empty stomach. 
The following data points may also be collected, if available, by self-report or EHR review: 
o Name; Date of birth; Medical record number (if applicable); Phone number; Email 
o Contact information for family members to assist with follow-up if needed  
o Age; biologic sex; Race; Ethnicity; Insurance status (if available); Zip code 
o Location of initial sample collection for diagnosis, Location of assessment  
o Date and time of initial sample collection for diagnosis 
o Date and time of positive test result for COVID-19 
o Date of first symptoms  
o Date of first fever, if applicable (temperature >100.5°F) 
o Patient-reported comorbidities [for example: hypertension (requiring or not requiring 
medication), diabetes mellitus (insulin or non-insulin dependent), coronary artery disease, 
myocardial infarction, congestive heart failure (with preserved or reduced ejection fraction, 
if known), pacemaker or AICD, asthma (with or without emergency department evaluation 
and / or hospital admission in the past year), chronic obstructive pulmonary disease, chronic 
bronchitis, chronic steroid use, history of transplant (with type), arrhythmias including 
atrial fibrillation, dialysis, angina, pulmonary hypertension and obstructive sleep apnea, 
renal disease, liver disease, tobacco and alcohol use history, recent or current pregnancy or 
breastfeeding history, and height and weight at study start and completion.] 
o Self-reported home medications [for example: antihypertensives, insulin, non-insulin 
diabetes medications, corticosteroids (inhaled, systemic), other immunosuppressants 
hydroxychloroquine, other COVID-directed treatments or vaccines] or home oxygen use 

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o Use of outpatient COVID-directed treatments (such as Tylenol, ibuprofen, azithromycin, 
or others); whether or not they received the 2020/21influenza or COVID-19 vaccines. 
o Medication adherence, known exposures, symptoms and side effects 
 
The following data points may also be collected, if available, by self-report or EHR review: 
o Vital signs at presentation to ER or urgent care (if recorded) 
o Clinical laboratory results at presentation (if recorded) 
o Hospital admission (with date, if applicable) 
o Date of death (if applicable) 
o Study withdrawal, with date and time (if applicable) 
5.4.2 Retention: 
All study staff members will be informed of the importance of retention and steps to 
prevent missing data. RC’s will be advised to contact participants a second time per 
patient contact point if they are not able to reach the participant after the 1st contact. RC’s 
may call, video, text, or email with patients on Day 2 to assess side effects or questions. 
If patients experience side effects, the RC’s may remind patients of approaches to 
minimize side effects (See Section 4.3), and to advise the patients that side effects usually 
subside after about 5 days. 
5.4.3 Lab Collection: 
Labs will be considered optional if patients want to participate but not collect the nasal 
swab and/or stool. For interested and willing patients, labs will be done on approximately 
Day 1, 5, and 10.  
The SARS-CoV-2 PCR may be assessed via self-collect anterior nasal swab, which may 
be done over phone or video with the RC if the patient prefers this aid. Detailed 
instructions for the patient are in Appendix B, the patient manual.*  
The GFR blood tests may be collected by the clinic, mobile phlebotomy, or finger-prick, 
with the option of it being done while on secure video or phone with the RC if the patient 
prefers this aid. Blood will be collected in a microtainer tube and placed in approved 
shipping materials that will then be returned to the lab via courier or mail.  
Stool sample collection is optional and would be done with a self-collect microbiome kit. 
Patients will be given detailed lab collection procedures for each test. 
Missing biospecimens will not constitute protocol deviations. 
5.4.4 Seeking Medical Care:   
Patients will be advised to seek medical care, as they would if they were not in the study, 
including other treatments of Covid-19. Participants will be advised that the distribution 
of home oxygen monitors is not meant to prevent them from seeking medical care, and 
that they should seek medical care as they would whether they were in the study or not. 
 Follow-up Procedures: 

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Data on clinical progression may be collected on any consented patient by EHR review, 
from contact if patient not available, by patient self-report (phone, survey, email, text), or 
by vital records search. 
RC’s may contact patients on Day 2 to assess side effects or questions. If patients 
experience side effects that they find distressing, the RC’s will discuss approaches to 
minimize side effects (See Section 4.6 Dose Modification), and to advise the patients that 
side effects usually subside after about 5 days.  
Participants will be asked to track symptoms (including temperature and oxygen 
saturation), and medication adherence daily. Patients will receive a thermometer and 
oxygen saturation monitor with their study drug (details below). Study personnel will 
attempt to contact with patients about every 2 to 3 days during the 14-day intervention 
window to review study drug adherence, and review symptoms for possible adverse 
events. 
Patients will be followed for 28 days for disease severity. Follow-up contact with patient 
or family and electronic medical record review will determine the primary and secondary 
efficacy endpoints. 
A patient who has a visit to an emergency department for COVID-19 related symptoms, 
(determined by current CDC definition of COVID-19 related symptoms or treating team), 
or hypoxia (two measurements of O2 saturation ≤ 93% or supplemental oxygen required 
to maintain saturation >93%) will have achieved a positive result for the primary 
outcome. 
Patients who experience a primary outcome before enrollment (i.e. ED visit at which they 
received their +SARS-CoV-2 result) will be followed for occurrence of a primary or 
secondary outcome after T0 (Day 1 in the study).   
 Patients who are hospitalized will stop the study drugs.  
 Secondary outcomes will be assessed at 14 and 28 days, including in patients who 
drop out of doing the study tasks. EHR search of outcomes will be assessed of all 
patients who enroll.  
 Patients in the treatment arm who visit an urgent care or emergency department and 
are sent home without being admitted should continue the study drug through day 14, 
unless otherwise directed by the treating physician in the emergency department or 
urgent care.  
 Long-Covid symptoms will be assessed at approximately 1-month intervals after the 
completion of the 14-day study treatment period.  
Oxygen Saturation:  
For the daily oxygen saturation recording, participants will be asked to measure their 
oxygen level ideally in the afternoon or evening. They may take a reading at any time, 
especially if they feel short of breath or are breathing faster than normal. If they have an 
oxygen saturation ≤ 93% on room air on 2 readings or more, they will be advised to 
call their doctor’s office (or go to the ED if they feel they need to). If a study participant 
develops a decrease in oxygen saturation to less than 90% on room air on >2 readings, 

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the research staff will direct them to seek emergency medical care at the nearest ED. 
Research staff may call 911 on behalf of the patient, or otherwise engage the patient’s 
medical provider, if they feel the patient is not able to do this on their own.  
Referral to medical care: If the research staff feels a patient is unwell, they will advise 
the patient to reach out to their doctor. Physician investigators may also 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 identify themselves to EMS or to the ED staff as having been diagnosed with 
COVID-19.  
5.5.1 Survey Data Collection:  
Participants will be given a hard-copy symptom log to capture COVID-19 related 
symptoms daily (Appendix B). Patients will be asked to record their medication 
adherence, their temperature, and their oxygen saturation with a home O2 monitor every 
day for the 14 days of participation.  
The symptom log may also be available by Part-11 approved means (such as via text or 
app). For patients not using app, RC’s will assess whether the symptom logs are being 
filed out daily at each contact point with patients. Adherence with taking the medication 
will be assessed via self-report daily in the log or software to record adherence.  
Survey questions will be listed in a physical paper study log that is included in the study 
box that is sent to patients. Patients can fill out the survey on these paper logs and then 
send a picture of the logs to study staff (no identifying information on the pages of the 
logs); patients can also receive the survey questions via Part 11-certified electronic 
means; or patients can report the survey question answers to the RC over the phone if 
they prefer. 
5.5.2 Timeline of Events: 
Every attempt will be made for the contact points with patients to be done in the way that 
they prefer (i.e. text, phone, email, video): 
Day 1 Contact: Verify receipt of study drug, participant starts study drug. If multiple 
participants live in the same household, they will be reminded to keep all of their study 
materials labeled with their own participant ID and separated from the other participants.   
 Phone or video visit to walk through procedures for obtaining lab values if the 
patient desires. 
 RC will arrange for the lab samples to be returned.  
 Patient records symptoms (via symptom log adapted from FDA suggestions, 
Appendix B), RC does not need to collect over phone. 
Day 2 Contact:  
 Patient records side-effects (PROMIS diarrhea survey, Appendix C) 
 Patient records symptom/adherence log (adapted from FDA suggestions, Appendix 
B) 
 Assessment of clinical progression 

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 Query for medication-related side effects / AEs 
 
Day 3/4: RC will follow-up results of GFR for patients for whom GFR was indicated. If 
the GFR is < 45ml/min, the RC will have the patient return the remaining study drug in 
one of the return envelopes provided and will arrange for this shipping.  
 
Day 3, 4: Symptom/adherence log (adapted from FDA suggestions, Appendix B) 
 
Day 5 Contact:  
 Symptom/adherence log (adapted from FDA suggestions, Appendix B) 
 Assist with return shipping of optional labs (viral load, stool) 
 Assess clinical progression 
 
Day 6-9: Symptom/adherence log (adapted from FDA suggestions, Appendix B) 
 
Day 10 Contact: 
 Symptom/adherence log (adapted from FDA suggestions, Appendix B) 
 Assess clinical progression (Query for hospitalization or ER visit or SAEs) 
 Assist with return shipping of optional labs (viral load stool) 
 
Day 11-13: Symptom/adherence log (adapted from FDA suggestions, Appendix B) 
 
Day 14 Contact: 
 Symptom/adherence log (Appendix B) 
 Assess clinical progression  
 
Day 28 Contact: 
 Symptom log (adapted from FDA suggestions, Appendix B) 
 Assess clinical progression (Query for hospitalization or ER visit or SAEs that 
occurred between Day 14 and Day 28) 
 Assess other medicines used during study period 
 
A vital status search will be conducted on all randomized patients.  
Days are +/- 3 days, for the first 14 days every attempt will be made to capture data +/- 1 
day. 
Patients will be advised to seek medical care for symptoms in the same way that they 
would if they were not in the study.  
Participants will be reimbursed for their time via a trackable means (i.e. Clin card or Visa 
card), after completion of these study activities: enrollment; Day 1 labs; Day 5 labs; Day 
10 labs; Day 14 log returned; and Day 28 follow-up. 
Monthly Contact: Patients will be assessed approximately once/month for 9 months after 
the completion of their Day 28 contact to assess for ongoing symptoms suggestive of 
post-acute sequelae of COVID-19. Patients will receive reimbursement for each of these 
monthly follow-ups completed.  

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 Study Duration:  
14 days of treatment with follow-up, and a follow-up survey at 28 days then monthly for 
9 months. 
Schedule of Assessments: 
Symptoms: Days 1- 14, 28.  
Side effects: Day 2 
AE’s/SAE’s: Days 2, 5, 10, 14, 28 
Clinical Progression: Days 5, 10, 14, 28 
PASC: Monthly after Day 28 
 Retention:  
We will make every effort to keep participants engaged through the entirety of the study so as to 
minimize missing data (for example regular calls, texts, emails, assessment via vital records 
search, and contact with family members if needed). The principal investigators have recent 
experience working with patients on COVID-19 trials, and they will leverage this experience.  
6.0 
Study Population 
 Study Population:  
Adults age 30-85 years with no prior history of SARS-CoV-2 infection and with BMI in 
overweight or obesity category. We will not exclude patients who have diabetes, but we will 
exclude patients on insulin or a sulfonylurea. Symptoms are not a requirement to enroll in the 
because of their subjective nature and because of wanting to start patients on study drug early in 
the disease course.   
 Inclusion and Exclusion Criteria: 
Inclusion criteria 
Exclusion criteria 
- Positive laboratory test for active SARS-CoV-2 
viral infection based on local laboratory standard 
(i.e. +PCR) within 3 days of randomization. 
-  no known history of confirmed SARS-CoV-2 
infection 
- Age >=30 years and < 85 years  
- BMI >= 25kg/m2 by self-report height/weight or 
>= 23kg/m2 in patients who self-identify in  
Asian or Latinx background.72-74 
- Has an address and electronic device for 
communication 
- GFR>45ml/min within 2 weeks for patients 
>75 years old, or with history of heart, kidney, or 
liver failure.  
 
-  Hospitalized, for COVID-19 or other reasons. 
- Symptom onset greater than 7 days before 
randomization (symptoms not required for inclusion). 
- immune compromised state (solid organ transplant, 
bone marrow transplant, AIDS, on chronic high dose 
steroids) 
- Hepatic impairment (Child-Pugh B and C) or 
that in the opinion of the investigator, would affect  safety  
- Inability to obtain informed consent 
- Enrollment in another blinded RCT for COVID-19 
- Already received an effective (FDA approved/EUA*) 
therapy for COVID-19 (currently monoclonal antibody 
treatment) 
- Alcohol use disorder 

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- Other unstable medical condition or combination of 
home medications that in the view of the PI make it 
unsafe for the individual to participate 
 
- History of severe kidney disease i.e.: 
 Stage 4 or 5 CKD, or Estimated Glomerular 
Filtration Rate (eGFR) of < 45ml/min/1.73 m2  
 Other kidney disease that in the opinion of the 
investigator would affect clearance  
- Unstable heart failure (Stage 3 or 4 heart failure) 
- Current use of metformin, fluvoxamine, or ivermectin  
- Bipolar disease: individuals who report they have 
bipolar disorder or are taking medication for bipolar 
disorder (lithium, valproate, high-dose antipsychotic), 
unless the investigator concludes that the risk for mania 
is unlikely (i.e. it is doubtful that the patient actually has 
bipolar disorder).  
- allergic reaction to metformin in the past  
- allergic reaction to fluvoxamine in the past 
- allergic reaction to ivermectin in the past 
 
current loa loa or onchocerciasis infection 
 
typhoid, BCG, or cholera vaccination within the 14-
days or 3 days after 
Medication Exclusions:75 
- 
cimetidine, hydroxychloroquine, insulin, 
sulfonylurea, dolutegravir, patiromer, ranolazine, 
tafenoquine.  
- 
rasagiline, selegiline, or monoamine oxidase 
inhibitors, linezolid, methadone 
- 
Duloxetine, methylene blue  
- 
Tizanidine, ramelteon, sodium picosulfate 
- 
Alosetron, agomelatine, bromopride, dapoxetine, 
tamsimelteon, thioridazine, urokinase, pimozide 
 
The following medications may not need to be excluded 
when dose for that individual is considered alongside the 
low dose of fluvoxamine being used and other 
medications being used. The PI or site PI may review and 
decide if the patient should be excluded from the 
fluvoxamine arms: 
1. Taking SSRIs, SNRIs, or tricyclic antidepressants, 
unless these are at a low dose such that a study 
investigator concludes that a clinically significant 
interaction with fluvoxamine (ie either serotonin 
syndrome or TCA overdose) is unlikely (examples: 
participant takes escitalopram but only at 10mg daily; 
that dose plus 100mg fluvoxamine would be 
insufficient to cause serotonin syndrome; or, 
participant takes amitriptyline but only at 25mg 

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*Additional COVID-19 treatments to exclude will be decided by a panel of at least 3 Co-Investigators 
on this study. The additional treatments to exclude will be documented and submitted to the IRB but 
may be implemented before formal IRB approval is complete. We take this approach because of the 
rapidly changing treatment landscape of COVID-19. 
 Vulnerable Populations:  
By nature of the disease and the fact COVID-19 is a rapidly evolving pandemic, with uncertain 
clinical course but potentially significant morbidity and mortality, all participants enrolled in this 
study are considered to be vulnerable. Some participants have additional characteristics that add 
to this vulnerability. Our criteria for inclusion and exclusion of each of these groups is 
summarized below, followed by our rationale and additional safeguards built into our study 
design. Our group has significant experience enrolling vulnerable patients in emergency care 
trials, and experience with a diverse population of potential participants in high stress situations.  
COVID-19 is disproportionately impacting low-income communities and persons of color, and 
these reasons are multifactorial. It is important to include individuals of diverse backgrounds in 
nightly; even if fluvoxamine inhibits its metabolism, it 
would be an insufficient dose to cause QTc 
prolongation or problematic side effects). Risk Class 
C, monitor therapy. 
2. Individuals who take alprazolam or diazepam and are 
unwilling to cut the medication by 20% (rationale: 
fluvoxamine modestly inhibits the metabolism of 
these drugs). Risk Class C, monitor therapy 
3. Participants taking theophylline, clozapine, or 
olanzapine (drugs with a narrow therapeutic index 
that are primarily metabolized by CYP 1A2, which is 
inhibited by fluvoxamine) will be reviewed with a 
study investigator and excluded unless the 
investigator concludes that the risk to the participant 
is low (this would be unlikely; example: participant 
takes clozapine only as needed and is willing to avoid 
it for the 14 days of the study). 
4. Patients will be advised that there is a small risk that 
the following substances will be affected by 
fluvoxamine, but that significant effects are not likely 
at the low dose being used:  
1. caffeine, nicotine, melatonin. Risk Class 
C, monitor therapy 
5. Taking warfarin-also known as Coumadin, NSAIDs, 
and Aspirin (rationale: increased risk of bleeding), 
phenytoin (rationale: fluvoxamine inhibits its 
metabolism), clopidogrel (rationale: fluvoxamine 
inhibits its metabolism from pro-drug to active drug 
which raises risk of cardiovascular events), and St 
John's wort (rationale: fluvoxamine + St John's wort 
are considered contraindicated because of the risk of 
serotonin syndrome) Risk C, monitor therapy. 

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this research. It is also important to not present this research in a coercive way to individuals with 
low income and who come from traditionally marginalized backgrounds. We have chosen 
participating sites throughout the US based on sampling diverse populations throughout the US 
(i.e. areas serving primarily Black and Latinx populations), areas where there are high incident 
rates, and areas with experienced PI’s.  
6.3.1 Additional Safeguards:  
● Non-English speakers: Excluding this group would compromise the principle of justice 
in clinical research. For groups likely to be enrolled given our known demographics (for 
example, Spanish-speaking and Somali-speaking), we will translate informed consent 
forms (ICF) and use professional interpreters during both the consent and follow-up 
periods. These interpreters are available to our group during daytime hours by telephone. 
We will request the use of the Short Form Consent for non-English speaking participants, 
and adhere to the regulations surrounding its use. When the translated ICFs become 
available, they will be used for non-English speakers. We will make every effort to have 
Spanish-speaking research coordinators on our team and access to interpreter services.  
● Employees or students of the researcher: This group will be excluded. 
● Undervalued or disenfranchised social group: We will assure confidentiality, that they 
have the right to withdraw at any time without penalty, and they have the freedom to 
refuse to answer questions.  
● Active members of the military (service members), DoD personnel (including civilian 
employees): The status of participants of this group is not asked during the study nor 
known by study staff, and therefore vulnerability is not increased for anyone in this 
group.  
● Individual or group that is disadvantaged in the distribution of social goods and services 
such as income, housing, or healthcare: We will assure that information from participants 
in this study will be treated with the strictest confidentiality, that participants have the 
right to withdraw at any time without penalty, and they have the freedom to refuse to 
answer questions. When needed, every effort at making accommodations will be made 
for those who do not have a home address, such as medication pick-up space in a local 
shelter or emergency department. If the potential participant needs a phone in order to 
comply with study needs, one will be provided for the duration of the individual’s 
enrollment. 
● Individual or group with a serious health condition for which there are no satisfactory 
standard treatments: We will assure confidentiality, that they have the right to withdraw 
at any time without penalty, and they have the freedom to refuse to answer questions. We 
will also employ the teach-back method to ensure participants understand risks and 
demands of study participation.  
● Individual or group with a fear of negative consequences for not participating in the 
research (e.g. institutionalization, deportation, disclosure of stigmatizing behavior): The 
status of participants from these groups is not asked during the study nor known by study 
staff, and that vulnerability is not increased for anyone in this group. 
 Number of Participants 
Enrollment will occur remotely via the previously described methods for interested participants 
presenting to one of the PCR-testing sites or via self-referral to the study. Patients in assisted 

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living facilities do qualify for this study. The total number at each site will be affected by local 
incidence rates at the time of enrollment. We anticipate that at least 100 participants will be 
enrolled at each participating institution.   
7.0 
Sharing of Results with Participants 
 Sharing of results:  
Data collected within this study will be obtained from the participants themselves or will be 
obtained from the electronic medical record and thus are already available to the patient and 
treatment team.  Any testing of biospecimens will occur at a later time point and do not have 
specific clinical relevance. Research results will be shared with the participant and/or the 
participant’s primary care provider when determined by the research clinician to be clinically 
relevant. 
 Sharing of genetic testing 
Not applicable. No genetic testing will be conducted 
8.0 
Withdrawal of Participants 
 Withdrawal Circumstances: 
Participants may withdraw from the study at any time for any reason. Participants may be 
withdrawn from the study without their consent if at any point they develop an exclusion criteria 
that makes it unsafe for them to continue in the study. All data from patients withdrawn from the 
study will be analyzed up until time of withdraw. Clinical progression after withdrawal may be 
assessed via EHR or vital status review or by reaching out to patients or their contacts. 
 Withdrawal Procedures:   
If patients choose to withdraw, study procedures including intervention and follow-ups will stop. 
Given the remote nature of this study, written notification is not required. If the patient chooses 
to withdraw, the study team will ask if the patient is willing to allow continued electronic medical 
record evaluation for the determination of study endpoints (partial withdrawal). We will also ask 
if the patient wishes to withdraw consent for the use of future biologic specimens. If the patient 
declines to participate in any component of research, no further study data will be collected, 
biologic samples will be destroyed, but existing study data may be used. Each of these 
circumstances will be documented and stored as a study document. 
 Termination Procedures:  
Upon trial termination, study outcomes will be followed until completion. Case report forms and 
collection templates will be maintained in paper format (when applicable) and electronically for 
7 years in accordance with regulations. Collected data will be used for secondary analyses with 
approval of the principal investigators in a deidentified fashion. Data entry will be completed, 
checked for accuracy, and locked for analysis within 1 year of enrollment of the final patient. 
9.0 
Risks to Participants 

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Metformin: Metformin has been safely used since the 1920s, making it an appealing option for 
treatment in asymptomatic individuals.76 The most common side effects are gastrointestinal (GI), 
and typically happen in fewer than 15% of patients; GI side effects are minimized when 
metformin is taken at the end of a meal (rather than at the beginning or “with” a meal), and often 
subside after 5 days of regular use.68 The most common GI side effects are: 
 nausea, vomiting, stomach pain; 
 lose bowel movements 
 diarrhea  
We are not obtaining safety labs after starting the trial because we are not including patients on 
medications that increase risk for hypoglycemia (insulin and sulfonylureas), and the package 
insert recommends GFR monitoring only every 12 months, and monitoring B12 levels every 2-
3 years in patients at risk for B12 deficiency, as participants will not be taking study drug for 
more than 14 days.  
Fluvoxamine: Fluvoxamine has been safely used since the 1980s. The most common side effects 
are central nervous system and gastro-intestinal. About 10 to 30% of patients may experience 
headaches or insomnia, particularly at higher doses. About 10 to 40% or patients may experience 
nausea or diarrhea, particularly at higher doses. The dose used in this trial is lower than the dose 
typically used in clinical care with fluvoxamine.  
Ivermectin: Ivermectin has been safely used since the 1980’s. Use during infection with 
onchocerciasis is associated with more side effects, so persons with concomitant infection are 
excluded. In the absence of onchocerciasis, about 4% of persons will have tachycardia; 2% will 
have diarrhea/nausea; and 3% will have dizziness. About 2% to 3% of persons will also have 
laboratory changes (changes in CBC or transaminase levels).  
See Metformin, Fluvoxamine, and Ivermectin Packet Inserts for additional drug information and 
risks. 
 Mitigation of Risk:   
Metformin: 
 Elevated levels of NDMA have not been found in metformin IR, immediate release. We will 
only use immediate release metformin, not extended release.  
 In order to reduce the risk of lactic acidosis, we are excluding patients with advanced heart 
failure, liver failure, or renal failure, or known alcohol use disorder 
 We are requiring a baseline GFR in persons > age 75, or with history of heart, liver, or renal 
failure, within 2 weeks before enrolling to ensure those high risk patients have a GFR > 45. 
 
Fluvoxamine: 
 We are using a low dose of fluvoxamine with only 1 dose on the first day to mitigate side 
effects from BID dosing on the first day.  
 
 Ivermectin: 
 While the range of acceptable and safe per kilo doses of ivermectin is large, we are using 
weight-based dosing. 

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All arms: 
 We will use careful screening of exclusion criteria so that participants are excluded from arms 
that may include a contraindication or medication interaction.   
 We are recommending that study drug be taken at the end of a small meal, and that patients 
abstain from alcohol use during the study period. 
 We are creating an upper age limit in order to reduce the likelihood of a patient experiencing 
reduced GFR during the study period.  
 Patients will be advised to let their providers know that they are in a research study that 
involves metformin, ivermectin, or fluvoxamine, and thus that they should discontinue the 
study medication at the time of hospitalization or before a CT scan with contrast.  
 Every effort will be made to enter a Research Note into the electronic health record stating 
that the patient is in a double-blinded randomized trial of metformin, fluvoxamine, 
ivermectin, and placebo with the study number and contact information for participants who 
are enrolled from participating health systems.  
 Reproduction Risks:  
While fluvoxamine and ivermectin may be used in pregnancy and have no known teratogenic 
effects, they have not been assessed in prospective randomized trials in pregnancy as often as 
metformin has.  Thus, we will close the randomization arms that include ivermectin or 
fluvoxamine to pregnant women. We will have a separate group of blinded study packs for 
pregnant and lactating women, so that study staff will know that pregnant and breastfeeding 
participants are getting only either metformin or placebo, but will remain blinded to whether they 
are receiving metformin or placebo. Additionally, because pregnant and lactating women will be 
considered their own sub-study in this trial, and an important sub-study, we will enroll 
pregnant/lactating women down to age 18 years old. Thus, pregnant women may be analyzed as 
a separate substudy.  
Metformin has not been found to have teratogenic effects and is commonly used in pregnancy, 
so we do not have a justification to exclude pregnant women.77-80 Pregnant women will be 
advised to inform their care providers that they are in this study. As with all participants, study 
procedures may be done completely virtually. If a participant prefers in-person lab draws or other 
procedures, every possible effort will be made to follow current standards of protecting the 
subject and study staff against transmission of the virus. 
10.0 Outcomes 
that 
are 
specific 
to 
pregnancy, 
https://www.cdc.gov/reproductivehealth/maternalinfanthealth/smm/severe-
morbidity-ICD.htm, will also be analyzed (they would all be captured as a 
hospitalization or ED visit, the primary outcomes for the main study). 
Potential Benefits of Treatment Arms 
 COVID-related potential benefits of Metformin:  
10.1.1 Observational data show associations of reduced  mortality from COVID-19 in patients 
using metformin.2,81,82 There is un-published observational data showing decreased 
likelihood of being hospitalized for patients on home metformin. Metformin has been 

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associated with improved outcomes in other viruses (Influenza and Zika, another RNA 
virus).42,45 
 COVID-related potential benefits of Fluvoxamine: 
10.2.1 Fluvoxamine has been shown in a phase 2 trial and prospective cohort, as well as in 
vitro-studies and computer modeling, to decrease severity of COVID-19 disease.4,50 
 Covid-related potential benefits of Fluvoxamine: 
10.3.1 A recent trial assessing a multi-therapy including 12mg one-time dose of ivermectin 
found a 75% reduction in hospitalizations.56 Another small double-blinded RCT showed 
significant increased chance of viral clearance after a 5-day course of ivermectin.57   
 Other possible benefits: 
Metformin has been associated with reduced incidence of blood clots, improved outcomes in 
some cancer, improved cholesterol, and improved insulin resistance, in patients with and without 
diabetes.7,9,10,83,84 
Metformin is commonly used as a chronic medication for type 2 diabetes, pre-diabetes, and often 
off-label use for weight management, poly-cystic ovarian syndrome, and preventing anti-
psychotic related weight gain.80 
Additionally, 34.5% of adults in the US have prediabetes,85 and 90% of them have never been 
told about this diagnosis.86 Metformin is indicated for many persons with prediabetes, however 
only about 1% of persons with prediabetes have been prescribed metformin.87  
11.0 Data and Specimen Banking 
 Storage and Access:  
Study data will be recorded and retained within a University of Minnesota REDCap database 
with study personnel being granted access to the database based on need as listed in the 
Delegation of Authority log.  
The electronic consent (eConsent) forms will be maintained in a University of Minnesota 
REDCap database.  
Biologic specimens intended for research beyond the study outcomes, provided by patients, may 
be processed by the University of Minnesota BSL2+ laboratory and frozen at -80 C. Samples 
will be deidentified and labeled only with a patient’s study ID number. 
Only authorized study team members will have access to data/specimens, expect as detailed in 
section 11.2. 
 Release/Sharing:  
Data will be shared among members of the study team with appropriate access based on study 
role, training, and delegation of authority. Data will be made available to assigned study 
monitors, the data safety monitoring board, the appropriate University of Minnesota oversight 

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authorities, the Food and Drug Administration, and other state and federal regulatory authorities 
as required by state and federal law.  
De-identified specimens and data may be shared for future research. Requests will be evaluated 
on a case-by-case basis. No data will be released without proof of IRB approval or determination. 
Agreements as required by local policies will be completed when necessary, including data use 
agreements and material transfer agreements.  
12.0 Statistical Considerations 
A detailed statistical analysis plan (SAP) will be included as an appendix and developed by the 
statisticians prior to analyzing unblinded data. The SAP may be amended as needed thereafter 
by the blinded statistician(s). All analyses will follow a modified intention to treat (mITT) 
approach, excluding participants who were screen failures or who did not ingest any study drug, 
unless specified otherwise. 
 Randomization: 
Eligible and consenting participants who test positive will be enrolled and randomized evenly 
among the arms for which they are eligible, i.e. 1:1:1:1:1:1 for participants who are eligible for 
all 6 arms. Randomization will be stratified by study site from which their IP is dispensed. 
Stratum specific schedules will be preemptively generated using mass-weighted urn 
randomization with a total mass of α = 6, which is a generalization of randomly permuted blocks 
that reduces predictability of future assignments.88 Patients eligible for one study drug and 
ineligible for another, who are still interested in the trial, may be randomized amongst the study 
drug arm for which they are eligible. Randomization schedules will be generated for each 
possible drug eligibility pattern, and assignments will be drawn sequential from each stratum 
specific sequence therein. Statistical analyses will be study drug specific and consist of all 
participants who were eligible for and randomized into the relevant arms. Direct comparisons of 
study drugs and evaluation of drug-drug interactions will be conducted amongst participants who 
were eligible for both drugs in the comparison/interaction. 
 Blinding: 
Study drug will be prepared by an unblinded study pharmacy team. Study personnel and 
participants will be blinded to participant assignments and outcomes data for the duration of the 
study, excepting lab data as detailed below and situations that require the blind to be broken for 
safety reasons. These instances will be recorded and reported to the PI and DSMB.  An un-
blinded analysis of the laboratory outcomes from the treatment cohort sub-study will be carried 
out by the unblinded statisticians and shared with the blinded investigators and potential sponsors 
of the trial.  
 Sample Size Assumptions: 
The statistical design is for the comparison of metformin vs placebo, controlling for the effect 
of fluvoxamine and ivermectin.  
 
Sample size estimates are based on a marginal test of metformin versus placebo comparison, 
controlling for fluvoxamine and ivermectin use, and selected to provide at least 80% power with 

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5% two-sided type I error rate for the target effect indicated by the event rates in the above figure 
and described in detail in subsection 12.3.1. The sample size estimates are also inflated by 11% 
and rounded to account for interim analysis plan (see subsection 13.4) and study withdrawals.  
 
These considerations result in a planned enrollment of 1,124 participants (187-188 in each arm). 
Because these sample size calculations are based on marginal tests, the actual power may be 
higher when based on the planned tests using adjusted logistic regression models adjusted for 
various predictive factors as described later.  
Factorial design maximizes the use of placebo
Metformin 
(n=563)
Placebo 
(n=187)
Fluvoxamine
(n = 375)
Metformin / Fluvoxamine
n =188
6% event rate if both effective
Fluvoxamine / placebo
n=187
11% event rate
Ivermectin
(n=375)
Metformin/Ivermectin
n = 188
6% event rate if both effective
Ivermectin/Placebo
n = 187
11% event rate
Metformin / placebo
n = 187
11% event rate
Placebo / Placebo
n=187
20% event rate
Total
563
561
1,124
Each patient gets 2 types of pills
•
If two medications are effective, we will have 80% power to detect a difference over placebo. 
•
If only one medication is effective, we will have 90% power to detect a difference over placebo. 
•
Assumes a 10% loss to follow-up rate.

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12.3.1 Hypothesized Rates: 
We hypothesize that metformin is superior to placebo for the primary endpoint 
controlling for possible use of fluvoxamine or ivermectin. Similarly, we hypothesize that 
fluvoxamine is superior to placebo for the primary endpoint controlling for possible use 
of metformin; and ivermectin is superior to placebo for the primary endpoint controlling 
for possible use of metformin. Let 𝜋𝑇 and 𝜋𝐶 denote the rate of the composite primary 
endpoint in the treatment and control groups, respectively. We will evaluate the following 
hypotheses:  
𝐻0: 𝜋𝑇≥𝜋𝐶 versus 𝐻𝐴: 𝜋𝑇< 𝜋𝐶 
The hypothesized marginal rate of the primary endpoint under placebo is 20%.89 The 
expected event rate for the primary outcome in the single medication treatment arms is 
11% which corresponds to a relative risk reduction of 45%. To detect this effect with 80% 
power using a marginal test with 5% two-sided type I error requires 337 participants in 
each comparison group. To account for effects of other drugs used in combination, which 
may reduce the event rate of the control group, for the interim analysis plan, and for losses 
to follow-up, we plan to enroll 1,124 participants in total.    
 
Prespecified analyses:  
A detailed SAP will be submitted to the DSMB and updated if needed prior to analyses. 
The primary efficacy analysis for each study drug, metformin, fluvoxamine, and 
ivermectin, will be based on a logistic regression model with a main effect for the relevant 
drug controlling for study site, and use of the other study drugs. In particular, no 
interaction effects will be included in this analysis. Prespecified subgroup analyses 

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include: pregnant women, and individuals who have already received a SARS-CoV-2 
vaccine.  
 
The SAP includes a sample-size re-calculation procedure that was pre-specified for the 
analysis of futility and efficacy on the first 2/3 of participants enrolled. This procedure 
was presented to and approved by the DSMB at the DSMB analysis of futility and 
efficacy done after 2/3 of participants were enrolled, + 14 days of follow-up. The updated 
total sample size for the study based on this sample size re-calculation is 1,350. This re-
estimation accounts for a larger portion of participants being vaccinated and greater 
prevalence of monocloncal antibody use after enrollment than was envisioned when the 
protocol was written in fall 2020, and the resultant impact on the event rate in the placebo 
control arm; and external evidence from the Together Trial indicating a 33% relative 
reduction from fluvoxamine for which the original sample size would not provide 
adequate power.. The updated sample size is expected to provide 80% power to detect a 
35% relative reduction from fluvoxamine, and similarly for ivermectin, while accounting 
for the recent impact of vaccination and therapeutics by using a projected estimate of the 
event rate for the primary outcome in the participants randomized to the placebo control 
arm. 
 DSMB Monitoring Guidelines: 
Safety, efficacy and futility will be monitored for both cohorts by an independent DSMB (more 
info below). Timing of analyses will be with respect to information time defined as the proportion 
of participants who have completed the primary endpoint follow-up interval relative to the 
planned sample size. Interim analyses will include all participants who have been followed for 
specified window so as to exclude participants with possibly yet to be determined outcome status 
and thereby ensure unbiased estimates of the primary event rate in each arm. Safety data will be 
reviewed regularly by the DSMB. The first interim analysis of efficacy data (Stage 1) will focus 
on safety and feasibility, while still allowing early stopping for efficacy. Subsequent interim 
analyses of efficacy data (Stage 2) will focus on efficacy, futility and any ongoing safety or 
feasibility concerns.   
12.4.1 Safety Monitoring: 
Safety monitoring will be undertaken for each agent and combination. Regular reports 
will be provided to the DSMB at a mutually agreeable interval with an evaluation of 
safety outcomes that focus on comparisons of the frequency of deaths, SAEs and grade 4 
events between the active treatment arms and placebo arm irrespective of attribution to 
study drug. Proportions and 95% exact confidence intervals will be used to summarize 
the results with unconditional exact tests and corresponding exact intervals to evaluate 
differences. Cumulative counts of adverse reactions and numbers of participants 
experiences and adverse reaction will be reported and compared similarly. Further safety 
assessments may be considered as demanded by the DSMB as well. The purpose of these 
reports is to catch any unexpected severe adverse reactions to metformin in the study 
populations. Formal statistical comparisons of safety endpoints using p-values will be 
undertaken at the request of the DSMB, and will otherwise not be reported. 
12.4.2 Efficacy Monitoring: 

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Efficacy monitoring will be undertaken for each of the three active agents against its 
control. Efficacy monitoring boundaries will be based on a Kim and DeMets alpha-
spending function that mimics O’Brien-Fleming boundaries (parameter value of 3). This 
upper boundary controls one-sided type I error at 2.5%, and will be modified according 
to the information fractions at the time of the actual analyses (defined by the current 
evaluable sample size / maximum sample size). The monitoring boundaries that will be 
provided to the DSMB for each cohort are reported in Table 2 and updated based on the 
actual sample size(s) available at the time of each analysis. The lower futility boundary 
will be treated as non-binding and supplemented with conditional power calculations in 
conjunction with the DSMB. This futility boundary is based on a Kim and DeMets beta 
spending function with a parameter value of 1.5. The lower Haybittle-Peto boundary for 
harm of -2.5 with 50% or less of the planned enrollment and -2.0 otherwise will be 
considered binding, though harm will be assessed in conjunction with safety data and 
may be declared by the DSMB despite the primary efficacy endpoint analysis not 
achieving this lower boundary. (Monitoring boundary calculations have been and will be 
carried out using the gsDesign package in R version 3.6.1 or newer.)  
Following the sample size re-estimation procedure, the upper efficacy boundary will be 
calculated by spending the remaining type I error rate in proportion to the specified Kim 
and DeMets alpha-spending function where the information fraction is calculated with 
respect to the updated sample size. This approach corrects for over-spending alpha 
relative to the revised sample size and controls the overall one-sided type I error rate at 
the intended 2.5% level (or equivalently the two-sided 5% level).  
 
Table 2: Monitoring Boundary Guidelines on Z-Score Scale. The futility boundary will be 
considered non-binding and supplemented by conditional power calculations. The harm boundary 
will be considered binding.  
Sample Size 
62 
386 
774 
1,124 
Efficacy 
3.737 
3.116 
2.461 
2.001 
Futility 
-2.130 
-0.093 
1.087 
2.001 
Harm 
-2.500 
-2.500 
-2.000 
-2.000 
 Sub-Study of Laboratory Outcomes: 
The first approximately 62 to 82 patients will be analyzed as a sub-study to compare changes 
(from day 1 to days 5 and 10) in continuous laboratory outcomes between those on metformin 
to those on placebo (CRP, albumin, viral load, and microbiome changes (optional)), to help 
further understand mechanisms and apply for further funding early in the course of the 
trial.65,66,90 The study procedures are the same for those in the sub-study as the rest of the trial. 
 Data Analysis: 
A detailed SAP will be developed by the statisticians and included in the appendix prior to 
carrying out any unblinded data analysis of either cohort. Amendments to the SAP will be 
considered and developed by the blinded statistician(s). For secondary and tertiary outcomes, the 
unblinded statistician may participate in drafting amendments to the SAP but only for data for 
which their blind is not compromised. A brief analysis plan is outlined here. All analyses will 

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follow a modified intent to treat (mITT) principle, excluding participants who were post-
randomization screen failures and who did not ingest any study drug. Formal comparisons will 
use 2-sided tests with a 5% significance level.  
Descriptive statistics will be reported for baseline covariate information. Continuous variables 
will be summarized using mean and standard deviations, as well as median and interquartile 
range for skewed variables. Binary and categorical variables will be summarized using counts 
and percentages. Differences in important prognostic variables will be monitored visually with 
formal statistical testing undertaken only at the request of the DSMB.  
Each study drug version control comparison will be separate. Each control group will consist of 
the participants who were eligible to receive the study drug but were assigned to a relevant 
placebo control arm instead. The metformin comparison will control for fluvoxamine and 
ivermectin use, and the fluvoxamine and ivermectin versus control comparisons will each control 
for metformin use. Primary hypotheses will be evaluated using logistic regression with a main 
effect for the relevant drug adjusted for study site and use of the other study drugs. The statistical 
significance of the main effect will be evaluated using a likelihood ratio test with interim 
monitoring boundaries specified above.  
A secondary analysis for each study drug versus control comparison will control for age and BMI 
as well. Metformin effect heterogeneity with respect to biologic sex will be assessed in both 
cohorts though a logistic regression model with an interaction term, as well as separate logistic 
regression models fit to the data from males and females. During interim analyses, some 
participants will not have been followed adequately long for inclusion in the primary analysis. 
As a secondary analysis, marginal cumulative incidence rates in each arm at the specified follow-
up interval will be estimated using the Kaplan-Meier method by censoring those in the midst of 
follow-up who have yet to experience the primary endpoint at their point of last study contact.  
Laboratory outcomes, which are continuous longitudinally measured outcome, will be evaluated 
using generalized estimating equations with a treatment effect and adjustments for the 
corresponding outcome at baseline. 
Secondary outcomes will be analyzed using generalized linear models with an appropriate 
distributional assumption and/or normalizing transformations. These analyses will adjust for 
study site and other prognostic information as appropriate. Time-to-event outcomes will be 
compared using Kaplan-Meier and log-rank tests as well as Cox proportional hazards models 
that adjust for prognostic variables. Ordinal endpoints will be analyzed using proportional odds 
regression models that adjust for prognostic variables and supplemented by logistic regression 
models for each ordinal threshold. These analyses will be supplemented by descriptive 
cumulative statistics for each ordinal category by treatment group.  Detailed plans for primary, 
secondary and supplemental analyses will be provided in the SAP prior to conducting any 
unblinded data analyses.  
All analyses will be carried out  using R version 3.6.1 or newer. 
 Data Integrity: 
The principal investigator will manage oversight of quality control for collected data. 
Recruitment of subjects will be performed using inclusion/exclusion criteria defined above Study 
data will be recorded within a REDCap database, which is HIPAA complaint, password protected 

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with variable assignable security access and an audit trail consistent with all regulatory 
requirements for maintenance of clinical trial data. Data summaries and quality control checks 
will be run routinely. 
 Missing Data: 
Research coordinators will make a consistent effort to ascertain all study data within the protocol 
specified windows, as well as outside these windows as needed. Participants who fail to respond 
will be contacted by study staff multiple times, and family will be contacted as well, prior to 
being recorded as lost to follow up. All data collected on a participant prior to loss to follow up 
or withdrawal of consent will be included in analyses. Missing values will be multiply imputed 
using chained equations and predictive mean matching via the mice package  and the effect 
estimate and confidence intervals will reflect the uncertainty in these missing values. For the 
primary outcome variables, sensitivity analyses that are biased towards the null will be carried 
out by assuming missing outcomes in the placebo arm follow the estimated distribution in the 
treatment arm, and vice versa for missing outcomes in the treatment arm. Additional details will 
be provided in the SAP. 
13.0 Safety 
 Adverse Event (AE)  
At every study visit, participants will be asked a standard nonleading question to elicit any 
medically related changes in their well-being. They will also be asked if they have been 
hospitalized, had any accidents, used any new medications, or changed concomitant medication 
regimens (both prescription and OTC medications). 
An AE is any symptom, sign, illness, or experience that develops or worsens in severity during 
the course of the study but does not necessarily have a causal relationship with study 
agent/intervention or procedures. Any medical condition that is present at the time that the 
participant is screened but does not deteriorate should not be reported as an AE. However, if it 
deteriorates at any time during the study, it should be recorded as an AE. 
A clinical trial adverse event is defined as any untoward medical event associated with the use 
of a drug or study procedure. Non-serious adverse events will be collected during the period from 
enrollment (randomization) through the period on study drug, day 14. Any adverse event that is 
being collected as an expected Covid outcome by the Daily Covid Symptom Log or Clinical 
Outcomes assessments, or an expected side effect being collected by the Side Effect Survey, will 
only be recorded in those eCRF’s and not additionally recorded in an adverse event eCRF. They 
will be reported to the DSMB at interim analyses. 
Any adverse event that is not captured in the Covid Daily Symptom Log questions, Side Effect 
Survey, or Clinical Outcomes assessments will be recorded as an adverse event and reported to 
the DSMB at interim analyses. AE’s will not be followed to resolution unless worsening during 
the course of the trial.  
 Serious Adverse Event (SAE) 
Serious adverse events will be collected from enrollment through day 14 and 28. Investigators 
will determine if the event is serious or related to the study drug. 

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An SAE is any AE that is: 
 
Fatal, 
 
life-threatening, 
 
requires or prolongs a hospital stay, 
 
results in persistent or significant disability or incapacity, 
 
a congenital anomaly or birth defect, or 
 
an important medical event*. 
*Important medical events are those that may not be immediately life threatening, but are 
clearly of major clinical significance.  They may jeopardize the subject, and may require 
intervention to prevent 1 of the other serious outcomes noted above.  For example, drug 
overdose or abuse, a seizure that did not result in in-patient hospitalization, or intensive 
treatment of bronchospasm in an emergency department would typically be considered 
serious. 
SAEs must be entered into the study database within 24 hours of investigator awareness of the 
event.  
 Assessment of Safety 
Scale used to Grade Severity of Adverse Events. Toxicity Grading Scale for Healthy Adult and 
Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials 
https://www.fda.gov/media/73679/download). The scale provides a grading severity scale for 
AEs with unique clinical descriptions of severity based on this general guidance, and for this 
study an ED visit (without hospitalization) is considered Grade 3, not Grade 4 (a hospitalization 
is Grade 4).  
 Investigator Assessment of Serious Adverse Events 
The Investigator will evaluate all SAEs with respect to Seriousness and Causality (relationship 
to study agent and relationship to research) as defined below. 
 Causality 
The likelihood that the SAE is related to the study agent will be assessed by the investigator 
considering the following categorization. Due to the severity of COVID-19 illness further 
detailed breakdown will not occur: 
 
Definitely Related: There is clear evidence to suggest a causal relationship, and other possible 
contributing factors can be ruled out. The clinical event, including an abnormal laboratory 
test result, occurs in a plausible time relationship to study agent/intervention administration 
and cannot be explained by concurrent disease or other drugs or chemicals. The response to 
withdrawal of the study agent/intervention (de-challenge) should be clinically plausible. The 
event must be pharmacologically or phenomenologically definitive, with use of a satisfactory 
re-challenge procedure if necessary. 
 
Probably Related: There is evidence to suggest a causal relationship, and the influence of 
other factors is unlikely. The clinical event, including an abnormal laboratory test result, 
occurs within a reasonable time sequence to administration of the study agent/intervention, 
is unlikely to be attributed to concurrent disease or other drugs or chemicals, and follows a 

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clinically reasonable response on withdrawal (de-challenge). Re-challenge information is not 
required to fulfill this definition. 
 
Possibly Related: There is some evidence to suggest a causal relationship (e.g., the event 
occurred within a reasonable time after administration of the trial medication). However, the 
influence of other factors may have contributed to the event (e.g., the subject’s clinical 
condition, other concomitant events). Although an adverse drug event may rate only as 
“possible” soon after discovery, it can be flagged as requiring more information and later be 
upgraded to probable or certain as appropriate. 
 
Unlikely: A clinical event, including an abnormal laboratory test result, whose temporal 
relationship to study agent/intervention administration makes a causal relationship 
improbable (e.g., the event did not occur within a reasonable time after administration of the 
trial medication) and in which other drugs or chemicals or underlying disease provides 
plausible explanations (e.g., the subject’s clinical condition, other concomitant treatments). 
 
Not related: The AE is completely independent of study agent/intervention administration, 
and/or evidence exists that the event is definitely related to another etiology. There must be 
an alternative, definitive etiology documented by the clinician. 
 
 Investigator Reporting Responsibilities: 
13.6.1 Serious Adverse Events 
All SAEs must be reported on the Serious Adverse Event case report form (SAE CRF) 
within 24 hours of awareness of the event. All other AEs must be reported within 5 
business days of site awareness. The safety medical monitor will review all SAEs and 
determine the expectedness of each SAE. 
13.6.2 Unanticipated Problems 
An Unanticipated Problem is any event, incident, experience, or outcome that is 
 
 unexpected in terms of nature, severity, or frequency in relation to 
o the research risks that are described in the IRB-approved research protocol and 
informed consent document; Package Insert, or other study documents; 
o the characteristics of the subject population being studied (persons with COVID-
19); and 
 
possibly, probably, or definitely related to participation in the research; and 
 
places subjects or others at a greater risk of harm (including physical, psychological, 
economic, or social harm) than was previously known or recognized. 
  
Unanticipated Problems will be reported in the study database. Unanticipated problems 
may include problems with protocol implementation, participant safety, and/or concerns 
regarding informed consent.  Initial reports must be submitted within 7 calendar days of 
site awareness of the event. 
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All unresolved SAEs will be followed by the CRC until the event is resolved or 14 days past the 
participants final study visit.  
 Sponsor’s Reporting Responsibilities 
Serious and unexpected suspected adverse reactions as defined in ICH E6 5.17 and as determined 
by the IND Sponsor will be reported to FDA, all participating country regulatory authorities, and 
all participating Investigators as IND Safety Reports. 
The IND Sponsor will also submit an IND Annual Report of the progress of the investigation to 
the FDA and all participating country regulatory authorities. 
14.0 Data Monitoring 
 Data Integrity Monitoring 
Data entry will be performed by trained members of the research team who have received 
documented delegation of authority. Data integrity will be overseen by the PIs and the statistical 
team. A study monitor will review the electronic consent documents, study drug administration 
data, and SAE reporting. Additionally, a random sampling of subjects will undergo full 
evaluation and comparison of source documentation with data entered into the study database if 
source documentation is needed. Source documentation will be collected according to each 
institution’s requirements for source documentation.  
The first data monitoring visit will be scheduled within an appropriate time after the first subject 
is enrolled, with subsequent visits thereafter at designated time intervals. Monitors will evaluate 
study team members to ensure access is consistent with training and delegation of authority logs.  
Sites will maintain binders (either paper or electronic) containing pertinent documents and 
information including IRB approval letters, documentation of GCP training, licenses, human 
subjects research ethics training certificates, curriculum vitae, and correspondence. 
 Data Safety Monitoring Board (DSMB) 
A data safety monitoring board (DSMB) has been convened and includes individuals meeting 
the key element criteria below, it includes a biostatistician with prior clinical trials experience. 
The DSMB will follow the guidance as outlined in the application and the DSMB charter unless 
there is a compelling, unanticipated reason to deviate from these rules. Data regarding the 
primary outcome will be reported to the DSMB at weekly intervals or according to the frequency 
decided by the DSMB. The DSMB may recommend stopping the trial early only for safety, 
following these guidelines: 
A. Patient Safety 
A recommendation to suspend, alter the study, or stop for harm would occur if the lower 
bound for harm is crossed at any interim analysis for the primary efficacy outcome, or 
there is concerning evidence in the opinion of the DSMB, there is concerning evidence 
in the opinion of the DSMB that the rate of IRB-reported SAEs is higher in the 
experimental group than in the placebo group.  
Despite the lower number of formal preplanned analyses, the DSMB will still receive 
near timely reports of hospitalizations and deaths, and can deviate from this strategy and 

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perform earlier testing if desired. They retain authority to change this plan if the reporting 
suggests harm prior to the first formal planned assessment if they feel that a formal 
hypothesis test is warranted.  
B. Efficacy 
Efficacy monitoring will be monitored in accordance to the guidelines in Section 12.4.2.  
The DSMB will operate in accordance with guidelines established by the FDA in “Guidance for 
Clinical Trial Sponsors: Establishment and Operation of Clinical Trial Data Monitoring 
Committee” jointly published by the CBER, CDER and CDRH of the FDA 
(https://www.fda.gov/regulatory-information/search-fda-guidance-documents/establishment-
and-operation-clinical-trial-data-monitoring-committees). The key elements include: 
1. Expertise and independence: The members must have expertise in the area of study, not 
be study authors and have no financial conflict of interest. 
2. Members will sign a confidentiality agreement. 
3. It is preferred that the DSMB have a face-to-face initial meeting, but can meet by 
telephone thereafter more frequently. 
4. All meetings must follow standard operating procedures (SOPs). 
If the DSMB recommends closure of the study, then the DSMB Chair will email the principal 
investigator who will notify the IRB. If the trial is stopped for patient safety and a repairable 
cause of unacceptably high adverse events can be identified, the action must be reviewed and 
approved by the DSMB and IRB prior to resuming enrollment. For example, if one additional 
exclusion criterion is discovered that would account for the majority of unexpected events, this 
new exclusion criterion could be added, and the study could proceed. 
 Data Security:  
All standard confidentiality procedures will be observed for this study. Research staff will be 
trained on protocol and GCP standards before they will be allowed contact with participants or 
data. All data will be stored in a secure HIPAA compliant manner. No indefinable data will be 
stored on individual research computers or flash drives.  
15.0 Provisions to Protect the Privacy Interests of Participants 
  Protecting Privacy:  
Conversations will be held in a private room whenever possible. Telephone calls will be 
performed one on one.  The electronic consent process will take place using a REDCap program 
that is secure and HIPAA compliant. 
  Access to Participants:   
Conduct of the study and determination of both safety and efficacy of the intervention requires 
access of the medical records. All study personnel undergo human subjects protection training 
and understand and value privacy standards set forth by HIPAA. Participants enrolled in the trial 
are made aware during the informed consent procedure that study personnel will be required to 

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access this private information for trial conduct, and consent to this access prior to agreeing to 
participate. 
16.0 Compensation for Research-Related Injury 
 Compensation for Research-Related Injury:  
The sponsor does not have funds for research-related injury compensation. 
 COVID-19 PREP Act 
Due to the coronavirus public health crisis, the federal government has issued an order that may 
limit your ability to recover damages if you are injured or harmed while participating in this 
COVID-19 clinical study. If the order applies, it limits your ability to recover damages from the 
University, researchers, healthcare providers, study sponsor, manufacturer or distributor involved 
with the study. However, the federal government has a program that may provide compensation 
to you or your family if you experience serious physical injuries or death due to this study. To 
find out more about this “Countermeasures Injury Compensation Program” go 
to https://www.hrsa.gov/cicp/about/index.html or call 1-855-266-2427. 
17.0 Multi-Site Research 
 Study-Wide Number of Participants:  
Up to 1,160 participants will be enrolled in the study to achieve the needed number of completed 
data sets.   
 Study-Wide Recruitment:  
Each site will determine appropriate recruitment methods. A study brochure will be made 
available to all sites. Coordinators from the central site may help call positive patients at 
participating sites if a site becomes overwhelmed at any given time, given the rapidly changing 
geographic nature of this pandemic.   
 Communication with Sites: 
All sites will be given access to study documents through the University of Minnesota BOX.  
A project manager will be tasked with coordinate all communication, regulatory efforts, and 
ensuring sites are informed of study changes. The Project Manager will also work with the PI 
to ensure all non-compliance, adverse events, and other reportable events are reviewed and 
reported in accordance with local policies. 
All study data will be entered into REDCap with each site being assigned a specific data access 
group so that staff at one site cannot see participant data from another site. 
Personnel from all sites will participate in monthly progress meeting calls, which will include 
discussion of any problems including reportable events, interim results, and completion of the 
study. More frequent meetings may be planned, as necessary. 
18.0 Appendices 

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