A Randomized Trial of Lipid Metabolism Modulation with Fenofibrate for Acute Coronavirus Disease 2019

Julio Chirinos, Patricio Lopez-Jaramillo, Evangelos Giamarellos-Bourboulis, Gonzalo Dávila-Del-Carpio, Abdul Bizri, Jaime Andrade-Villanueva, Oday Salman, Carlos Cure-Cure, Nelson Rosado-Santander, Mario Cornejo Giraldo, Luz González-Hernández, Rima Moghnieh, Rapti Angeliki, María Cruz Saldarriaga, Marcos Pariona, Carola Medina, Ioannis Dimitroulis, Charalambos Vlachopoulos, Corina Gutierrez, Juan Rodriguez-Mori, Edgar Gomez-Laiton, Rosa Pereyra, Jorge Ravelo Hernández, Hugo Arbañil, José Accini-Mendoza, Maritza Pérez-Mayorga, Haralampos Milionis, Garyfallia Poulakou, Gregorio Sánchez, Renzo Valdivia-Vega, Mirko Villavicencio-Carranza, Ricardo Ayala-Garcia, Carlos Castro-Callirgos, Rosa Alfaro Carrasco, Willy Lecca Danos, Tiffany Sharkoski, Katherine Greene, Bianca Pourmussa, Candy Greczylo, Jesse Chittams, Paraskevi Katsaounou, Zoi Alexiou, Styliani Sympardi, Nancy Sweitzer, Mary Putt, Jordana Cohen, Julio Chirinos, Patricio Lopez-Jaramillo, Evangelos Giamarellos-Bourboulis, Gonzalo Dávila-Del-Carpio, Abdul Bizri, Jaime Andrade-Villanueva, Oday Salman, Carlos Cure-Cure, Nelson Rosado-Santander, Mario Cornejo Giraldo, Luz González-Hernández, Rima Moghnieh, Rapti Angeliki, María Cruz Saldarriaga, Marcos Pariona, Carola Medina, Ioannis Dimitroulis, Charalambos Vlachopoulos, Corina Gutierrez, Juan Rodriguez-Mori, Edgar Gomez-Laiton, Rosa Pereyra, Jorge Ravelo Hernández, Hugo Arbañil, José Accini-Mendoza, Maritza Pérez-Mayorga, Haralampos Milionis, Garyfallia Poulakou, Gregorio Sánchez, Renzo Valdivia-Vega, Mirko Villavicencio-Carranza, Ricardo Ayala-Garcia, Carlos Castro-Callirgos, Rosa Alfaro Carrasco, Willy Lecca Danos, Tiffany Sharkoski, Katherine Greene, Bianca Pourmussa, Candy Greczylo, Jesse Chittams, Paraskevi Katsaounou, Zoi Alexiou, Styliani Sympardi, Nancy Sweitzer, Mary Putt, Jordana Cohen

Abstract

Background Abnormal cellular lipid metabolism appears to underlie SARS-CoV-2 cytotoxicity and may involve inhibition of peroxisome proliferator activated receptor alpha (PPARα). Fenofibrate, a PPAR-α activator, modulates cellular lipid metabolism. Fenofibric acid has also been shown to affect the dimerization of angiotensin-converting enzyme 2, the cellular receptor for SARS-CoV-2. Fenofibrate and fenofibric acid have been shown to inhibit SARS-CoV-2 replication in cell culture systems in vitro . Methods We randomly assigned 701 participants with COVID-19 within 14 days of symptom onset to 145 mg of fenofibrate (nanocrystal formulation with dose adjustment for renal function or dose-equivalent preparations of micronized fenofibrate or fenofibric acid) vs. placebo for 10 days, in a double-blinded fashion. The primary endpoint was a ranked severity score in which participants were ranked across hierarchical tiers incorporating time to death, duration of mechanical ventilation, oxygenation parameters, subsequent hospitalizations and symptom severity and duration. ClinicalTrials.gov registration: NCT04517396. Findings: Mean age of participants was 49 ± 16 years, 330 (47%) were female, mean BMI was 28 ± 6 kg/m 2 , and 102 (15%) had diabetes mellitus. A total of 41 deaths occurred. Compared with placebo, fenofibrate administration had no effect on the primary endpoint. The median (interquartile range [IQR]) rank in the placebo arm was 347 (172, 453) vs. 345 (175, 453) in the fenofibrate arm (P = 0.819). There was no difference in various secondary and exploratory endpoints, including all-cause death, across randomization arms. These results were highly consistent across pre-specified sensitivity and subgroup analyses. Conclusion Among patients with COVID-19, fenofibrate has no significant effect on various clinically relevant outcomes.

Figures

Figure 1. Participant Enrolment, Randomization, and Follow-up…
Figure 1. Participant Enrolment, Randomization, and Follow-up in the FERMIN trial
* Pre-screening information was only available for the Penn site due to regulatory limitations and lack of collection at other sites
Figure 2. Key Outcomes Among Participants in…
Figure 2. Key Outcomes Among Participants in Each Randomization Arm
Panel A shows the distribution of the primary endpoint (ranked severity score) between the randomization arms. The y-axis represents the range of ranked severity scores, and the x-axis represents the frequency density of distributions of the ranks in each treatment arm. The white dot represents the median ranked severity score, the solid box represents the interquartile range, and the vertical lines represent the upper- and lower-adjacent values. The upper adjacent value and the interquartile range values were identical. Panel B shows the cumulative incidence for all-cause death at 30-days.
Figure 3. Forest Plot of the Differences…
Figure 3. Forest Plot of the Differences in Ranked Severity Scores Across Subgroups
The dots represent the differences in median ranked severity scores between participants randomized to fenofibrate vs. placebo in each subgroup. Positive values indicate better outcomes in the fenofibrate arm. The bars represent the 95% confidence intervals.
Figure 4
Figure 4
Primary endpoint of the trial (ranked severity score)

References

    1. Bornstein S. R., Dalan R., Hopkins D., Mingrone G. & Boehm B. O. Endocrine and metabolic link to coronavirus infection. Nat Rev Endocrinol 16, 297–298, doi:10.1038/s41574-020-0353-9 (2020).
    1. Zhou F. et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet 395, 1054–1062, doi:10.1016/S0140-6736(20)30566-3 (2020).
    1. Guan W. J. et al. Clinical Characteristics of Coronavirus Disease 2019 in China. The New England journal of medicine 382, 1708–1720, doi:10.1056/NEJMoa2002032 (2020).
    1. Wu C. et al. Risk Factors Associated With Acute Respiratory Distress Syndrome and Death in Patients With Coronavirus Disease 2019 Pneumonia in Wuhan, China. JAMA Intern Med, doi:10.1001/jamainternmed.2020.0994 (2020).
    1. Zhu L. et al. Association of Blood Glucose Control and Outcomes in Patients with COVID-19 and Pre-existing Type 2 Diabetes. Cell Metab 31, 1068–1077 e1063, doi:10.1016/j.cmet.2020.04.021 (2020).
    1. Wu Z. et al. Palmitoylation of SARS-CoV-2 S protein is essential for viral infectivity. Signal Transduct Target Ther 6, 231, doi:10.1038/s41392-021-00651-y (2021).
    1. Li D., Liu Y., Lu Y., Gao S. & Zhang L. Palmitoylation of SARS-CoV-2 S protein is critical for S-mediated syncytia formation and virus entry. J Med Virol 94, 342–348, doi:10.1002/jmv.27339 (2022).
    1. Nguyen H. T. et al. Spike glycoprotein and host cell determinants of SARS-CoV-2 entry and cytopathic effects. J Virol, doi:10.1128/JVI.02304-20 (2020).
    1. Ehrlich E. et al. The SARS-CoV-2 Transcriptional Metabolic Signature in Lung Epithelium. Cell Sneak Peak (submission only) (2020).
    1. Davies S. P. et al. The Hyperlipidaemic Drug Fenofibrate Significantly Reduces Infection by SARS-CoV-2 in Cell Culture Models. Front Pharmacol 12, 660490, doi:10.3389/fphar.2021.660490 (2021).
    1. Schaefer M. B. et al. Peroxisome proliferator-activated receptor-alpha reduces inflammation and vascular leakage in a murine model of acute lung injury. Eur Respir J 32, 1344–1353, doi:10.1183/09031936.00035808 (2008).
    1. Hecker M. et al. PPAR-alpha activation reduced LPS-induced inflammation in alveolar epithelial cells. Exp Lung Res 41, 393–403, doi:10.3109/01902148.2015.1046200 (2015).
    1. Huang D., Zhao Q., Liu H., Guo Y. & Xu H. PPAR-alpha Agonist WY-14643 Inhibits LPS-Induced Inflammation in Synovial Fibroblasts via NF-kB Pathway. J Mol Neurosci 59, 544–553, doi:10.1007/s12031-016-0775-y (2016).
    1. Nardacci R. et al. Evidences for lipid involvement in SARS-CoV-2 cytopathogenesis. Cell Death Dis 12, 263, doi:10.1038/s41419-021-03527-9 (2021).
    1. Sagan S. M. et al. The influence of cholesterol and lipid metabolism on host cell structure and hepatitis C virus replication. Biochem Cell Biol 84, 67–79, doi:10.1139/o05-149 (2006).
    1. Dorobantu C. M. et al. Modulation of the Host Lipid Landscape to Promote RNA Virus Replication: The Picornavirus Encephalomyocarditis Virus Converges on the Pathway Used by Hepatitis C Virus. PLoS Pathog 11, e1005185, doi:10.1371/journal.ppat.1005185 (2015).
    1. Yan B. et al. Characterization of the Lipidomic Profile of Human Coronavirus-Infected Cells: Implications for Lipid Metabolism Remodeling upon Coronavirus Replication. Viruses 11, doi:10.3390/v11010073 (2019).
    1. Lamers M. M. & Haagmans B. L. SARS-CoV-2 pathogenesis. Nat Rev Microbiol 20, 270–284, doi:10.1038/s41579-022-00713-0 (2022).
    1. Alipoor S. D. et al. COVID-19: Molecular and Cellular Response. Front Cell Infect Microbiol 11, 563085, doi:10.3389/fcimb.2021.563085 (2021).
    1. Wiersinga W. J., Rhodes A., Cheng A. C., Peacock S. J. & Prescott H. C. Pathophysiology, Transmission, Diagnosis, and Treatment of Coronavirus Disease 2019 (COVID-19): A Review. JAMA 324, 782–793, doi:10.1001/jama.2020.12839 (2020).
    1. Ling H., Luoma J. T. & Hilleman D. A Review of Currently Available Fenofibrate and Fenofibric Acid Formulations. Cardiol Res 4, 47–55, doi:10.4021/cr270w (2013).
    1. Ladabaum U., Mannalithara A., Myer P. A. & Singh G. Obesity, abdominal obesity, physical activity, and caloric intake in US adults: 1988 to 2010. Am J Med 127, 717–727 e712, doi:10.1016/j.amjmed.2014.02.026 (2014).
    1. O’Connor C. M. et al. Cardiovascular Outcomes With Minute Ventilation-Targeted Adaptive Servo-Ventilation Therapy in Heart Failure: The CAT-HF Trial. Journal of the American College of Cardiology 69, 1577–1587, doi:10.1016/j.jacc.2017.01.041 (2017).
    1. Margulies K. B. et al. Effects of Liraglutide on Clinical Stability Among Patients With Advanced Heart Failure and Reduced Ejection Fraction: A Randomized Clinical Trial. JAMA 316, 500–508, doi:10.1001/jama.2016.10260 (2016).
    1. Felker G. M. & Maisel A. S. A global rank end point for clinical trials in acute heart failure. Circ Heart Fail 3, 643–646, doi:10.1161/CIRCHEARTFAILURE.109.926030 (2010).
    1. van Elteren P. H. On the combination of independent two sample tests of Wilcoxon. Bull Internat Statist Inst 37, 351–361 (1960).
    1. Fay M. P. & Malinovsky Y. Confidence intervals of the Mann-Whitney parameter that are compatible with the Wilcoxon-Mann-Whitney test. Statistics in medicine 37, 3991–4006, doi:10.1002/sim.7890 (2018).
    1. WHO R&D Blueprint. Novel Coronavirus. COVID-19 Therapeutic Trial Synopsis Draft. 18 Feb 2020. . Accessed 28 Apr 2020.
    1. Wang D. et al. Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus-Infected Pneumonia in Wuhan, China. JAMA, doi:10.1001/jama.2020.1585 (2020).
    1. Hozo S. P., Djulbegovic B. & Hozo I. Estimating the mean and variance from the median, range, and the size of a sample. BMC Med Res Methodol 5, 13, doi:10.1186/1471-2288-5-13 (2005).
    1. Julious S. A. Tutorial in Biostatistics. Sample sizes for clinical trials with Normal data. Statistics in medicine 23, 1921–1986 (2004).
    1. O’Brien P. C. & Fleming T. R. A multiple testing procedure for clinical trials. Biometrics 35, 549–556 (1979).
    1. PASS 16 Power Analysis and Sample Size Software. NCSS, LLC. Kaysville, Utah, USA, . (2018).

Source: PubMed

Sponsor e collaboratori

Condizioni mediche

Interventi farmacologici

3
Sottoscrivi