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Antimicrobial resistance (AMR) is a major public health threat that will cause an estimated 10 million deaths worldwide by 2050. Because antimicrobial use drives selection and transmission of AMR, there is an urgent need to continue to develop, evaluate, and implement effective, evidence-based antimicrobial stewardship (AMS) interventions that safely reduce antimicrobial use in both primary and secondary healthcare.

Background: Antivirals are infrequently prescribed in primary care for influenza-like-illness (ILI), mostly because of perceived ineffectiveness in real world primary care, and as individuals who will especially benefit have not been identified in independent trials. We aimed to determine whether adding antiviral treatment to usual primary care for patients with ILI reduces time to recovery overall and in key subgroups. Methods: We conducted an open-label, pragmatic, randomized controlled trial of adding oseltamivir to usual care in patients aged one year and older consulting with ILI in primary care. The primary endpoint was time to recovery (return to usual activities, with fever, head- and muscle-ache minor/absent), following a Bayesian piece-wise exponential model. Baseline nasopharyngeal swabs were analyzed after study completion. Findings: We ascertained the primary outcome for 3059 of the 3266 participants recruited in 15 European countries during three seasonal influenza seasons (2015-2018); 52.0% (1590/3059) had PCR-confirmed influenza infection. Time to recovery was shorter in those given oseltamivir by 1.02 days (95% Bayesian CI: 0.73-1.32). Hazard ratios of proportional benefit were similar across pre-specified subgroups; absolute benefit in time to recovery varied, with an estimated benefit of >2 days in older patients, more severe illness, comorbidity, or longer prior illness duration. The effect was independent of influenza status. Fewer antibiotics were prescribed in the oseltamivir arm (9.3% vs 13.2%, mean difference 4.0; 95% CI: 1.7-6.3), while nausea and/or vomiting was shorter in usual care patients (HR 0.92; 95% CI: 0.85-1.00). Interpretation: Primary care patients with ILI treated with oseltamivir recovered sooner than those managed by usual care alone, irrespective of influenza virus test results. Older, sicker, patients with comorbidities and longer prior illness duration showed greater absolute benefit. Trial Registration: The trial is registered with the ISRCTN Registry, number ISRCTN27908921. Funding Statement: CB reports receiving advisory board fees from Roche Molecular Systems and grant support from Roche Molecular Diagnostics; CB was supported by funding from an NIHR Protection Research Unit on Health Care Associated Infections and Antimicrobial Resistance, by the NIHR MedTech and In Vitro Diagnostics Co-Operative at Oxford NHS Foundation Trust, and by an NIHR Senior Investigator Award. TV is PI in a project that is funded by Innovative Medicines Initiative (IMI) of the European Union, in which Janssen Pharmaceutica is a partner and researcher in another IMI project in which Biocartis, Janssen, Biomerieux and Berry Consultants are partners. In addition he is co PI of a NIHR funded RCT, and PI in several studies funded by the Netherlands Organization of Health Research and Development. CL has received advisory boards fees from MSD and grant support from GILEAD, Global Bridges, Servier, Galenica-Olvos. Declaration of Interests: CB reports receiving advisory board fees from Roche Molecular Systems and grant support from Roche Molecular Diagnostics; CB was supported by funding from an NIHR Protection Research Unit on Health Care Associated Infections and Antimicrobial Resistance, by the NIHR MedTech and In Vitro Diagnostics Co-Operative at Oxford NHS Foundation Trust, and by an NIHR Senior Investigator Award. TV is PI in a project that is funded by Innovative Medicines Initiative (IMI) of the European Union, in which Janssen Pharmaceutica is a partner and researcher in another IMI project in which Biocartis, Janssen, Biomerieux and Berry Consultants are partners. In addition he is co PI of a NIHR funded RCT, and PI in several studies funded by the Netherlands Organization of Health Research and Development. CL has received advisory boards fees from MSD and grant support from GILEAD, Global Bridges, Servier, Galenica-Olvos. All other authors declare no conflict of interest. Ethics Approval Statement: All participating countries gained national research ethics committees and CTA approval as required. Ethics Ref: 15/SC/0138.

Background: The public and patients are primary contributors and beneficiaries of pandemic-relevant clinical research. We aimed to understand their views regarding participation in clinical research during a hypothetical influenza pandemic. Methods: International cross-sectional survey involving nationally representative samples in Belgium, Poland, Spain, Ireland, United Kingdom, Canada, Australia and New Zealand, using a scenario-based instrument during the 2017 regional influenza season. Descriptive and regression analyses were conducted. Findings: Of the 6804 respondents, 5572 (81·8%) thought pandemic-relevant research was important and 5089 (74·8 %) thought "special rules" should apply to make this research feasible. Respondents indicated willingness to take part in lower-risk (4715, 69·3%) and higher-risk (3585 52·7%) primary care, and lower-risk (4780, 70·3%) and higher-risk (4113, 60·4 %) Intensive Care Unit (ICU) study scenarios. For primary care studies, most (3972, 58·4%) participants preferred standard enrolment procedures such as prospective written informed consent, but 2327 (34·2%) thought simplified procedures would be acceptable. For ICU studies, 2800, (41·2%) preferred deferred consent and 2623 (38·6%) preferred prospective third-party consent. Greater knowledge about pandemics, trust in a health professional, trust in government, therapeutic misconception and experience of ICU as a patient or carer predicted increased willingness to participate in pandemic-relevant research. Interpretation: There is public support for pandemic-relevant clinical research. Tailored information, and initiatives to advance research literacy and maintain trust are required to support pandemic-relevant research participation and engagement. Funding: European Commission FP7 (grant agreement 602525); St Vincent's Anaesthesia Foundation; Cardiff University. Declaration of Interest: None declared. Ethical Approval: Ethical approval not required. The survey was administered outside of a healthcare setting by Ipsos Mori, an international ISO 20252 accredited market research company. Respondents voluntarily signed up in advance to the question panel and completion of the questionnaire indicated consent to participate. Respondents were able to refuse to participate in the questionnaire at any stage in the process. All data were processed in accordance with the UK Data Protection Act 1998.

Background Patients and the public are primary beneficiaries and contributors to pandemic-relevant clinical research. We aimed to understand their views about participation in and enrolment to comparative effectiveness research in primary and critical care settings during an influenza pandemic. Methods As part of the Platform for European Preparedness Against (Re-)emerging Epidemics (PREPARE), we conducted an international cross-sectional survey involving nationally representative samples of people in Belgium, Poland, Spain, Ireland, the UK, Canada, Australia, and New Zealand. Data were collected online using a scenario-based instrument during the 2017 regional influenza season. Scenarios involved research comparing routinely available treatments (low-risk research) and research to evaluate a new anti-viral treatment (higher risk). Descriptive and regression analyses were conducted. Findings 6804 individuals responded to the survey, of whom 5572 (82%) supported pandemic-relevant research and 5089 (75%) thought that “special rules” should apply to make it happen. Between 62% (Belgium, 530 of 850) and 67% (Spain, 572 of 850) of respondents would participate in low-risk primary care research. 48% (New Zealand, 408 of 850) to 58% (Australia, 491 of 851) would participate in a higher-risk primary care scenario. Between 66% (Spain, 558 of 850) and 75% (Australia, 639 of 851) of respondents would participate in low-risk intensive care unit (ICU) research. 54% (Spain, 445 of 850) to 66% (Australia, 559 of 851) would take part in a higher-risk ICU scenario. Therapeutic misconception was predictive of willingness to participate in all research scenarios (primary care low risk odds ratio 8·56 [95% CI 6·61–11·07], p Interpretation The public support pandemic-relevant clinical research. Public education, engagement, and policy initiatives to build research literacy are required to include a broader section of the population. Funding European Commission's FP7 programme (grant agreement 602525) for PREPARE, St Vincents Anaesthetic Foundation, Cardiff University.

Background Pandemics of infectious disease are recurrent events that impact global health and security. International, collaborative planning for future pandemics is a priority for public health officials, the research community, and the general public. However, little is known about the public's attitudes to participating in pandemic research and about their views on associated ethical dilemmas. We aimed to determine public perceptions about involvement in clinical research conducted in primary and critical care during a pandemic. Methods We conducted ten, 2 hour focus groups (6–10 participants each) and 16 one-to-one follow-up interviews involving 80 members of the public in Belgium, Poland, Spain, and the UK between Sept 1 and Dec 31, 2015. Recruitment was through local advertisement. Data were collected by local researchers who followed a scenario-based topic guide, transcribed verbatim and translated into English. We used framework analysis to identify the range and diversity of participants' perspectives. Findings Public understandings of pandemics were shaped by personal factors (illness during the H1N1 pandemic, experience of life-threatening illness) and social factors (historical references, media, public health information). Motivations to participate in pandemic research were influenced by altruism, therapeutic misconception, trust, and perception of risk. Use of routinely collected data and clinical samples without explicit prior consent was supported in principle, but was less acceptable when a profit motive was perceived. Participants recognised and appreciated the protections provided by ethically robust research procedures. However, they described having become desensitised to the importance and meaning of consent processes because of the frequency with which they authorise terms and conditions in everyday life. Participants proposed different models that might apply in a pandemic context (eg, advanced consent, verbal consent). Interpretation Public engagement in clinical research on pandemic planning is possible, useful, but as yet underdeveloped in Europe. Effective pandemic preparation for clinical research requires active public engagement to mitigate therapeutic misconception and engender trust. This bottom-up approach to ascertaining public views on pandemic research participation has identified support for minimising disproportionate research protection procedures for publicly funded, low risk studies. Funding European Union Seventh Framework Programme under the project Platform foR European Preparedness Against (Re-)emerging Epidemics (PREPARE) (grant agreement 602525).