Covid-19 Living Data

Trial ISRCTN86534580 ; EudraCT 2020-001209-22
Publication PRINCIPLE - Butler C, Lancet (2021) (published paper)
Dates: 2020-05-22 to 2020-11-30
Funding: Public/non profit (UK Research and Innovation and UK Department of Health and Social Care)
Conflict of interest: No

Methods
	RCT Blinding: Unblinded
	Location : * / UK Follow-up duration (days): 28
Inclusion criteria	People in the community aged 65 years and older, or 50 years and older with comorbidities ongoing symptoms from PCR-confirmed or suspected COVID-19 (in accordance with the UK National Health Service [NHS] syndromic case definition of high temperature, a new, continuous cough, or a change in sense of smell or taste) Symptoms must have started within the past 14 days Comorbidities required for eligibility in those aged 50–65 years were as follows: known weakened immune system due to a serious illness or medication (eg, chemotherapy) known heart disease or a diagnosis of high blood pressure known asthma or lung disease known diabetes known mild hepatic impairment or known stroke or neurological problems.
Exclusion criteria	Already receiving acute antibiotics contraindication to azithromycin as identified in the summary of product characteristics and British National Formulary
Interventions
	Treatment Azithromycin 500 mg/day orally for 3 days
	Control Standard care
Participants
	Randomized NR Analyzed 1129 participants Standard care=629 Azithromycin=500
	Characteristics of participants N= 1129 Mean age : NR 486 males Severity : Mild: n= 1129/ Asymptomatic: n=0 Number of vaccinated participants: NR
Primary outcome
	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 Coprimary endpoints: time to first self-reported recovery within 28 days from random assignment, with time to recovery defined as the first instance that a participant reported feeling recovered; and hospital admission or death within 28 days of random assignment.
Documents available	Protocol Yes. In English Statistical plan Yes Data-sharing willing stated in the publication: Yes
Risk of bias Overall The overall risk of bias reported in the table corresponds to the highest risk of bias for the outcomes assessed for the systematic review	High
General comment	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 azithromycin 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 a single primary outcome: hospitalisation or death within 28 days. However, the proportions of people in the community requiring hospitalisation were much lower in the UK than seen in initial data from China, meaning a different outcome would be required to allow rapid evaluation of various interventions within reasonable sample sizes. The trial management and steering committees therefore recommended that the primary outcome be amended to include a measure of illness duration. This change was approved by the research ethics committee and the MHRA on September 16, 2020, and implemented before any interim analyses were done. Thus, the trial has coprimary endpoints, as follows: time to first self-reported recovery within 28 days from random assignment, with time to recovery defined as the first instance that a participant reported feeling recovered (ascertained by answering the question, “Do you feel recovered today? ie, symptoms associated with illness are no longer a problem. Yes/No”); and hospital admission or death within 28 days of random assignment." The published article reported comparisons of the azithromycin and usual care arms in both a primary analysis population (which included participants randomized to usual care before azithromycin arm was added to the platform trial) and a concurrent randomization analysis population (including only participants concurrently randomized to either azithromycin 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; therefore, the risk of bias due to missing data was unclear. Recruitment to the trial was terminated for futility.