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

Abstract

Background Doxycycline is often used for treating COVID-19 respiratory symptoms in the community despite an absence of evidence from clinical trials to support its use. We aimed to assess the efficacy of doxycycline to treat suspected COVID-19 in the community among people at high risk of adverse outcomes. Methods We did a national, open-label, multi-arm, adaptive platform randomised trial of interventions against COVID-19 in older people (PRINCIPLE) across primary care centres in the UK. We included people aged 65 years or older, or 50 years or older with comorbidities (weakened immune system, heart disease, hypertension, asthma or lung disease, diabetes, mild hepatic impairment, stroke or neurological problem, and self-reported obesity or body-mass index of 35 kg/m 2 or greater), who had been unwell (for ≤14 days) with suspected COVID-19 or a positive PCR test for SARS-CoV-2 infection in the community. Participants were randomly assigned using response adaptive randomisation to usual care only, usual care plus oral doxycycline (200 mg on day 1, then 100 mg once daily for the following 6 days), or usual care plus other interventions. The interventions reported in this manuscript are usual care plus doxycycline and usual care only; evaluations of other interventions in this platform trial are ongoing. The coprimary endpoints were time to first self-reported recovery, and hospitalisation or death related to COVID-19, both measured over 28 days from randomisation and analysed by intention to treat. This trial is ongoing and is registered with ISRCTN, 86534580. Findings The trial opened on April 2, 2020. Randomisation to doxycycline began on July 24, 2020, and was stopped on Dec 14, 2020, because the prespecified futility criterion was met; 2689 participants were enrolled and randomised between these dates. Of these, 2508 (93·3%) participants contributed follow-up data and were included in the primary analysis: 780 (31·1%) in the usual care plus doxycycline group, 948 in the usual care only group (37·8%), and 780 (31·1%) in the usual care plus other interventions group. Among the 1792 participants randomly assigned to the usual care plus doxycycline and usual care only groups, the mean age was 61·1 years (SD 7·9); 999 (55·7%) participants were female and 790 (44·1%) were male. In the primary analysis model, there was little evidence of difference in median time to first self-reported recovery between the usual care plus doxycycline group and the usual care only group (9·6 [95% Bayesian Credible Interval [BCI] 8·3 to 11·0] days vs 10·1 [8·7 to 11·7] days, hazard ratio 1·04 [95% BCI 0·93 to 1·17]). The estimated benefit in median time to first self-reported recovery was 0·5 days [95% BCI −0·99 to 2·04] and the probability of a clinically meaningful benefit (defined as ≥1·5 days) was 0·10. Hospitalisation or death related to COVID-19 occurred in 41 (crude percentage 5·3%) participants in th...

Efficacy of COVID-19 Treatments: A Bayesian Network Meta-Analysis of Randomized Controlled Trials

“…The SOC group with the largest number of patients ( 23 ) was used. Clinical results of the PRINCIPLE trial (ISRCTN86534580) were shown in three studies ( 28 – 30 ) comparing azithromycin, budesonide and doxycycline with SOC, respectively. Due to no overlap between the enrolment periods of the azithromycin and budesonide studies, we created a new SOC group by combining the two SOC groups and the PRINCIPLE trial was considered as a four-arm trial in the primary analysis.…”

“…Under the random-effects model, the estimated treatment effects relative to SOC were similar to those under the fixed-effects model but with wider credible intervals, e.g., tocilizumab with an OR of 0.91 (95% CrI [0.74,1.16]). In the sensitivity analysis by treating part A in the main randomization of RECOVERY ( 3 , 22 , 23 , 26 ), PRINCIPLE ( 28 – 30 ), REMAP-CAP ( 31 , 32 ), BLAZE-1 and two therapeutic-dose anticoagulation trials for critical and noncritical patients ( 36 , 37 ) as separated trials, all estimates were close to those in the primary analysis except for dexamethasone, which reported an OR of 0.97 (95% CrI [0.87,1.08]) in the primary analysis but 0.85 (95% CrI [0.76,0.95]) in the sensitivity analysis. The difference in the 28-day mortality rate between the SOC arm with the largest number of patients (22.4%, 1,162/5,181) and the SOC arm of the dexamethasone study ( 22 ) (25.7%, 1,110/4,321) mainly contributed to the discrepancy in the estimates of OR for dexamethasone vs. SOC.…”

“…Under the random-effects model, baricitinib plus remdesivir (OR 0.57, 95% CrI [0.25, 1.23]) and dexamethasone (OR 0.82, 95% CrI [0.58,1.25]) reported no significant difference from SOC, while colchicine (OR 0.40, 95% CrI [0.17, 0.91]), recombinant human GSCF (OR 0.40, 95% CrI [0.16, 0.78]) and tocilizumab (OR 0.72, 95% CrI [0.53,0.95]) yielded a significantly lower mechanical ventilation rate compared with SOC. Whether RECOVERY and PRINCIPLE were treated as multi-arm trials or multiple two-arm trials had no influence on the estimates of relative effects since the mechanical ventilation rates in the SOC groups of the four RECOVERY studies ( 3 , 22 , 23 , 26 ) were similar and so was the PRINCIPLE trial ( 28 – 30 ). For mild/moderate COVID-19 patients, colchicine (OR 0.43, 95% CrI [0.20, 0.84]), dexamethasone (OR 0.62, 95% CrI [0.51, 0.76]), recombinant human GCSF (OR 0.22, 95% CrI [0.12, 0.42]) and intravenous immunoglobulin (OR 0.44, 95% CrI [0.20, 0.95]) led to a lower mechanical ventilation rate.…”

PRINCIPLE trial demonstrates scope for in-pandemic improvement in primary care antibiotic stewardship: a retrospective sentinel network cohort study

“…The PRINCIPLE trial has provided a robust in-pandemic trials platform. 2 , 3 , 13 The strength of this analysis is that the RSC has good data quality and is able to capture routine data about RTIs and their incidence. 14,15…”

“…The UK, primary care, prospective adaptive Platform Randomised trial of INterventions against COVID-19 In older peoPLE (PRINCIPLE) 1 has reported that two antibiotics, azithromycin and doxycycline, show no meaningful benefit in patient-reported recovery for coronavirus 2019 disease (COVID-19). 2 , 3 Azithromycin was included in PRINCIPLE between 23 May and 30 November 2020; doxycycline between 24 July and 14 December.…”