Hydroxychloroquine fails first meaningful RCT – April 16, 2020

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Salient Points

Hydroxychloroquine has been a controversial potential treatment for COVID-19.

As of writing this article, available evidence has consisted of in vitro data as well as some flawed studies from France. A new pre-print from China offers the most meaningful investigation of hydroxychloroquine to date.

According to the article, a study was conducted which involved 150 patients who were diagnosed positive for COVID-19 were administered with hydroxychloroquine. The dose of hydroxychloroquine used was 1,200 mg daily for three days, followed by 800 mg daily for 2-3 weeks. The 150 adult patients hospitalized with COVID-19 were randomized in an open-label, non-blinded fashion.

  • Hydroxychloroquine had no effect on the duration of viral detection
  • Clinically, there was no obvious beneficial effect of hydroxychloroquine.
  • Further studies on hydroxychloroquine will likely be emerging soon. For now, the best available evidence does not support the use of hydroxychloroquine in COVID-19.

Given evidence of harm without evidence of benefit, it seems prudent to restrict

the use of hydroxychloroquine to randomized controlled studies for the time being.

Detailed Summary

According to a study, 150 patients who were diagnosed positive for COVID-19 were administered with hydroxychloroquine. The dose of hydroxychloroquine used was 1,200 mg daily for three days, followed by 800 mg daily for 2-3 weeks.

This is considered to be a high dose of hydroxychloroquine (in comparison, the most commonly used regimen in the United States currently seems to be 800 mg on the first day followed by 400 mg daily for four days).

Note – Patients with severe renal or hepatic disease were excluded, to avoid potential

drug accumulation.

Patients were fairly well-matched at baseline. Most patients had relatively mild disease

(e.g. with a low rate of dyspnea or hypoxemia). Treatment was initiated late, an average

of 16-17 days after disease onset:

Numerous lab values were tracked among patients (e.g. CRP, ESR, IL-6, TNF-alpha). Hydroxychloroquine did not affect most of these parameters. There was a small difference in C-reactive protein levels, of unclear clinical or statistical significance.

The study had major limitations, for example:

  • Lack of blinding or placebo control.
  • Performance of the study by a contract research organization, rather than directly by the investigators.
  • Early termination due to recruitment problems and the impression of benefit
  • Relatively long delay between symptom onset and treatment initiation (16-17 days).

Nonetheless, this study currently represents the highest available quality of evidence

regarding hydroxychloroquine.

It is possible that earlier use of hydroxychloroquine could be beneficial (e.g.,

perhaps at the first signs of illness on an out-patient basis). This is under investigation and

additional data is likely to be forthcoming soon. Even if this does work in the outpatient

clinic, it would probably have little impact on the management of these patients within the

intensive care unit.

Conclusion

  • This is the first multicenter RCT investigating the use of hydroxychloroquine for

COVID-19. 150 adult patients hospitalized with COVID-19 were randomized in an

open-label, non-blinded fashion.

  • Hydroxychloroquine had no effect on the duration of viral detection (despite the use

of high doses and a prolonged 2-3 week course).

  • Clinically, there was no discernible beneficial effect from hydroxychloroquine.

However, hydroxychloroquine did appear to cause some side-effects (most notably

diarrhea).

  • Further studies on hydroxychloroquine will likely be emerging soon. For now, the

best available evidence does not support the use of hydroxychloroquine in COVID-

  1. Given evidence of harm without evidence of benefit, it seems prudent to restrict

the use of hydroxychloroquine to randomized controlled studies for the time being.

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