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Doxycycline for community treatment of suspected COVID-19 in people at high risk of adverse outcomes in the UK (PRINCIPLE): a randomised, controlled, open-label, adaptive platform trial

Our take —

This randomized controlled trial conducted in the UK provides strong evidence that doxycycline use did not affect time-to-recovery, risk of hospitalization or death within 28 days compared to usual care in patients with COVID-19 who were older than 65 years, or older than 50 years with a comorbidity that put them at higher risk of severe COVID-19. These findings suggest that routine use of doxycycline in the treatment of COVID-19 is unlikely to be of benefit, except plausibly in cases of known bacterial super-infection.

Study design

Randomized Controlled Trial

Study population and setting

Data for this study come from a subset of participants in the randomized trial of interventions against COVID-19 in older people (PRINCIPLE) trial, which compares therapies for the treatment of COVID-19 patients in the community who are a high-risk for severe disease. The study recruited 2689 patients in the United Kingdom between April 2 and December 14, 2020. Patients were aged 65+ years or 50+ years with comorbidities that increase the risk for severe COVID-19 disease, including being immunocompromised, heart disease, hypertension, lung disease, diabetes, hepatic impairment, neurological problem/stroke, or self-reported BMI >35 kg/m2, and were within 14 days of onset of symptoms with either suspected or PCR-confirmed COVID-19 at the time of enrollment. The study compared the 28-day hospitalization or mortality rates of patients receiving usual care (n = 1013) to patients receiving oral doxycycline in addition to usual care (n = 827). Due to a lower rate of hospitalization and death than anticipated, a Bayesian analysis of self-reported time to recovery was added as a study outcome before any interim analyses were done.

Summary of Main Findings

A Bayesian analysis method was employed in this study to allow for adaptive design of this multi-arm trial. 76.4% of patients who received doxycycline reported recovery within 28 days of randomization, compared to 75.6% in the usual care group. The median time to recovery was 9.6 days in the doxycycline group, vs. 10.1 days in the usual care group (HR 1.04, 95% credible interval 0.93 – 1.17). Probability that time to recovery was shorter in the doxycycline group was 0.74, and the probability of a clinically meaningful benefit (recovery hastened by >1.5 days) was 0.10, failing to meet the 0.99 threshold of superiority via the Bayesian analysis. Rate of hospitalization or death within 28 days was 5.3% in the doxycycline group, vs. 4.5% in the usual care group (absolute % difference = -0.5%, 95% credible interval -2.6 – 1.4), which gives a probability of superiority of 0.30.

Study Strengths

This study targets a population for which early outpatient treatment of COVID-19 may greatly reduce the morbidity associated with severe COVID-19 and a possible extended hospital or intensive care stay. The study was large, and part of a larger multiplatform, multi-center study, which has previously published findings about other pharmaceutical interventions for COVID-19, including hydroxychloroquine, azithromycin, and budesonide, which suggests that the results are reliable.

Limitations

Only 51.2% of the participants had a PCR-confirmed SARS-CoV-2 infection, which means that almost half the patients were enrolled based on clinical judgment, which means that many patients may not have had COVID-19. The overall rate of hospitalization and mortality was low overall, and so one of the co-primary endpoints was self-reported time to initial recovery. COVID-19 can occasionally continue to cause chronic symptoms after the initial recovery phase, and this was not closely monitored in this study, especially beyond 28 days.

Value added

This is the first major published randomized clinical trial regarding the use of doxycycline in an outpatient setting for mild cases of COVID-19 among persons at high risk for COVID-19 hospitalization and death and fails to show any benefit of doxycycline treatment in the community.

This review was posted on: 8 October 2021