Most likely EVAPORATE used mineral oil placebo for consistency with REDUCE-IT trial.
Deterioration in placebo arm assumed due to untreated plaque progression, placebo assumed to be inert
Authors of Evaporate previously "demonstrated that progression rates on mineral oil placebo is similar to non-mineral oil placebo cohort using same methodology, scanner and laboratory."
"In light of the previous comments regarding mineral oil as a placebo, it was decided to compare the rates of progression of total plaque and total non-calcified plaque on coronary computed tomography angiography in the mineral oil placebo group from EVAPORATE with the non-mineral oil placebo group (per 100 mg: microcrystalline cellulose 89.83 mg, hydroxypropyl cellulose 10.07 mg, and caramel 0.10 mg) from the Garlic 5 study [Citation138]. This comparison found no significant differences in progression of log total plaque volume (ß: 0.03 ± 0.13; P = 0.84) or log total non-calcified plaque volume (ß: 0.01 ± 0.16; P = 0.94) between the mineral oil and non-mineral oil placebo groups. Conversely, the HEARTS trial, which investigated the effects of a mixed EPA plus DHA product on plaque, failed to show a significant difference in the change from baseline of non-calcified plaque, fibrous plaque, fatty plaque, calcified plaque, and total plaque when compared with placebo at 30 months [Citation139]."
"There has been some interest in the effect of different placebos used in the REDUCE-IT trial (mineral oil) versus the STRENGTH trial (corn oil) on the differential outcomes of the trials. Concerns have been raised regarding the validity of results in the REDUCE-IT trial, in part questioning the stipulated biological activity of the mineral oil placebo linked to observed changes in cardiac biomarkers in the placebo arm of the trial. In a post-hoc analysis comparing serial CCTA in the mineral oil placebo arm in EVAPORATE to a cellulose-based placebo cohort in the GARLIC5 study, no differences were observed in the rate of coronary plaque progression in the two groups.56,57 In addition, consistent and significant benefits of EPA on coronary atherosclerosis and CV outcomes have been demonstrated in Japanese populations in the open-label CHERRY and JELIS trials, where no placebo comparator groups were included.40,58
A detailed review of literature has shown that mineral-oil-related changes in TGL, low-density lipoprotein cholesterol and other biomarkers have been mostly inconsistent across studies, and are not clinically meaningful to explain the substantially positive results of REDUCE-IT.59 In a review of REDUCE-IT by the US Food and Drug Administration (FDA), they concluded that the magnitude of difference in outcomes between IPE and mineral oil groups could not be explained by the stipulated harmful effects of mineral oil placebo.60 Therefore, a summary of current evidence supports the validity of CV benefits with IPE in the REDUCE-IT and EVAPORATE trials, and attests to the results not being influenced by the small amount of mineral oil used in the placebo capsules."
That's what the CHERRY Study did: => SOC (Statin only) vs. Statin + EPA. Unfortunately, This study was only 6-8 months. The slowing of the Total Plaque Progression in CHERRY was very similar to the 9 months EVAPORATE Interim Study. Also, keep in mind that the dose for CHERRY was only 1.8g EPA/d. I believe that if CHERRY had continued for 18-24 months the results would have been proportional to to the FINAL EVAPORATE.
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