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Roger J Lewis - One of the best experts on this subject based on the ideXlab platform.
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oseltamivir plus usual care versus usual care for influenza like Illness in primary care an open label pragmatic randomised controlled trial
The Lancet, 2020Co-Authors: Christopher Collett Butler, Adrianus W. M. Van Der Velden, Emily Bongard, Johanna Cook, Nick A Francis, Jane Holmes, Roger J Lewis, Benjamin R Saville, Samuel CoenenAbstract:BACKGROUND: Antivirals are infrequently prescribed in European primary care for Influenza-Like Illness, mostly because of perceived ineffectiveness in real world primary care and because 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 Influenza-Like Illness reduces time to recovery overall and in key subgroups. METHODS: We did an open-label, pragmatic, adaptive, randomised controlled trial of adding oseltamivir to usual care in patients aged 1 year and older presenting with Influenza-Like Illness in primary care. The primary endpoint was time to recovery, defined as return to usual activities, with fever, headache, and muscle ache minor or absent. The trial was designed and powered to assess oseltamivir benefit overall and in 36 prespecified subgroups defined by age, comorbidity, previous symptom duration, and symptom severity, using a Bayesian piece-wise exponential primary analysis model. The trial is registered with the ISRCTN Registry, number ISRCTN 27908921. FINDINGS: Between Jan 15, 2016, and April 12, 2018, we recruited 3266 participants in 15 European countries during three seasonal influenza seasons, allocated 1629 to usual care plus oseltamivir and 1637 to usual care, and ascertained the primary outcome in 1533 (94%) and 1526 (93%). 1590 (52%) of 3059 participants had PCR-confirmed influenza infection. Time to recovery was shorter in participants randomly assigned to oseltamivir (hazard ratio 1·29, 95% Bayesian credible interval [BCrI] 1·20-1·39) overall and in 30 of the 36 prespecified subgroups, with estimated hazard ratios ranging from 1·13 to 1·72. The estimated absolute mean benefit from oseltamivir was 1·02 days (95% [BCrI] 0·74-1·31) overall, and in the prespecified subgroups, ranged from 0·70 (95% BCrI 0·30-1·20) in patients younger than 12 years, with less severe symptoms, no comorbidities, and shorter previous Illness duration to 3·20 (95% BCrI 1·00-5·50) in patients aged 65 years or older who had more severe Illness, comorbidities, and longer previous Illness duration. Regarding harms, an increased burden of vomiting or nausea was observed in the oseltamivir group. INTERPRETATION: Primary care patients with Influenza-Like Illness treated with oseltamivir recovered one day sooner on average than those managed by usual care alone. Older, sicker patients with comorbidities and longer previous symptom duration recovered 2-3 days sooner. FUNDING: European Commission's Seventh Framework Programme.
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oseltamivir plus usual care versus usual primary care for influenza like Illness an open label pragmatic randomized controlled trial
Social Science Research Network, 2019Co-Authors: Christopher C Butler, Emily Bongard, Johanna Cook, Nick A Francis, Jane Holmes, Roger J Lewis, Benjamin R Saville, Samuel Coenen, Alike W Van Der Velden, Maciek GodyckicwirkoAbstract: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.
Emily Bongard - One of the best experts on this subject based on the ideXlab platform.
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oseltamivir plus usual care versus usual care for influenza like Illness in primary care an open label pragmatic randomised controlled trial
The Lancet, 2020Co-Authors: Christopher Collett Butler, Adrianus W. M. Van Der Velden, Emily Bongard, Johanna Cook, Nick A Francis, Jane Holmes, Roger J Lewis, Benjamin R Saville, Samuel CoenenAbstract:BACKGROUND: Antivirals are infrequently prescribed in European primary care for Influenza-Like Illness, mostly because of perceived ineffectiveness in real world primary care and because 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 Influenza-Like Illness reduces time to recovery overall and in key subgroups. METHODS: We did an open-label, pragmatic, adaptive, randomised controlled trial of adding oseltamivir to usual care in patients aged 1 year and older presenting with Influenza-Like Illness in primary care. The primary endpoint was time to recovery, defined as return to usual activities, with fever, headache, and muscle ache minor or absent. The trial was designed and powered to assess oseltamivir benefit overall and in 36 prespecified subgroups defined by age, comorbidity, previous symptom duration, and symptom severity, using a Bayesian piece-wise exponential primary analysis model. The trial is registered with the ISRCTN Registry, number ISRCTN 27908921. FINDINGS: Between Jan 15, 2016, and April 12, 2018, we recruited 3266 participants in 15 European countries during three seasonal influenza seasons, allocated 1629 to usual care plus oseltamivir and 1637 to usual care, and ascertained the primary outcome in 1533 (94%) and 1526 (93%). 1590 (52%) of 3059 participants had PCR-confirmed influenza infection. Time to recovery was shorter in participants randomly assigned to oseltamivir (hazard ratio 1·29, 95% Bayesian credible interval [BCrI] 1·20-1·39) overall and in 30 of the 36 prespecified subgroups, with estimated hazard ratios ranging from 1·13 to 1·72. The estimated absolute mean benefit from oseltamivir was 1·02 days (95% [BCrI] 0·74-1·31) overall, and in the prespecified subgroups, ranged from 0·70 (95% BCrI 0·30-1·20) in patients younger than 12 years, with less severe symptoms, no comorbidities, and shorter previous Illness duration to 3·20 (95% BCrI 1·00-5·50) in patients aged 65 years or older who had more severe Illness, comorbidities, and longer previous Illness duration. Regarding harms, an increased burden of vomiting or nausea was observed in the oseltamivir group. INTERPRETATION: Primary care patients with Influenza-Like Illness treated with oseltamivir recovered one day sooner on average than those managed by usual care alone. Older, sicker patients with comorbidities and longer previous symptom duration recovered 2-3 days sooner. FUNDING: European Commission's Seventh Framework Programme.
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oseltamivir plus usual care versus usual primary care for influenza like Illness an open label pragmatic randomized controlled trial
Social Science Research Network, 2019Co-Authors: Christopher C Butler, Emily Bongard, Johanna Cook, Nick A Francis, Jane Holmes, Roger J Lewis, Benjamin R Saville, Samuel Coenen, Alike W Van Der Velden, Maciek GodyckicwirkoAbstract: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.
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antivirals for influenza like Illness a randomised controlled trial of clinical and cost effectiveness in primary care alic4 e the alic4 e protocol
BMJ Open, 2018Co-Authors: Emily Bongard, Philippe Beutels, Johanna Cook, Alike W Van Der Velden, Ben Saville, Rune Aabenhus, Curt Brugman, Slawomir ChlabiczAbstract:Introduction Effective management of seasonal and pandemic influenza is a high priority internationally. Guidelines in many countries recommend antiviral treatment for older people and individuals with comorbidity at increased risk of complications. However, antivirals are not often prescribed in primary care in Europe, partly because its clinical and cost effectiveness has been insufficiently demonstrated by non-industry funded and pragmatic studies. Methods and analysis Antivirals for Influenza-Like Illness? An rCt of Clinical and Cost effectiveness in primary CarE is a European multinational, multicentre, open-labelled, non-industry funded, pragmatic, adaptive-platform, randomised controlled trial. Initial trial arms will be best usual primary care and best usual primary care plus treatment with oseltamivir for 5 days. We aim to recruit at least 2500 participants ≥1 year presenting with Influenza-Like Illness (ILI), with symptom duration ≤72 hours in primary care over three consecutive periods of confirmed high influenza incidence. Participant outcomes will be followed up to 28 days by diary and telephone. The primary objective is to determine whether adding antiviral treatment to best usual primary care is effective in reducing time to return to usual daily activity with fever, headache and muscle ache reduced to minor severity or less. Secondary objectives include estimating cost-effectiveness, benefits in subgroups according to age ( 64 years), severity of symptoms at presentation (low, medium and high), comorbidity (yes/no), duration of symptoms (≤48 hours/>48–72 hours), complications (hospital admission and pneumonia), use of additional prescribed medication including antibiotics, use of over-the-counter medicines and self-management of ILI symptoms. Ethics and dissemination Research ethics committee (REC) approval was granted by the NRES Committee South Central (Oxford B) and Clinical Trial Authority (CTA) approval by The Medicines and Healthcare products Regulatory Agency. All participating countries gained national REC and CTA approval as required. Dissemination of results will be through peer-reviewed scientific journals and conference presentations. Trial registration number ISRCTN27908921; Pre-results.
Johanna Cook - One of the best experts on this subject based on the ideXlab platform.
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oseltamivir plus usual care versus usual care for influenza like Illness in primary care an open label pragmatic randomised controlled trial
The Lancet, 2020Co-Authors: Christopher Collett Butler, Adrianus W. M. Van Der Velden, Emily Bongard, Johanna Cook, Nick A Francis, Jane Holmes, Roger J Lewis, Benjamin R Saville, Samuel CoenenAbstract:BACKGROUND: Antivirals are infrequently prescribed in European primary care for Influenza-Like Illness, mostly because of perceived ineffectiveness in real world primary care and because 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 Influenza-Like Illness reduces time to recovery overall and in key subgroups. METHODS: We did an open-label, pragmatic, adaptive, randomised controlled trial of adding oseltamivir to usual care in patients aged 1 year and older presenting with Influenza-Like Illness in primary care. The primary endpoint was time to recovery, defined as return to usual activities, with fever, headache, and muscle ache minor or absent. The trial was designed and powered to assess oseltamivir benefit overall and in 36 prespecified subgroups defined by age, comorbidity, previous symptom duration, and symptom severity, using a Bayesian piece-wise exponential primary analysis model. The trial is registered with the ISRCTN Registry, number ISRCTN 27908921. FINDINGS: Between Jan 15, 2016, and April 12, 2018, we recruited 3266 participants in 15 European countries during three seasonal influenza seasons, allocated 1629 to usual care plus oseltamivir and 1637 to usual care, and ascertained the primary outcome in 1533 (94%) and 1526 (93%). 1590 (52%) of 3059 participants had PCR-confirmed influenza infection. Time to recovery was shorter in participants randomly assigned to oseltamivir (hazard ratio 1·29, 95% Bayesian credible interval [BCrI] 1·20-1·39) overall and in 30 of the 36 prespecified subgroups, with estimated hazard ratios ranging from 1·13 to 1·72. The estimated absolute mean benefit from oseltamivir was 1·02 days (95% [BCrI] 0·74-1·31) overall, and in the prespecified subgroups, ranged from 0·70 (95% BCrI 0·30-1·20) in patients younger than 12 years, with less severe symptoms, no comorbidities, and shorter previous Illness duration to 3·20 (95% BCrI 1·00-5·50) in patients aged 65 years or older who had more severe Illness, comorbidities, and longer previous Illness duration. Regarding harms, an increased burden of vomiting or nausea was observed in the oseltamivir group. INTERPRETATION: Primary care patients with Influenza-Like Illness treated with oseltamivir recovered one day sooner on average than those managed by usual care alone. Older, sicker patients with comorbidities and longer previous symptom duration recovered 2-3 days sooner. FUNDING: European Commission's Seventh Framework Programme.
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oseltamivir plus usual care versus usual primary care for influenza like Illness an open label pragmatic randomized controlled trial
Social Science Research Network, 2019Co-Authors: Christopher C Butler, Emily Bongard, Johanna Cook, Nick A Francis, Jane Holmes, Roger J Lewis, Benjamin R Saville, Samuel Coenen, Alike W Van Der Velden, Maciek GodyckicwirkoAbstract: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.
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antivirals for influenza like Illness a randomised controlled trial of clinical and cost effectiveness in primary care alic4 e the alic4 e protocol
BMJ Open, 2018Co-Authors: Emily Bongard, Philippe Beutels, Johanna Cook, Alike W Van Der Velden, Ben Saville, Rune Aabenhus, Curt Brugman, Slawomir ChlabiczAbstract:Introduction Effective management of seasonal and pandemic influenza is a high priority internationally. Guidelines in many countries recommend antiviral treatment for older people and individuals with comorbidity at increased risk of complications. However, antivirals are not often prescribed in primary care in Europe, partly because its clinical and cost effectiveness has been insufficiently demonstrated by non-industry funded and pragmatic studies. Methods and analysis Antivirals for Influenza-Like Illness? An rCt of Clinical and Cost effectiveness in primary CarE is a European multinational, multicentre, open-labelled, non-industry funded, pragmatic, adaptive-platform, randomised controlled trial. Initial trial arms will be best usual primary care and best usual primary care plus treatment with oseltamivir for 5 days. We aim to recruit at least 2500 participants ≥1 year presenting with Influenza-Like Illness (ILI), with symptom duration ≤72 hours in primary care over three consecutive periods of confirmed high influenza incidence. Participant outcomes will be followed up to 28 days by diary and telephone. The primary objective is to determine whether adding antiviral treatment to best usual primary care is effective in reducing time to return to usual daily activity with fever, headache and muscle ache reduced to minor severity or less. Secondary objectives include estimating cost-effectiveness, benefits in subgroups according to age ( 64 years), severity of symptoms at presentation (low, medium and high), comorbidity (yes/no), duration of symptoms (≤48 hours/>48–72 hours), complications (hospital admission and pneumonia), use of additional prescribed medication including antibiotics, use of over-the-counter medicines and self-management of ILI symptoms. Ethics and dissemination Research ethics committee (REC) approval was granted by the NRES Committee South Central (Oxford B) and Clinical Trial Authority (CTA) approval by The Medicines and Healthcare products Regulatory Agency. All participating countries gained national REC and CTA approval as required. Dissemination of results will be through peer-reviewed scientific journals and conference presentations. Trial registration number ISRCTN27908921; Pre-results.
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a trial like alic4e why design a platform response adaptive open randomised controlled trial of antivirals for influenza like Illness
ERJ Open Research, 2018Co-Authors: Christopher C Butler, Johanna Cook, Benjamin R Saville, Samuel Coenen, Alike W Van Der Velden, Jane Homes, Menno De Jong, Paul Little, Herman Goossens, Philippe BeutelsAbstract:ALIC4E is the first publicly funded, multicountry, pragmatic study determining whether antivirals should be routinely prescribed for Influenza-Like Illness in primary care. The trial aims to go beyond determining the average treatment effect in a population to determining effects in patients with combinations of participant characteristics (age, symptom duration, Illness severity, and comorbidities). It is one of the first platform, response-adaptive, open trial designs implemented in primary care, and this article aims to provide an accessible description of key aspects of the study design. 1) The platform design allows the study to remain relevant to evolving circumstances, with the ability to add treatment arms. 2) Response adaptation allows the proportion of participants with key characteristics allocated to study arms to be altered during the course of the trial according to emerging outcome data, so that participants' information will be most useful, and increasing their chances of receiving the trial intervention that will be most effective for them. 3) Because the possibility of taking placebos influences participant expectations about their treatment, and determining effects of the interventions on patient help seeking and adherence behaviour in real-world care is critical to estimates of cost-effectiveness, ALIC4E is an open-label trial.
Samuel Coenen - One of the best experts on this subject based on the ideXlab platform.
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oseltamivir plus usual care versus usual care for influenza like Illness in primary care an open label pragmatic randomised controlled trial
The Lancet, 2020Co-Authors: Christopher Collett Butler, Adrianus W. M. Van Der Velden, Emily Bongard, Johanna Cook, Nick A Francis, Jane Holmes, Roger J Lewis, Benjamin R Saville, Samuel CoenenAbstract:BACKGROUND: Antivirals are infrequently prescribed in European primary care for Influenza-Like Illness, mostly because of perceived ineffectiveness in real world primary care and because 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 Influenza-Like Illness reduces time to recovery overall and in key subgroups. METHODS: We did an open-label, pragmatic, adaptive, randomised controlled trial of adding oseltamivir to usual care in patients aged 1 year and older presenting with Influenza-Like Illness in primary care. The primary endpoint was time to recovery, defined as return to usual activities, with fever, headache, and muscle ache minor or absent. The trial was designed and powered to assess oseltamivir benefit overall and in 36 prespecified subgroups defined by age, comorbidity, previous symptom duration, and symptom severity, using a Bayesian piece-wise exponential primary analysis model. The trial is registered with the ISRCTN Registry, number ISRCTN 27908921. FINDINGS: Between Jan 15, 2016, and April 12, 2018, we recruited 3266 participants in 15 European countries during three seasonal influenza seasons, allocated 1629 to usual care plus oseltamivir and 1637 to usual care, and ascertained the primary outcome in 1533 (94%) and 1526 (93%). 1590 (52%) of 3059 participants had PCR-confirmed influenza infection. Time to recovery was shorter in participants randomly assigned to oseltamivir (hazard ratio 1·29, 95% Bayesian credible interval [BCrI] 1·20-1·39) overall and in 30 of the 36 prespecified subgroups, with estimated hazard ratios ranging from 1·13 to 1·72. The estimated absolute mean benefit from oseltamivir was 1·02 days (95% [BCrI] 0·74-1·31) overall, and in the prespecified subgroups, ranged from 0·70 (95% BCrI 0·30-1·20) in patients younger than 12 years, with less severe symptoms, no comorbidities, and shorter previous Illness duration to 3·20 (95% BCrI 1·00-5·50) in patients aged 65 years or older who had more severe Illness, comorbidities, and longer previous Illness duration. Regarding harms, an increased burden of vomiting or nausea was observed in the oseltamivir group. INTERPRETATION: Primary care patients with Influenza-Like Illness treated with oseltamivir recovered one day sooner on average than those managed by usual care alone. Older, sicker patients with comorbidities and longer previous symptom duration recovered 2-3 days sooner. FUNDING: European Commission's Seventh Framework Programme.
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oseltamivir plus usual care versus usual primary care for influenza like Illness an open label pragmatic randomized controlled trial
Social Science Research Network, 2019Co-Authors: Christopher C Butler, Emily Bongard, Johanna Cook, Nick A Francis, Jane Holmes, Roger J Lewis, Benjamin R Saville, Samuel Coenen, Alike W Van Der Velden, Maciek GodyckicwirkoAbstract: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.
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a trial like alic4e why design a platform response adaptive open randomised controlled trial of antivirals for influenza like Illness
ERJ Open Research, 2018Co-Authors: Christopher C Butler, Johanna Cook, Benjamin R Saville, Samuel Coenen, Alike W Van Der Velden, Jane Homes, Menno De Jong, Paul Little, Herman Goossens, Philippe BeutelsAbstract:ALIC4E is the first publicly funded, multicountry, pragmatic study determining whether antivirals should be routinely prescribed for Influenza-Like Illness in primary care. The trial aims to go beyond determining the average treatment effect in a population to determining effects in patients with combinations of participant characteristics (age, symptom duration, Illness severity, and comorbidities). It is one of the first platform, response-adaptive, open trial designs implemented in primary care, and this article aims to provide an accessible description of key aspects of the study design. 1) The platform design allows the study to remain relevant to evolving circumstances, with the ability to add treatment arms. 2) Response adaptation allows the proportion of participants with key characteristics allocated to study arms to be altered during the course of the trial according to emerging outcome data, so that participants' information will be most useful, and increasing their chances of receiving the trial intervention that will be most effective for them. 3) Because the possibility of taking placebos influences participant expectations about their treatment, and determining effects of the interventions on patient help seeking and adherence behaviour in real-world care is critical to estimates of cost-effectiveness, ALIC4E is an open-label trial.
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influenza like Illness and clinically diagnosed flu disease burden costs and quality of life for patients seeking ambulatory care or no professional care at all
PLOS ONE, 2014Co-Authors: Joke Bilcke, Samuel Coenen, Philippe BeutelsAbstract:This is one of the first studies to (1) describe the out-of-hospital burden of Influenza-Like-Illness (ILI) and clinically diagnosed flu, also for patients not seeking professional medical care, (2) assess influential background characteristics, and (3) formally compare the burden of ILI in patients with and without a clinical diagnosis of flu. A general population sample with recent ILI experience was recruited during the 2011–2012 influenza season in Belgium. Half of the 2250 respondents sought professional medical care, reported more symptoms (especially more often fever), a longer duration of Illness, more use of medication (especially antibiotics) and a higher direct medical cost than patients not seeking medical care. The disease and economic burden were similar for ambulatory ILI patients, irrespective of whether they received a clinical diagnosis of flu. On average, they experienced 5–6 symptoms over a 6-day period; required 1.6 physician visits and 86–91% took medication. An average episode amounted to €51–€53 in direct medical costs, 4 days of absence from work or school and the loss of 0.005 quality-adjusted life-years. Underlying Illness led to greater costs and lower quality-of-life. The costs of ILI patients with clinically diagnosed flu tended to increase, while those of ILI patients without clinically diagnosed flu tended to decrease with age. Recently vaccinated persons experienced lower costs and a higher quality-of-life, but this was only the case for patients not seeking professional medical care. This information can be used directly to evaluate the implementation of cost-effective prevention and control measures for influenza. In particular to inform the evaluation of more widespread seasonal influenza vaccination, including in children, which is currently considered by many countries.
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is c reactive protein associated with influenza a or b in primary care patients with influenza like Illness a cross sectional study
Scandinavian Journal of Primary Health Care, 2020Co-Authors: Karin Rystedt, Nicolay Jonassen Harbin, Morten Lindbaek, Ruta Radzeviciene, Ronny Gunnarsson, Robert Eggertsen, Christopher C Butler, Alike W Van Der Velden, Theo J M Verheij, Pardaniel SundvallAbstract:Identifying influenza A or B as cause of Influenza-Like Illness (ILI) is a challenge due to non-specific symptoms. An accurate, cheap and easy to use biomarker might enhance targeting influenza-spe...
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oseltamivir plus usual care versus usual primary care for influenza like Illness an open label pragmatic randomized controlled trial
Social Science Research Network, 2019Co-Authors: Christopher C Butler, Emily Bongard, Johanna Cook, Nick A Francis, Jane Holmes, Roger J Lewis, Benjamin R Saville, Samuel Coenen, Alike W Van Der Velden, Maciek GodyckicwirkoAbstract: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.
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antivirals for influenza like Illness a randomised controlled trial of clinical and cost effectiveness in primary care alic4 e the alic4 e protocol
BMJ Open, 2018Co-Authors: Emily Bongard, Philippe Beutels, Johanna Cook, Alike W Van Der Velden, Ben Saville, Rune Aabenhus, Curt Brugman, Slawomir ChlabiczAbstract:Introduction Effective management of seasonal and pandemic influenza is a high priority internationally. Guidelines in many countries recommend antiviral treatment for older people and individuals with comorbidity at increased risk of complications. However, antivirals are not often prescribed in primary care in Europe, partly because its clinical and cost effectiveness has been insufficiently demonstrated by non-industry funded and pragmatic studies. Methods and analysis Antivirals for Influenza-Like Illness? An rCt of Clinical and Cost effectiveness in primary CarE is a European multinational, multicentre, open-labelled, non-industry funded, pragmatic, adaptive-platform, randomised controlled trial. Initial trial arms will be best usual primary care and best usual primary care plus treatment with oseltamivir for 5 days. We aim to recruit at least 2500 participants ≥1 year presenting with Influenza-Like Illness (ILI), with symptom duration ≤72 hours in primary care over three consecutive periods of confirmed high influenza incidence. Participant outcomes will be followed up to 28 days by diary and telephone. The primary objective is to determine whether adding antiviral treatment to best usual primary care is effective in reducing time to return to usual daily activity with fever, headache and muscle ache reduced to minor severity or less. Secondary objectives include estimating cost-effectiveness, benefits in subgroups according to age ( 64 years), severity of symptoms at presentation (low, medium and high), comorbidity (yes/no), duration of symptoms (≤48 hours/>48–72 hours), complications (hospital admission and pneumonia), use of additional prescribed medication including antibiotics, use of over-the-counter medicines and self-management of ILI symptoms. Ethics and dissemination Research ethics committee (REC) approval was granted by the NRES Committee South Central (Oxford B) and Clinical Trial Authority (CTA) approval by The Medicines and Healthcare products Regulatory Agency. All participating countries gained national REC and CTA approval as required. Dissemination of results will be through peer-reviewed scientific journals and conference presentations. Trial registration number ISRCTN27908921; Pre-results.
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a trial like alic4e why design a platform response adaptive open randomised controlled trial of antivirals for influenza like Illness
ERJ Open Research, 2018Co-Authors: Christopher C Butler, Johanna Cook, Benjamin R Saville, Samuel Coenen, Alike W Van Der Velden, Jane Homes, Menno De Jong, Paul Little, Herman Goossens, Philippe BeutelsAbstract:ALIC4E is the first publicly funded, multicountry, pragmatic study determining whether antivirals should be routinely prescribed for Influenza-Like Illness in primary care. The trial aims to go beyond determining the average treatment effect in a population to determining effects in patients with combinations of participant characteristics (age, symptom duration, Illness severity, and comorbidities). It is one of the first platform, response-adaptive, open trial designs implemented in primary care, and this article aims to provide an accessible description of key aspects of the study design. 1) The platform design allows the study to remain relevant to evolving circumstances, with the ability to add treatment arms. 2) Response adaptation allows the proportion of participants with key characteristics allocated to study arms to be altered during the course of the trial according to emerging outcome data, so that participants' information will be most useful, and increasing their chances of receiving the trial intervention that will be most effective for them. 3) Because the possibility of taking placebos influences participant expectations about their treatment, and determining effects of the interventions on patient help seeking and adherence behaviour in real-world care is critical to estimates of cost-effectiveness, ALIC4E is an open-label trial.