Conclusion: Research challenges on the use of 4-aminoquinones in
SARS-CoV-2
The COVID-19 pandemic continues to pose a serious threat to public
health. Hydroxychloroquine’s established safety record and plausible
efficacy supported clinical investigation of its use for treatment of
COVID-19. Investigation of clinical outcomes of large numbers of
patients treated with low-dose hydroxychloroquine, as a result of
emergency use authorizations across the world, reached conflicting
conclusions. In general, the methodology of these studies were flawed;
even when randomized controlled trials have been conducted, selection
bias and residual confounding bias have been observed.[51] We
believe a high-dose short-term dosing of hydroxychloroquine maximizes
the likelihood of efficacy for treatment of COVID-19. Unfortunately, the
current climate is unlikely to allow for further rigorous and controlled
testing now that the lower doses have demonstrated poor efficacy. As a
result, hydroxychloroquine may never be adequately evaluated at doses or
in clinical settings where it may provide the most benefit. This outcome
underlies the importance of utilizing sound pharmacologic principles in
the initial design in clinical trials. The risks of hydroxychloroquine
at higher doses, particularly in an acutely ill population, likely
contributed to reluctance to utilize high-dose regimens in initial
studies. We believe the risks are not prohibitive if appropriate
exclusion criteria and monitoring is utilized. In particular, real-time
QTc monitoring could be considered in future studies.
Perhaps the most important lesson learnt from our collective experience
with hydroxychloroquine and COVID-19 is the danger of allowing public
and political pressure to influence trial design and study review
processes. When there is enormous pressure to produce results in a
timely fashion, any early findings are likely to receive intense
interest and scrutiny, thereby impacting the feasibility of future
trials. Interest in our trial declined as the media emphasized severe,
but rare, side effects and spurious endorsements were made by political
figures.[52] Conflicting reports of efficacy supported by results
made publicly available before peer-revision heightened confusion about
the efficacy and safety of the drug for treatment of COVID-19.[32]
This lead to correction of messaging, and in some cases retraction of
published studies after receiving further scrutiny.[38] Of
particular concern, the rapid ebb and flow of both positive and negative
information deepens public mistrust of the scientific community. These
forces had a substantial impact on the recruitment of patients to our
study and contributed to its early termination.[52] This same
scenario has reoccurred in the context of the Emergency Use
Authorization for convalescent plasma, despite ongoing NIH-funded phase
III trials to ascertain whether convalescent plasma is effective. We
hope that the critical COVID-19 vaccine studies do not meet a similar
fate. This experience could provide a valuable teaching module in
pharmacological and medical training programs in future to highlight the
pitfalls in abandoning scientific protocol and procedure, even with the
best intentions of ameliorating public health.
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