A total of 701 participants were enrolled and randomized (156 in Colombia, 133 in Greece, 116 in the USA, 116 in Peru, 113 in Lebanon, and 67 in Mexico). General characteristics of study participants are shown in Table 1. The mean age of enrolled participants was 49±16 years, 330 (47%) were female, mean BMI was 28±6 kg/m2, 102 (15%) had a history of diabetes mellitus, 47 (7%) had a history of ischemic heart disease, 186 (27%) participants had a history of hypertension, and 302 (43%) were enrolled as inpatients. A total of 351 participants were randomized to fenofibrate and 350 participants were randomized to placebo (Figure 1). Only 17 participants (2%) were excluded, withdrew following randomization or were lost to follow-up. Most participants (n=438; 62%) participants were positive for SARS-CoV-2 by real time polymerase chain reaction testing and the remaining were positive by rapid antigen testing.
In the primary intent-to-treat analyses, the distribution of the ranked severity scores between participants assigned to fenofibrate vs. placebo was remarkably similar. The median (interquartile range [IQR]) ranked severity score in the placebo arm was 347 (172, 453) vs. 345 (175, 453) in the fenofibrate arm (P=0.819), where a lower value signifies more severe COVID-19 course (Table 2 and Figure 2A). After adjusting for age, sex, inpatient vs. outpatient status, baseline FiO2/SpO2, race, ethnicity, BMI, baseline diabetes status, and country, and clustered by site, subjects assigned to fenofibrate exhibited mean ranked severity scores that were 0.09 (95% CI -0.04, 0.21) units higher than those assigned to control (P-value=0.152). The individual components of the ranked severity score are described in Table S1.
Secondary and Exploratory Endpoints
The number of days alive, out of the intensive care unit, free of mechanical ventilation (invasive and non-invasive), extracorporeal membrane oxygenation (ECMO) or maximal available respiratory support in the 30 days following randomization was similar among the arms (median time in both arms, 30 [IQR 30, 30]; P=0.134). The seven-category WHO ordinal scale was similar between the arms (placebo median 1 [IQR 1, 2]; fenofibrate median 1 [IQR 1, 1]; P-value 0.246). Similarly, the modified ranked severity scores (constructed like the primary endpoint but using a more comprehensive COVID-19 symptom scale instead of the dyspnea Borg scale) were very similar across arms (placebo median score 358 [IQR 174, 513]; fenofibrate median score 343 [IQR 177, 525]; P-value 0.740).
Kaplan-Meier curves for deaths in the two arms are shown in Figure 2B. A total of 41 deaths occurred; 22 in the placebo arm and 19 in the fenofibrate arm (hazard ratio, 0.880 [95%CI=0.465, 1.663]; P-value=0.693). After adjusting for age, sex, inpatient vs. outpatient status, baseline FiO2/SpO2, race, ethnicity, BMI, baseline diabetes status, and country, and clustered by site, there was no significant difference in all-cause death at 30 days between the arms (adjusted HR 0.983; 95% CI 0.562, 1.718; P-value 0.952). The Kaplan-Meier failure estimates were not significantly different between the arms (P-value=0.692).
The number of days alive and out of the hospital during the 30 days following randomization were similar between the two arms (median days in the placebo arm, 30 [IQR 25, 30]; median days in the fenofibrate arm, 30 [IQR 25, 30]; P-value=0.834). The additional modified ranked severity score (similar to the primary endpoint, but built only with factors 1-4) was similar across the arms (placebo median score 317 [IQR 172, 317]; fenofibrate median score 317 [IQR 175, 317]; P-value=0.836). In analyses restricted to the 398 participants enrolled as outpatients, the risk of hospitalization was not significantly different in participants randomized to fenofibrate compared with placebo (1 vs. 4 participants hospitalized; unadjusted HR 0.249; 95% CI 0.028, 2.227; P-value 0.214; Figure S1). In analyses restricted to the 302 participants enrolled as inpatients, the cause-specific hazard for hospital discharge, considering death as a competing risk, was essentially identical between the arms (unadjusted HR 1.001; 95% CI 0.792, 1.267; P-value=0.990; Figure S2).
Analyses of all secondary and exploratory endpoints via pre-specified linear regression analyses that adjusted for age, sex, inpatient vs. outpatient status, baseline FiO2/SpO2, race, ethnicity, BMI, baseline diabetes status, and country and clustered by site, were consistent with the primary results obtained with the van Elteren test (Table 2).
Pre-specified Subgroup Analyses
As shown in detail in Figure 3, there was no evidence of effect modification by age, sex, race, diabetes status, obesity status, inpatient vs. outpatient status at the time of enrolment, FiO2/SpO2 at the time of enrollment (< vs. ≥ median), duration of symptoms (<7 vs. ≥7 days), WHO disease severity, country, formulation, adherence to therapy, or compound (fenofibrate vs. fenofibric acid).
There were 61 (17%) adverse events in the placebo arm compared with 46 (13%) in the fenofibrate arm. Adverse events are summarized in Table S2. There were no appreciable differences in the incidence of adverse events classified by organ system, except for a slightly greater incidence of gastrointestinal adverse events with fenofibrate (9 events [3%] in the placebo arm; 19 [5%] in the fenofibrate arm).