High-dose chloroquine study for COVID-19 stopped with worse outcomes: high risk of cardiovascular events
17 April 2020. Related: COVID-19: investigational drugs, COVID-19.
Simon Collins, HIV i-Base
A randomised, double-blind phase 2 study of chloroquine (CQ) to treat COVID-19 in Brazil has discontinued further treatment in a high dose arm following early reports of significantly worse outcomes.
As with many new papers on COVID-19, the results are reported before peer-review. The paper had approximately 50 co-authors.
The recommendation from the Data and Safety Monitoring Board (DSMB) was based on the results from the first 81 participants (out of a planned 440) who were randomised to either high dose CQ (600 mg CQ twice daily for 10 days; total dose 12 g) or low dose CQ (450 mg for 5 days, twice daily only on the first days; total dose 2.7 g). All patients also received ceftriaxone and azithromycin.
History of heart diseases was higher in the high-dose group and participants older than 75 years (n=5) were also only included in this arm.
The high dose arm resulted in more QTc >500 ms (25%), and a trend toward higher mortality (17%) than the lower dosage. Two patients in the high dose arm had ventricular tachycardia before they died, . severe arrythmia associated when QTc is prolonged.
The mortality rate was 13.5% (95%CI: 6.9 to 23.0%) which overlaps with the CI of historical data from a meta-analysis of similar patients in two other studies not using CQ (95%CI: 14.5 to 19.2%). Two of the eleven deaths were in participants older than 75.
Many participants in this study were also taking oseltamivir (when seasonal influenza suspected) which can prong the QT interval.
The study also failed to show an antiviral effect of CQ with no evidence of viral clearance by day five, irrespective of dosage,
comment
It is difficult to understand the rationale for either dose in this study. One likely to produce toxicity problems and the other being too low to see benefit.
The controversial study by Gautret et al used a dose of 600 mg/day and the high dose recommended in Chinese guidelines uses 10 mg/day.
It is shocking to see the mortality reported for oldest participants who were at highest both for COVID-19 and CG side effects.
Note: a subsequent paper published on 29 April 2020 based on drug levels from intentional overdose studies reported that the high dose arm using 600 mg base chloroquine twice daily for ten days represented the standard malaria loading dose repeated 19 times at 12 hour intervals. [3]
This paper also suggests that there may have been confusion between salt and base weights. The Chinese guidelines on which this study was based recommended 500 mg salt twice daily (two tablets of 250 mg, comprising 155 mg base each). The dose used in this study in Brazil was almost twice as high.
Note: The comments to this article were updated on 23 May to include references to the PK study from Watson et al.
References
- Borba, M et al. Chloroquine diphosphate in two different dosages as adjunctive therapy of hospitalized patients with severe respiratory syndrome in the context of coronavirus (SARS-CoV-2) infection: Preliminary safety results of a randomized, double-blinded, phase IIb clinical trial (CloroCovid-19 Study). medRxix doi: 10.1101/2020.04.07.20056424.
https://www.medrxiv.org/content/10.1101/2020.04.07.20056424v1 - Gautret P et al. Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial. International Journal of Antimicrobial Agents 2020 (ahead of print).
https://www.sciencedirect.com/science/article/pii/S0924857920300996 - Watson JA et al. Concentration-dependent mortality of chloroquine in overdose. Before peer review. DOI: 10.1101/2020.04.24.20078303. (29 April 2020).
https://www.medrxiv.org/content/10.1101/2020.04.24.20078303v1