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).