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https://www.medrxiv.org/content/10.1...558v1.full.pdf

Hydroxychloroquine [HCQ] in patients with COVID-19: an open-label, randomized, controlled trial

Done in China on 150 hospitalized patients. The HCQ arm was treated for 2 - 3 wks.

The endpoint was to see if their Covid test became negative sooner than the untreated arm. HCQ was given at 1200 mg on day one and 800 daily for the duration. This is a dose close to the high dose arm in Brazil that was halted because of EKG changes.

Covid testing was done on days 4, 7, 10, 14, 21 and 28

The treated patients did NOT have more rapid clearing of the virus at any of those dates.

Several other clinical measures were also followed.

Patients were assessed on each scheduled visit for vital signs, C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), Tumor necrosis factor (TNF)- α, Interleukin-6 (IL-6), complete blood cells count with differential, blood chemistry, coagulation panel, pulse oximetry, and respiratory symptoms.

At 28 days the symptom alleviation was the same in both arms.

Alleviation of clinical symptoms was
1) resolving from fever to an axillary temperature of ≤ 36.6 and;
2) normalization of SpO2 (>94% on room air) and;
3) disappearance of respiratory symptoms including nasal congestion, cough, sore throat, sputum production and shortness of breath.

However some patients were also on anti-virals.

A significant efficacy of HCQ on alleviating symptoms was observed when the confounding effects of anti-viral agents were removed in the post-hoc analysis

The authors do not report which symptoms were alleviated nor how rapidly other than saying "within the 28 day period"

This confounding factor in symptom measurement by anti-viral is not explained other than it was found. Other analysis checking for significant differences by removing other lab tests or other medications did not alter the no effect of HCQ finding

There were two statistically significant results between the arms.

1. The HCQ arm had more adverse effects. 30% of the treated group vs 9% of the not treated group. Most of the adverse effects were minor and diarrhea. There is no comment at all in the study about checking EKG or monitoring for QT changes.

2. The HCQ arm had a greater decrease in one lab test, CRP than the not treated arm. CRP is a measure of inflammation. Higher numbers are worse. Other measures of inflammation were also followed and are not reported as showing a difference in normalizing. The authors used the drop from initial CPR to final CPR. Notably the two arms while random had a difference in their initial CPR. The no HCQ group began at 7.4 while the treated group began at 9.9. This may be important as obviously the higher you start the more opportunity there is to drop more points. HCQ does have some anti-inflammatory actions, thus its use in rheumatology. So lowering a measure of inflammation is reasonable.

My opinions: This is a large study. It enrolled mild and moderately ill hospitalized patients. It was randomized. It may or may not be important that the median duration of symptoms before hospitalization was 16 days. The goal was to show that HCQ made patients virus negative and the result was it did not. Becoming virus negative was the claim that got the HCQ momentum going in the non-randomized study of 20 patients from France. This much larger study could not find any benefit to HCQ on the final nor any intermediate date extending out 4 weeks.

The finding of one lab test getting better more quickly in the treatment arm is valuable. A hint in a post-hoc analysis removing from analysis patients who also got anti-virals of more rapid clinical improvement is also important. The authors do not present any reason why anti-virals would make a difference.

The authors concluded that HCQ failed to achieve the goal being evaluated but encourage other studies to further evaluate for other possible benefits.