FEnofibRate as a Metabolic INtervention for COVID-19

Study Overview
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Brief Summary
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The severe acute respiratory syndrome coronavirus 2 (SARS-CoC-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 dyslipemias) 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 (145 mg/d of Tricor or dose-equivalent preparations for 10 days, with dose adjustment in chronic kidney disease ([CKD]) to improve clinical outcomes in patients with COVID-19.

Official Title
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FEnofibRate as a Metabolic INtervention for Coronavirus Disease 2019

Conditions
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Covid19

Intervention / Treatment
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* Other: Fenofibrate/fenofibric acid
* Other: Placebo
* Other: Usual care


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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 compatible pulmonary infiltrates on chest x-ray (bilateral, intersticial or ground glass opacities) or chest CT. Able to provide informed consent. Fewer than 14 days since symptom onset. Exclusion Criteria: Known pregnancy or breastfeeding Estimated glomerular filtration rate (eGFR) <30 mL/min/1.73m2 or undergoing dialysis (CKD stages 4-5). 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. Known hypersensitivity to fenofibrate or fenofibric acid. Ongoing treatment with fenofibrate, clofibrate, warfarin and other coumarin anticoagulants, glimepiride, cyclosporine, tacrolimus Use of statins other than simvastatin, pravastatin or atorvastatin ≤40 mg/d or rosuvastatin ≤20 mg/d Prisoners/incarcerated individuals Inability to read, write or no access to a smart phone, computer or tablet device Intubated patients.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Fenofibrate + Usual Care<br>The randomized intervention will be Fenofibrate, in combination with usual care. Dosing: 145 mg of Tricor or a dose-equivalent preparation | Other: Fenofibrate/fenofibric acid<br>* The randomized intervention will be fenofibrate (Tricor) at a dose of 145 mg/d or dose-equivalent preparation of fenofibrate or fenofibric acid, for 10 days. In all cases, appropriate dose reductions will be implemented for patients with chronic kidney disease as per the approved preparation label. The intended duration of randomized treatment will be for 10 days.<br>Other: Usual care<br>* All participants will otherwise receive usual medical care<br>|
| Placebo Comparator: Placebo + Usual Care<br>The randomized intervention will a matching placebo, in combination with usual care. | Other: Placebo<br>* The control intervention will be a placebo, for 10 days.<br>Other: Usual care<br>* All participants will otherwise receive usual medical care<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Primary Hierarchical Composite Endpoint | The primary endpoint of the trial is a global rank score that ranks patient outcomes according to 5 factors. The global rank score, or global severity score, is a nonparametric, hierarchically ranked outcome. The global rank score was generated by ranking all 701 participants on a scale of 1 to 701, from worst to best clinical outcomes. Participants were ranked by (1) time to death; (2) the number of days supported by invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO); (3) The inspired concentration of oxygen/percent oxygen saturation (FiO2/SpO2) ratio area under the curve; (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; (5) For participants enrolled as outpatients who don't get hospitalized during the 30-day observation period, the modified Borg dyspnea scale | 30 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Days Alive, Out of the Intensive Care Unit, Free of Mechanical Ventilation/Extracorporeal Membrane Oxygenation, or Maximal Available Respiratory Support in the 30 Days Following Randomization | Number of days participants were alive, out of the intensive care unit, free of mechanical ventilation/extracorporeal membrane oxygenation, or maximal available respiratory support during the 30 days that followed randomization | Up to 30 days | 
| Seven-category Ordinal Scale | 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. | At 15 days | 
| Secondary Hierarchical Composite Endpoint | The secondary global rank score, or global severity score, is a nonparametric, hierarchically ranked outcome. The global rank score was generated by ranking all 701 participants on a scale of 1 to 701, from worst to best clinical outcomes. Participants were ranked by (1) time to death; (2) the number of days supported by invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO); (3) The inspired concentration of oxygen/percent oxygen saturation (FiO2/SpO2) ratio area under the curve; (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; (5) For participants enrolled as outpatients who don't get hospitalized during the 30-day observation period, a COVID-19 symptom scale rating fever, cough, dyspnea, muscle aches, sore throat, loss of smell or taste, headache, diarrhea, fatigue, nausea/vomiting, chest pain (each are rated from 0-10 then summed). | Up to 30 days |