1. Funded by the European Union Wellcome! Antivirals for 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 Launch meeting, Oxford 9 January 2014. Funded by the European Union

2. Prepare Platform foR European Preparedness Against (Re-)emerging Epidemics

3. Funded by the European Union Oxford: Scholarship here for >1000 years

4. Funded by the European Union Sir William Osler The first duties of the physician is to educate the masses not to take medicine. The desire to take medicine is perhaps the greatest feature which distinguishes man from animals. Medicine is a science of uncertainty and an art of probability.

5. Funded by the European Union P ARTICIPATING C OUNTRIES

6. Funded by the European Union WELCOME Annelies, Samuel, Curt, Herman, Menno: Hartelijk welkom Ania, Maciek, Slawomir: Obfite mile widziane Arturas, Darius: Nuoširdžiai sveikiname Femke, Julia, Heiner, Dominik: Herzlich willkommen Jane, Emmanuelle, Julie, Mina, Andrew, Tom, Paul, Peter, Mike: Warm welcome Anca, Florian: Primire călduroasă Bernadett, László: őszinte üdvözlet Beti, Marjeta: Izvrste dobrodošli Patricia: Bienvenida cordial Pia, Pascale: Accueil chaleureux Siri, Camilla, Nicolay, Lars, Kristian: Hjertelig velkommen Marketa, Bohumil: Srdečné přivítání Dragan: Srdačna dobrodošlica Ioanna: εγκάρδιο καλωσόρισμα Mel, Nick: Croeso

7. Funded by the European Union Equipoise

8. 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? No currently available point-of-care test ideally suited for primary care to diagnose respiratory tract infection and guide the use of antiviral treatment: all 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. Changing current practice has far reaching implications on primary health care delivery and organisation and patients (help seeking). Meta-analyses: insufficient evidence to support a widespread change in clinical practice and a consequent fundamental re- organisation of primary care

9. Funded by the European Union 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. Available trial data is insufficient and subject to publication bias

10. Funded by the European Union The updated BMJ systematic reviews Oseltamivir: 23 trials, 9623 patients Time to first symptom reduction reduced by 16.8h (adults), 29h (children) No effect on hospital admission Self-report pneumonia NNT 100 Risks –Headache –Renal –Psychiatric (1.06% CI0.07% - 2.76%)

11. Funded by the European Union Muthuri et al Lancet Respir Med 2014 Examination of effectiveness of NIs in reducing mortality in patients admitted to hospital with influenza during the 2009-10 pandemic. Individual patient meta-analysis: patients of all ages who were admitted to hospital with laboratory confirmed or clinically diagnosed pandemic influenza A during the 2009-10 pandemic. Data from over 29,000 patients from 78 studies were included. Propensity scoring used for adjustments. In adults, neuraminidase inhibitor treatment led to a reduction in mortality risk compared with no treatment. Treatment within two days of symptom onset reduced mortality compared to later treatment. However, the associations with reduced mortality risk were less pronounced and not significant in children. Advocates early treatment with NIs for adults hospitalised with suspected or proven flu.

12. 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

13. 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)

14. Funded by the European Union

16. 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 arictecture Open, pragmatic trial Adaptive platform design: –Bayesian approach –More efficient –Arms can be dropped or added Sample size –4500 POCT substudies

19. Funded by the European Union More about design Key trial characteristics, such as randomisation proportions and treatment arms, may evolve during the course of the trial according to pre-specified rules. The adaptions are guided by the data accruing within the trial itself. Goals of the adaptive approach include higher statistical efficiency, improved patient outcomes, or a better ethical balance. ALIC 4 E may be described as both a personalized medicine trial and a comparative effectiveness trial. Adaptive approaches, such as response adaptive randomisation, place more patients in the trial on the best performing interventions. This leads to trial participants more often receiving more effective treatments. In addition, by focusing patient resources to the few treatments that emerge as being the best, adaptive trials may also come to a comparative effectiveness conclusion more efficiently, thus allowing a more rapid announcement of results and more rapid uptake of better treatment of future patients. A “platform trial” is a trial in which multiple drugs for the same indication are tested simultaneously. The backbone of the trial is an adaptive clinical trial design. Then rules are overlaid that may allow for dropping a drug for futility, declaring a drug superior, or adding a new drug to be tested. Because the process of dropping and adding drugs may be on going for an indefinite period of time, platform trials may be better conceived of as a process rather than a singular clinical trial.

20. Funded by the European Union Statistical significance If, at an interim analysis, an arm has at least a 97.5% probability of being the most effective treatment arm, then arm will be considered superior to the other two arms. According to the adaptive randomization algorithm, enrolment to the other two arms will be suspended and patients will continue to be enrolled to the one remaining arm. Arms may be declared superior in one subgroup of patients, but not within others. Arms may be declared superior within a patient subgroup if there is at least a 97.5% probability it is the most effective treatment arm. This corresponds to a one-sided 2.5% level of statistical significance.

21. 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 Is able and willing to comply with all trial requirements Participant or legal guardian(s) of a child is willing and able to give informed consent Agrees not to take antiviral agents apart from a study antiviral agents according to patient randomisation

22. 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

23. 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

24. Funded by the European Union Point of care test evaluation *Idylla™ respiratory panel (RP1) in PREPARE Janssen Diagnostics Ease-of-use and Speed –No need for highly skilled technicians –Minimal operator time and training –30-60 min turn-around-time Random Access & Scalable –Sample can immediately be tested and results can be provided when needed –For smaller and larger labs Broad Menu Capability –Detection of 1-25 targets per sample –Ability to process swabs, whole blood, frozen or fixed tissue

25. Funded by the European Union The Cartridge http://icpc2010.di.uminho.pt/presentations/ICPC2010-LouisStroucken.pdf Sample types Swabs Blood, plasma Tissue Feces Respiratory and Cerebrospinal Fluids Multiplexing 6-channel capability with 5 PCR wells for 30-plex

26. Funded by the European Union Respiratory Panel One (RP1) 26 CONFIDENTIAL RP1: respiratory panel 1; RSV: respiratory syncytial virus; Targets Influenza A Influenza A H1 Influenza A H3 Influenza A H1 ‘09 H275Y mutation Influenza B RSV A RSV B

27. Funded by the European Union 27 RP1 assay: sample processing RT: real-time; PCR: polymerase chain reaction RT-PCR Nucleic acid extraction Cell lysis Data analysis sample in qualitative result out

28. Funded by the European Union To assess the utility and cost effectiveness of Idylla RP1 To estimate the conviviality and diagnostic value of Idylla RP1 RP1: respiratory panel 1; POCT: point of care treatment Objectives

29. Funded by the European Union Testing with Idylla: 1. Laboratory based assessment from frozen sample Determine the prevalence of RSV in this population Recruitment — † Exclusion criteria — I † LI symptoms — Stratifications — Etc. Patients presenting to PC over 3 years Oseltamivir arm N = 800/year Control arm N = 800/year Patients recruited N = 1600/year Randomisation Proposed additional analyses with Idylla Idylla RP1 -- N = 1600/year ( 1 mL NP swab in UTM, frozen and shipped to lab) 1 NP swab in 3 mL UTM ITT ref. test -- N = 1600/year (1 mL NP swab in UTM, frozen and shipped to lab) Current main study design Screening Baseline 3 2 1

30. Funded by the European Union a Exclusions= pregnancy, breast-feeding, known renal failure (creatinine glomerular filtration rate < 60 mg/l), a condition or treatment associated with impaired immunity (e.g. long-term oral steroids or chemotherapy, immune disorder), and those recommended for immediate treatment by Guidelines ILI : sudden onset of fever, muscle ache and at least one of the following: cough, sore throat or chest pain; RP1: respiratory panel 1; RSV: respiratory syncytial virus; UTM™: universal transport medium; NS: nasal swab; NP: nasopharyngeal swab; Testing with Idylla 2: Fresh vs. frozen sample test Recruitment — † Exclusion criteria — I † LI symptoms — Stratifications — Etc. Patients presenting to PC over 3 years Oseltamivir arm N = 800/year Control arm N = 800/year Patients recruited N = 1600/year Randomisation Proposed additional analyses with Idylla Idylla RP1 -- N ≥100/year 1 (1 mL NP in UTM, fresh sample tested at PC) Idylla RP1 -- N = 1600/year ( 1 mL NP swab in UTM, frozen and shipped to lab) H275Y - + BlindedBlinded 1 NP swab in 3 mL UTM ITT ref. test -- N = 1600/year (1 mL NP swab in UTM, frozen and shipped to lab) Current main study design Screening Baseline 1 3 2

31. Funded by the European Union Testing with Idylla 3: Idylla guided treatment assessment Recruitment — a Exclusion criteria — ILI symptoms Patients presenting to PC Oseltamivir “Treatment with oseltamivir in patients diagnosed with influenza by POCT” (nasal swab; sample-in/result-out; Idylla RP1) Feedback questionnaires (Clinicians and Patients) - Flu Patients recruited N ≥100 Screening Baseline Treatment Follow up Idylla RP1 Testing (NS swab) Idylla RP1 Diagnostic (NS swab) b H275Y - - + + + + + + At least one positive test

32. Funded by the European Union Research Work 2: Process evaluation A quantitative survey and qualitative study of the perspectives of clinicians and patient participants evaluate logistics, organisation, and perceptions of barriers and opportunities for effective inter- and intra- pandemic clinical research All clinicians recruiting participants into the trial will be asked to fill in a brief questionnaire. A 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). IDYLLA ‘conviviality study’

33. Funded by the European Union WP3: Pathogeneis, obesrvational study Opportunity to contribute a smaller number of more intensively sampled patients for an observational, pathogenesis study

34. Funded by the European Union Deliverables 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)

35. Funded by the European Union

36. 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

37. Funded by the European Union Three muskateers Paul Little, Co-P lead

38. Funded by the European Union

39. Leadership and primary care network Central coordination Chris Butler (Ox) Johanna Cook (Ox) Alike van der Velden (U) Theo Verheij (U) Additional staff when needed (Ox/U) National network Coordinator Supporting staf National network Coordinator Supporting staff National network Coordinator Supporting staff Local laboratory Health centres

40. Funded by the European Union 40 >600 PC in 19 EU countries Partners and persons involved in WP-Coordination Team Greet Ieven PREDICT Frank Leus CRISP Perer Horby WP2 and 3 Alastair Nichol WP1 Laurence Rimsky Janssen Diagnostics Andre’ Capt Jannsens Diagnostics

41. Funded by the European Union Organisation primary care network Central coordination Chris Butler (WP leader) (Ox) Johanna Cook (Trial Manager) (Ox) Supporting staff (Ox, to be appointed) 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

42. Funded by the European Union Network development paper

43. Funded by the European Union