Publication Butler C, Lancet Respir Med, 2021 (published paper)
Dates: 2020-07-24 to 2020-12-14
Funding: Public/non profit (UK Research and Innovation; Department of Health and Social Care; National Institute for Health Research)
Conflict of interest: No
Multicenter / UK |
Follow-up duration (days): 28
|Inclusion criteria||Living in the community;
aged 65 years or older, or 50 years or older with comorbidities;
had ongoing symptoms (for ≤14 days);
PCR-confirmed SARS-CoV-2 infection or suspected COVID-19 (in accordance with the UK National Health Service [NHS] definition of high temperature, new continuous cough, or change in sense of smell or taste).
Comorbidities required for eligibility in people aged 50–64 years were:
weakened immune system;
asthma or lung disease;
mild hepatic impairment;
stroke or neurological problem;
self-reported obesity or body-mass index of 35 kg/m² or greater.
|Exclusion criteria||currently an inpatient in hospital;
almost recovered (general condition much improved and COVID-19 symptoms now mild or almost absent);
in the judgement of the recruiting clinician was deemed ineligible;
previously been assigned to a group in the PRINCIPLE trial;
already taking antibiotics for an acute condition;
if doxycycline was contraindicated
Initial dose: 200 mg orally once daily on day 1
Maintenance dose: 100 mg orally once daily for following 6 days
Standard care ( / )
Definition of Standard care: Usual care in the NHS for suspected uncomplicated COVID-19 in the community is largely supportive. Antibiotics are only recommended for suspected COVID-19 pneumonia if bacterial infection is suspected or if the patient is at high risk of adverse outcomes, in which case the guidelines recommend doxycycline
827 participants (n1=827 / n2= *)
|Characteristics of participants|
Mean age : NR
Severity : Mild: n=0 / Moderate: n=0/ Severe: n=0 Critical: n=0
|In the register|
1. Time taken to self-reported recovery, defined as the first instance that a participant reports feeling recovered from possible COVID-19
2. Hospitalisation and/or death
|In the report|
Time to first self-reported recovery within 28 days from random assignment; Hospital admission or death within 28 days of random assignment
Yes. In English
|Risk of bias
The overall risk of bias reported in the table corresponds to the highest risk of bias for the outcomes assessed for the systematic review
This trial is pending contact with authors.
In addition to the published article, the trial registries, study protocol, statistical analysis plan and supplementary materials were used in data extraction and assessment of risk of bias. This trial of doxycycline versus usual care for community treatment of suspected COVID-19 in people at increased risk of an adverse clinical course was part of the PRINCIPLE adaptive platform trial. There were no substantive differences between the article and the trial registries, study protocol and statistical analysis plan in population, procedures, interventions.
Quote: "The trial commenced with the primary outcome of hospitalisation or death related to COVID-19 within 28 days of randomisation. However, the proportion of patients requiring admission to hospital in the UK was lower than initially expected. Therefore, the trial management group and steering committee recommended amending the primary outcome to include a measure of illness duration. Duration of illness is an important outcome for patients and has important economic and social impacts. Furthermore, treatments that do not shorten illness duration are also unlikely to provide a benefit in COVID-19-related hospitalisations or deaths. This change received ethical approval on Sept 16, 2020, and was implemented before any interim analyses were done. Thus, the trial had two coprimary endpoints measured over 28 days from randomisation: time to first self-reported recovery (defined as the first instance that a participant reported feeling recovered), and hospitalisation or death related to COVID-19."
The published article reported comparisons of the doxycycline and usual care arms in both a primary analysis population (which included participants randomized to usual care before doxycycline arm was added to the platform trial) and a concurrent randomization analysis population (including only participants concurrently randomized to either doxycycline or usual care). It was determined that the latter concurrent randomization analysis population was most appropriate for the COVID NMA. The total number randomized, numbers missing from analysis and reasons were only reported in the usual care arm for the primary analysis population. Recruitment to the trial was terminated for futility.