Inadequate assessment of treatment harms and patient safety
Chloroquine, and its derivate HQ, are antimalarial drugs; HQ is approved by the Food and Drug Administration (FDA) since 195520and it is also important in the treatment of immune-mediated diseases such as lupus erythematosus and rheumatoid arthritis.25 Both drugs are known to induce irreversible retinal damage, cardiomyopathy and QTc prolongation, severe hypoglycemia and dermatologic adverse events.20 The severity of these adverse effects range from mild to severe; occasionally these agents have been found to cause death.
Since we can anticipate a set of adverse events that are highly relevant to patients and clinical practice, the proposal of RCTs should contain plans to systematically assess fully defined adverse events according to appropriate timeframes.12, 16, 26 For instance, QTc prolongation and drug-induced arrhythmias like torsades de pointes, are of concern in critically ill patients with COVID-1927and should, therefore, be carefully ascertained. Monitoring QTc through electrocardiographic tracings on a regular basis would represent a systematic approach to the problem; even if monitoring is required to be performed remotely for safety reasons. The systematic assessment of adverse events can improve the accuracy of estimates within trials28 while also minimizing bias.29Finally, the assessment of defined anticipated adverse events, together with their seriousness, severity and duration, would be more informative than the mere documentation of generic events.
In this study, we showed that retinopathy, cardiac and dermatologic adverse events, and hypoglycemia were planned to be assessed in a single clinical trial among the 51 trials that had been registered to evaluate the treatment with HQ or chloroquine for patients diagnosed with COVID-19. Outcomes of safety were not included among the outcomes defined in several of the proposed trials (24, 47%), while the remaining RCTs reported a non-specific approach of observation of safety outcomes. Based on these results, and the fact the many adverse effects are rare in small clinical trials, we are concerned that the evidence on the harms of these investigational drugs to patients diagnosed with COVID-19 may likely be incomplete and biased.