Key 2 – Leverage Innovative trial designs
Traditional Phase II studies on COVID-19 are largely missing due to the
time pressure to produce clinically relevant results. Instead, many
teams have progressed directly to exploratory, open-labelled studies,
but these were often underpowered and led to inconclusive results. The
few robust Phase III trials that exist lack COVID-19 applicable Phase II
data and producing them may not be feasible under pandemic conditions.
Instead, simultaneous combination of supportive care and RCTs
(Randomized Clinical Trials) has been recommended as the way to find
effective and safe treatments for COVID-19 and any other future
outbreak.5 In addition, there are two types of trial
designs, particularly useful in infectious diseases, that all parties
involved in planning, designing and conducting COVID-19 like trials
should be aware of through educational programs:
Adaptive platform (multi-arm, multi-stage) design.
This approach studies multiple targeted therapies in the context of a
single disease in a continuous manner utilizing a shared control arm.
Individual investigational therapies are allowed to enter or leave the
platform on the basis of a decision algorithm (see Figure
1).6 The advantages to this approach include its
flexible design, which allows for multiple drugs to be evaluated,
reduced control population and potential for international deployment.
However, international deployment would require a high degree of
regulatory coordination and normalization of clinical operations across
many different settings.
2) Prophylactic design: These studies focus on a less-studied population
in the COVID-19 pandemic; the close contacts (household or healthcare
workers) of COVID-19 patients. These individuals have a high likelihood
of contracting disease and limiting spread of disease is critical for
managing this crisis. Prospective, cluster-randomized, double-blind,
placebo-controlled studies designed to investigate the efficacy of
anti-viral drugs in prevention of the secondary spread of disease to
close contacts have gained popularity through anti-influenza
trials.7 We designed a post exposure prophylaxis (PEP)
trial in Wuhan, China using hydroxychloroquine in mid-February 2020 (see
Figure 2), but it didn’t proceed due to the dwindling number of patients
in Wuhan. Scientifically, it would be better if hydroxychloroquine’s
antiviral effect toward SARS-CoV-2 was confirmed prior to a PEP trial.
Similarly designed trials and its variations, including pre-exposure
prophylaxis (PrEP) and progression prevention trial in diagnosed
patients using HCQ, are on-going in the US/UK (see Table 4).