A randomized clinical trial of lipid metabolism modulation with fenofibrate for acute coronavirus disease 2019

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) cytotoxicity may involve inhibition of peroxisome proliferator-activated receptor alpha. Fenofibrate activates peroxisome proliferator-activated receptor alpha and inhibits SARS-CoV-2 replication in vitro. Whether fenofibrate can be used to treat coronavirus disease 2019 (COVID-19) infection in humans remains unknown. Here, we randomly assigned inpatients and outpatients with COVID-19 within 14 d of symptom onset to 145 mg of oral fenofibrate nanocrystal formulation versus placebo for 10 d, in a double-blinded fashion. The primary endpoint was a severity score whereby participants were ranked across hierarchical tiers incorporating time to death, mechanical ventilation duration, oxygenation, hospitalization and symptom severity and duration. In total, 701 participants were randomized to fenofibrate (n = 351) or placebo (n = 350). The mean age of participants was 49 ± 16 years, 330 (47%) were female, mean body mass index was 28 ± 6 kg/m² and 102 (15%) had diabetes. Death occurred in 41 participants. Compared with placebo, fenofibrate had no effect on the primary endpoint. The median (interquartile range) rank in the placebo arm was 347 (172, 453) versus 345 (175, 453) in the fenofibrate arm (P = 0.819). There was no difference in secondary and exploratory endpoints, including all-cause death, across arms. There were 61 (17%) adverse events in the placebo arm compared with 46 (13%) in the fenofibrate arm, with slightly higher incidence of gastrointestinal side effects in the fenofibrate group. Overall, among patients with COVID-19, fenofibrate has no significant effect on various clinically relevant outcomes ( NCT04517396 ).

Fig. 1

Participant enrolment, randomization and follow-up in the FEnofibRate as a Metabolic INtervention for COVID-19 (FERMIN) trial.

Fig. 2. Key outcomes among participants in each randomization arm.

a, Distribution of the primary endpoint (ranked severity score) between the randomization arms (placebo N = 347 participants; fenofibrate N = 347 participants). 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 IQR, and the vertical lines represent the upper-adjacent and lower-adjacent values. The upper-adjacent value and the IQR values were identical. b, Cumulative incidence for all-cause death at 30 d.

Fig. 3. Forest plot of the differences in ranked severity scores across subgroups.

The plot represents the differences in median ranked severity scores between participants randomized to fenofibrate versus placebo in each subgroup. Positive values indicate better outcomes in the fenofibrate arm. Negative values indicate better outcomes in the placebo group. The central dot represents the difference in median scores and the error bars represent the 95% CIs.

Fig. 4. Primary endpoint of the trial (ranked severity score).

Participants were ranked hierarchically according to their clinical course. The primary endpoint of the trial was a global rank score that ranked patient outcomes according to five factors, shown as tiers from top to bottom (labelled as subsets 1–5). The left-sided icons (walking person and person in hospital bed) indicate the participant status at the time of enrolment (outpatient and inpatient, respectively). The top tier included inpatients and outpatients, whereas other subsets included inpatients or outpatients, but not both. Outcomes of hypothetical participants are represented within each tier by the right-pointing arrows. The icons on the right of the arrows represent the participant status at trial completion or at the time of the relevant outcome event (such as death, hospital discharge or hospital admission). Participants were ranked within each tier according to the following specific criteria: tier 1, time to death (ranked from shortest to longest, up to 30 d after randomization); tier 2, for participants enrolled as inpatients, the number of days supported by mechanical ventilation (invasive or noninvasive) or ECMO (until hospital discharge, up to 30 d after randomization, ranked from longest to shortest); tier 3, for participants enrolled as inpatients who did not require mechanical ventilation or ECMO, the FiO₂/SpO₂ ratio area under the curve until hospital discharge, up to 30 d after randomization, ranked from highest to lowest; tier 4, for participants enrolled as outpatients who were subsequently hospitalized, the number of days out of the hospital during the 30-d period following randomization (ranked from lowest to highest); tier 5, for participants enrolled as outpatients who did not get hospitalized during the 30 d observation period, the modified dyspnoea Borg scale (mean value of assessments at ~5, ~10 and ~15 d, ranked from highest to lowest). AUC, area under the curve.

Extended Data Fig. 1

Kaplan–Meier curve of time to hospitalization (among participants enrolled as outpatients).

Extended Data Fig. 2

Cumulative incidence curve of time to discharge (among participants enrolled as inpatients).