Covid19
Conditions
Brief summary
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.
Interventions
OTHERFenofibrate/fenofibric acid
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.
OTHERPlacebo
The control intervention will be a placebo, for 10 days.
OTHERUsual care
All participants will otherwise receive usual medical care
Sponsors
University of Arizona
Universidad Católica de Santa María
Hospital Nacional Adolfo Guevara Velasco
Hospital Nacional Edgardo Rebagliati Martins
Hospital Nacional Alberto Sabogal Sologuren
Hospital Nacional Guillermo Almenara Irigoyen
Hospital Nacional Carlos Alberto Seguin Escobedo - EsSalud
Universidad de Santander
National Center for Advancing Translational Sciences (NCATS)
Hospital Civil de Guadalajara
Hospital Nacional Dos De Mayo
Hospital Central Fuerza Aérea del Perú
Hospital Militar Central.Coronel Luis Arias Schereiber
Hospital Victor Lazarte Echegaray
University Hospital, Ioannina
AHEPA University Hospital
Sotiria Thoracic Diseases Hospital of Athens
Thriasio General Hospital of Elefsina
University Hospital, Alexandroupolis
G.Gennimatas General Hospital
Biomelab S.A.S.
Fundación Oftalmológica de Santander. Santander, Colombia
IPS Centro Científico Asistencial. Barranquilla, Colombia
Fundación Cardiomet. Quindio, Colombia
ClÍnica de Marly
Clínica Internacional
University of Pennsylvania
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Primary Hierarchical Composite Endpoint | 30 days | 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 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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 | Up to 30 days | 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 |
| Seven-category Ordinal Scale | At 15 days | 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. |
| Secondary Hierarchical Composite Endpoint | Up to 30 days | 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). |
Other
| Measure | Time frame | Description |
|---|---|---|
| Number of Days Alive and Out of the Hospital During the 30 Days Following Randomization | Up to 30 days | Number of days that participants were alive and out of the hospital during the 30 days following randomization |
| Exploratory Hierarchical Composite Endpoint | Up to 30 days | The exploratory 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) The number of days out of the hospital during the 30 day-period following randomization. |
| All-Cause Death | Up to 30 days | Death from any cause during the observation period |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Fenofibrate + Usual Care The randomized intervention will be Fenofibrate, in combination with usual care. Dosing: 145 mg of Tricor or a dose-equivalent preparation
Fenofibrate/fenofibric acid: 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.
Usual care: All participants will otherwise receive usual medical care | 351 |
| Placebo + Usual Care The randomized intervention will a matching placebo, in combination with usual care.
Placebo: The control intervention will be a placebo, for 10 days.
Usual care: All participants will otherwise receive usual medical care | 350 |
| Total | 701 |
Baseline characteristics
| Characteristic | Fenofibrate + Usual Care | Total | Placebo + Usual Care |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 58 Participants | 119 Participants | 61 Participants |
| Age, Categorical Between 18 and 65 years | 293 Participants | 582 Participants | 289 Participants |
| Borg Scale | 2.6 units on a scale STANDARD_DEVIATION 2.8 | 2.7 units on a scale STANDARD_DEVIATION 3 | 2.9 units on a scale STANDARD_DEVIATION 3.1 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 173 Participants | 350 Participants | 177 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 178 Participants | 351 Participants | 173 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 2 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 3 Participants | 3 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 24 Participants | 49 Participants | 25 Participants |
| Race (NIH/OMB) More than one race | 133 Participants | 267 Participants | 134 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 21 Participants | 41 Participants | 20 Participants |
| Race (NIH/OMB) White | 168 Participants | 338 Participants | 170 Participants |
| Region of Enrollment Colombia | 79 participants | 156 participants | 77 participants |
| Region of Enrollment Greece | 67 participants | 133 participants | 66 participants |
| Region of Enrollment Lebanon | 56 participants | 113 participants | 57 participants |
| Region of Enrollment Mexico | 34 participants | 67 participants | 33 participants |
| Region of Enrollment Peru | 58 participants | 116 participants | 58 participants |
| Region of Enrollment United States | 57 participants | 116 participants | 59 participants |
| Sex: Female, Male Female | 164 Participants | 330 Participants | 166 Participants |
| Sex: Female, Male Male | 187 Participants | 371 Participants | 184 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 19 / 351 | 22 / 350 |
| other Total, other adverse events | 74 / 351 | 55 / 350 |
| serious Total, serious adverse events | 46 / 351 | 61 / 350 |
Outcome results
Primary
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
Time frame: 30 days
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Fenofibrate + Usual Care | Primary Hierarchical Composite Endpoint | 5.32 Ranked Severity Score |
| Placebo + Usual Care | Primary Hierarchical Composite Endpoint | 5.33 Ranked Severity Score |
Secondary
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
Time frame: Up to 30 days
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Fenofibrate + Usual Care | 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 | 28.8 days | Standard Deviation 4.9 |
| Placebo + Usual Care | 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 | 28.3 days | Standard Deviation 6.1 |
Secondary
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).
Time frame: Up to 30 days
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Fenofibrate + Usual Care | Secondary Hierarchical Composite Endpoint | 5.05 score on a scale |
| Placebo + Usual Care | Secondary Hierarchical Composite Endpoint | 5.05 score on a scale |
Secondary
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.
Time frame: At 15 days
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Fenofibrate + Usual Care | Seven-category Ordinal Scale | 1 score on a scale |
| Placebo + Usual Care | Seven-category Ordinal Scale | 1 score on a scale |
Other Pre-specified
All-Cause Death
Death from any cause during the observation period
Time frame: Up to 30 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Fenofibrate + Usual Care | All-Cause Death | 19 Participants |
| Placebo + Usual Care | All-Cause Death | 22 Participants |
Other Pre-specified
Exploratory Hierarchical Composite Endpoint
The exploratory 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) The number of days out of the hospital during the 30 day-period following randomization.
Time frame: Up to 30 days
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Fenofibrate + Usual Care | Exploratory Hierarchical Composite Endpoint | 5.03 score on a scale |
| Placebo + Usual Care | Exploratory Hierarchical Composite Endpoint | 5.03 score on a scale |
Other Pre-specified
Number of Days Alive and Out of the Hospital During the 30 Days Following Randomization
Number of days that participants were alive and out of the hospital during the 30 days following randomization
Time frame: Up to 30 days
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Fenofibrate + Usual Care | Number of Days Alive and Out of the Hospital During the 30 Days Following Randomization | 30 days |
| Placebo + Usual Care | Number of Days Alive and Out of the Hospital During the 30 Days Following Randomization | 30 days |