FEnofibRate as a Metabolic INtervention for Coronavirus Disease 2019
Phase: PHASE2
Conditions: Covid19
Sponsor: University of Pennsylvania

 
FERMIN trial 
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CLINICAL TRIAL PROTOCOL 
 
FEnofibRate as a Metabolic INtervention for Coronavirus Disease 2019 (COVID-19):  
A randomized controlled trial 
(FERMIN trial) 
 
Version:  V5: November 3rd, 2021 
 
NCT04517396 
 
Investigators, Steering Committee Members, Center Investigators, Project Manager and 
DSMB Members are listed in Appendix 4 
 
 
 

 
FERMIN trial 
Table of Contents 
SUMMARY AND TRIAL OVERVIEW ....................................................................................... 3 
1. 
BACKGROUND AND SIGNIFICANCE .............................................................................. 4 
2. 
STUDY DESIGN AND POPULATION ................................................................................ 5 
2.1. Overview of study design ................................................................................................ 5 
2.2. Study Sites......................................................................................................................... 5 
2.3. Study Population .............................................................................................................. 5 
2.4. Screening and enrollment ............................................................................................... 6 
2.6. Randomization procedure ............................................................................................... 6 
2.7. Participant withdrawal / Early termination .................................................................... 7 
2.8. Concomitant Medication .................................................................................................. 7 
2.9. Drug dispensing ....................................................................................................................... 7 
2.10. Follow-up assessments ................................................................................................. 7 
3. 
ENDPOINTS .......................................................................................................................... 8 
4. 
ADVERSE EVENTS ............................................................................................................ 10 
4.1. Adverse Event Reporting .............................................................................................. 10 
4.2. Key definitions ................................................................................................................. 10 
4.3. Classification of AEs ...................................................................................................... 10 
4.4. Pregnancy ........................................................................................................................ 11 
5. 
DATA COLLECTION ......................................................................................................... 11 
6. DATA SAFETY MONITORING BOARD .................................................................... 11 
7. 
STATISTICAL CONSIDERATIONS.................................................................................. 12 
7.1. Power calculations ......................................................................................................... 12 
7.2. Data Analysis Plan ......................................................................................................... 12 
7.3. Subgroup analyses and effect modification ............................................................... 14 
8. 
PROTECTION OF HUMAN SUBJECTS ........................................................................... 14 
8.1. Potential benefits of the proposed research, importance of the knowledge to be 
gained, and risk/benefit ratio ................................................................................................ 14 
8.2. Risks to study subjects .................................................................................................. 14 
8.3. Adequacy of Protection Against Risks ........................................................................ 16 
8.3.1. Recruitment and Informed Consent ..................................................................... 16 
8.3.2 Measures to minimize the risk of breach in confidentiality: ............................... 16 
9. 
REGULATORY STANDARDS .......................................................................................... 17 
10. 
ADAPTIVE DESIGN ........................................................................................................ 17 

 
FERMIN trial 
SUMMARY AND TRIAL OVERVIEW  
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for 
coronavirus disease 2019 (COVID-19), is associated with a high incidence of acute respiratory 
distress syndrome (ARDS) and death. Aging, obesity, diabetes, hypertension and other risk 
factors associated with abnormal lipid and carbohydrate metabolism are risk factors for death in 
COVID-19.  
Recent studies suggest that COVID-19 progression is dependent on metabolic mechanisms. 
Moreover, gene expression analyses in cultured human bronchial cells infected with SARS-CoV-
2 and lung tissue from patients with COVID-19, indicated a marked shift in cellular metabolism, 
with excessive intracellular lipid generation. In this cell culture system, fenofibrate (a widely 
available low-cost generic drug approved by the FDA and multiple other regulatory agencies 
around the world to treat dyslipidemias) at concentrations that can be achieved clinically, 
markedly inhibited SARS-CoV-2 viral replication. Fenofibrate also has immunomodulatory effects 
that may be beneficial in the setting of COVID-19. The aim of this trial is to assess the clinical 
impact of fenofibrate (administered for 10 days) to improve clinical outcomes in patients with 
COVID-19.  
 
The primary endpoint of the trial will be a global rank score that ranks patient outcomes 
according to 5 factors: (1) time to death (ranked from shortest to longest, up to 30 days post-
randomization), (2) the number of days supported by mechanical ventilation (invasive or non-
invasive) or extracorporeal membrane oxygenation (until hospital discharge, up to 30 days post-
randomization, ranked from longest to shortest); (3) The inspired concentration of oxygen/percent 
oxygen saturation (FiO2/SpO2) ratio area under the curve (until hospital discharge, up to 30 days 
post-randomization, ranked from highest to lowest); (4) For participants enrolled as outpatients 
who are subsequently hospitalized, the number of days out of the hospital during the 30 day-
period following randomization (ranked from lowest to highest); (5) For participants enrolled as 
outpatients who don’t get hospitalized during the 30-day observation period, the modified Borg 
dyspnea scale (mean value of assessments at ~5, and ~10 and ~15 days).  
 
Secondary endpoints will include: 
(1) Number of days alive, out of the intensive care unit, free of mechanical ventilation (invasive 
and non-invasive), extracorporeal membrane oxygenation (ECMO) or maximal available 
respiratory support in the 30 days following randomization. 
(2) A seven-category ordinal scale consisting of the following categories: 1, not hospitalized with 
resumption of normal activities; 2, not hospitalized, but unable to resume normal activities; 3, 
hospitalized, not requiring supplemental oxygen; 4, hospitalized, requiring supplemental 
oxygen; 5, hospitalized, requiring nasal high-flow oxygen therapy, noninvasive mechanical 
ventilation, or both; 6, hospitalized, requiring extracorporeal membrane oxygenation (ECMO), 
invasive mechanical ventilation, or both; and 7, death. 
(3) A global rank score similar to the primary endpoint, but using a more comprehensive COVID-
19 symptom scale instead of the dyspnea Borg scale (Appendix 1). 
 
Exploratory endpoints will include: 
(1) All-cause death. 
(2) Number of days alive and out of the hospital during the 30 days following randomization. 
(3) A global rank score similar to the primary endpoint, but built only with factors 1-4. 
 
All primary analyses will be performed on an intent-to-treat basis.  
 
 

 
FERMIN trial 
1. BACKGROUND AND SIGNIFICANCE  
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for 
coronavirus disease 2019 (COVID-19), is associated with a high incidence of acute respiratory 
distress syndrome (ARDS) and death.1  
Recent studies suggest that COVID-19 progression is dependent on metabolic 
mechanisms.2 T2DM and hypertension have been identified as the most common comorbidities 
for other serious coronavirus infections, such as severe acute respiratory syndrome (SARS) and 
Middle East respiratory syndrome (MERS-CoV).2,3 Individuals infected with COVID-19 who 
developed ARDS and death have been characterized by older age and a higher prevalence of 
hypertension, diabetes, and cardiovascular diseases compared to those individuals with milder 
disease.2,4-6 Hyperglycemia and hyperlipidemia are also risk factors for acute respiratory distress 
in the setting of COVID-19.2,7 Indeed, patients with T2DM and the metabolic syndrome appear to 
have up to ten-times greater risk of death when they contract COVID-19.2  
Several experimental studies suggest a mechanistic link between abnormal metabolism and 
the severity of SARS-CoV-2 and other coronavirus infections. Palmitoylation of SARS-CoV spike 
proteins has been shown to be essential for virion assembly and for partitioning into detergent-
resistant membranes and for cell-cell fusion.8 For other coronaviruses, lipid accumulation occurs 
upon infection.9 Recent gene expression analyses in cultured human bronchial cells infected with 
SARS-CoV-2 and lung tissue from patients with COVID-19, indicated a marked shift in cellular 
metabolism, with excessive intracellular lipid generation.9 Ehrlich et al studied the metabolic 
rewiring induced by SARS-CoV-2 infection in the transcriptional signature of primary bronchial 
epithelial cells, validating their results in lung biopsy samples of COVID-19 patients. This study 
reported a significant metabolic response in SARS-CoV-2 infected lungs, covering ~60% of the 
differentially expressed genes.9 This transcriptional signature was characterized by changes in 
metabolism and pathways of endoplasmic reticulum stress, including upregulation of glycolysis 
and dysregulation of the citric acid cycle, upregulation of fatty acid and cholesterol synthesis, and 
the suppression of fatty acid oxidation. Peroxisome proliferator-activated receptor-alpha (PPAR) 
inhibition was shown to be in involved in abnormalities in lipid metabolism in these experiments.  
In further cell culture experiments, the PPAR-agonist fenofibrate (a widely available low-
cost generic drug approved by the FDA and multiple other regulatory agencies around the world 
to treat dyslipidemias) at concentrations that are likely to be achieved clinically, reversed the 
metabolic changes induced by SARS-CoV-2, and inhibited viral production/replication.9 
Treatment of SARS-CoV-2 infected cells with fenofibrate (concentration: 20 μM) blocked 
phospholipid accumulation and increased glycolysis, reversing the metabolic effects of infection. 
Viral replication was effectively blocked, reduced by 3-log over 5 days period to below the assay 
detection limit, while cell viability was unaffected. Fibrates also appear to exert immunomodulatory 
effects that could be beneficial in the setting of COVID-19.10-12 10,11PPAR-α activation by fibrates 
has been described to beneficially influence inflammation and experimental lung injury.  
 Whereas these pre-clinical studies suggest that fenofibrate could directly target host 
metabolic pathways to minimize virus replication and possibly suppress its pathogenesis in lung 
tissue, a well-designed and rigorously executed randomized controlled trial is urgently needed to 
assess the potential efficacy and clinical benefit of fenofibrate in COVID-19. Fenofibrate is a 
widely-available, generic and inexpensive drug with a proven track record of safety for other 
indications (i.e., dyslipidemia). If effective for COVID-19, this trial could have a major public health 
impact.   
The aim of this randomized controlled trial is to assess the clinical impact of fenofibrate to 
improve clinical outcomes in patients with COVID-19.  
 
 
 

 
FERMIN trial 
2. 
STUDY DESIGN AND POPULATION 
2.1. Overview of study design 
This will be a prospective randomized controlled trial of fenofibrate therapy (administered for 10 
days) among patients with COVID-19. A general overview of the trial design is shown in Figure 
1. A schedule of events is shown in Appendix 2. 
 
Figure 1. General workflow of the trial  
 
2.2. Study Sites 
The trial will be executed at several sites in several countries, including the USA and various Latin 
American countries. Prior to initiation of the research in each site, IRB approval will be obtained 
for each site, and Health Authority approval will be obtained as per each country’s regulations. In 
each country, there will be a qualified national PI / sponsor for regulatory processes. 
 
2.3. Study Population 
We will enroll 700 subjects meeting the following criteria:   
 
Inclusion Criteria 
(1) Age 18 years or older  
(2) A diagnosis of COVID-19, based on: (a) A compatible clinical presentation with a positive 
laboratory test for SARS-CoV-2, or (b) Considered by the primary team to be a Person Under 
Investigation undergoing testing for COVID-19 with a high clinical probability, in addition to 
Screened for eligibility
Excluded
•
Pregnancy or breastfeeding
•
Advanced renal or active liver disease, 
cholelithiasis, hypothyroidism, or rhabdomyolysis
•
Sensitivity to fenofibrate
•
Ongoing treatment with medications that may 
interact with fenofibrate
•
Prisoners
•
Decline to participate or no access to smart phon
computer or tablet device
Randomized
Diagnosis of COVID-19
Daily data collection 
(inpatients) or at ~5, ~10 
and ~15 days post-
randomization (outpatients)
30-days post-
randomization
(all patients)
Fenofibrate
(145 mg/d of Tricor or dose 
equivalent preparation, 
dose adjusted for renal 
dysfunction*) + Usual Care
Usual Care 
±
Placebo
Assess for vital status, 
readmissions, additional 
major adverse events
Assess for vital status, 
readmissions, additional 
major adverse events
* According to the approved label/package insert for each particular preparation

 
FERMIN trial 
compatible pulmonary infiltrates on chest x-ray (bilateral, interstitial or ground glass opacities) 
or chest CT. 
(3) Able to provide informed consent. 
(4) Fewer than 14 days since symptom onset.  
 
Exclusion Criteria: 
(1) Known pregnancy or breastfeeding.  
(2) Estimated glomerular filtration rate (eGFR) <30 mL/min/1.73m2 or undergoing dialysis (CKD 
stages 4-5).  
(3) History of active liver disease, cholelithiasis, uncontrolled hypothyroidism, or rhabdomyolysis 
(suspected or confirmed). Patients with a history of hypothyroidism receiving a stable dose 
of thyroid replacement therapy for at least 6 weeks, with a documented normal TSH (primary 
hypothyroidism) or free thyroxine (secondary or tertiary hypothyroidism) level at least 6 
weeks after the last dose change will be considered eligible for enrollment.  
(4) Known hypersensitivity to fenofibrate or fenofibric acid.  
(5) Ongoing treatment with fenofibrate, clofibrate, warfarin and other coumarin anticoagulants, 
glimepiride, cyclosporine, tacrolimus. 
(6) Use of statins other than simvastatin, pravastatin or atorvastatin ≤40 mg/d or rosuvastatin 
≤20 mg/d. 
(7) Prisoners/incarcerated individuals 
(8) Inability to read, write or no access to a smart phone, computer or tablet device. 
(9) Intubated patients. 
 
2.4. Screening and enrollment 
Patients being evaluated in the emergency room, outpatient clinics, other urgent/emergent care 
settings, or admitted to the hospital with COVID-19 will be screened for eligibility. We will also 
consider interested participants who reach out to us as a result of advertisements or other 
outreach efforts. Inclusion and exclusion criteria will be reviewed to ensure participant suitability. 
After participant eligibility is confirmed, informed consent will be obtained from study participants 
using documents and processes approved by the respective Institutional Review Board 
(IRB)/Ethics Comittee. Specific consent mechanisms and other unique aspects applied to meet 
regulatory requirements in a specific country are specified in Appendix 3. Participants will be 
given the opportunity to have all questions regarding their participation answered. Enrollment will 
be competitive (will occur across all active sites, without an enrollment cap per site) until a total 
of 700 patients have been recruited. 
 
2.5. Randomized intervention 
The randomized intervention will be: (1) fenofibrate (or its active metabolite, fenofibric acid) 
administered for 10 days (see Appendix 3 for specific preparations and dosing), 13,14 with  
appropriate dose reductions or exclusions will be implemented for patients with chronic kidney 
disease as per the approved preparation label; (2) Placebo of similar appearance (1:1 ratio). 
These interventions will be added to usual care. Participants and investigators (including research 
team members who administer the Dyspnea Borg scale and symptoms questionnaires) will be 
blinded to the randomized intervention. Primary analyses will be performed on an intent-to-treat 
basis.  
 
2.6. Randomization procedure 
Following informed consent, participants will be randomized to one of the 2 treatment arms.  A 
stratified blocked randomization with randomly permuted blocks will be performed based on site, 

 
FERMIN trial 
sex, age group, and inpatient vs. outpatient status, given the strong impact of these factors on 
outcomes in COVID-19. A sufficient number of complete blocks will be generated for each stratum 
so that randomized assignments are available for every eligible subject. Each block will contain 
an equal number of allocations to each arm.  
 
2.7. Participant withdrawal / Early termination 
Participants may voluntarily withdraw from the study at any time and for any reason. The reason 
for study discontinuation will be recorded on the source documents and in all such participants, 
we will document: (1) vital signs (inpatients only); (2) compliance with the treatment; (3) adverse 
effects. (4) specific reason for withdrawal if possible; (5) functional status and symptoms 
(including the dyspnea Borg scale). 
 
The study medication will be discontinued if any of the following occur at any time: (1) 
acute kidney injury with eGFR<30 ml/m2/min; (2) Suspected or confirmed rhabdomyolysis; (3) 
Red or brown urine, which may indicate myoglobinuria, unless considered by the investigator to 
be clearly not due to rhabdomyolysis (for instance, in the presence of normal circulating creatine 
kinase); (4) Liver failure or increased AST or ALT to >3 times the upper limit of normal. In cases 
in which the medication is discontinued, data collection will continue normally as per the usual 
study protocol. 
 
2.8. Concomitant Medication 
Participants will be treated by their clinicians, at their discretion, with standard of care medications 
for COVID-19 and associated comorbidities. Participants will be allowed to receive antiviral, 
immunomodulatory, or convalescent plasma. Since fenofibrate/fenofibric acid are well-known 
medications, enrollment in other clinical trials will be allowed as long as fenofibrate/fenofibric acid 
use is not an exclusion criterion for other trials. 
We will remind inpatient clinicians to consider potential interactions with fenofibrate, 
particularly in patients who require de novo warfarin treatment (which should ultimately be guided 
by INR checks as per standard practice). We will also ask them to try avoiding the de novo use 
of medications that may interact with fenofibrate or fenofibric acid (colchicine, glimepiride, 
cyclosporine, tacrolimus, statins) unless clear indications exist in the absence of suitable 
therapeutic alternative agents; if glimepiride, cyclosporine or tacrolimus are required, we will 
discontinue the study medication. For colchicine, atorvastatin and simvastatin, we will ask 
clinicians to be mindful of a potential interaction, which is however, not anticipated to constitute a 
significant risk with only 10 days of treatment (see section on “Risks to study subjects”). If 
cholestyramine or colestipol are part of the medical regimen at baseline or during the period of 
study medication administration, we will ask participants to take the study medication at least 1 
hour before or 6 hours after the bile acid binding resin to avoid a pharmacokinetic interaction 
(reduced absorption). For outpatients, we will ask participants to contact us if any new medication 
is initiated by their physicians during the treatment period, and we will establish a similar approach 
in communication with the prescribing clinician.  
 
2.9. Drug dispensing 
The drug will be dispensed by a Pharmacy within each country and/or institution, or directly by 
the investigators. At the University of Pennsylvania, the medication and placebo will be 
dispensed by the UPenn Investigational Drug Pharmacy.   
 
 
2.10. Follow-up assessments 

 
FERMIN trial 
For participants randomized as inpatients, daily assessments (via medical record review) will be 
performed to assess clinical status, with particular attention to the study endpoints (death, 
mechanical ventilation and the FiO2/SpO2 ratio), until hospital discharge or 30 days (whichever is 
shortest). For participants discharged prior to 30 days-post randomization, a follow-up call will be 
performed at the ~30-day time point to assess vital and functional status, symptoms and major 
adverse events, including hospitalizations.  
For participants randomized as outpatients or discharged within 24 hours of receiving the first 
dose of the study medication, participants will be called at approximately 5, 10, 15 and 30 days 
post-randomization, in order to assess vital and functional status, hospitalization status, the 
severity of dyspnea (via the modified Dyspnea Borg Scale, Appendix 1) and major adverse 
events. An effort will be made to make these assessments at the exact time points, but we 
recognize that this is often not possible due to work schedules and inability to get in touch with 
participants for various reasons. In these instances, we will make the assessments at time points 
that are as close as possible to the scheduled time points. 
 
 
3. ENDPOINTS 
The primary endpoint of the trial will be a global rank score that ranks patient outcomes 
according to 5 factors: (1) time to death (ranked from shortest to longest, up to 30 days post-
randomization), (2) the number of days supported by mechanical ventilation (invasive or non-
invasive) or extracorporeal membrane oxygenation (until hospital discharge, up to 30 days post-
randomization, ranked from longest to shortest); (3) The inspired concentration of oxygen/percent 
oxygen saturation (FiO2/SpO2) ratio area under the curve (until hospital discharge, up to 30 days 
post-randomization, ranked from highest to lowest); (4) For participants enrolled as outpatients 
who are subsequently hospitalized, the number of days out of the hospital during the 30 day-
period following randomization (ranked from lowest to highest); (5) For participants enrolled as 
outpatients who don’t get hospitalized during the 30-day observation period, the modified Borg 
dyspnea scale (mean value of assessments at ~5, ~10 and ~15 days). Patients who are enrolled 
as inpatients but discharged within 24 hours of receiving the first dose of the study medication will 
be ranked similarly to outpatients. 
 
The global rank score has several advantages compared to binary outcomes (e.g., all-cause 
death) or time-to-event outcomes (e.g., time to death).15-17 It incorporates information about each 
of the highest-priority events in COVID-19, but allows these events to be prioritized within a single 
endpoint. For instance, the principal outcome of interest is death, but even if there is no difference 
in rate of death, we would still be interested in a shorter duration of invasive respiratory support, 
a shorter duration of hospital admission with better oxygenation parameters, and so on. This 
maximizes study power and minimizes the number of participants that need to be enrolled in order 
to detect clinically-meaningful differences.  
 
Figure 2 demonstrates how participants will be ranked hierarchically according to their 
clinical course. All primary analyses will be performed on an intent-to-treat basis.  
 
Secondary endpoints will include: 
(1) Number of days alive, out of the intensive care unit, free of mechanical ventilation (invasive 
and non-invasive), extracorporeal membrane oxygenation (ECMO) or maximal available 
respiratory support in the 30 days following randomization. 
(2) A seven-category ordinal scale consisting of the following categories: 1, not hospitalized with 
resumption of normal activities; 2, not hospitalized, but unable to resume normal activities; 3, 
hospitalized, not requiring supplemental oxygen; 4, hospitalized, requiring supplemental 

 
FERMIN trial 
oxygen; 5, hospitalized, requiring nasal high-flow oxygen therapy, noninvasive mechanical 
ventilation, or both; 6, hospitalized, requiring extracorporeal membrane oxygenation (ECMO), 
invasive mechanical ventilation, or both; and 7, death. 
(3) A global rank score similar to the primary endpoint, but using a more comprehensive COVID-
19 symptom scale instead of the dyspnea Borg scale (Appendix 1). 
 
Exploratory endpoints will include: 
(1) All-cause death. 
(2) Number of days alive and out of the hospital during the 30 days following randomization. 
(3) A global rank score similar to the primary endpoint, but built only with factors 1-4. 
 
 
Figure 2. Hierarchial ranking for the primary endpoint 
 
 
 
 
* For participants enrolled as inpatients, inpatient mandatory data collection will occur until discharge or 
30 days (whichever is shorter) 
 
 
 
Subset 1, Rank 1death
.
.
.
Subset 1, Rank Ndeath
Subset 2, Rank 1ventilated
.
.
Subset 2, Rank Nventilated
Subset 5, Rank 1ddyspnea
.
Subset 5, Rank Ndyspnea
Rank 1all
Rank Nall
High Dyspnea 
Borg Scale
Subset 3, Rank 1FIO2/SPO2
.
Subset 3, Rank NFIO2/SPO2
FiO2 / SPO2 area under the curve (followed until discharge*)
Higher AUC FiO2/ SPO2
Lower AUC FiO2/ SPO2
Days on mechanical ventilation (followed until discharge*)
Subset 4, Rank 1hospitalized
.
.
.
Subset 4, Rank hospitalized
Days out of the hospital (30-day period following randomization as outpatient)
Dyspnea Borg Scale (Mean of ~5, ~10, and ~15-day values)
Low Dyspnea 
Borg Scale

 
FERMIN trial 
 
4. ADVERSE EVENTS 
4.1. Adverse Event Reporting 
Adverse events (AEs) will be captured in our data entry tool (RedCap). The DSMB will examine 
data periodically in order to compare the incidence of adverse events in both arms. Expedited 
reporting of individual AEs (within 48 hours or discovery by site investigators) will be required for 
severe AEs that are unexpected and felt to be probably or definitely associated with the study 
intervention. Such expedited reporting of AEs will be done from site investigators to the University 
of Pennsylvania study team, and the study team will in turn communicate these to the DSMB. 
 
4.2. Key definitions 
An AE is any untoward medical occurrence associated with the use of a drug in a study 
participant whether or not considered drug or biologic related. An AE can therefore be any 
unfavorable and unintended sign, symptom or disease temporally associated with the use of the 
pharmaceutical product. 
 
4.3. Classification of AEs  
A medically-qualified investigator will assess AEs in terms of causal relationship to intervention, 
seriousness, and expectedness using the following guidelines: 
 
Classification of Adverse Events for Causal Relationship to the Study Intervention 
Not related or unlikely 
related 
There is not a reasonable causal relationship to the investigational 
product and the adverse event, or there is a low likelihood that a causal 
relationship exists. 
Probably or definitely 
related  
There is reasonable or definite evidence to suggest a causal relationship 
between the drug and adverse event. 
 
The events will be classified as serious or non-serious adverse events: 
 
Serious Adverse Events (SAE) are adverse events, in which the investigator or sponsor believe 
that any of the following outcomes occur: 
 
Death 
 
Life-threatening AE:  Places the participant at immediate risk of death at the time of the 
event as it occurred. It does not include an AE that, had it occurred in a more severe 
form, might have caused death. 
 
Persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions. 
 
Inpatient hospitalization or prolongation of hospitalization.  
 
Important medical events that may not result in death, be life threatening, or require 
hospitalization may be considered a serious adverse event when, based upon 
appropriate medical judgment, they may jeopardize the participant and may require 
medical or surgical intervention to prevent one of the outcomes listed in this definition 
above. 
Expectedness:  Expected AEs will be those that are reported to be associated with COVID-19. 
 
The following AEs are expected, disease-related events in patients with COVID-19 
1. Arrhythmias, including ventricular arrhythmias and atrial fibrillation. 

 
FERMIN trial 
2. Acute coronary syndromes with or without coronary stenoses on coronary angiography 
3. Myocarditis or worsening cardiac function. 
4. Shortness of breath, pneumonia, acute respiratory distress syndrome and respiratory 
failure. 
5. Fever, malaise and myalgia. 
6. Worsening cognitive function. 
7. Limb ischemia, coagulopathy, thrombosis, embolus. 
8. Hypotension or hypertension. 
9. Diarrhea, nausea, or vomiting. 
10. Anosmia (loss of sense of smell). 
11. Leukopenia or leukocytosis, thrombocytopenia. 
12. Worsening renal function (resulting in various electrolyte abnormalities).  
13. Worsening liver function. 
14. Death. 
 
4.4. Pregnancy:  
Limited available data of fenofibrate use in pregnant women are insufficient to determine any 
association between fenofibrate and the risk of major birth defects, miscarriage or adverse 
maternal or fetal outcomes. In animal reproduction studies, no evidence of embryo-fetal toxicity 
was observed with oral administration of fenofibrate in rats and rabbits during organogenesis at 
doses less than or equivalent to the dose used in this trial, based on body surface area (mg/m2). 
Known pregnancy will be an exclusion criterion for enrollment. In addition, sexually active females 
of reproductive age who are not receiving active contraception will undergo a pregnancy test prior 
to randomized drug initiation. A positive test will prompt exclusion and/or discontinuation from the 
study. Additional processes related to pregnancy risks may be implemented in specific countries, 
to meet national regulatory requirements. 
 
 
5. DATA COLLECTION 
The data coordinating center (DCC) will be established under the direction of Dr. Jordana Cohen. 
The DCC will oversee randomization, data entry, and DSMB meetings. The data for this trial will 
be collected in ad hoc source electronic case report forms. All source documents collected in this 
trial will be housed by the site principal investigators.  
Data capture and storage will be accomplished within the framework of the Research 
Electronic Data Capture (REDCap) project. REDCap is a secure, web-based application designed 
exclusively to support data capture for research studies. It provides an intuitive interface for data 
entry with data validation, audit trails for tracking data manipulation and export procedures, 
automated export procedures for seamless data downloads to common statistical packages, 
including SAS and STATA, and procedures for importing data from external sources.  
All electronic data at the DCC will be housed in a secure server at the University of 
Pennsylvania. This will allow efficient workflows regardless of location, quarantine, and social 
distance policies, since investigators and research staff can access these documents using 
existing secure VPN mechanisms. 
 
 
6. DATA SAFETY MONITORING BOARD  
A DSMB will be assembled to provide independent oversight of the project. The DSMB will be 
responsible for assessing: 1) baseline comparability between groups; 2) participant accrual rate 
and retention; 3) data quality with special emphasis on eligibility data; and 4) participant safety. 
The board will make recommendations regarding: study continuation, protocol modification, and 

 
FERMIN trial 
review of additional data. The conference call meetings and progress reports will be set by the 
DSMB. The DSMB will review detailed safety data according to pre-defined milestones (i.e., after 
50% of participants are enrolled) which can be adapted as the trial proceeds, as per DSMB 
member decision.  
 
7. STATISTICAL CONSIDERATIONS 
7.1. Power calculations 
We will enroll 700 participants. Participants will be randomized to one of 2 interventions 
(fenofibrate plus usual care vs. placebo plus usual care). Assuming feasible distributions of 
participants across each of the five hierarchies from the available published evidence,4,18,19 we 
performed 10,000 simulations of rank distributions of 700 participants, and determined that there 
will be 80% power at an alpha of 0.0492 (allowing for one interim analysis at 50% of enrollment 
with an alpha of 0.005420,21) to observe an 11% difference in median rank scores between the 
treatment arms. Power calculations were performed using python and PASS16.22  
 
Enrollment of 700 participants will increase our power for secondary outcomes. For the secondary 
outcome of number of days alive, out of the intensive care unit, free of mechanical ventilation 
(invasive and non-invasive), extracorporeal membrane oxygenation (ECMO) or maximal available 
respiratory support in the 30 days following randomization, assuming a standard deviation of 7 
(the SD from the REPLACE COVID trial for this outcome),23 a sample size of 700 would have 
90% power to estimate a 1.7 day mean difference between treatment arms.24,25 Assuming that 
the SD may be higher in the current study with the inclusion of outpatients, we would have a 
sufficient power to estimate a 3.4 day mean difference between treatment arms with a SD of 14. 
 
For the secondary outcome of the WHO ordinal scale, based on the ordinal scale distributions 
from the Remdesevir trial,26 we would have 90% power to observe an OR of 1.5 for clinical 
improvement in the ordinal scale.24,27 Given the expected lower severity of illness in our 
participants, with an adjusted reasonable distribution towards the lower end of the scale, we would 
have 90% power to observe an OR of 1.7. 
 
For the exploratory outcome of all-cause death, assuming a death rate of 14% (observed in 
REPLACE COVID),23 we would have sufficient statistical power to detect a HR of 1.4.28,29 
Considering the mixed inclusion of inpatients and outpatients, if the death rate is 5%, we would 
have sufficient statistical power to detect a HR of 1.7. 
 
For the exploratory outcome of number of days alive and out of the hospital, assuming a standard 
deviation of 8 (the SD from the REPLACE COVID trial for this unpublished outcome),23 a sample 
size of 700 would have 90% power to estimate a 2 day mean difference between treatment 
arms.24,25 Assuming that the SD may be higher in the current study with the inclusion of 
outpatients, we would have a sufficient power to estimate a 3.9 day mean difference between 
treatment arms with a SD of 16. 
 
7.2. Data Analysis Plan  
The sample, both the baseline characteristics and the outcomes, will be explored and described 
using graphical techniques and summary statistics (means, medians, proportions and measures 
of variability) as appropriate.  The initial description will consider the sample as a whole as well 
as by treatment arm.  
 

 
FERMIN trial 
The primary outcome variable will be the global rank score, as used previously in several similar 
randomized controlled trials to facilitate evaluation of composite outcomes of binary and 
continuous findings accounting for censorship for death.15-17 The predictor of interest for all 
outcomes will be randomized intervention (fenofibrate vs. control), with analyses based upon 
the total number of randomized participants. Initial descriptive estimates of all measures will be 
generated for study participants by treatment group. Statistics will include estimates of central 
tendency, measures of variability, and derived moments of skewness and kurtosis. Analyses of 
distributional properties will be performed to determine if variance stabilizing or normalizing 
transformations should be applied. Outliers will be assessed via visual inspection of distributions 
and checked for accuracy. Additionally, the intervention groups will be compared using Fisher’s 
Exact tests.  
 
The primary and secondary outcomes will be analyzed using a two-sided Wilcoxon rank sum test. 
Estimation, and 95% confidence intervals,  of the differences between arms will be based on the 
Hodges-Lehman median difference as well as the Mann-Whitney Parameter, the probability that 
a subject from the fenofibrate arm has a score greater or equal to that of a subject for the control.30 
This will be followed by a more comprehensive linear regression analysis allowing for 
assessments of the treatment effect on each continuous outcome of interest while controlling for 
effects of covariates including age, sex, inpatient vs. outpatient status at enrollment, FiO2/SpO2 at 
the time of enrollment, ethnicity, body mass index, altitude above sea level and history of diabetes 
at baseline.  
 
For non-normal distributed continuous outcomes, we will utilize non-parametric methods or 
consider distribution-stabilizing transformations. Levine’s tests will be used to assess 
homogeneity of variance. The models will include data from dropouts.31-33 Model assumptions will 
be examined (eg, QQ plots to assess  normally distributed residuals for valid Wald tests).   
 
All-cause death will be evaluated using Cox proportional hazards models. The proportional 
hazards assumption will be assessed via weighted versions of Kaplan–Meier curves, using log–
log plots and graphical displays based on the Schoenfeld and scaled Schoenfeld residuals, and 
violations of the proportional hazards assumption will be addressed with a time-interaction term.34  
 
We will make every possible effort to minimize missing data and ensure final assessments for 
participants opting to discontinue study participation.  Missing data, however, is an inevitable 
problem in a longitudinal study. The mechanism for missingness-missing completely at random 
(MCAR), missing at random (MAR), nonignorable or not missing at random (NMAR)-will be 
evaluated prior to implementing methodology intended to minimize bias from missing data.35 We 
anticipate that <5% of randomized subjects will have missing data in the components required to 
compute the study outcomes. Imputation procedures will be applied as needed for missing data, 
and the primary analyses will use the imputed data.36 
 
The intent-to-treat principle of including all randomized participants in the outcome models will be 
followed. Analytic methods described above will take advantage of all available data. Sensitivity 
analyses will be performed including only participants with laboratory confirmation of COVID-19 
and using an ‘as-treated’ analysis. The ‘as-treated’ analysis will take into account subjects in the 
control arm who begin fenofibrate as part of their clinical care, and those in the fenofibrate arm 
who stop using fenofibrate for any reason. We will also perform sensitivity analyses in which the 
FiO2/SpO2 ratio will be theoretically normalized for altitude above sea level (athmospheric 
pressure).  
 

 
FERMIN trial 
Sequential monitoring and early stopping: Incidence rates of outcomes will be monitored 
throughout the trial and used for an interim analysis of efficacy and futility at 50% of enrollment. 
Group sequential methods for event rates will be used to control the Type I error to be 0.05 across 
repeated analyses. Critical values for interim testing will be defined based on an O'Brien-Fleming 
type bound (alpha 0.0052).21 With this approach, the interim test is conservative and the reduction 
in the overall power of the trial caused by interim testing is small. If needed, conditional power 
calculations will be used to assess the futility of continuation in the presence of a negative 
treatment effect. The DSMB will review data on adverse events and other safety issues 
to make an overall recommendation concerning the safety of continuing the trial. 
 
7.3. Subgroup analyses and effect modification 
We will assess for effect modification and exploratory subgroup analyses will be performed 
according to sex, age (categorized by < or ≥ the median value in the study population), race, 
presence of pre-existing diabetes, body mass index (categorized by obese or non-obese), 
inpatient vs. outpatient status at the time of enrollment, FiO2/SpO2 at the time of enrollment 
(categorized by < or ≥ the median value in the study population), duration of symptoms prior to 
randomization (<7d vs. ≥7 days) and fasting triglyceride levels (when available, categorized by < 
or ≥ the standard median value).  
 
8. PROTECTION OF HUMAN SUBJECTS 
8.1. Potential benefits of the proposed research, importance of the knowledge to be 
gained, and risk/benefit ratio 
Potential benefits: There are no known direct benefits to the subjects as a result of their 
participation in this study nor will this be implied when obtaining consent.  
 
Potential risks: please refer to section 8.2  
 
Importance of the knowledge to be gained: Our study will address a highly important clinical 
question that may impact the care of a large number of patients affected by the COVID-19 
pandemic. This study will provide randomized trial evidence about the impact of a wide available, 
generic and inexpensive drug with a proven track record of safety for other indications (i.e., 
dyslipidemia). However, it is essential to rigorously and promptly study its potential clinical efficacy 
in a randomized controlled trial.  
 
Risk/benefit ratio: given the importance of knowledge to be gained and the proven track record of 
safety of this medication, the risk/benefit ratio of our trial is favorable. 
 
8.2. Risks to study subjects 
All subjects will be adults able to give informed consent. Subjects will be enrolled regardless of 
sex, race or ethnicity, aiming to assure adequate representation of women and ethnic minorities. 
Children will not be enrolled.  
The risks to study subjects are related to the potential side effects of the study intervention. 
The dose used in this trial is the starting dose for primary hypercholesterolemia and mixed 
dyslipidemia14 and is utilized as a chronic therapy, for months or years. We propose to administer 
this dose for only 10 days.  
With chronic therapy, adverse reactions > 2% and at least 1% greater than placebo include 
abnormal liver blood tests (increased AST and ALT) increased creatine kinase (CPK), and rhinitis.  
Rhabdomyolysis have been reported in patients taking fenofibrate, but is considered extremely 

 
FERMIN trial 
rare,37-39 with <20 cases reported worldwide for fibrate monotherapy. Moreover, the median 
duration of therapy prior to rhabdomyolysis was 17.5 days.39 In the Fenofibrate Intervention and 
Event Lowering in Diabetes (FIELD) trial, 9,795 were randomized to fenofibrate or placebo for 5 
years. This provided >8 million patient-days of observation in the active arm alone. In this trial, 
only 3 patients allocated to fenofibrate had rhabdomyolysis, which in each case fully resolved; 
this incidence was not significantly different than that of the placebo arm (1 case of 
rhabdomyolysis).40 The risk of rhabdomyolysis may be increased during co-administration with a 
statin, in renal failure, or hypothyroidism. Accordingly, we will exclude all patients with advanced 
renal dysfunction and those with a history of hypothyroidism.  
Regarding statins, although there is an increase in reports of rhabdomyolysis with statin-
fibrate combined therapy, this risk appears to be much higher when statins are combined with 
gemfibrozil than fenofibrate.41 In a meta-analysis of 6 trials including 1,628 subjects taking 
fenofibrate in combination with statin therapy, no case of myopathy or rhabdomyolysis was 
reported. 42 This included data from the LCP-AtorFen trial, in which atorvastatin (40 mg/d) was 
administered alone or with fenofibrate for 12 weeks,43 as well as some studies with simvastatin 
(20 mg/d). 
The negligible risk of rhabdomyolysis with combination therapy has been repeatedly 
confirmed in subsequent studies. In the SAFARI trial (in which 411 patients received simvastatin 
20 mg plus fenofibrate 160 mg/day) for 12 weeks, no cases of rhabdomyolysis were seen. In the 
FIELD trial of fenofibrate vs. placebo, no cases of rhabdomyolysis were seen among patients 
taking statin therapy. Finally, in the large ACCORD lipid trial,44 in which 5,518 patients with type 
2 diabetes who were already being treated with simvastatin were assigned to receive either 
fenofibrate (160 mg) or placebo and followed for a mean of 4.7 years (representing ~12,995 
patient-years of observation or ~4.7 M patient-days, in the fenofibrate+simvastatin arm alone), no 
increased risk of rhabdomyolysis was seen. In this trial, the administered simvastatin dose was 
up to 40 mg/d. The authors concluded that this is compatible with evidence that fenofibrate, in 
contrast to gemfibrozil, does not increase plasma concentrations of statins.45 Clinical data in large 
numbers of patients are also available for pravastatin46 and rosuvastatin.47 The lack of significant 
increase in concentrations of statins induced by fenofibrate has been shown specifically for 
simvastatin,45 pravastatin48,49 atorvastatin50,51 and rosuvastatin.52,53 For pravastatin, fenofibrate 
may slightly increase the AUC for its metabolite 3-alpha-hydroxy-iso-pravastatin, which is not 
considered clinically concerning given its much lower potency and lack of toxicity compared to 
the parent drug48; moreover, subsequent careful studies with dosing of up to 15 days showed no 
increased AUC for pravastatin or its metabolite 3alpha-hydroxy-iso-pravastatin.49 The lack of 
clinically significant interactions with these statins is a clear difference with gemfibrozil, which 
unlike fenofibrate, does increase the AUC of atorvastatin, simvastatin, and multiple other 
statins.50,54-56 There is, however, an increased AUC for  pravastatin and fluvastatin14 and there is 
much less data for newer statins. Cases of myopathy, including rhabdomyolysis, have been 
reported with fenofibrates co-administered with colchicine. A Pubmed search of “colchicine AND 
fenofibrate” (search performed on August 10th, 2020) returned 11 articles, of which only one was 
a report of a case of myopathy in patient receiving these drugs, which actually worsened upon 
discontinuation of fenofibrate and was ultimately proven to be due to inflammatory/autoimmune 
myopathy (based on biopsy data) and associated with multisystemic autoimmune disease.57 In 
contrast, we found a reported case with co-administration of colchicine and gemfibrozil58 and one 
with bezafibrate59, both of which resolved upon discontinuation of the medications. Therefore, this 
does not appear to be a significant problem with fenofibrate and in fact, fenofibrate has been 
suggested as a treatment for gout, a patient population in which colchicine is very common.60-65  
Given that we will only administer 10 days of therapy, we consider the risk of 
rhabdomyolysis, even in patients taking statins or colchicine, to be negligible. Nevertheless, as a 
precaution, we will exclude patients who are taking statins other than simvastatin and atorvastatin; 
similarly, we will exclude patients who are taking simvastatin or atorvastatin at doses >40 mg/d, 

 
FERMIN trial 
since doses >40 mg/d of these 2 drugs in combination with fenofibrate have not been specifically 
studied. Finally, we will ask site investigators to communicate any occurrence of rhabdomyolysis 
to the Principal Investigator, who in turn will immediately communicate them to the DSMB for a 
formal assessment (with unblinding of the DSMB if required). We will inquire about potential 
manifestations of rhabdomyolysis (particularly hemoglobinuria) in all data collection forms and the 
study medication will be discontinued immediately upon suspected or confirmed rhabdomyolysis.  
Fenofibrate can increase serum transaminases and/or serum creatinine and periodic 
monitoring is recommended during chronic therapy. However, we will only utilize it for 10 days in 
this trial and will exclude patients with active liver disease or advanced renal disease. Therefore, 
the need for periodic monitoring does not apply for such as short treatment. Moreover, the mild 
increase in serum creatinine is not thought to be due to impaired true glomerular function, as 
measured by inulin clearance, the gold standard measure of renal function. This creatinine rise 
does not increase the risk of adverse renal outcomes or cardiovascular events, and is fully 
reversible upon discontinuation.66 
Fenofibrate increases cholesterol excretion into the bile, leading to risk of cholelithiasis. 
This is not anticipated to be a problem with 10 days of therapy, and our trial will exclude patients 
with a history of gallbladder disease. As recommended by the approved prescribing information, 
we will also exclude nursing mothers, and patients with known hypersensitivity to fenofibrate or 
fenofibric acid.   
Fenofibrate can also rarely cause allergic reactions and mild to moderate changes in blood 
cell counts. Pancreatitis has been observed (in post-marketing case reports) in people taking 
fenofibrate for dyslipidemia, but is an extremely rare occurrence. Of note, the overwhelming 
majority of these reports involved patients who had other, more strongly associated risk factors 
for acute pancreatitis and it is unclear whether and to what degree was fenofibrate causally 
involved.67,68 Moreover, the incidence of pancreatitis has been estimated to be very low (0.13 
per 100 patient years on monotherapy and 0.16 per 100 patient years in combination with a 
statin) and such a complication is extremely unlikely with 10 days of therapy. 68 
 
Drugs that exhibit significant interactions with fenofibrate include coumarin anticoagulants, 
immunosuppresants and glimepiride. We will exclude patients taking these medications. 
 
8.3. Adequacy of Protection Against Risks 
8.3.1. Recruitment and Informed Consent:  
Electronic informed consent will be obtained from the subjects or their authorized representatives 
prior to entry into the research study. Potential subjects will receive the IRB approved informed 
consent form in person or electronically to minimize risk of exposure to SARS-CoV-2. The 
principal investigator or sub-investigators will conduct the informed consent process in person, or 
via phone or video conferencing, which maximizes the efficiency of workflow and minimizes 
exposure of the research staff to SARS-CoV-2. When a physical ICF is utilized, for safety reasons, 
the copy of the physical ICF will not be retrieved from the patient’s room or hospital area, and only 
a photograph of the signed page of the informed consent form will be kept in the electronic 
regulatory files.  
The study intervention and potential associated risks will be explained to study subjects 
and they will have adequate time to ask questions. No study interventions will be initiated until the 
study team receives either the signed informed consent form or attestation documenting the 
subjects’ agreement to participate.  
 
8.3.2 Measures to minimize the risk of breach in confidentiality: All records will be treated 
with strict confidentiality according to guidelines and regulations related to Sensitive Patient 
Health Information in respective countries. Our eCRFs will be contained in secure servers at the 
University of Pennsylvania.  A secure database of patient information will be maintained. All 

 
FERMIN trial 
documents for this trial will be electronic, but any unanticipated paper files that contain protected 
health information will be saved under lock in a secure area.   
 
 
9. REGULATORY STANDARDS 
The study will be submitted to the site’s IRB/EC for approval. During the study, any amendment 
or modification to the protocol will be sent to the IRB/EC. Protocol deviations will be handled 
according to Institutional guidelines. In each country, the National Principal Investigator will lead 
and hold responsibility for federal regulatory processes. All site PIs will be responsible for 
obtaining IRB/research ethics committee approval from their respective boards and to comply 
with their national and institutional regulations. 
 
 
10. 
ADAPTIVE DESIGN 
 
The trial, including any interim safety and efficacy analyses, will be monitored by an independent 
DSMB. The DSMB will have the capacity to recommend termination of enrollment based on new 
available evidence of interim data analyses, as detailed in our DSMB charter. If the trial is 
terminated prematurely for any reason, follow-up will continue for all randomized participants.  
An increase in the sample size will be considered depending on feasibility and pace of enrollment, 
to enhance the power of the study for secondary endpoints. New trial arms can be added as 
evidence emerges that other candidate therapeutics should be evaluated. Any modification to the 
protocol will require approval by applicable institutional review boards/Ethics committees at 
enrollment sites, as well as applicable regulatory agencies in each enrollment country.  
 
 

 
FERMIN trial 
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patients with gout. Sci Rep. 2018;8(1):16767. 
64. 
Khanna PP. Gout: a patrician malady no more. Lancet Diabetes Endocrinol. 
2018;6(4):263-264. 
65. 
Waldman B, Ansquer JC, Sullivan DR, et al. Effect of fenofibrate on uric acid and gout in 
type 2 diabetes: a post-hoc analysis of the randomised, controlled FIELD study. Lancet 
Diabetes Endocrinol. 2018;6(4):310-318. 
66. 
Ting R-D, Keech A. Fenofibrate and renal disease: clinical effects in diabetes. Clinical 
Lipidology. 2013;8(6):669-680. 
67. 
McDonald KB, Garber BG, Perreault MM. Pancreatitis associated with simvastatin plus 
fenofibrate. Ann Pharmacother. 2002;36(2):275-279. 
68. 
Enger 
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Pharmacoepidemiology safety study of fibrate and statin concomitant therapy. Am J 
Cardiol. 2010;106(11):1594-1601. 

 
FERMIN trial 
APPENDIX 1. DYSPNEA BORG SCALE AND COVID-19 SYMPTOM SCALE 
 
“This is a scale that asks you to rate the difficulty of your breathing. It starts at number 0 where 
your breathing is causing you no difficulty at all and progresses through to number 10 where 
your breathing difficulty is maximal. How much difficulty is your breathing causing you with your 
usual activities today?”  
 
 
COVID-19 Symptom scale 
 
Rate each of the following symptoms from 0-10 (scale similar to the one above) 
Fever or Chills 
Cough  
Muscle or body aches 
Sore throat 
Loss of smell or taste 
Headache 
Diarrhea  
Fatigue 
Nausea or vomiting 
Chest pain or discomfort 
 
All scores for individual symptoms (including dyspnea, as per the dyspnea Borg scale) are 
added to compute the final score. 
 
 

 
FERMIN trial 
APPENDIX 2. SCHEDULE OF EVENTS 
 
 
 
At 
Enrollment 
Daily 
During 
admission 
~5 days 
post-
enrollment 
~10 days 
post-
enrollment 
~15 days 
post-
enrollment  
~30 days 
post-
enrollment 
All participants 
 
 
 
 
 
 
Screening for Inclusion 
eCRF 
X 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
Randomization 
X 
 
 
 
 
 
Baseline Medical 
Information eCRF 
X 
 
 
 
 
 
Inpatients 
 
 
 
 
 
 
Daily Inpatient Information 
eCRF 
 
X 
 
 
 
 
Follow-up call eCRF 
 
 
 
 
 
X 
Outpatients 
 
 
 
 
 
 
Follow-up call eCRF  
 
 
X 
X 
X 
X 
 
Adverse Event Forms, deviation event logs and withdrawal forms will be filled at any time 
during the study, as needed.  
 
 
 

 
FERMIN trial 
APPENDIX 3. COUNTRY-SPECIFIC FENOFIBRATE PREPARATION, INFORMED CONSENT 
MECHANISM AND REGULATORY ISSUES 
 
 
NOTE: This appendix varies in each country according to various factors in each country, 
including the fenofibrate preparation utilized and applicable regulatory requirements in a given 
country. Only information about the preparation that applies to each country will be submitted for 
review and regulatory approval in the respective country. 
 
UNITED STATES:  
 
 
Fenofibrate preparation and dosing 
In the US, the drug and placebo will be prepared (encapsulated) by the Penn Investigational Drug 
Pharmacy. It will be shipped to IDS services in other enrollment sites. Administration will be 
double-blinded (Investigators and patient).  
 
We will utilize Tricor tablets. The dose will be 145 mg/day with appropriate dose correction for 
patients with chronic kidney disease (CKD). The daily dose of Tricor for patients with CKD stage 
2 will be 96 mg/d and the dose for CKD stage 3 will be 48 mg/d. In all cases, the intended duration 
of randomized treatment will be for 10 days.  
 
The medication will be administered by mouth regardless of meals; in patients who are intubated, 
we will administer the crushed tablet (or placebo) via nasogastric tube. The latter procedure 
requires opening the capsule and therefore unblinds the administering nurse, which is acceptable, 
since in that setting (once the patient is intubated), subjective endpoints do not influence the study 
primary (only time to death and days of mechanical ventilation do, in tiers 1 and 2). The same is 
true for all secondary outcomes. Moreover, the patient and investigator will remain blinded. We 
have considered the alternative of preparing a blinded solution of active medication vs. placebo 
by IDS to be sent to the floor for administration via NG tube; however, we lack reliable data 
regarding the stability of the medication in solution at ambient temperature for various periods of 
time. Therefore, we have opted against this option. 
 
Baseline evaluation 
In addition to documentation of SARSCoV  infection, baseline laboratory test should include at a 
mininum, a creatinine level for assessment of eGFR (to determine the appropriate medication 
dose). These are done routinely as part of clinical care at Penn (Emergency room visits or 
inpatient assessments). We will also consider outpatients who reach out to us as a result of 
advertisements. If these participants have already had these tests elsewhere (i.e., other medical 
facilities), we will accept documentation of such tests. Otherwise, we will invite outpatient patients 
to the Center for Human Phenomics Sciences to undergo any necessary tests as per protocol.  
 
Consent mechanism 
To avoid exposure of the research team, we will perform verbal consent of study subjects. 
Potentially interested participants will receive an electronic version (in PDF format) of the 
combined ICF/HIPAA authorization form via email or other method of their choice. After they have 
had an opportunity to read it, we will finalize the consent process over the phone, including an 
opportunity to clear any doubts/questions about the protocol. At that point, if patients decide to 
participate, we will invite a witness to record the verbal consent. The study team will document 
the consent process in writing. Participants will also fill a brief RedCap survey (using their unique 
4-digit ID provided by the team) further documenting their consent. An example is shown below. 
Alternatively, patients may print the consent form at home, sign it and send us a digital photograph 

 
FERMIN trial 
of the last page. The latter mechanism will likely be used predominantly for outpatients. Consent 
by legally authorized patient representatives will be allowed. 
 
 
 
 
 
 

 
FERMIN trial 
APPENDIX 4. Investigators, Steering Committee Members, Center Investigators, Project 
Manager and DSMB Members 
 
 
National Principal Investigators  
(to be modified with trial progress as needed, without the need for IRB review) 
Julio A. Chirinos, MD, PhD (National PI, USA; U. of Pennsylvania) 
Mario Cornejo Giraldo, MD (National PI, Perú; U. Católica de Santa María, Arequipa, Perú) 
Patricio López-Jaramillo, MD (Investigador Principal Nacional, Colombia. U. de Santander; 
Bucaramanga, Colombia) 
Dr. Jaime Andrade Villanueva (National PI Universidad de Guadalajara, Méjico) 
Evangelos Giamarellos, MD, PhD (National PI, Greece; Attikon University Hospital, Athens, 
Greece) 
 
Steering Committee Members  
(to be modified with trial progress as needed, without the need for IRB review) 
Julio A. Chirinos, MD, PhD (U. of  Pennsylvania, Chair) 
Jordana Cohen, MD, MSCE (U. of Pennsylvania) 
Nancy Sweitzer (University of Arizona) 
Juan Ortega Legaspi (U. of Pennsylvania) 
Patricio López-Jaramillo, MD (Universidad de Santander, Colombia. National PI, Colombia) 
Gonzalo Dávila Del Carpio, DSc (Universidad Católica de Santa María, Arequipa, Perú) 
Mario P. Cornejo Giraldo, MD (EsSalud, Arequipa, Perú) 
Nelson Ramiro Rosado Santander, MD (EsSalud, Arequipa, Perú) 
Dr. Jaime Andrade Villanueva (Universidad de Guadalajara, Méjico) 
Juan Rodriguez Mori (EsSalud, Lima; Perú) 
Carola Medina (EsSalud; Lima; Perú) 
Maria Cruz Saldarriaga (EsSalud; Cusco, Perú) 
Rosa Cotrina Pereyra (EsSalud, Lima; Perú) 
Evangelos Giamarellos, MD, PhD (Attikon University Hospital, Greece) 
 
Data Coordinating Center:   
Jordana Cohen, MD, MSCE 
Jesse Chittams, MSc 
 
Center Principal Investigators (A file with a list of Study Center PIs in each country will be 
kept separately) 
 
 
Project Manager (UPenn): Sharkoski, Tiffany 
 
Data Safety Monitoring Board: 
John Younger, MD 
Salim Virani, MD 
Michael Campos, MD 
Todd A. Miano, PharmD, PhD 
Version Control (Summary of Changes) 
 
 
 

 
FERMIN trial 
V2 (August 15th, 2020):  
 
- 
Fixed typo, in which one component of the primary endpoint (FiO2/SpO2 ratio area under 
the curve) was incorrectly specified to be ranked from lowest to highest (the correct 
ranking is from highest to lowest). 
- 
Fixed some typos throughout. 
- 
Eliminated possible open label administration.  
- 
Deleted mention of interim analysis at 75% enrollment (only one interim analysis, at 50% 
enrollment, is planned). 
- 
Added mention of possibility of consent by the subject’s authorized representative. 
- 
Corrected time points in Figure 2 according to protocol text. 
- 
Added sensitivity analysis with normalization for effect of athmospheric pressure on FiO2 
above sea level. 
- 
In order to have a universal main protocol while facilitating regulatory review/approval for 
countries outside the US, we have: 
o Eliminated specific mention to the preparation that will be used in the main 
protocol, and have placed it in Appendix 3 (Fenofibrate prescribing information).  
o We have also specified the consent process specific to the US in Appendix 3. 
o Other country-specific regulatory requirements (particularly for countries outside 
the US) will be specified in appendix 3 as needed, when IRB and other regulatory 
submissions are prepared within a specific country. 
 
V3 (November 10th, 2020) 
 
- 
Added exclusion criteria of intubated patients. 
- 
Added possibility of participation for patients on pravastatin or rosuvastatin. 
- 
Added that patients discharged within 24 hours of enrollment will be ranked as 
outpatients. 
- 
Update of National Leaders (addition of new countries) 
- 
Replaced Dr. Heresi with Dr. Campos in DSMB (due to the fact that Dr. Heresi declared 
a  COI). 
 
V4 (January 10th, 2021) 
- 
Eliminated possibility of single blinding administration, since with new grant support, full 
blinding (patient, investigator and adjudicator for symptom questionnaire) can be 
successfully implemented and mandated at all sites. Of note, no patient has been 
enrolled in single-label administration. Therefore, the entire trial will be double-blinded. 
- 
Added fenofibric acid as a dose-equivalent preparation (which will be used in Colombia). 
- 
Changed the number of participants enrolled to 700 and added power calculations for 
primary and secondary outcomes. 
- 
Specified the exclusion of uncontrolled hypothyroidism, allowing enrollment of patients 
receiving a stable dose of thyroid replacement therapy for at least 6 weeks, with a 
documented normal TSH (primary hyperthyroidism) or free thyroxine (secondary or 
tertiary hypothyroidism) level at least 6 weeks after the last dose change. This is 
because concerns of thyroid myopathy (due to genetic/metabolic effects of thyroid 
deficiency on skeletal muscle) do not apply to patients who are on adequate thyroid 
replacement therapy.  
 
V5 (November 2021) 

 
FERMIN trial 
- 
Included the possibility of enrolling patients from outside of PennMedicine who reach out 
to us as a result of advertisements. In these instances, it may be necessary to perform 
laboratory testing through the Center for Human Phenomics Sciences.