Covid-19 living Data

Azithromycin vs Standard care/Placebo (RCT)

Mild outpatients

FOREST PLOTS -2022-04-29

Studies description

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
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 avalaible	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.

Trial NCT04381962
Publication ATOMIC2 - Hinks T, Lancet Respir Med (2021) (published paper)
Dates: 2020-06-03 to 2021-01-29
Funding: Mixed (NIHR Oxford BRC, University of Oxford and Pfizer Inc)
Conflict of interest: Yes

Methods
	RCT Blinding: Unblinded
	Location : Multicenter / UK Follow-up duration (days): 28
Inclusion criteria	aged at least 18 years, assessed by the attending clinical team as appropriate for ambulatory (outpatient) management clincial diagnosis of highly-probably or confirmed COVID-19 infection with onset of first symptoms within the last 14 days no medical history that might put the patient at significant risk able to understand written English and able to give informed consent
Exclusion criteria	known hypersensitivity to any Macrolide including azithromycin, ketolide antibiotic, or the excipients including an allergy to soya or peanuts known fructose intolerance, glucose-galactose malabsorption, or sucrose-isomaltose insufficiency currently on macrolide antibiotic (Clarithromycin, Azithromycin, Erythromycin, Telithromycin, Spiramycin) Elevated cardiac troponin at initial assessment suggestive of significant myocarditis evidence of QTc prolongation: QTc>480ms Significant electrolyte disturbance (e.g. hypokalemia K+<3.5 mmol/L) clinically relevant bradycardia (P<50 bpm), non-sustained ventricular tachycardia or unstable severe cardiac insufficiency currently on hydroxychloroquine or chloroquine
Interventions
	Treatment Azithromycin 500 mg orally once daily for 14 days
	Control Standard care
Participants
	Randomized participants : Azithromycin=147 Standard care=148
	Characteristics of participants N= 295 Mean age : NR 152 males Severity : Mild: n= 293/ Asymptomatic: n=0
Primary outcome
	In the register Proportion progressing to respiratory failure or death (all clinically-diagnosed participants) [ Time Frame: Determined at day 28 from randomisation.]
	In the report Proportion of participants with hospital admission or death from any cause within 28 days from randomisation
Documents avalaible	Protocol Yes. In English Statistical plan Yes Data-sharing willing stated in the publication:
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	Some concerns
General comment	In addition to the pre-print article, the trial registry, protocol and statistical analysis plan were used in data extraction and assessment of risk of bias. There were no differences between the article and the registry or protocol in population, procedures and interventions. The primary outcome in the pre-print article (proportion of participants with hospital admission or death from any cause) was changed on advice from the data safety monitoring committee and with ethical approval from the original primary outcome in the registry and protocols (proportion progressing to hospitalization with respiratory failure or death) due to lack of events at interim analysis. The sample size in the registry was recalculated in accordance WHO recommendations that a pilot phase with 100 patients would be sufficient to inform follow-on clinical research and reduced from 800 to 291. Some outcomes reported in the registry are not reported in the paper (mechanistic analysis of blood and nasal biomarkers). This study was updated on July 28th, 2021 with data from contact with authors and publication.

Trial NCT04332107
Publication Oldenburg CE, JAMA (2021) (published paper)
Dates: 2020-05-22 to 2021-03-16
Funding: Mixed (Bill & Melinda Gates Foundation, intervention drugs were donated by Pfizer Inc.)
Conflict of interest: No

Trial NCT04622891
Publication Rashad A, Scientific Reports (2021) (published paper)

Funding: Public/non profit (South Valley University, faculty of Medicine, Qena83523, Egypt)
Conflict of interest: No

Methods
	RCT Blinding: double blinding
	Location : Single center / Egypt Follow-up duration (days): 15
Inclusion criteria	mild COVID-19 according to WHO classification Oxygen saturation > 90% on room air Imaging shows less than 25% infiltrates on CT chest
Exclusion criteria	Patients <18 years patients with Oxygen saturation < 93% patients with Diabetes mellitus or heart failure patients on chemotherapy or immunosuppressive therapy
Interventions
	Treatment Azithromycin 500 mg orally once a day for 7 days Clarithromycin 500 mg orally twice a day for 7 days
	Control Standard care
Participants
	Randomized NR Analyzed 305 participants Azithromycin=107 Clarithromycin=99 Standard care=99
	Characteristics of participants N= 305 Mean age : NR 214 males Severity : Mild: n= 305/ Asymptomatic: n=0
Primary outcome
	In the register Time to fever control [ Time Frame: 15 days ] time to complete resolution of fever
	In the report NR
Documents avalaible	Protocol NR Statistical plan NR Data-sharing willing stated in the publication: Not reported
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	*
General comment	This study is pending contact with authors. No review-specific outcomes reported/extracted. The journal and pre-print articles was used in data extraction and risk of bias assessment. No protocol or statistical analysis plan was available. Consequently, there was no information on whether the trial was conducted and analyzed as planned. There was a large proportion of missing outcome data. The primary outcome, exclusion criteria and the proportion of participants randomized per arm were not reported. No outcome data were reported in a manner that allowed for extraction. This trial was updated on September 27th, 2021 with data from the peer-reviewed journal publication.

Methods
	RCT Blinding: quadruple blinding
	Location : Multicenter / USA Follow-up duration (days): 21
Inclusion criteria	Documented positive SARS-CoV-2 test result (nucleic acid amplification or antigen) within 7 days before enrollment not required to be symptomatic
Exclusion criteria	Younger than 18 years self-reported macrolide allergy concurrently taking hydroxychloroquine if they were older than 55 years (to reduce the potential risk of QT-interval prolongation) concurrently taking nelfinavir or warfarin currently pregnant (self-report) unable to receive study drug in the mail or to complete online questionnaires
Interventions
	Treatment Azithromycin 1.2 g orally once-off
	Control Placebo
Participants
	Randomized participants : Azithromycin=171 Placebo=92
	Characteristics of participants N= 263 Mean age : NR 86 males Severity : Mild: n= 245/ Asymptomatic: n=18
Primary outcome
	In the register Binary assessment of whether the participant is experiencing any symptoms at Day 14 (yes or no)
	In the report Self-reported absence of COVID-19 symptoms at day 14
Documents avalaible	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	Some concerns
General comment	In addition to the published article, the study registry, protocol, and statistical analysis plan were used in data extraction and risk of bias assessment. The study was terminated at interim analysis by the data monitoring board due to futility, consequently, planned sample size was not reached. There is no change from the trial registration in the intervention and control treatments. The primary outcome changed from hospitalization to absence of symptoms during the course of the trial, with consultation and approval by the data monitoring board.