he COVID-19 outbreak became a public health emergency of international concern and a global pandemic very quickly. As of this writing, COVID-19 has infected more than 50 million people and caused 1.2 million deaths worldwide. Industry and academic researchers took prompt action to search for a treatment. Although more than 3,400 anti-COVID clinical trials have been launched globally, there is still no effective drug to cure COVID-19.

Key Takeaways

• COVID-19, caused by SARS-CoV-2, is a syndrome that affects many more organs and systems beyond pneumonia. Anti-viral drugs have not shown significant efficacy (based on disclosed clinical trial results). Abnormal blood clotting is a high-risk factor in severe COVID-19 patients, so timely anticoagulant therapy is important. Identification of early warning signals and early interventions are critical to prevent disease progression to severe status and then death.
• The first clinical trial of remdesivir was initiated in early February 2020 in Wuhan and enrolled 237 severe COVID-19 patients within one month. This trial provided valuable experience in fast trial set-up and execution, infectious disease laboratory assessment, investigational medicinal product supply, and staff security under pandemic conditions. It also reminds us how difficult it is to design a trial to combat a new infectious disease in its early stages.
• The major challenge to designing COVID-19 clinical trials was insufficient pre-clinical and early clinical research data to support initiating phase 3 studies on the basis of the urgent public health need to initiate trials quickly. It remains essential to consider the 4R rule –Right Patient, Right Drug, Right Dose, and Right Timing – in randomized controlled trial design. Adaptive platform and post-exposure prophylaxis trials were recommended COVID-19 study design approaches.

COVID-19 Clinical Trial Experience and Challenges

Tingting Shi (TigerMed), who led the remdesivir study in Wuhan, shared these experiences from conducting a clinical trial per GCP requirements during a pandemic:

• Randomized controlled trial (RCT) design with a feasible efficacy endpoint is recommended.
• Staff security is critical when conducting a clinical trial on an infectious disease; clinical research associates, investigators, and other study site staff must be provided with protective approaches and materials and be sufficiently trained in their use.
• Develop a business continuity plan to mitigate organizational and study risks presented by the pandemic.
• Manage infectious samples carefully (a temporary central lab was set up in Wuhan for this study).
• The investigational medicinal product (IMP) supply should be secured within the epidemic area, and the process of IMP management customized to the infectious disease.
• Establish an Independent Data & Safety Monitoring Board (DSMB) to assess patient safety and data integrity.

Although the result of this study (published in The Lancet in May 2020) did not show any clinical improvement or shortened hospitalization discharge time compared to placebo, it triggered deeper thinking into how to optimize study design and identify efficacy endpoints for COVID-19 trials.

COVID-19 Disease Mechanism and Treatment Strategy

Anti-viral drugs, including Lopinavir/Ritonavir, Remdesivir, and hydroxychloroquine (HCQ), did not show significant efficacy to treat COVID-19 based on published results. In the WHO Solidarity study with more than 12,000 COVID-19 patients enrolled worldwide, the arms of remdesivir, lopinavir, HCQ, and Lopinavir+interferon β-1a did not show significant clinical benefit (based on interim analysis results released October 15, 2020).

Glucocorticoid (e.g., dexamethasone) showed efficacy in reducing the 28-day death rate and shortening hospital discharge time in the RECOVERY study conducted in more than 10,000 COVID-19 patients in the U.K. Although anti-IL-6 monoclonal antibody demonstrated certain improvements in several single-arm studies with small sample sizes, it didn’t show significant efficacy in a randomized clinical trial.

Development strategies for COVID-19 therapies should consider disease mechanism, clinical symptoms, and abnormal laboratory test values. Comprehensive treatment, including oxygen therapy and supportive therapy, anti-virus therapy, anti-inflammatory therapy and correction of abnormal blood clotting, were all recommended per disease stage. Anti-viral treatments may be effective during the first two or three days after infection, but because many infections have no clinical symptoms in the early stage, these cases can be difficult to detect.

Clinical trials for SARS-COV-2 antibodies and other new COVID-19 therapies are ongoing. High-dose immune globulin (IVIG) showed clinical benefit in a retrospective study but more evidence from RCTs is desired. Vaccine research now holds significant hope for the future, based on results announced in November 2020 for two distinct vaccines.

Optimizing Study Design and Repurposing HCQ for COVID-19

The doses of hydroxychloroquine (HCQ) used in clinical trials were respectively reviewed via in vitro-in vivo translation, which disclosed that the clinical dose of HCQ used in trials could not reach the effective concentration in lung extracellular space compared to the positive in vitro experiment result.

Conclusion