The COVID-19 pandemic is a new and serious malady in search of effective therapies. Randomised clinical trials (RCTs) have been conducted to gauge the efficacy of dexamethasone and remdesivir. But SARS-CoV-2’s infectivity underscores the need for prophylactic treatments which can reduce the chances of transmission of the virus and/or prevent the development of the disease. In the absence of vaccines, many potential prophylactic therapies are being used in trials. However, prophylactic RCTs for a pandemic require in-depth consideration of many design issues in the planning stage.
Prophylactic RCT could be 1) Pre-exposure trials in persons at high risk for SARS-CoV-2 exposure with no symptoms, e.g. health care workers (HCW), or 2) Post-exposure trials in HCW or household contacts with no symptoms and with a documented exposure to a definite or clinically presumed case. Participants are enrolled only if they do not have a previously confirmed diagnosis of COVID-19.
It would not be particularly useful to select participants from the community population who are at a low risk of exposure to the pandemic or of developing COVID-19 and in whom the specificity of reported symptoms are low and the time of exposure to the virus is uncertain.
The selection of therapy is based on potential mechanisms: e.g. antiviral activity and immunomodulation. In Oxford COPCOV study in HCW, chloroquine (CQ) / hydroxychloroquine (HCQ) was used because of its significant antiviral activity against SARS-CoV-2 in cell culture, and the wide human experience of its use in malaria and rheumatoid arthritis. HCQ is given at a loading dose of 10mg base /kg on the first day, followed by 5mg base /kg for 90 days. In this study, the primary endpoint — the occurrence of RT-PCR-confirmed SARS-CoV-2 infection (with or without symptoms) would be compared between CQ/HCQ and placebo control. Serology antibody estimation at study enrollment would be useful in the ascertainment of the efficacy endpoint, based on a combination of observed symptoms of COVID-19 and RT-PCR tests.
Several herbal prophylactic studies use immunomodulators such as Tinospora cordifolia. Most trials conducted in low-risk healthy community populations are open comparative studies between those taking the drugs and those not taking the drugs. The efficacy endpoint — incidence of clinical symptoms without confirmation by RT-PCR — puts a question mark on the validity of the results.
The sample size in prophylactic trials should be large enough to provide reasonable evidence of the efficacy and safety of the intervention. The Oxford trial plans to recruit 20,000 participants – 10,000 each on CQ and HCQ and 20,000 on marching placebo, based on the assumption of 3% incidence of symptomatic COVID-19 during the trial period and the likelihood of the reduction of incidence by 23% in the CQ/HCQ group.
Prophylactic trials in a large number of participants need robust oversight and efficient project management of multiple clinical trial sites over several months. Critical processes – such as the ethics committee approval, informed consent, training, randomisation, blinding, supervised drug administration, compliance check by tablet count and drug levels, mobile app-based reporting of symptoms and adverse events, monthly follow-up to assess critical data on efficacy and safety, nose and throat swab for RT-PCR and antibody estimation – require meticulous planning and team effort to ensure the quality and validity of prophylactic trials.