News recently came out that hydroxychloroquine—an anti-malaria drug highlighted by President Donald Trump as a promising coronavirus therapy—disappointed in a China clinical trial on mild COVID-19 patients. But a careful examination of the study reveals a more complicated situation.

According to investigators, adding hydroxychloroquine (HCQ), a more tolerable form of chloroquine, on top of conventional therapy didn’t shorten the time to SARS-CoV-2 clearance in a 30-patient trial. No significant differences were observed across the two arms in terms of the time it took to bring body temperature to normal or the number of patients with disease progression as shown in CT scans.

However, most patients in the study's control group were actually treated with other antiviral therapies at the same time, including AbbVie’s HIV combo med Kaletra and flu drug Arbidol. Most, but not all, patients in the hydroxychloroquine group were also treated with Arbidol. All patients got interferon-alpha.

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Those meds had already been added to China National Health Commission’s COVID-19 treatment guidelines after showing some promise against the novel coronavirus. As a FiercePharma reader pointed out, “If that is the case, and even one of them has some effect on the virus, then one cannot tell if hydroxychloroquine worked or not.”

The study, published in the Journal of Zhejiang University (Chinese), found that the median time from hospitalization to conversion to virus-negative status was four days in the HCQ group, “comparable to” the two days observed in the control group. After one week of treatment, 13 patients (86.7%) had turned negative in a throat swab test, while 14 (93.3%) in the control group could say that. Again, no significant difference.

Then the question comes down to, do Kaletra or Arbidol work? At least Kaletra has stumbled in a 199-patient clinical trial in serious Chinese patients. But industry watchers also have expressed different opinions on ruling Kaletra a complete dud in the fight against COVID-19.

In a separate, retrospective study published in the Chinese Journal of Infectious Diseases on 134 patients conducted by several members of the same team, researchers reported that both Kaletra patients and Arbidol patients restored normal temperature after a median of six days, while those who got no antiviral med saw their temperatures drop after four days.

All three groups’ median time to viral clearance was seven days, and the disease progression rate on CT scans at day seven also showed no statistically significant difference.

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Separately, in another clinical trial on 44 mild-to-moderate COVID-19 patients, neither Kaletra nor Arbidol demonstrated benefits in viral clearance or symptom relief compared with no antiviral treatment.

Nevertheless, the majority of patients in the new study had restored normal temperature after just one day or turned viral negative after two days, the authors noted. Cross-trial comparison of these two important endpoints revealed that fever clearance as a major difference.

It’s possible that the virus itself has changed, reducing COVID-19 severity, the researchers speculated. The new study enrolled patients from Feb. 6 to 25, while the old one looked at those accepted between Jan. 20 and Feb. 6.

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Perhaps more importantly, the viral clearance and temperature-lowering data in the HCQ study's control arm were already quite impressive, reaching a “ceiling effect” that makes finding a better treatment more difficult, they wrote.

Let’s not forget the small sample size of just 30 patients. The new study’s authors argue that to reach a conclusion of whether HCQ works, a study needs to enroll around 900 patients, taking potential drop-out into consideration. That would be a major challenge during an ongoing pandemic, so they suggest testing whether the med can lower mortality rate in serious or critically-ill COVID-19 patients.

The World Health Organization is already planning a large-scale global trial, dubbed Solidarity, to test promising antivirals in thousands of patients around the globe. The treatments to be examined include chloroquine and hydroxychloroquine; Kaletra alone; a cocktail of Kaletra plus interferon-beta; and Gilead Sciences’ remdesivir.