Oseltamivir plus usual care versus usual care for influenza-like illness in primary care: an open-label, pragmatic, randomised controlled trial

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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
 
Butler, Christopher C; van der Velden, Alike W; Bongard, Emily; Saville, Benjamin R; Holmes, Jane; Coenen, Samuel; Cook, Johanna; Francis, Nick A; Lewis, Roger J; Godycki-Cwirko, Maciek; Llor, Carl; Chlabicz, Sławomir; Lionis, Christos; Seifert, Bohumil; Sundvall, Pär-Daniel; Colliers, Annelies; Aabenhus, Rune; Bjerrum, Lars; Jonassen Harbin, Nicolay; Lindbæk, Morten; Glinz, Dominik; Bucher, Heiner C; Kovács, Bernadett; Radzeviciene Jurgute, Ruta; Touboul Lundgren, Pia; Little, Paul; Murphy, Andrew W; De Sutter, An; Openshaw, Peter; de Jong, Menno D; Connor, Jason T; Matheeussen, Veerle; Ieven, Margareta; Goossens, Herman; Verheij, Theo J
(2020) The Lancet, volume 395, issue 10217, pp. 42 - 52
(Article)
Abstract
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 ... read more
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Keywords: General Medicine, Journal Article
DOI: https://doi.org/10.1016/S0140-6736(19)32982-4
ISSN: 0140-6736
Publisher: Elsevier
Note: Funding Information: This work was supported by the European Commission's Seventh Framework Programme (grant HEALTH-F3-2013-602525). In addition to the authors, we would like to acknowledge the contribution of the other members of the 21 ALIC4E coordinating centers: Ana García Sangenís, Ana Moragas Moreno, Helena Pera Pujadas, Rosa Morros Pedrós, Sofia Sundvall, Curt Brugman, Patricia Fernandez-Vandellos, Carmen Rodriguez-Tenreiro, Cristina Serén Trasorras, Antonio Torres Marti, Federico Martinon-Torres, Markéta Pfeiferová, Pascale Bruno, Christine Pintaric, Voltyraki Filothei, Jozsef Pauer, Reka Pauer, Muireann De Paor, Anna Gryko, Barbara Pytel-Krolczuk, and Anna Kowalczyk. We also acknowledge and thank the hard work and dedication of all the networks recruitment teams, practices, and local laboratories. Without the selfless contribution of the study participants, this research could not have been done. The authors would like to acknowledge the contribution of the Trial Steering Committee members, Patrick Bindels, Gordon Taylor, Åke Örtqvist, and Keith Shankland (patient and public representative), the independent data monitoring committee members, Deborah Ashby, Sonia Saxena, and Simon Gates, and the members of the patient and public involvement group that contributed to the study design and development. The authors would also like to acknowledge the other members of the collaborative PREPARE work packages, in particular: Philippe Beutels (WP5), Susan van Hemert, Frank Leus, and Joost Schotsman (WP8), Nina Gobat and Micaela Gal (WP1), Mandy Kuijstermans, Pieter Moons, and Katherine Loens. UK investigators gratefully acknowledge support from the NIHR, Comprehensive Local Research Networks and Biomedical Research Centre. We also acknowledge the help and support from the Nuffield Department of Primary Care Health Sciences and Primary Care Clinical Trials Unit, University of Oxford, in particular Sonya Beecher and Julie Allen for their respective administrative and trial management support. Funding Information: After publication of the full trial report, formal requests for study data should be made to the corresponding author (CCB) using a bespoke data request form delineating research aims, methods, and the variables needed. Such requests will be considered by the core ALIC 4 E team (CCB, TV, BS, AWV, and EB) and the PREPARE coordinator (HG). If research questions and methods are considered relevant and valid, the Data Management Department of the Julius Center, UMC Utrecht, will securely transfer the requested, fully anonymised data in the desired format to the party under data transfer agreements. The ALIC 4 E team will decide about co-authorships, after discussion with the interested party about this. The study protocol, statistical analysis plan, and informed consent form will be made available. Acknowledgments This work was supported by the European Commission's Seventh Framework Programme (grant HEALTH-F3-2013-602525). In addition to the authors, we would like to acknowledge the contribution of the other members of the 21 ALIC 4 E coordinating centers: Ana García Sangenís, Ana Moragas Moreno, Helena Pera Pujadas, Rosa Morros Pedrós, Sofia Sundvall, Curt Brugman, Patricia Fernandez-Vandellos, Carmen Rodriguez-Tenreiro, Cristina Serén Trasorras, Antonio Torres Marti, Federico Martinon-Torres, Markéta Pfeiferová, Pascale Bruno, Christine Pintaric, Voltyraki Filothei, Jozsef Pauer, Reka Pauer, Muireann De Paor, Anna Gryko, Barbara Pytel-Krolczuk, and Anna Kowalczyk. We also acknowledge and thank the hard work and dedication of all the networks recruitment teams, practices, and local laboratories. Without the selfless contribution of the study participants, this research could not have been done. The authors would like to acknowledge the contribution of the Trial Steering Committee members, Patrick Bindels, Gordon Taylor, Åke Örtqvist, and Keith Shankland (patient and public representative), the independent data monitoring committee members, Deborah Ashby, Sonia Saxena, and Simon Gates, and the members of the patient and public involvement group that contributed to the study design and development. The authors would also like to acknowledge the other members of the collaborative PREPARE work packages, in particular: Philippe Beutels (WP5), Susan van Hemert, Frank Leus, and Joost Schotsman (WP8), Nina Gobat and Micaela Gal (WP1), Mandy Kuijstermans, Pieter Moons, and Katherine Loens. UK investigators gratefully acknowledge support from the NIHR, Comprehensive Local Research Networks and Biomedical Research Centre. We also acknowledge the help and support from the Nuffield Department of Primary Care Health Sciences and Primary Care Clinical Trials Unit, University of Oxford, in particular Sonya Beecher and Julie Allen for their respective administrative and trial management support. Funding Information: The ALIC 4 E trial was a large-scale, international, publicly-funded, pragmatic, randomised controlled trial of the effectiveness of adding oseltamivir to usual primary care for people with influenza-like illness over three influenza seasons powered to detect effects in key clinical subgroups. Overall, these patients returned to their usual activities with mild residual symptoms minimally interfering after about 6·5 days, and about one day earlier with oseltamivir addition, which is consistent with previous placebo-controlled evidence in adults and children. 6,7,15,16 Moreover, we found that participants at higher risk of adverse outcome—older, sicker, with comorbid conditions, or longer previous symptom duration—might expect to return 2–3 days earlier with oseltamivir. Participants with confirmed influenza did not benefit more than those testing negative in our study. Furthermore, we found no evidence of a differential effect between participants who were positive for influenza and those positive for other viruses or between those infected with influenza A or B. A systematic review and meta-analysis of published and unpublished placebo-controlled studies of oseltamivir for influenza-like illness found a clinically unimportant difference of less than 5 h in the mean reduction of symptom duration between individuals in the intention-to-treat population (5 studies, 3833 patients) and individuals with confirmed influenza infection (7 studies, 2690 patients). 15 Because we asked participants to complete the symptom diary once a day, we might not have detected such a small difference. Another explanation might be that oseltamivir's mode of action might include some generalised non-specific mechanisms, or an action on a wider range of viruses. 6 We might also have missed cases of influenza infection due to variable virus shedding over time. The Flu Watch study 17 found that only a quarter of people with serologically confirmed influenza had PCR confirmed disease, and a study in intensive care units 18 found that nucleic acid testing underestimated pandemic (H1Na) influenza when compared with paired serology by about a third. Other possible explanations include inconsistent swabbing techniques (which seems unlikely given data from the recruiting Network 11 ), that our primary outcome captured a range of factors (eg, deterioration after initial recovery) and social influences (eg, thresholds for returning to work) that might be less affected by antiviral activity earlier in the illness, or that we found a placebo effect. However, there was no evidence of a differential relative benefit in subgroups such as those with lower illness severity where systematic reviews suggest a more marked placebo response. 19 Moreover, our overall estimate is similar to effects found in placebo-controlled trials. 6,7,15,16 The inclusion criterion of fever means we have not been able to document benefit in some elderly individuals where the febrile response can be less marked. Predicting the effect in a more highly vaccinated population is difficult. There could be a lesser effect due to partial protection, but it could also plausibly be greater, because individuals presenting with influenza-like illness would be more likely to be vulnerable individuals with a poor vaccine response. Some might consider the absence of a placebo control as a limitation. We deliberately chose to do an open-label trial in the context of everyday practice, because effect sizes identified by placebo-controlled, efficacy studies with tight inclusion criteria might not be reproduced in routine care. We also wished to estimate time to patient-reported recovery from the addition of an antiviral agent to usual care rather than benefit from oseltamivir treatment compared with placebo. 20 This pragmatic, open trial design makes our findings likely to reflect real-world effects in primary care, because knowledge of what medication one is taking could affect subsequent help seeking and health behaviour and use of symptomatic medications. 21,22 However, the design did not allow us to be sure of mechanisms or how much of the observed effect can be attributed to specific oseltamivir or other possible effects, and the relative contribution of such possible effects which might differ for the various subgroups. Previous trials have found relatively greater benefits in individuals treated within 24 h of symptom onset. 5,23 Additional benefit from earlier treatment was not apparent in our trial, but it was specifically powered to detect subgroup effects in a representative primary care population. A community-based trial 24 of oseltamivir for uncomplicated influenza found a similar effect to our study overall and observed reductions in the duration of symptoms and virus shedding even when treatment was started more than 48 h after illness onset. An open, randomised trial 25 of oseltamivir added to usual care in adults hospitalised with influenza-associated lower respiratory tract infections with a median time to oseltamivir initiation of 6 days found no reductions in terms of clinical failures. In our population, individuals presenting with longer previous duration (>48 h) had a longer natural history, so although relative benefit did not differ, the absolute benefit was greater. In individuals with a shorter natural course of influenza-like illness, a ceiling effect might also exist, so that the effect on viral replication might be too brief for benefit to become apparent, especially in a largely healthy primary care population. A possible explanation for the observation of the greatest effect in subgroups who were older and at higher risk, 26 is that viral replication continues for longer, with a longer natural history of the illness in such individuals. Meta-analyses have found that oseltamivir reduced the risk of self-reported pneumonia but not of clinically diagnosed pneumonia, 6,7 and that treatment with oseltamivir might reduce the risk of complications and hospitalisation in patients tested positive for influenza. 6 Although our study was not powered on secondary outcomes, we found no evidence of an effect on pneumonia or hospitalisation, although oseltamivir was associated with slightly lower antibiotic use and reported new infections in household members. Regarding harms, we did not identify meaningful differences in patient-reported repeat visits with health care services, hospitalisations, or serious adverse events, but found evidence for increased burden of vomiting or nausea in the usual care plus oseltamivir group, which is a common side-effect of oseltamivir. One participant who tested positive for influenza had a below knee amputation following arterial occlusion after having started oseltamivir 5 days previously. A search by the study team and also by an independent medicines information service did not find reports of arterial thrombosis linked with oseltamivir, although we did find reports of thrombotic events related to influenza. We decided to err on the side of caution by classifying this event as a possible suspected unexpected serious adverse reaction owing to the temporal relationship between oseltamivir and the thrombosis. One serious adverse event (urticaria) was considered related, and a further ten unrelated. Previous trials have generally reported either time to first alleviation of symptoms or return to usual activities as their primary outcome. Our composite outcome captured both specific symptoms of influenza-like illness and return to usual activities. Baseline body temperature was lower in our participants than reported in hospital-based studies, suggesting applicability to a typical primary care population. As in many other studies, children and older people were under-represented, but this might reflect consulting behaviour. In conclusion, adding oseltamivir to usual primary care for influenza-like illness is likely to accelerate recovery by about a day in patients with influenza-like illness and slightly more in those with risk factors. The effect does not appear to be mediated by influenza virus status, as measured using PCR analysis of swabs, and is unlikely to be due to a placebo effect alone. Although the reason for this effect is unclear, the real-world estimates are what patients and clinicians can anticipate will occur in daily practice. Furthermore, oseltamivir started more than 48 h after symptom onset has a similar effect. Although the average benefit for many patients is modest, and advocation of widespread use of oseltamivir is difficult owing to concerns about possible side effects and the medicalisation of a largely self-limiting illness, clinicians and patients might wish to consider adding oseltamivir to routine treatment where a day less of illness is particularly important for patients. Clinicians might especially want to consider treatment in patients who are sicker or older, who have comorbidities, and who have been unwell for longer, in whom the absolute benefit might decrease recovery time by as much as 2–3 days. Contributors CCB and TJV were co-chief investigators of this trial and act as guarantors of the study in its entirety. CCB and TJV led the development of the research question, study design, and obtaining the funding with AWvdV, JC, PL, PO, MDdJ, and HG. AWvdV, EB, and JC managed the trial and coordinated the operational delivery of the study protocol to the networks coordinating centres. SCo and NAF, members of the trial management group, provided scientific and practical input. BRS, JH, RJL, and JTC were the trial statisticians. VM and MI led the microbiological analysis. MG-C, CLl, SCh, CLi, BS, P-DS, AC, RA, LB, NJH, ML, DG, HCB, BK, RRJ, PTL, AWM, and ADS represented the collaborating coordinating centres responsible for their network's participation in the trial. CCB led and produced the first draft of this manuscript. All authors provided critical review and final approval of the manuscript. Declaration of interests CCB reports grants from National Institute for Health Research (NIHR) Health as NIHR Senior Investigator, grants from the NIHR Health Technology Assessment Programme to support the study, grants from NIHR Health Protection Research Unit on Health Care Associated Infections and Antimicrobial Resistance, grants from NIHR Health for the MedTech and In Vitro Diagnostics Cooperative for innovative diagnostics and monitoring technology to enhance Community Healthcare during the conduct of the study, personal fees from Pfizer and Roche Molecular Systems, grants from Roche Molecular Diagnostics. AWvdV reports personal fees from Reckitt Benckiser. BRS reports grants from the EU Innovative Medicines Initiative, during the conduct of the study. RJL is the Senior Medical Scientist at Berry Consultants. Berry Consultants was compensated for work related to the design and implementation of the clinical trial. CLl reports grants from Abbott Diagnostics. HCB or his institute has received, in the 36 months before the submission of this manuscript, grants, support for travelling, consultancy fees, and honoraria from Gilead, BMS, Viiv Healthcare, Idorsia, and Roche, outside the submitted work. He serves as the president of the association contre le HIV et autres infections transmissibles. In this function he has received support from the Swiss HIV Cohort Study from ViiV Healthcare, Gilead, Bristol-Myers Squibb, Merck Sharp & Dohme, and Abbvie. PO reports personal fees from Janssen and European Respiratory Society, grants from Medical Research Council Global Challenge Research Fund, the EU, and NIHR Biomedical Research Centre, collaborative grants with GSK, and an NIHR Senior Investigator Award, outside the submitted work. MDdJ reports fees paid to his institution for contribution to study oversight boards from GSK, Vertex, and Janssen and advisory committees from Roche and Cidara Therapeutics. TJV reports grants from the NIHR, Netherlands Organization of Health Research and Development, and the EU Innovative Medicines Initiative, which has Janssen Pharmaceuticals, Biocartis, Janssen, BioMerieux, and Berry Consultants as partners, all outside the submitted work. All other authors declare no competing interests. Publisher Copyright: © 2020 Elsevier Ltd
(Peer reviewed)