Fenofibrate for Patients With COVID-19 Requiring Hospitalization

Phase 3

• Conditions: Respiratory Distress Syndrome; SARS-CoV-2 Infection; Corona Virus Disease (COVID-19)
• Interventions: Drug: TriCor® 145mg tablets; Other: Placebo; Other: Usual care

• Registration Number: NCT04661930
• Lead Sponsor: Yaakov Nahmias

Brief Summary

This is an open-label run-in followed by a randomized, double-blind drug treatment study of COVID-19 infected patients requiring inpatient hospital admission.

Detailed Description

This is an open-label run-in followed by a randomized, double-blind drug treatment study of COVID-19 infected patients requiring inpatient hospital admission. Open-label patients will be matched at least 1:10 with observational retrospective Propensity score-matched (PSM) patients' medical files. The double-blinded step will be randomized 2:1 to daily Fenofibrate or placebo for 10 days or hospital discharge.

Study Timeline

• Study First Submitted: 2020-12-09
• Study First Submitted QC: 2020-12-09
• Study First Posted: 2020-12-10
• Study Start: 2021-01-01
• Status Verified: 2022-04
• Last Update Submitted: 2022-04-17
• Last Update Posted: 2022-04-19
• Primary Completion: 2022-05-01
• Study Completion: 2022-07-01

Recruitment & Eligibility

• Status: UNKNOWN
• Sex: All
• Target Recruitment: 55

Inclusion Criteria

• Presumptive positive laboratory test for SARS-CoV-2 based on local laboratory standard

• Age greater than or equal to 18 years of age

• Severe COVID-19, defined by:

  • A disease severity score of 3 (Hospitalized, on non-invasive ventilation or high flow oxygen devices) to 4 (Hospitalized, requiring supplemental oxygen).

AND o A respiratory SOFA >=1 and increased oxygen requirement compared to baseline among those on home O2, a blood oxygen saturation of 93% or less on room air, a ratio of the partial pressure of oxygen to the fraction of inspired oxygen (PaO2/FiO2) of less than 300 mm Hg, respiratory rate >30 breaths/min, or lung infiltrates >50% on chest CT

• Enrollment within 72 hours of presentation of hospital admission or within 72 hours of a positive test result, whichever is later

Exclusion Criteria

• Enrollment > 72 hours of admission order or positive test result, whichever is later

• Admission to the hospital with a respiratory SOFA >=5 , Critical COVID-19, or Disease Severity Score >5 (requiring extracorporeal membrane oxygenation (ECMO), invasive mechanical ventilation, or all)

• Known hypersensitivity to fenofibrate

• For female subjects:

  1. Pregenant, determined by a human chorionic gonadotropin (HCG) rapid detection kit or a blood test
  2. Breastfeeding
  3. Undergoing fertility treatments

• Patient-reported history or electronic medical record history of kidney disease, defined as:

  1. Any history of dialysis
  2. History of chronic kidney disease stage IV
  3. Estimated Glomerular Filtration Rate (eGFR) of < 30ml/min/1.73 m2 at the time of enrollment

• Acute pre-renal azotemia at the time of enrollment in the opinion of the investigator or bedside clinician

• Most recent mean arterial blood pressure prior to enrollment <65 mmHg

• Patient-reported history or electronic medical record history of severe liver disease, defined as:

  1. Cirrhosis
  2. History of hepatitis B or C
  3. Documented AST or ALT > 10 times the upper limit of normal measured within 24 hours prior to enrollment

• Patient-reported history or electronic medical record history of gallbladder disease

• Potassium >5.0 within 24 hours prior to enrollment unless a repeat value was <=5.0

• Treatment with coumarin anticoagulants (e.g., Warfarin), immunosuppressants (e.g. cisplatin), bile acid resins, or sulfonylurea.

• Inability to obtain informed consent from participant or legally authorized representative

• Enrollment in another blinded randomized clinical trial for COVID

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Fenofibrate + Usual Care	TriCor® 145mg tablets	Participants in this arm will receive the study drug, Fenofibrate, in combination with usual care.
Fenofibrate + Usual Care	Usual care	Participants in this arm will receive the study drug, Fenofibrate, in combination with usual care.
Placebo + Usual Care	Placebo	Participants in this arm will receive placebo treatment, in combination with usual care.
Placebo + Usual Care	Usual care	Participants in this arm will receive placebo treatment, in combination with usual care.

Primary Outcome Measures

Name	Time	Method
Length of Hospital Stay	14 days	Outcome reported as the mean length of in-patient hospital stay (in days) for participants in each arm
Difference in Plasma Monocytes at 14 days	14 days	Blood will be collected every second day for the duration of study participation. Difference will be calculated based on the first measurement after admission to the study.
Viral Clearance by Nasopharyngeal Swab	14 days	Nasopharyngeal swabs will be collected every second day for the duration of study participation. Viral clearance is measured as fold change in viral genetic copies per mL
Difference in Estimated P/F Ratio at 14 days	14 days	Outcome calculated from the partial pressure of oxygen or peripheral saturation of oxygen by pulse oximetry divided by the fraction of inspired oxygen (PaO2 or SaO2 : FiO2 ratio). PaO2 is preferentially used if available.
Number of Therapeutic Oxygen-Free Days	14 days	Outcome reported as the mean number of days participants in each arm did not require therapeutic oxygen usage during an in-patient hospital admission.
Difference in Plasma Neutrophils at 14 days	14 days	Blood will be collected every second day for the duration of study participation. Difference will be calculated based on the first measurement after admission to the study.
Difference in Plasma Lymphocytes at 14 days	14 days	Blood will be collected every second day for the duration of study participation. Difference will be calculated based on the first measurement after admission to the study.
Difference in Plasma Procalcitonin (PCT) at 14 days	14 days	Blood will be collected every second day for the duration of study participation. Difference will be calculated based on the first measurement after admission to the study.
Difference in Plasma C-Reactive Protein (CRP) at 14 days	14 days	Blood will be collected every second day for the duration of study participation. Difference will be calculated based on the first measurement after admission to the study.
Difference in Plasma IL-6 at 14 days	14 days	Blood will be collected every second day for the duration of study participation. Difference will be calculated based on the first measurement after admission to the study.
Difference in Plasma Ferritin at 14 days	14 days	Blood will be collected every second day for the duration of study participation. Difference will be calculated based on the first measurement after admission to the study.
Difference in NLR (Neutrophils to Lymphocytes Ratio) at 14 days	14 days	Blood will be collected every second day for the duration of study participation. Difference will be calculated based on the first measurement after admission to the study.

Secondary Outcome Measures

Name	Time	Method
Number of Abnormal Biomarker Days - Alanine Aminotransferase (ALT)	14 days	Outcome reported as the mean number of days participants in each arm had abnormal plasma levels.
Difference in Organ Injury Plasma markers at 14 days - D-dimer	14 days	Blood will be collected every second day for the duration of study participation. Difference will be calculated based on the first measurement after admission to the study.
14-Day Mortality	14 days	Outcome reported as the number of participants who have expired at 14 days post enrollment.
Difference in Organ Injury Plasma markers at 14 days - Platelets (PLT)	14 days	Blood will be collected every second day for the duration of study participation. Difference will be calculated based on the first measurement after admission to the study.
Number of Abnormal Biomarker Days - Monocytes	14 days	Outcome reported as the mean number of days participants in each arm had abnormal plasma levels.
Number of Abnormal Biomarker Days - Lactate	14 days	Outcome reported as the mean number of days participants in each arm had abnormal plasma levels.
Number of Abnormal Biomarker Days - Alkaline Phosphatase (ALP)	14 days	Outcome reported as the mean number of days participants in each arm had abnormal plasma levels.
Difference in Organ Injury Plasma markers at 14 days - Lactate	14 days	Blood will be collected every second day for the duration of study participation. Difference will be calculated based on the first measurement after admission to the study.
Difference in Organ Injury Plasma markers at 14 days - Cardiac Troponin (TRO)	14 days	Blood will be collected every second day for the duration of study participation. Difference will be calculated based on the first measurement after admission to the study.
Number of Abnormal Biomarker Days - Lymphocytes	14 days	Outcome reported as the mean number of days participants in each arm had abnormal plasma levels.
Number of Abnormal Biomarker Days - C-Reactive Protein (CRP)	14 days	Outcome reported as the mean number of days participants in each arm had abnormal plasma levels.
Number of Abnormal Biomarker Days - Procalcitonin (PCT)	14 days	Outcome reported as the mean number of days participants in each arm had abnormal plasma levels.
Difference in Organ Injury Plasma markers at 14 days - Creatine Kinase (CK)	14 days	Blood will be collected every second day for the duration of study participation. Difference will be calculated based on the first measurement after admission to the study.
Difference in Organ Injury Plasma markers at 14 days - Alanine Aminotransferase (ALT)	14 days	Blood will be collected every second day for the duration of study participation. Difference will be calculated based on the first measurement after admission to the study.
Difference in Organ Injury Plasma markers at 14 days - Alkaline Phosphatase (ALP)	14 days	Blood will be collected every second day for the duration of study participation. Difference will be calculated based on the first measurement after admission to the study.
Hypotension Requiring Vasopressors	14 days	Outcome reported as the number of participants in each arm requiring the use of vasopressors for hypotension.
Number of Abnormal Biomarker Days - D-dimer	14 days	Outcome reported as the mean number of days participants in each arm had abnormal plasma levels.
Number of Abnormal Biomarker Days - Neutrophils	14 days	Outcome reported as the mean number of days participants in each arm had abnormal plasma levels.
Number of Abnormal Biomarker Days - Platelets (PLT)	14 days	Outcome reported as the mean number of days participants in each arm had abnormal plasma levels.
Number of Abnormal Biomarker Days - IL-6	14 days	Outcome reported as the mean number of days participants in each arm had 2 or more abnormal plasma levels.
Number of Abnormal Biomarker Days - Cardiac Troponin (TRO)	14 days	Outcome reported as the mean number of days participants in each arm had abnormal plasma levels.
Number of Abnormal Biomarker Days - Creatine Kinase (CK)	14 days	Outcome reported as the mean number of days participants in each arm had abnormal plasma levels.
Number of Abnormal Biomarker Days - Ferritin	14 days	Outcome reported as the mean number of days participants in each arm had abnormal plasma levels.
Difference in Oxygenation at 14 days	14 days	PaO2 or SaO2 and FiO2. Partial pressure of oxygen or peripheral saturation of oxygen by pulse oximetry. FiO₂ is estimated from oxygen flow/delivery rates
Difference in Estimated PEEP adjusted P/F Ratio at 14 days	14 days	Outcome calculated from the partial pressure of oxygen or peripheral saturation of oxygen by pulse oximetry divided by the fraction of inspired oxygen (PaO2 or SaO2 : FiO2 ratio) and Expiratory Pressure.
Daily Hypotensive Episodes	14 days	Outcome reported as the mean number of daily hypotensive episodes (MAP \< 65 mmHg) prompting intervention (indicated by a fluid bolus \>=500 mL, new treatment with pressures, increase in 50% pressure or fluid rate) per participant in each arm.
Acute Kidney Injury	14 days	Outcome reported as the number of participants in each arm who experience acute kidney injury as defined by the Kidney Disease Improving Global Outcomes (KDIGO) guidelines: Increase in serum creatinine by 0.3mg/dL or more within 48 hours OR Increase in serum creatinine to 1.5 times baseline or more within the last 7 days OR Urine output less than 0.5 mL/kg/h for 6 hours.
Change in PROMIS Dyspnea Severity	14 days	The PROMIS Dyspnea (shortness of breath) item banks and pools assess self-reported Functional Limitations, Severity, Activity Motivation, Activity Requirements, Airborne Exposure, Assistant Devices Resources, Characteristics, Emotional Response, Task Avoidance and Time Extension as they related to dyspnea. The 33-item Severity bank assesses the severity of difficulty breathing during various specific activities (the same 33 activities assessed in Dyspnea Functional Limitations). Each activity is rated in terms of degree of dyspnea (0 = no shortness of breath, 1 = mildly short of breath, 2 = moderately short of breath, 3 = severely short of breath) while engaging in the activity over the past 7 days. Total scores range from 0 to 99 with higher scores reflecting greater levels of dyspnea during daily activity.
Disease Severity Rating	14 days	Outcome reported as the number of participants in each arm who fall into each of 7 categories. Lower scores indicate greater condition severity. The ordinal scale is an assessment of the clinical status at the first assessment of a given study day. The scale is as follows: 1) Death; 2) Hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO); 3) Hospitalized, on non-invasive ventilation or high flow oxygen devices; 4) Hospitalized, requiring supplemental oxygen; 5) Hospitalized, not requiring supplemental oxygen; 6) Not hospitalized, limitation on activities; 7) Not hospitalized, no limitations on activities.
Viral Load by Nasopharyngeal Swab	14 days	Nasopharyngeal swabs will be collected every fourth day for the duration of study participation. Viral load is measured as number of viral genetic copies per mL.
Viral Load by Blood	14 days	Blood will be collected every third day for viral load assessment for the duration of study participation. Viral load is measured as number of viral genetic copies per mL.
Sequential Organ Failure Assessment (SOFA) Total Score	14 days	The SOFA assessment is used to track a person's risk status during stay in the Intensive Care Unit (ICU). The score is based on six different scores, one each for the respiratory, cardiovascular, hepatic, coagulation, renal, and neurological systems. Each organ system is assigned a point value from 0 (normal) to 4 (high degree of dysfunction/failure). Total score is calculated by entering patient data into a SOFA calculator, a widely available software. Total scores range from 0-24, with higher scores indicating greater risk of mortality.
Oxygen Saturation / Fractional Inhaled Oxygen (F/S)	14 days	Oxygen saturation (percent) is measured by pulse oximeter. Fraction of inspired oxygen (FiO2) (unitless) is the volumetric fraction of oxygen to other gases in respiratory support. The F/S ratio is unitless.
90-Day Mortality	90 days	Outcome reported as the number of participants who have expired at 90 days post enrollment.
Number of Vasopressor-Free Days	14 days	Outcome reported as the mean number of days participants in each arm did not require vasopressor usage during an in-patient hospital admission.
Abnormal Biomarkers after recovery - D-dimer	1 day	Outcome reported as the mean number of days participants in each arm had abnormal plasma levels.
Abnormal Biomarkers after recovery - Neutrophils	1 day	Outcome reported as the mean number of days participants in each arm had abnormal plasma levels.
Abnormal Biomarkers after recovery - Lymphocytes	1 day	Outcome reported as the mean number of days participants in each arm had abnormal plasma levels.
Abnormal Biomarkers after recovery - C-Reactive Protein (CRP)	1 day	Outcome reported as the mean number of days participants in each arm had abnormal plasma levels.
Abnormal Biomarkers after recovery - Lactate	1 day	Outcome reported as the mean number of days participants in each arm had abnormal plasma levels.
Abnormal Biomarkers after recovery - Creatine Kinase (CK)	1 day	Outcome reported as the mean number of days participants in each arm had abnormal plasma levels.
Abnormal Biomarkers after recovery - Ferritin	1 day	Outcome reported as the mean number of days participants in each arm had abnormal plasma levels.
PROMIS Dyspnea Functional Limitations after recovery	1 day	The PROMIS Dyspnea (shortness of breath) item banks and pools assess self-reported Functional Limitations, Severity, Activity Motivation, Activity Requirements, Airborne Exposure, Assistant Devices Resources, Characteristics, Emotional Response, Task Avoidance and Time Extension as they related to dyspnea. In the 33-item Functional Limitations bank, 33 daily activities are rated in terms of degree of difficulty while engaging in the activity over the past 7 days (0 = no difficulty, 1 = a little difficulty, 2 = some difficulty, 3 = much difficulty). Total scores range from 0 to 99, with higher scores reflecting greater functional limitations. Measured at the end of quarantine period.
28-Day Mortality	28 days	Outcome reported as the number of participants who have expired at 28 days post enrollment.
ICU Admission	14 days	Outcome reported as the number of participants in each arm who require admission to the Intensive Care Unit (ICU).
Number of Ventilator-Free Days	14 days	Outcome reported as the mean number of days participants in each arm did not require mechanical ventilation during an in-patient hospital admission.
Incidence of Respiratory Failure	14 days	Outcome reported as the number of participants requiring BiPAP OR high flow nasal cannula OR mechanical ventilation OR extracorporeal membranous oxygenation (ECMO) utilization during in-patient hospital care in each arm.
Length of ICU Stay	14 days	Outcome reported as the mean length of stay (in days) in the Intensive Care Unit (ICU) for participants in each arm.
Change in PROMIS Dyspnea Functional Limitations	14 days	The PROMIS Dyspnea (shortness of breath) item banks and pools assess self-reported Functional Limitations, Severity, Activity Motivation, Activity Requirements, Airborne Exposure, Assistant Devices Resources, Characteristics, Emotional Response, Task Avoidance and Time Extension as they related to dyspnea. In the 33-item Functional Limitations bank, 33 daily activities are rated in terms of degree of difficulty while engaging in the activity over the past 7 days (0 = no difficulty, 1 = a little difficulty, 2 = some difficulty, 3 = much difficulty). Total scores range from 0 to 99, with higher scores reflecting greater functional limitations.
Viral Clearance by Blood	14 days	Blood will be collected every third day for viral load assessment for the duration of study participation. clearance is measured as fold change in viral genetic copies per mL.
Abnormal Biomarkers after recovery - Platelets (PLT)	1 day	Outcome reported as the mean number of days participants in each arm had abnormal plasma levels.
Abnormal Biomarkers after recovery - Monocytes	1 day	Outcome reported as the mean number of days participants in each arm had abnormal plasma levels.
Abnormal Biomarkers after recovery - IL-6	1 day	Outcome reported as the mean number of days participants in each arm had abnormal plasma levels.
Abnormal Biomarkers after recovery - Cardiac Troponin (TRO)	1 day	Outcome reported as the mean number of days participants in each arm had abnormal plasma levels.
Abnormal Oxygenation after recovery	1 day	Outcome reported as the mean number of participants in each arm had abnormal PaO2 or SaO2 and FiO2 levels at the end of quarantine period. Partial pressure of oxygen or peripheral saturation of oxygen by pulse oximetry. FiO₂ is estimated from oxygen flow/delivery rates
PROMIS Dyspnea Severity after recovery	1 day	The PROMIS Dyspnea (shortness of breath) item banks and pools assess self-reported Functional Limitations, Severity, Activity Motivation, Activity Requirements, Airborne Exposure, Assistant Devices Resources, Characteristics, Emotional Response, Task Avoidance and Time Extension as they related to dyspnea. The 33-item Severity bank assesses the severity of difficulty breathing during various specific activities (the same 33 activities assessed in Dyspnea Functional Limitations). Each activity is rated in terms of degree of dyspnea (0 = no shortness of breath, 1 = mildly short of breath, 2 = moderately short of breath, 3 = severely short of breath) while engaging in the activity over the past 7 days. Total scores range from 0 to 99 with higher scores reflecting greater levels of dyspnea during daily activity. Measured at the end of quarantine period.
Abnormal Biomarkers after recovery - Procalcitonin (PCT)	1 day	Outcome reported as the mean number of days participants in each arm had abnormal plasma levels.
Abnormal Biomarkers after recovery - Alkaline Phosphatase (ALP)	1 day	Outcome reported as the mean number of days participants in each arm had abnormal plasma levels.
Abnormal Biomarkers after recovery - Alanine Aminotransferase (ALT)	1 day	Outcome reported as the mean number of days participants in each arm had abnormal plasma levels.

Trial Locations

Locations (3)

Barzilai Medical Center; 🇮🇱 Ashkelon, Israel

Rambam Health Care Campus; 🇮🇱 Haifa, Israel

Nazareth Hospital EMMS; 🇮🇱 Nazareth, Israel