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Yet another randomized trial found no clinical benefit for hydroxychloroquine (HCQ) in COVID-19, this time in outpatients with early, mild symptoms.

Those receiving HCQ had no significant difference in a change in symptom severity over 14 days (relative difference 12%; absolute difference -0.27, 95% CI -0.61 to 0.07; P=0.117), reported David Boulware, MD, of the University of Minnesota, and colleagues.

While the proportion of patients reporting symptoms at 14 days was lower in the HCQ group compared to placebo, that difference also was nonsignificant (24% vs 30%, respectively, P=0.21), Boulware and colleagues wrote in .

Notably, a post-hoc subgroup analysis found no benefit for HCQ in patients also reporting use of zinc or vitamin C.

However, one major limitation noted by the authors was a lack of COVID-19 testing. While 82% of patients either had laboratory-confirmed COVID-19 or contact with a case, only 58% of participants were actually tested due to "severe testing shortages."

The book on evidence for HCQ as COVID-19 therapy was considered closed, due to lack of solid evidence of benefit. Interim results from the large RECOVERY trial in the U.K. found no survival benefit in hospitalized patients, and the National Institutes of Health .

But HCQ crashed the news cycle again when , published July 1, found the drug did have mortality benefit, and the key was administering it early, according to reports from CNN.

Still, Boulware noted that gaps still remained in HCQ research: "[T]here may be clinical benefits for the treatment of mild or moderate disease when therapy is given earlier in the disease course," and acknowledged that "no randomized clinical trials to date have investigated agents for early COVID-19 in non-hospitalized patients."

They hoped to address these in the current trial, a companion to the group's study of HCQ for preventing COVID-19 in individuals exposed on the job to infected people, results of which were reported in June.

The treatment substudy . They were non-hospitalized adults with 4 or fewer days of COVID-19 symptoms, who had either PCR-confirmed COVID-19 infection or high-risk exposure to someone with confirmed COVID-19 infection. Symptomatic healthcare workers with high-risk exposure, but a pending test, were enrolled after symptom review by an infectious diseases physician, the authors said. The trial was conducted from March 22 to May 20.

Self-reported symptom severity was measured on a 10-point visual analog scale. Primary endpoint was a change in symptom severity over 14 days, though the authors noted it was originally an ordinal outcome of not hospitalized, hospitalized, intensive care unit stay or death. However, prior to the first interim analysis on April 24, the authors said "the pooled event rate of hospitalization or death was substantially below our initial 10% expectation."

Of 423 participants, more than half (57%) were healthcare workers, 25% were household contacts and 18% had other exposures. Median age was 40, and 56% were women. Hypertension and diabetes were the most common comorbidities at 11% apiece, though 68% reported no chronic medical conditions.

Cough (65%), fatigue (52%), and headache (51%) were the most common symptoms. Overall, 56% of patients enrolled within a day of symptom onset, the authors said.

Boulware and colleagues acknowledged that the 12% relative improvement in symptoms with HCQ, despite the lack of statistical significance, could nevertheless reflect a genuine benefit. But they sought to put it in perspective by comparing it to the 25%-35% reduction in flu symptom severity seen in studies of oseltamivir (Tamiflu).

That benefit, usually described as modest, "is still two-fold greater than that observed with hydroxychloroquine," they wrote.

HCQ was also associated with greater incidence of adverse effects versus placebo (34% vs 22%, respectively). There were 10 hospitalizations and one hospitalized death in the placebo arm and four hospitalizations and one non-hospitalized death in the HCQ arm.

An by Neil Schluger, MD, of New York Medical College, said the new study, taken together with other randomized trials, "provides strong evidence that hydroxychloroquine offers no benefit in patients with mild illness."

"If the peer-reviewed findings confirm the preliminary reports of no benefit in sicker patients in the National Institutes of Health and RECOVERY trials, the saga of hydroxychloroquine and COVID-19 will likely reach its sad end," he wrote.

However, Schluger added this shouldn't be surprising, as 90% of all novel drugs entering clinical phases of testing fail to demonstrate effectiveness and safety and there is no shame in acknowledging "many good ideas in medicine do not work."

"It is time to move on from hydroxychloroquine," he concluded.

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