Cochrane COVID-19 Study Register
Study record
ISRCTN86534580First Published: 2020 May 4Updated Date: 2021 Nov 4

Platform Randomised trial of INterventions against COVID-19 In older peoPLE (PRINCIPLE)

  1. Study Type
  2. Interventional
  3. Adaptive/Platform
  1. Study Aim
  2. Treatment and Management
  1. Study Design
  2. Parallel/Crossover
  1. Intervention Assignment
  2. Randomised
  1. Population (7)
  2. Male and Female
  3. Suspected COVID-19
  4. COVID-19
  5. Adult
  6. Aged (65+)
  1. Intervention (14)
  2. Hydroxychloroquine
  3. Usual Care
  4. Azithromycin
  5. Doxycycline
  6. Ivermectin
  1. Comparison (1)
  2. Usual Care
  1. Outcome (3)
  2. Symptom severity
  3. Death
  4. Hospital admission
Reference record

Platform Randomised trial of INterventions against COVID-19 In older people

EUCTR2020-001209-22-GB
Trial registry record
No Results
INTERVENTION: trade Name: plaquenil-Hydroxychloroquine Product Name: plaquenil-Hydroxychloroquine Pharmaceutical Form: film-coated tablet INN or Proposed INN: hydroxychloroquine Sulfate 200 mg Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 200- Trade Name: azithromycin Product Name: azithromycin Pharmaceutical Form: film-coated tablet INN or Proposed INN: azithromycin 250 mg or 500 mg Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 500- Trade Name: doxycycline Product Name: doxycycline Pharmaceutical Form: capsule, hard INN or Proposed INN: doxycycline hyclate equivalent to 100mg of Doxycycline base Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 100- CONDITION: suspected COVID-19 ; MedDRA version: 23.0 Level: lLT Classification code 10053983 Term: corona virus infection System Organ Class: 100000004862 Therapeutic area: diseases [C] - Virus Diseases [C02] PRIMARY OUTCOME: main Objective: to assess the effectiveness of trial treatments in reducing the need for hospital admission or death for patients aged =50 years with serious comorbidity, and aged =65 with or without comorbidity and suspected COVID-19 infection during time of prevalent COVID-19 infections. Primary end point(s): hospital admission or mortality related to suspected COVID-19. Secondary Objective: to explore whether trial treatment reduces; 1) Duration of severe symptoms; 2) Time taken to resumption of usual daily activities; 3) Contacts with the health services ; 4) Consumption of antibiotics; 5) Hospital assessment not leading to admission; 6) Oxygen administration; 7) Intensive Care Unit admission ; 8) Mechanical ventilation; 9) To determine if effects are specific to those with the infections syndrome but who test positive for COVID-19; 10) Duration of hospital admission ; Timepoint(s) of evaluation of this end point: within 28 days. SECONDARY OUTCOME: secondary end point(s): to explore whether trial treatment reduces the following: ; ; 1. Duration of severe symptoms; 2. Time taken to resumption of usual daily activities; ; Measured by daily online symptoms score and the day the patient reports they returned to usual activities.; ; 3. Contacts with health services; ; Reported by patients and captured by reports of patientsa€˜ medical records where the practice is a member of RSC.; ; 4. Consumption of antibiotics; ; Measured using bi-weekly reports from participants primary care medical records.; ; 5. Hospital assessment not leading to admission; 6. Oxygen administration; 7. Intensive Care Unit admission ; 8. Mechanical ventilation; ; All measured using patient report/carer report/medical record in primary care and hospital care. HES/ONS data linkage after 28 days where patients have been assessed in hospital. ; ; 9. To determine if effects are specific to those with the infections syndrome but who test positive for COVID-19.; ; Swab results for COVID-19 will indicate an a€œIntention to Treat Infecteda€? group within the overall cohort for sub analysis (Swab result available once processed from GP record and from PHE laboratory).; ; 10. Duration of hospital admission; Measured using patient report/carer report/medical record in primary care and hospital care. HES/ONS data linkage after 28 days where patients have been assessed in hospital. ; ; ; Timepoint(s) of evaluation of this end point: within 28 days INCLUSION CRITERIA: a€¢ Participant is willing and able to give informed consent for participation in the study. a€¢ Participant is willing to comply with all trial procedures a€¢ Onset of symptoms of possible COVID-19 in the community (continuous cough and/or high temperature) within 7 days of inclusion a€¢ Patients aged =50-64 years with any of the following listed comorbidities: - known weakened immune system due to a serious illness or medication (e.g. chemotherapy) - known heart disease - known asthma or lung disease - known diabetes not treated with insulin - known mild hepatic impairment - known stroke or neurological problem OR a€¢ Patients aged =65 with or without comorbidity Are the trial subjects under 18? no Number of subjects for this age range: 0 F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 500 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for
Reference record

Inhaled budesonide for COVID-19 in people at higher risk of adverse outcomes in the community: interim analyses from the PRINCIPLE trial (preprint)

Yu L-M, Bafadhel M, Dorward J, Hayward G, Saville BR, Gbinigie O, van Hecke O, Ogburn E, Evans PH, Thomas NPB, Patel MG, Berry N, Detry MA, Saunders CT, Fitzgerald M, Harris V, de Lusignan S, Andersson MI, Barnes PJ, Russell REK, Nicolau DV, Ramakrishnan S, Hobbs FDR, Butler CC
Unpublished article (preprint)
Report Results
BACKGROUND Inhaled budesonide has shown efficacy for treating COVID-19 in the community but has not yet been tested in effectiveness trials. METHODS We performed a multicenter, open-label, multi-arm, adaptive platform randomized controlled trial involving people aged ≥65 years, or ≥50 years with comorbidities, and unwell ≤14 days with suspected COVID-19 in the community (PRINCIPLE). Participants were randomized to usual care, usual care plus inhaled budesonide (800μg twice daily for 14 days), or usual care plus other interventions. The co-primary endpoints are time to first self-reported recovery, and hospitalization/death related to COVID-19, both measured over 28 days from randomisation and analysed using Bayesian models. RESULTS The trial opened on April 2, 2020. Randomization to inhaled budesonide began on November 27, 2020 and was stopped on March 31, 2021 based on an interim analysis using data from March 4, 2021. Here, we report updated interim analysis data from March 25, 2021, at which point the trial had randomized 4663 participants with suspected COVID-19. Of these, 2617 (56.1%) tested SARS-CoV-2 positive and contributed data to this interim budesonide primary analysis; 751 budesonide, 1028 usual care and 643 to other interventions. Time to first self-reported recovery was shorter in the budesonide group compared to usual care (hazard ratio 1.208 [95% BCI 1.076 - 1.356], probability of superiority 0.999, estimated benefit [95% BCI] of 3.011 [1.134 - 5.41] days). Among those in the interim budesonide primary analysis who had the opportunity to contribute data for 28 days follow up, there were 59/692 (8.5%) COVID-19 related hospitalizations/deaths in the budesonide group vs 100/968 (10.3%) in the usual care group (estimated percentage benefit, 2.1% [95% BCI -0.7% - 4.8%], probability of superiority 0.928). CONCLUSIONS In this updated interim analysis, inhaled budesonide reduced time to recovery by a median of 3 days in people with COVID-19 with risk factors for adverse outcomes. Once 28 day follow up is complete for all participants randomized to budesonide, final analyses of time to recovery and hospitalization/death will be published. (Funded by the National Institute of Health Research/ United Kingdom Research Innovation [MC_PC_19079]; PRINCIPLE ISRCTN number, ISRCTN86534580.)Competing Interest StatementDr. Bafadhel reports grants from AstraZeneca, personal fees from AstraZeneca, Chiesi, GSK, other from Albus Health, ProAxsis, outside the submitted work. Dr. Andersson reports grants from Prenetics and personal fees from Prenetics, outside the submitted work. Dr. Barnes reports grants and personal fees from AstraZeneca, grants and personal fees from Boehringer Ingelheim, personal fees from Teva, personal fees from Covis, during the conduct of the study. Dr. Russell is supported by the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre (BRC) and reports grants from AstraZeneca, personal fees from Boehringer Ingelheim, personal fees from Chiesi UK, personal fees from Glaxo-SmithKline, during the conduct of the study. Dr. Ramakrishnan reports grants and non-financial support from Oxford respiratory NIHR BRC, during the conduct of the study; non-financial support from AstraZeneca, personal fees from Australian Government Research Training Program, outside the submitted work. SdeL is Director of the Oxford-RCGP Research and Surveillance Centre. All other authors have no competing interests to declareClinical TrialISRCTN86534580Clinical Protocolshttps://www.principletrial.orgFunding StatementThe PRINCIPLE trial is funded by a grant to the University of Oxford from UK Research and Innovation and the Department of Health and Social Care through the National Institute for Health Research as part of the UK Government's rapid research response fund. The views expressed are those of the authors and not necessarily those of the National Institute for Health Research or the Department of Health and Social Care. Author DeclarationsI confirm all relevant ethical guidelines have b en followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:The UK Medicines and Healthcare products Regulatory Agency and the South Central-Berkshire Research Ethics Committee (Ref: 20/SC/0158) approved the trial protocol and all recruitment processes.All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.YesData can be shared with qualifying researchers who submit a proposal with a valuable research question as assessed by a committee formed from the TMG including senior statistical and clinical representation. A contract should be signed. [Preprints are preliminary reports of work that have not been peer reviewed. Refer to the original preprint or preprint server for specific information about the individual preprint.]
Reference record

A trial evaluating treatments for suspected coronavirus infection in people aged 50 years and above with pre-existing conditions and those aged 65 years and above

ISRCTN86534580
Trial registry record
No Results
Inclusion criteria: 1. Participant is willing and able to give informed consent for participation in the study 2. Participant is willing to comply with all trial procedures 3. Onset of symptoms of possible COVID-19 in the community (continuous cough and/or high temperature) should be within 7 days of inclusion 4. Patients aged =65 with or without comorbidity, and patients aged =50 years with the following listed comorbidities: 4.1. Known weakened immune system due to serious illness or infection (e.g. chemotherapy) 4.2. Known heart disease 4.3. Known asthma or lung disease 4.4. Known diabetes not treated with insulin 4.5. Known mild hepatic impairment 4.6. Known stroke or neurological problem The trial will initially be two-arm, comparing usual care to usual care with hydroxychloroquine treatment. The trial will be implemented in the first instance in practices that are already part of the RCGP RSC Network. Currently, over 500 practices are part of this network, with 100 already offering a sentinel viral swabbing service which is being scaled up and due to the pandemic, all practices in the UK have been asked to join the RCGP RSC Network. A platform trial, in contrast to say a traditional two-arm design, allows multiple arms to be considered simultaneously, and interventions can be dropped and replaced as evidence emerges for effectiveness or lack of it. The intent is to establish an on-going trial infrastructure within a master protocol that uses all the data already accumulated for the assessment of current and subsequently introduced interventions. New interventions will only be added after submission to the appropriate approval bodies. The PRINCIPLE trial will begin as a 1:1 randomised trial of usual care plus study-specific medication (in the first instance hydroxychloroquine) versus usual care alone but the study design has the capability to add additional interventions over time. The evaluation of any new interventions will be governed by the master protocol, including adaptive and decision criteria. In addition, the inclusion of any new interventions will require supplementary appendices to the protocol and SAP.The initial drug is hydroxychloroquine sulphate 200 mg tablets. The tablets are for oral administration. One tablet (200 mg) hydroxychloroquine to be taken twice daily for 7 days by mouth (14 tablets in total). Primary outcome: The need for hospital admission or death, for patients aged =50 years with comorbidity, and aged =65 with or without comorbidity and suspected COVID-19 infection during time of prevalent COVID-19 infections, measured by hospital admission or mortality related to suspected COVID-19 within 28 days
Reference record

Inhaled budesonide for COVID-19 in people at high risk of complications in the community in the UK (PRINCIPLE): a randomised, controlled, open-label, adaptive platform trial

Yu LM, Bafadhel M, Dorward J, Hayward G, Saville BR, Gbinigie O, Van Hecke O, Ogburn E, Evans PH, Thomas NPB, Patel MG, Richards D, Berry N, Detry MA, Saunders C, Fitzgerald M, Harris V, Shanyinde M, de Lusignan S, Andersson MI, Barnes PJ, Russell REK, Nicolau DV, Ramakrishnan S, Hobbs FDR, Butler CC, PRINCIPLE Trial Collaborative Group
Journal article
Report Results
BACKGROUND: A previous efficacy trial found benefit from inhaled budesonide for COVID-19 in patients not admitted to hospital, but effectiveness in high-risk individuals is unknown. We aimed to establish whether inhaled budesonide reduces time to recovery and COVID-19-related hospital admissions or deaths among people at high risk of complications in the community. METHODS: PRINCIPLE is a multicentre, open-label, multi-arm, randomised, controlled, adaptive platform trial done remotely from a central trial site and at primary care centres in the UK. Eligible participants were aged 65 years or older or 50 years or older with comorbidities, and unwell for up to 14 days with suspected COVID-19 but not admitted to hospital. Participants were randomly assigned to usual care, usual care plus inhaled budesonide (800 μg twice daily for 14 days), or usual care plus other interventions, and followed up for 28 days. Participants were aware of group assignment. The coprimary endpoints are time to first self-reported recovery and hospital admission or death related to COVID-19, within 28 days, analysed using Bayesian models. The primary analysis population included all eligible SARS-CoV-2-positive participants randomly assigned to budesonide, usual care, and other interventions, from the start of the platform trial until the budesonide group was closed. This trial is registered at the ISRCTN registry (ISRCTN86534580) and is ongoing. FINDINGS: The trial began enrolment on April 2, 2020, with randomisation to budesonide from Nov 27, 2020, until March 31, 2021, when the prespecified time to recovery superiority criterion was met. 4700 participants were randomly assigned to budesonide (n=1073), usual care alone (n=1988), or other treatments (n=1639). The primary analysis model includes 2530 SARS-CoV-2-positive participants, with 787 in the budesonide group, 1069 in the usual care group, and 974 receiving other treatments. There was a benefit in time to first self-reported recovery of an estimated 2·94 days (95% Bayesian credible interval [BCI] 1·19 to 5·12) in the budesonide group versus the usual care group (11·8 days [95% BCI 10·0 to 14·1] vs 14·7 days [12·3 to 18·0]; hazard ratio 1·21 [95% BCI 1·08 to 1·36]), with a probability of superiority greater than 0·999, meeting the prespecified superiority threshold of 0·99. For the hospital admission or death outcome, the estimated rate was 6·8% (95% BCI 4·1 to 10·2) in the budesonide group versus 8·8% (5·5 to 12·7) in the usual care group (estimated absolute difference 2·0% [95% BCI -0·2 to 4·5]; odds ratio 0·75 [95% BCI 0·55 to 1·03]), with a probability of superiority 0·963, below the prespecified superiority threshold of 0·975. Two participants in the budesonide group and four in the usual care group had serious adverse events (hospital admissions unrelated to COVID-19). INTERPRETATION: Inhaled budesonide improves time to recovery, with a chance of also reducing hospital admissions or deaths (although our results did not meet the superiority threshold), in people with COVID-19 in the community who are at higher risk of complications. FUNDING: National Institute of Health Research and United Kingdom Research Innovation
Reference record

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

Butler CC, Yu LM, Dorward J, Gbinigie O, Hayward G, Saville BR, Van Hecke O, Berry N, Detry MA, Saunders C, Fitzgerald M, Harris V, Djukanovic R, Gadola S, Kirkpatrick J, de Lusignan S, Ogburn E, Evans PH, Thomas NPB, Patel MG, Hobbs FDR, PRINCIPLE Trial Collaborative Group
Journal article(Butler, Yu, Gbinigie, Hayward, Van Hecke, Harris, de Lusignan, Ogburn, Hobbs) Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford, United Kingdom (Dorward) Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford, UK; Centre for the AIDS Programme of Research in South Africa (CAPRISA), University of KwaZulu-Natal, Durban, South Africa (Saville) Berry Consultants, Austin, TX, USA; Department of Biostatistics, Vanderbilt University School of Medicine, Nashville, TN, USA (Berry, Detry, Saunders, Fitzgerald) Berry Consultants, TX, Austin, United States (Djukanovic) Clinical and Experimental Science, National Institute for Health Research (NIHR) Southampton Biomedical Research Centre, Faculty of Medicine, University of Southampton, Southampton, United Kingdom (Gadola) Rheumatology and Pain Medicine, Bethesda Hospital, Basel, Switzerland (Kirkpatrick) Independent Researcher, Glatton, United Kingdom (Evans) College of Medicine and Health, University of Exeter, Exeter, UK; NIHR Clinical Research Network, NIHR, London, UK (Thomas) NIHR Clinical Research Network, NIHR, London, UK; Royal College of General Practitioners, London, UK (Patel) Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford, UK; School of Pharmacy and Medical Sciences, University of Bradford, Bradford, UK
Report Results
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. METHOD(S): 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/m2 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 the usual care plus doxycycline group and 43 (4.5%) in the usual care only group (estimated absolute percentage difference -0.5% [95% BCI -2.6 to 1.4]); there were five deaths (0.6%) in the usual care plus doxycycline group and two (0.2%) in the usual care only group. INTERPRETATION: In patients with suspected COVID-19 in the community in the UK, who were at high risk of adverse outcomes, treatment with doxycycline was not associated with clinically meaningful reductions in time to recovery or hospital admissions or deaths related to COVID-19, and should not be used as a routine treatment for COVID-19. FUNDING: UK Research and Innovation, Department of Health and Social Care, National Institute for Health Research.Copyright © 2021 Elsevier Ltd. All rights reserved
Copyright © 2021 Elsevier Ltd. All rights reserved
Reference record

A trial evaluating treatments for suspected coronavirus infection in people aged 50 years and above with pre-existing conditions and those aged 65 years and above

University of Oxford
Trial registry record
No Results
Inclusion criteria: 1. Participant is willing and able to give informed consent for participation in the study 2. Participant is willing to comply with all trial procedures 3. Onset of symptoms of possible COVID-19 in the community (continuous cough and/or high temperature) should be within 7 days of inclusion 4. Patients aged =65 with or without comorbidity, and patients aged =50 years with the following listed comorbidities: 4.1. Known weakened immune system due to serious illness or infection (e.g. chemotherapy) 4.2. Known heart disease 4.3. Known asthma or lung disease 4.4. Known diabetes not treated with insulin 4.5. Known mild hepatic impairment 4.6. Known stroke or neurological problem The trial will initially be two-arm, comparing usual care to usual care with hydroxychloroquine treatment. The trial will be implemented in the first instance in practices that are already part of the RCGP RSC Network. Currently, over 500 practices are part of this network, with 100 already offering a sentinel viral swabbing service which is being scaled up and due to the pandemic, all practices in the UK have been asked to join the RCGP RSC Network. A platform trial, in contrast to say a traditional two-arm design, allows multiple arms to be considered simultaneously, and interventions can be dropped and replaced as evidence emerges for effectiveness or lack of it. The intent is to establish an on-going trial infrastructure within a master protocol that uses all the data already accumulated for the assessment of current and subsequently introduced interventions. New interventions will only be added after submission to the appropriate approval bodies. The PRINCIPLE trial will begin as a 1:1 randomised trial of usual care plus study-specific medication (in the first instance hydroxychloroquine) versus usual care alone but the study design has the capability to add additional interventions over time. The evaluation of any new interventions will be governed by the master protocol, including adaptive and decision criteria. In addition, the inclusion of any new interventions will require supplementary appendices to the protocol and SAP.The initial drug is hydroxychloroquine sulphate 200 mg tablets. The tablets are for oral administration. One tablet (200 mg) hydroxychloroquine to be taken twice daily for 7 days by mouth (14 tablets in total). Primary outcome: The need for hospital admission or death, for patients aged =50 years with comorbidity, and aged =65 with or without comorbidity and suspected COVID-19 infection during time of prevalent COVID-19 infections, measured by hospital admission or mortality related to suspected COVID-19 within 28 days
Reference record

Platform Randomised trial of INterventions against COVID-19 In older peoPLE (PRINCIPLE): protocol for a randomised, controlled, open-label, adaptive platform, trial of community treatment of COVID-19 syndromic illness in people at higher risk

Hayward G, Butler CC, Yu LM, Saville BR, Berry N, Dorward J, Gbinigie O, van Hecke O, Ogburn E, Swayze H, Bongard E, Allen J, Tonner S, Rutter H, Tonkin-Crine S, Borek A, Judge D, Grabey J, de Lusignan S, Thomas NPB, Evans PH, Andersson MI, Llewelyn M, Patel M, Hopkins S, Hobbs FDR
Journal article(Hayward, Butler, Yu, Dorward, Gbinigie, Van Hecke, Ogburn, Swayze, Bongard, Allen, Tonner, Rutter, Tonkin-Crine, Borek, Judge, Grabey, De Lusignan, Patel, Hobbs) Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford, United Kingdom (Saville, Berry) Berry Consultants, Austin, TX, United States (Saville) Department of Biostatistics, Vanderbilt University School of Medicine, Nashville, TN, United States (Dorward) Centre for the Aids Programme of Research in South Africa, Durban, South Africa (De Lusignan) Department of Clinical and Experimental Medicine, University of Surrey, Guildford, United Kingdom (Thomas) Windrush Medical Practice, Witney, United Kingdom (Thomas) Royal College of General Practitioners, London, United Kingdom (Evans) St Leonard's Research Practice, Exeter, United Kingdom (Evans) University of Exeter Medical School, Exeter, United Kingdom (Andersson) Nuffield Department of Clinical Medicine, University of Oxford, Oxford, United Kingdom (Llewelyn) Department of Microbiology and Infection, University Hospitals Sussex NHS Foundation Trust, Brighton, United Kingdom (Llewelyn) Department of Global Health and Infection, Brighton and Sussex Medical School, Brighton, United Kingdom (Hopkins) Public Health England, London, United Kingdom
Report Results
INTRODUCTION: There is an urgent need to idenfy treatments for COVID-19 that reduce illness duration and hospital admission in those at higher risk of a longer illness course and complications. METHODS AND ANALYSIS: The Platform Randomised trial of INterventions against COVID-19 In older peoPLE trial is an open-label, multiarm, prospective, adaptive platform, randomised clinical trial to evaluate potential treatments for COVID-19 in the community. A master protocol governs the addition of new interventions as they become available, as well as the inclusion and cessation of existing intervention arms via frequent interim analyses. The first three interventions are hydroxychloroquine, azithromycin and doxycycline. Eligible participants must be symptomatic in the community with possible or confirmed COVID-19 that started in the preceding 14 days and either (1) aged 65 years and over or (2) aged 50-64 years with comorbidities. Recruitment is through general practice, health service helplines, COVID-19 'hot hubs' and directly through the trial website. Participants are randomised to receive either usual care or a study drug plus usual care, and outcomes are collected via daily online symptom diary for 28 days from randomisation. The research team contacts participants and/or their study partner following days 7, 14 and 28 if the online diary is not completed. The trial has two coprimary endpoints: time to first self-report of feeling recovered from possible COVID-19 and hospital admission or death from possible COVID-19 infection, both within 28 days from randomisation. Prespecified interim analyses assess efficacy or futility of interventions and to modify randomisation probabilities that allocate more participants to interventions with better outcomes. ETHICS AND DISSEMINATION: Ethical approval Ref: 20/SC/0158 South Central - Berkshire Research Ethics Committee; IRAS Project ID: 281958; EudraCT Number: 2020-001209-22. Results will be presented to policymakers and at conferences and published in peer-reviewed journals. TRIAL REGISTRATION NUMBER: ISRCTN86534580
Reference record

Azithromycin for community treatment of suspected COVID-19 in people at increased risk of an adverse clinical course in the UK (PRINCIPLE): a randomised, controlled, open-label, adaptive platform trial

PRINCIPLE Trial Collaborative Group
Journal article
Report Results
BACKGROUND: Azithromycin, an antibiotic with potential antiviral and anti-inflammatory properties, has been used to treat COVID-19, but evidence from community randomised trials is lacking. We aimed to assess the effectiveness of azithromycin to treat suspected COVID-19 among people in the community who had an increased risk of complications. METHODS: In this UK-based, primary care, open-label, multi-arm, adaptive platform randomised trial of interventions against COVID-19 in people at increased risk of an adverse clinical course (PRINCIPLE), we randomly assigned people aged 65 years and older, or 50 years and older with at least one comorbidity, who had been unwell for 14 days or less with suspected COVID-19, to usual care plus azithromycin 500 mg daily for three days, usual care plus other interventions, or usual care alone. The trial had two coprimary endpoints measured within 28 days from randomisation: time to first self-reported recovery, analysed using a Bayesian piecewise exponential, and hospital admission or death related to COVID-19, analysed using a Bayesian logistic regression model. Eligible participants with outcome data were included in the primary analysis, and those who received the allocated treatment were included in the safety analysis. The trial is registered with ISRCTN, ISRCTN86534580. FINDINGS: The first participant was recruited to PRINCIPLE on April 2, 2020. The azithromycin group enrolled participants between May 22 and Nov 30, 2020, by which time 2265 participants had been randomly assigned, 540 to azithromycin plus usual care, 875 to usual care alone, and 850 to other interventions. 2120 (94%) of 2265 participants provided follow-up data and were included in the Bayesian primary analysis, 500 participants in the azithromycin plus usual care group, 823 in the usual care alone group, and 797 in other intervention groups. 402 (80%) of 500 participants in the azithromycin plus usual care group and 631 (77%) of 823 participants in the usual care alone group reported feeling recovered within 28 days. We found little evidence of a meaningful benefit in the azithromycin plus usual care group in time to first reported recovery versus usual care alone (hazard ratio 1·08, 95% Bayesian credibility interval [BCI] 0·95 to 1·23), equating to an estimated benefit in median time to first recovery of 0·94 days (95% BCI -0·56 to 2·43). The probability that there was a clinically meaningful benefit of at least 1·5 days in time to recovery was 0·23. 16 (3%) of 500 participants in the azithromycin plus usual care group and 28 (3%) of 823 participants in the usual care alone group were hospitalised (absolute benefit in percentage 0·3%, 95% BCI -1·7 to 2·2). There were no deaths in either study group. Safety outcomes were similar in both groups. Two (1%) of 455 participants in the azothromycin plus usual care group and four (1%) of 668 participants in the usual care alone group reported admission to hospital during the trial, not related to COVID-19. INTERPRETATION: Our findings do not justify the routine use of azithromycin for reducing time to recovery or risk of hospitalisation for people with suspected COVID-19 in the community. These findings have important antibiotic stewardship implications during this pandemic, as inappropriate use of antibiotics leads to increased antimicrobial resistance, and there is evidence that azithromycin use increased during the pandemic in the UK. FUNDING: UK Research and Innovation and UK Department of Health and Social Care
Reference record

Erratum: department of Error (The Lancet (2021) 398(10303) (843–855), (S014067362101744X), (10.1016/S0140-6736(21)01744-X))

Journal article
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Yu L-M, Bafadhel M, Dorward J, et al. Inhaled budesonide for COVID-19 in people at high risk of complications in the community in the UK (PRINCIPLE): a randomised, controlled, open-label, adaptive platform trial. Lancet 2021; 398: 843–55—In this Article, in figure 1, “primary analysis” was corrected to “secondary analysis” in reference to the all participants population. In figure 2, the key was incorrect and has now been amended. In figure 3B, a typing error has been corrected in the p value for duration of illness. These corrections have been made to the online version as of Aug 18, 2021, and the printed version is correct. [This record is from Embase.com and was provided under license by Elsevier. All rights are retained by the license holder.]
Copyright 2021 Elsevier B.V., All rights reserved