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.