But positive trends warrant tricky larger study, investigator says
Prescription-strength omega-3 did not significantly reduce hospitalization or death from COVID-19 in the 2,000-outpatient decentralized PREPARE-IT 2 study, but with positive trends, strong safety profile and unexpectedly low event rates, a larger study is warranted, an investigator said.
Rafael Diaz, MD, of Estudios Clínicos Latinoamérica, Argentina, presented these findings Monday at the American Heart Association Scientific Sessions 2021 virtual meeting.
Still, despite stressing the need for a larger study in “about 7,000 to 8,000 people” to confirm a potential “moderate benefit” for treatment of non-hospitalized COVID-19 patients with a prescription-strength purified omega-3 fatty acid, Diaz stressed that the “practicability and feasibility” of such a trial – given leaps in prevention and treatment strategies for the pandemic infection – would be “very difficult.”
PREPARE-IT 2 tested the purified omega-3 fatty acid (eicosapentaenoic acid [EPA] ethyl ester) known as icosapent ethyl (IPE), which has been approved in the U.S. as an adjunct to maximally tolerated statins to reduce cardiovascular risk in adults with elevated triglyceride levels.
Despite the failure of the earlier PREPARE-IT 1 trial in IPE’s prevention of transmission in people who were at-risk of – but who did not have – COVID-19, it made sense to run PREPARE-IT 2 in those who already had the infection, Erin Michos, MD, of John Hopkins Medicine, Baltimore, noted during a panel discussion at the meeting.
She stressed the likely causal role of inflammation in progression to more severe illness with COVID-19 and highlighted potentially favorable anti-inflammatory and anti-thrombotic properties associated with IPE, as seen, for example, in the 8,000-patient REDUCE-IT trial.
The targeted triglyceride-lowering effect of the omega-3 in REDUCE-IT – in which 4 grams daily of IPE reduced major adverse cardiac events (MACE) events by 25% – add to the rationale because COVID-19 is known to be hypercoagulable, Michos noted. Earlier research in smaller patient numbers also demonstrated that IPE reduced C-reactive protein – an inflammatory marker – and improved COVID-19 symptoms, she said.
PREPARE-IT 2 was therefore set up, recruiting 2,052 patients (1,010 dosed with IPE and 1,042 given placebo) with the primary aim of reducing planned COVID-19-related hospitalizations or mortality in non-hospitalized patients with a clear COVID-19 diagnosis up to 28 days.
The trial ran remotely, with trial activity done via “the web,” Diaz said in his presentation.
Patients in the active arm received a “very high” loading dose of 8 grams per day for the first 3 days – twice the U.S. Food and Drug Administration (FDA)-approved dose – followed by the standard 4-gram dose from day 4 to 28, Diaz said, with identical placebo doses issued in control.
Those included were 40 years of age or older, had a COVID-19 diagnosis confirmed with a severe acute respiratory syndrome coronavirus 2 test (RT-PCR or rapid test) and were no more than 7 days from the onset of symptoms at baseline. These subjects also had no clear indication for hospitalization and had to have adequate internet access for the decentralized study.
Of the IPE group, 110 patients (11.16%) were hospitalized or died because of COVID-19 versus 135 (13.69%) in the placebo group (hazard ratio [HR]: 0.84; 95% confidence interval [CI]: 0.65 – 1.08; P = 0.166).
There were no statistically significant improvements with IPE treatment in any of the criteria for hospitalization on the primary outcome measure, according to Diaz’s slides.
However, Diaz stressed that for secondary outcomes, “actual COVID-19 hospitalizations or death were reduced in about 22%,” nevertheless with a non-significant P-value, occurring in 53 (5.38%) of the IPE patients versus 70 (6.80%) of control (HR: 0.78; CI 95: 0.55-1.12; P = 0.180).
Ten IPE patients (1.02%) were “not alive or not out of the hospital at day 28” compared to 14 (1.36%) of placebo patients (HR: 0.74; CI 95%: 0.29-1.81; P = 0.541).
The endpoints “trended in the same direction,” Diaz added, while no significant difference between safety profiles for placebo or active was observed.
“The most important and frequent [adverse events] were constipation or pain, but in any case, this was not significant,” he added.
In the IPE group, 27 patients (2.73%) had constipation versus 23 (2.23%) in placebo (P-value = 0.48), while three (0.30%) in the IPE group reported musculoskeletal pain compared to two (0.19%) in the control group (P = 0.68).
Larger, but trickier, trial needed
Diaz stressed that the IPE arm's non-significant – but still numerically lower – reduction for the primary outcome would be worth investigating in larger randomized clinical trials powered for the detection of moderate benefits, “like 15%,” to establish the potential role of IPE in managing COVID-19 outpatients.
“The very high dose that we included in the loading dose was very well-tolerated compared with placebo, although there was a slightly higher rate of discontinuation in the active arm,” he added.
Michos added that the 16% reduction in hospitalizations and death did not meet statistical significance “largely because there were fewer events than anticipated,” with just 164 (16.58%) events in the active group and 153 (14.85%) in placebo (P = 0.30).
“Fortunately, COVID hospitalizations are going down [because of] the broad adoption of vaccines, and so it didn’t quite meet its endpoint,” Michos said, adding that it was reassuring that the 8-gram loading dose did not increase the risk of atrial fibrillation within the 28 days as seen “with some of these omega-3 preparations, and there was no increased risk of bleeding.”
She agreed that a larger trial is needed to definitively show whether IPE can help COVID-positive outpatients.
Yet, with around 7,000 to 8,000 subjects needed to sufficiently power a trial to see a benefit of 15% reduction in the primary endpoint, “maybe it’s not worth [it], at this time of the pandemic, maybe the vaccination rate will lower the rate of infections on outpatients,” said Diaz.
Christie Ballantyne, MD, of the Baylor College of Medicine, Houston, added during the panel session that PREPARE-IT 2 shows the difficulty of garnering a large enough sample size to power such a study.
Given ongoing vaccination, prevention and other COVID-19 treatment strategies, Diaz added that there may not be enough patients to run such a trial, regardless of the potential benefit observed.