FEnofibRate as a Metabolic INtervention for COVID-19 (FERMIN)

• ClinicalTrials.gov Identifier: NCT04517396
• Recruitment Status: Completed
• First Posted: August 18, 2020
• Results First Posted: February 27, 2023
• Last Update Posted: March 24, 2023
• Sponsor: University of Pennsylvania
• Collaborators: University of Arizona; Universidad Católica de Santa María (National Sponsor in Perú); Hospital Nacional Adolfo Guevara Velasco, Peru; Hospital Nacional Edgardo Rebagliati Martins; Hospital Nacional Alberto Sabogal Sologuren, Peru; Hospital Nacional Guillermo Almenara Irigoyen, Peru; Hospital Nacional Carlos Alberto Seguin Escobedo - EsSalud; Universidad de Santander, Bucaramanga, Colombia (National Sponsor in Colombia); National Center for Advancing Translational Sciences (NCATS); Hospitales Civiles de Guadalajara, Mexico; Hospital 2 de Mayo. Lima, Peru; Hospital de la Fuerza Aérea del Perú. Lima, Peru; Hospital Militar Central "Coronel Luis Arias Schereiber"; Lima, Perú; Hospital Victor Lazarte Echegaray. Lima, Peru; Ioannina University General Hospital. Greece; AHEPA Thessaloniki University General Hospital. Greece; SOTIRIA Athens General University Hospital of Chest Diseases. Greece; THRIASIO Eleusis General Hospital. Greece; Alexandroupolis University General Hospital. Greece; G.Gennimatas General Hospital; Colombia Centro 1: BIOMELAB S.A.S. Barranquilla, Colombia; Fundación Oftalmológica de Santander. Santander, Colombia; IPS Centro Científico Asistencial. Barranquilla, Colombia; Fundación Cardiomet. Quindio, Colombia; Clínica de Marly. Bogotá, Colombia; Clinica Internacional. Lima, Peru
• Information provided by (Responsible Party): Julio A. Chirinos, University of Pennsylvania

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Covid19	Other: Fenofibrate/fenofibric acid; Other: Placebo; Other: Usual care	Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 701 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: FEnofibRate as a Metabolic INtervention for Coronavirus Disease 2019
• Actual Study Start Date: August 18, 2020
• Actual Primary Completion Date: March 30, 2022
• Actual Study Completion Date: March 30, 2022

Arms and Interventions

Arm	Intervention/treatment
Experimental: Fenofibrate + Usual Care; 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; 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.; Other: Usual care; All participants will otherwise receive usual medical care
Placebo Comparator: Placebo + Usual Care; The randomized intervention will a matching placebo, in combination with usual care.	Other: Placebo; The control intervention will be a placebo, for 10 days.; Other: Usual care; All participants will otherwise receive usual medical care

Outcome Measures

Primary Outcome Measures :

1. Primary Hierarchical Composite Endpoint [ Time Frame: 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 Outcome Measures :

1. 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 [ Time Frame: 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
2. Seven-category Ordinal Scale [ Time Frame: 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.
3. Secondary Hierarchical Composite Endpoint [ Time Frame: 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 Outcome Measures:

1. All-Cause Death [ Time Frame: Up to 30 days ]
   Death from any cause during the observation period
2. Number of Days Alive and Out of the Hospital During the 30 Days Following Randomization [ Time Frame: Up to 30 days ]
   Number of days that participants were alive and out of the hospital during the 30 days following randomization
3. Exploratory Hierarchical Composite Endpoint [ Time Frame: 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.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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.

Contacts and Locations

Locations

United States, Pennsylvania

University of Pennsylvania Health System

Philadelphia, Pennsylvania, United States, 19104

Sponsors and Collaborators

University of Pennsylvania

University of Arizona

Universidad Católica de Santa María (National Sponsor in Perú)

Hospital Nacional Adolfo Guevara Velasco, Peru

Hospital Nacional Edgardo Rebagliati Martins

Hospital Nacional Alberto Sabogal Sologuren, Peru

Hospital Nacional Guillermo Almenara Irigoyen, Peru

Hospital Nacional Carlos Alberto Seguin Escobedo - EsSalud

Universidad de Santander, Bucaramanga, Colombia (National Sponsor in Colombia)

National Center for Advancing Translational Sciences (NCATS)

Hospitales Civiles de Guadalajara, Mexico

Hospital 2 de Mayo. Lima, Peru

Hospital de la Fuerza Aérea del Perú. Lima, Peru

Hospital Militar Central "Coronel Luis Arias Schereiber"; Lima, Perú

Hospital Victor Lazarte Echegaray. Lima, Peru

Ioannina University General Hospital. Greece

AHEPA Thessaloniki University General Hospital. Greece

SOTIRIA Athens General University Hospital of Chest Diseases. Greece

THRIASIO Eleusis General Hospital. Greece

Alexandroupolis University General Hospital. Greece

G.Gennimatas General Hospital

Colombia Centro 1: BIOMELAB S.A.S. Barranquilla, Colombia

Fundación Oftalmológica de Santander. Santander, Colombia

IPS Centro Científico Asistencial. Barranquilla, Colombia

Fundación Cardiomet. Quindio, Colombia

Clínica de Marly. Bogotá, Colombia

Clinica Internacional. Lima, Peru

  Study Documents (Full-Text)

Documents provided by Julio A. Chirinos, University of Pennsylvania:

Study Protocol  [PDF] November 3, 2021

Statistical Analysis Plan  [PDF] April 6, 2022

More Information

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Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Chirinos JA, Lopez-Jaramillo P, Giamarellos-Bourboulis EJ, Davila-Del-Carpio GH, Bizri AR, Andrade-Villanueva JF, Salman O, Cure-Cure C, Rosado-Santander NR, Cornejo Giraldo MP, Gonzalez-Hernandez LA, Moghnieh R, Angeliki R, Cruz Saldarriaga ME, Pariona M, Medina C, Dimitroulis I, Vlachopoulos C, Gutierrez C, Rodriguez-Mori JE, Gomez-Laiton E, Cotrina Pereyra R, Ravelo Hernandez JL, Arbanil H, Accini-Mendoza J, Perez-Mayorga M, Milionis C, Poulakou G, Sanchez G, Valdivia-Vega R, Villavicencio-Carranza M, Ayala-Garcia RJ, Castro-Callirgos CA, Alfaro Carrasco RM, Garrido Lecca Danos W, Sharkoski T, Greene K, Pourmussa B, Greczylo C, Ortega-Legaspi J, Jacoby D, Chittams J, Katsaounou P, Alexiou Z, Sympardi S, Sweitzer NK, Putt M, Cohen JB; FERMIN Investigators. A randomized clinical trial of lipid metabolism modulation with fenofibrate for acute coronavirus disease 2019. Nat Metab. 2022 Dec;4(12):1847-1857. doi: 10.1038/s42255-022-00698-3. Epub 2022 Nov 7.

Chirinos J, Lopez-Jaramillo P, Giamarellos-Bourboulis E, Davila-Del-Carpio G, Bizri A, Andrade-Villanueva J, Salman O, Cure-Cure C, Rosado-Santander N, Giraldo MC, Gonzalez-Hernandez L, Moghnieh R, Angeliki R, Saldarriaga MC, Pariona M, Medina C, Dimitroulis I, Vlachopoulos C, Gutierrez C, Rodriguez-Mori J, Gomez-Laiton E, Pereyra R, Hernandez JR, Arbanil H, Accini-Mendoza J, Perez-Mayorga M, Milionis H, Poulakou G, Sanchez G, Valdivia-Vega R, Villavicencio-Carranza M, Ayala-Garcia R, Castro-Callirgos C, Carrasco RA, Danos WL, Sharkoski T, Greene K, Pourmussa B, Greczylo C, Chittams J, Katsaounou P, Alexiou Z, Sympardi S, Sweitzer N, Putt M, Cohen J. A Randomized Trial of Lipid Metabolism Modulation with Fenofibrate for Acute Coronavirus Disease 2019. Res Sq. 2022 Aug 10:rs.3.rs-1933913. doi: 10.21203/rs.3.rs-1933913/v1. Preprint.

• Responsible Party: Julio A. Chirinos, Associate Professor of Medicine at the Hospital of the University of Pennsylvania, University of Pennsylvania
• ClinicalTrials.gov Identifier: NCT04517396
• Other Study ID Numbers: 843729
• First Posted: August 18, 2020
• Results First Posted: February 27, 2023
• Last Update Posted: March 24, 2023
• Last Verified: March 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No
• Plan Description: Not making it available

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No

Additional relevant MeSH terms:

COVID-19; Pneumonia, Viral; Pneumonia; Respiratory Tract Infections; Infections; Virus Diseases; Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Lung Diseases; Respiratory Tract Diseases; Fenofibrate; Fenofibric acid; Hypolipidemic Agents; Antimetabolites; Molecular Mechanisms of Pharmacological Action; Lipid Regulating Agents; Anticholesteremic Agents