Discussion
death
SECONDARY
The results of this randomized, controlled trial provide evidence which suggests that doxycycline reduces the need for ICU admission in hospitalized COVID-19 patients. The trial was carried out in challenging circumstances during the second wave of the COVID-19 pandemic in India defined by the rapid rise of the delta variant of SARS-CoV-2 [The main reasons for selecting doxycycline for this trial were its pleiotropic, anti-inflammatory and anti-microbial effects, robust safety profile and low cost. Approved in 1967, doxycycline shows minimal side effects [No difference was seen in the secondary outcome measure of death between the two treatment arms. Possible reasons include the insufficient power of the trial to detect differences in mortality and the observed difference in ICU admission rates, which unintentionally disadvantaged patients treated with SoC plus doxycycline compared to those treated with SoC only.This study suggests that the antimicrobial effects of doxycycline were not important in defining the need for ICU. Approximately 40% of patients were enrolled before and 60% after the start of the second wave in mid-March 2021 when the delta variant B.1.617.2 became dominant, suggesting that its therapeutic effect was independent of SARS-CoV-2 variants. Approximately 90% of patients in both study arms received proven antiviral drugs with activity against SARS-CoV-2. Our The UK platform trial, PRINCIPLE, to which some members of our study team contributed (SDG, JK, RD), found that doxycycline was not associated with reduced hospital admissions or death when used in the community in patients with suspected early COVID-19 [Severe COVID-19 that requires critical care is associated with a hyperinflammatory state [In addition to its potential pharmacodynamic effects and safety profile, the pharmacokinetic (PK) properties of doxycycline made it a good choice for this trial, especially its high bioavailability after oral dosing, short time required to achieve effective blood levels, a half-life of 12-25h, and strong tissue penetration into respiratory tissues, with reach into the intracellular space [The selection of doxycycline for this trial was also strongly driven by our intent to identify cost-effective therapies that would benefit patients across the globe and not just those in affluent countries which can afford the effective, yet very expensive, drugs for which efficacy against COVID-19 has been reported so far. In the UK, a 14-day course of 200 mg doxycycline costs £ 6.50, while in India it is less than £5.00. The observed reduction in ICU admissions, when extrapolated to the large numbers of patients progressing to severe forms of COVID-19, also has the potential for major cost-savings. This is especially relevant in countries like India, where the cost of ICU–based care provided by private sector hospitals is estimated at $255 per day [This study has also shown that randomized controlled trials can be done at minimal cost during a pandemic, and it provides proof of concept for the use of an online app as a means of reliably collecting data in multi-centre trials. The only unavoidable, but ultimately trivial, cost was that of the server which enabled secure access to the application that served as an online eCRF. We sought help from a large Indian pharmaceutical company (Cipla) which generously provided a small unrestricted grant to support a research coordinator to help initiate the study by facilitating communication. None of the investigators or their institutions sought any compensation for the time and resources used. The study and the approach we took had its limitations, the main being the absence of the intensity of monitoring that drug trials usually entail. However, as a real-world study, this trial was just as determined and able as the major COVID-19 platform trials to obtain accurate data. We also recognize that we could not undertake the planned interim analyses because of strained communications during the second peak in India, something that may have been easier to cope with had more centres been recruited (meaning less burden per centre) and/or had trial monitors been assigned to each site, albeit raising the cost of the trial. Whilst we were confident about the main outcome (need for ICU admission) and mortality, we were less confident about collecting some of the secondary endpoints, so did not feel it justified to analyse these outputs. We conclude, therefore, that the approach taken, including the use of the eCRF, is less suited for collection of finer study details, although adjustments to improve the functionality of the app should make it possible to collect more complex datasets.In summary, this study has shown that doxycycline prevents progression of COVID-19 to the point where ICU admission is needed. This comes with significant implications for both patients and health services, in particular in countries where, because of limited financial resources, ICU admission is dependent on accessibility and affordability rather than clinical indication. A similar study is needed to seek evidence of treatment on mortality, requiring large numbers of patients similar to those enrolled in well-funded, platform trials.