1. Funded by the European Union Influenza like Illness? A rCt of Clinical and Cost effectiveness in primary CarE (ALIC 4 E ) Chris Butler, Theo Verheij, Alike van der Velden, Johanna Cook Venice 2015. Funded by the European Union

2. Chris Butler’s declaration of interests Gave a talk at the Alliance for the Prudent Use of Antibiotic’s in Boston Gave a talk at a MIMS Clinical update on urinary tract infection Attended a sponsored meeting on eustacean tube dysfunction Attended a sponsored advisory board on pain management for Grünenthal Gave a talk on point of care testing for common infections sponsored by Alere Attended and advisory meeting on point off care testing sponsored by Alere Alere is providing unconditional support in the form of providing of CRP testing devices and kits for a publically funded research project I am leading on acute exacerbations of chronic obstructive airways disease I have a range of publically funded research grants, which aim to generate evidence to enhance the management of common infections in primary care

3. Funded by the European Union Three muskateers

4. Funded by the European Union The engine room Central coordination Chris Butler (Ox) Johanna Cook (Ox) Alike van der Velden (U) Theo Verheij (U) National network Coordinator Supporting staf National network Coordinator Supporting staff National network Coordinator Supporting staff Local laboratory Health centres

5. Funded by the European Union Background and Research Gaps When reflecting on the recent H1N1 pandemic, primary care clinicians and public health physicians often ask whether the liberal use of oseltamivir was justified? Was syndromic diagnosis (as opposed to point-of-care test guided treatment) the most cost-effective? All POCs have problems of diagnostic performance, take too long, or are insufficiently user-friendly. The same questions arise annually for seasonal influenza. Currently, most European primacy care services promote self-care for patients with ILI, but guidelines suggest treat high risk groups and severe cases Changing current practice has far reaching implications on primary health care delivery and organisation and patients (help seeking).

6. Funded by the European Union Influenza in primary care is… Very unpleasant Can be dangerous Mean time off work and school Represents a big potential market Represents a big problem for health care delivery Represents opportunity for de-medicalising illness and promoting self care

7. Funded by the European Union

8. Oseltamivir… Sales of oseltamivir expected to reach 562 million Euro this year. First approval by the US FDA in 1999, yet no large-scale, international, non-industry sponsored pragmatic trial of cost-effectiveness of oseltamivir in primary care.

9. Funded by the European Union Key questions Are antivirals cost effective in primary care for high risk groups? Are antivirals cost effective in primary care for all with ILI? Are antivirals cost effective in primary care for flu positives?

10. Funded by the European Union Equipoise

11. Funded by the European Union Key reviews Dobson J, Whitley RJ, Pocock S, Monto AS. Lancet. 2015 Jan 30. pii: S0140- 6736(14)62449-1. doi: 10.1016/S0140-6736(14)62449-1) (MUGAS Multi-party Group for Advice on Science) Jefferson T, Jones MA, Doshi P, Del Mar CB, Hama R, Thompson MJ, Spencer EA, Onakpoya I, Mahtani KR, Nunan D, Howick J, Heneghan CJ. Neuraminidase inhibitors for preventing and treating influenza in healthy adults and children. Cochrane Database of Systematic Reviews 2014, Issue 4. Okoli GN, Otete HE, Beck CR, Nguyen-Van-Tam JS Use of Neuraminidase Inhibitors for Rapid Containment of Influenza: A Systematic Review and Meta-Analysis of Individual and Household Transmission Studies. PLoS ONE 2014 9(12): e113633. Muthuri SG et al. Effectiveness of neuraminidase inhibitors in reducing mortality in patients admitted to hospital with influenza A H1N1pdm09 virus infection: a meta- analysis of individual participant data. Lancet Respiratory Diseases 2014 Muthuri SG, Myles PR, Venkatesan S, Leonardi-Bee J, Nguyen-Van-Tam JS. Impact of neuraminidase inhibitor treatment on outcomes of public health importance during the 2009-10 influenza A(H1N1) pandemic: a systematic review and metaanalysis in hospitalized patients. Journal of Infectious Disease 2012 Hsu J, Santesso N, Mustafa R, Brozek J, Chen YL, Hopkins JP, et al. Ann Intern Med. 2012 Apr 3;156(7):512-24.)

12. Funded by the European Union The reviews and our questions… Jefferson 2014 (Cochrane) Dobson 2015 (MUGAS) Muthuri 2014 (PRIDE)Muthuri 2012 (PRIDE)Hsu 2102 Pandemic or seasonalSeasonal Pandemic H1N1 Seasonal Risk groupsNot addressedNo benefit in over 65’sBenefit in pregnant women Adj OR for mortality 0.27 p<0.001 Does not address this issue Oseltamivir compared with no treatment may reduce: mortality OR 0.23 [0.13 to 0.43]; (low-quality evidence) hospitalization (OR 0.75 [0.66 to 0.89]; low- quality evidence) Duration of symptoms (33 hours [CI, 21 to 45]; very low–quality evidence Healthy people who develop severe ‘flu Not addressed Adults admitted to critical care adj OR for mortality 0.72, p=0.02. No benefit in children Not addressed Treat allReduction in symptom duration : Oseltamivir 17 hrs, p<0.001: Zanamivir 0.6 days, p<0.001 Reduction in non- verified pneumonia with oseltamivir but not ‘confirmed’ pneumonia No effect o on hospitalisation No effect of zanamivir on pneumonia Reduction in time to alleviation of symptoms: 17 hours in all patients and 25 hours in patients with confirmed influenza Reduced LRTIs and hospitalisations NI treatment associated with lower mortality risk Adj OR 0.81, p<0.01 No benefit seen in children No benefit If treatment started >2 days: increased mortality with later treatment C rude mortality rates 9.2% (959/10 431) without treatment and 9.7% (1825/18 803) with NIs No benefit in mortality OR 0.72 0.51-1.01 Mortality benefit seen with treatment <48 hours after symptoms OR 0.35 0.18 -0.71 compared to no treatment “Therapy with oral oseltamivir and inhaled zanamivir May provide a net benefit over no treatment of influenza. However, as with the randomized trials, the confidence in the estimates of the effects for decision making is low to very low” Cost effectivenessNot addressed

13. Funded by the European Union Lots of controversy Pharma sponsorship….. Pre-published protocol? The missing trials and access to data Dobson: NNT to prevent 1 hospitalization >3000 Treating in primary care=spreading illness Self report ‘pneumonia’ or pre-established outcome measure in CRF and confirmed Subsequent antibiosis: a valid outcomes measure? Retrospective data from case notes… high levels of missing data Many primary studies did not control for confounders Many studies did not compare Nis to no antivirals

14. Funded by the European Union Nitazoxanide Licensed in the US giardia lamblia and cryptosporidium parvum diarrhoea since 1996. Nitazoxanide and its active metabolite, tizoxanide, active against a number of RNA and DNA viruses, Phase 2b/3 randomised, placebo controlled trial evaluated nitazoxanide in doses of 300mg and 600mg for patients with acute uncomplicated ILI aged between 12 and 65 years. 600mg twice daily for 5 days significantly reduced the time from first dose to alleviation of symptoms (from a mean of 117 hours to 96 hours) compared with placebo, with no increase in adverse events; the 300mg dose reduced time to first alleviation of symptom (to 109 hours): latter difference was not statistically significant. Symptomatic benefit from nitazoxanide treatment those patients with ILI who turned out to test positive for influenza as well as those with ILI who tested negative for influenza. Effect of nitazoxanide in adults and adolescents with acute uncomplicated influenza: a double-blind, randomised, placebo-controlled, phase 2b/3 trial. Haffizulla et al. Lancet 2014; 14 : 609 – 18

15. Funded by the European Union Conclusion of current state of art? “A large, definitive set of clinical trials performed by an independent group and focused on patient groups that are currently under studied, including children, has yet to be conducted. Until it is, we know too little about the heterogeneity of effects and whether there are people more likely to benefit and less likely to be harmed.” (BMJ 2014;348: G2548)

16. Funded by the European Union Objectives of ALIC 4 E To determine whether adding antiviral treatment to defined usual care: Reduces time to return to usual activities Is cost effective Decreases the incidence of hospital admissions Decreases complications related to ILI, especially pneumonia Decreases repeat attendance at the GP Decreases time to alleviation of ILI symptoms Decreases the incidence of new or worsening symptoms Decreases time to initial reduction in severity of symptoms Decreases duration of symptoms that are moderately severe or worse Reduces the use of additional symptomatic and prescribed medication, including antibiotics Reduces new household cases Recuses use of symptomatic medication POCT EVALUATION

17. Funded by the European Union

18. Trial architecture: with thanks to Berry Consulting for an inspiring collaboration! Open, pragmatic trial: We want to know the effect of a drug when people know what they are taking as in real life Adaptive platform design: –Bayesian approach –More efficient –Arms can be dropped or added: THANK HEAVENS –We will adapt for age ( 64 yrs), severity of symptoms (low, medium, high), comorbidity (yes/no), duration of symptoms ( 48hours). Sample size –4500 POCT sub studies: analytic performance and ‘congeniality’ study

19. Funded by the European Union IS there any point in the last horse continuing to run?

20. Funded by the European Union What if it becomes rapidly apparent that your thoroughbred is a donkey? Get another ‘stallion ’!

21. Funded by the European Union If it a tie, keep on running!

22. Funded by the European Union Inclusion criteria Presenting with ILI in primary care during a period of increased influenza activity. (ILI=sudden onset of self-reported fever, with at least one respiratory symptom (cough, sore throat, running or congested nose) and one systematic symptom (headache, muscle ache, sweats or chills or tiredness) symptom duration of 72 hours or less Able and willing to comply with all trial requirements Willing and able to give informed consent Agrees not to take antiviral agents apart from a study antiviral agents according to patient randomisation

23. Funded by the European Union Exclusion criteria Known chronic renal failure e.g. known or estimated creatinine glomerular filtration rate < 60 mg/l (known = recorded in GP notes) Known condition or treatment associated with significant impaired immunity (e.g. long-term oral steroids or chemotherapy, immune disorder) (known = recorded in GP notes) Those who in the opinion of the responsible clinician should be prescribed immediate antiviral treatment Allergic to oseltamivir, nitazoxanide, or any other trial medication Scheduled elective surgery or other procedures requiring general anaesthesia during the subsequent two weeks Participant with life expectancy estimate by a clinician to be less than 6 months Responsible clinician considers urgent hospital admission is required Any other significant disease or disorder which, in the opinion of the responsible clinician, may either put the participants at risk because of participation in the trial, or may influence the result of the trial, or may affect the participant’s ability to participate in the trial Involvement, including completion of any follow up procedures, in another clinical trial of an investigational medicinal product in the last 90 days Previous ALIC 4 E trial participation Patients unable to be randomised within 24 hours of initial eligibility check, or patients unable to be randomised with 72 hours after onset of symptoms Requirement for any live viral vaccine in next 7 days

24. Funded by the European Union Interventions Oseltamivir: Oral ≥12 years: 75mg tablets twice a day, for 5 days 1 - 40kg: 75mg oral suspension in water Nitazoxanide: Oral ≥13 years: 600mg tablets twice a day, for 5 days Reduced doses for under 12s as oral suspension in water Defined ususal care: includes a recommendation to take paracetamol in the recommended dose every six hours. Additional agents can be added in

25. Funded by the European Union Research Work 2: Process evaluation Quantitative survey and qualitative study of the perspectives of clinicians and patient participants to evaluate trail logistics, organisation, and perceptions of barriers and opportunities for effective inter- and intra-pandemic clinical research All clinicians recruiting participants will be asked to fill in a brief questionnaire. Purposive sub-sample of approximately 50 clinicians and 50 patient participants will be interviewed using a semi-structured topic guide (which is usually sufficient to achieve data saturation in qualitative studies of this kind). Opportunity to contribute a smaller number of more intensively sampled patients for an observational, pathogenesis study: WP3

26. Funded by the European Union Deliverables!

27. Funded by the European Union 4.1 Final report on the effects and cost-effectiveness of oseltamivir on patients with influenza-like illness and patients with confirmed influenza. M60 4.2 Final report on the diagnostic value of the POCT under study. M60 4.3 Final report on recommendations from clinicians participating in the trial on rapid and safe inter and intra- pandemic clinical research (M60)

28. Funded by the European Union Milestones MS6: Known efficacy and safety of ostltamivit for treating ILI and influenza in primary care M60 MS7: Known diagnostivc vaklue of POCT in PC M60

29. Funded by the European Union Many thanks!