funded by the european union wellcome! antivirals for influenza like illness? a rct of clinical and...

Funded by the European Union

Wellcome! Antivirals for influenza Like Illness? A

rCt of Clinical and Cost effectiveness in primary CarE (ALIC4E)

Chris Butler, Theo Verheij, Alike van der Velden, Johanna Cook

Launch meeting, Oxford 9 January 2014.



Prepare Platform foR European Preparedness

Against (Re-)emerging Epidemics


Oxford: Scholarship here for >1000 years


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.


PARTICIPATING COUNTRIES


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


Equipoise


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


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


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%)


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.


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


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)


Objectives of ALIC4E 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


Trial arictecture

• Open, pragmatic trial

• Adaptive platform design: – Bayesian approach– More efficient– Arms can be dropped or added

• Sample size– 4500

• POCT substudies


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. ALIC4E 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.


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.


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


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 ALIC4E 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


Interventions

•Oseltamivir: Oral

≥12 years: 75mg tablets twice a day, for 5 days

1 - <12:, 10-15kg: 30mg, 15-25kg: 45mg, 25-40kg: 60mg, >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


Point of care test evaluation

*Idylla™ respiratory panel (RP1) in PREPAREJanssen 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


The Cartridge

http://icpc2010.di.uminho.pt/presentations/ICPC2010-LouisStroucken.pdf

Sample types• Swabs• Blood, plasma• Tissue• Feces• Respiratory and

Cerebrospinal FluidsMultiplexing

• 6-channel capability with 5 PCR wells for 30-plex

http://icpc2010.di.uminho.pt/presentations/ICPC2010-LouisStroucken.pdf


Respiratory Panel One (RP1)

26

CONFIDENTIAL

RP1: respiratory panel 1; RSV: respiratory syncytial virus;

TargetsInfluenza A

Influenza A H1Influenza A H3

Influenza A H1 ‘09H275Y mutation

Influenza BRSV ARSV B


27

RP1 assay: sample processing

RT: real-time; PCR: polymerase chain reaction

RT-PCRNucleic

acid extraction

Cell lysis Data analysis

sample in qualitative result out


• 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


Testing with Idylla: 1. Laboratory based assessment from frozen sampleDetermine 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 armN = 800/yearPatients

recruitedN = 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

321


aExclusions= 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 GuidelinesILI : 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.


over 3 years Oseltamivir arm N = 800/year

Control armN = 800/yearPatients

recruitedN = 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

Flu A

Flu B

Flu A H1

Flu A H3

Flu A H1’09

RSVA

RSVB

+ -+ -+ -+ -+ -+ -+ -

-

+

Blinded1 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 32


Testing with Idylla 3: Idylla guided treatment assessment

Recruitment— aExclusion criteria— ILI symptoms


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 recruitedN ≥100

Screening Baseline Treatment Follow up

Idylla RP1 Testing (NS swab)

Idylla RP1 Diagnostic

(NS swab)

b

H275Y

Flu A

Flu B

Flu A H1

Flu A H3

Flu A H1’09

RSVA

RSVB

+ -+ -+ -+ -+ -+ -+ -

- +

+

+

At least one positive test


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’


WP3: Pathogeneis, obesrvational study

• Opportunity to contribute a smaller number of more intensively sampled patients for an observational, pathogenesis study


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)


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


Three muskateers

Paul Little, Co-P lead


Leadership and primary care networkCentral coordination• Chris Butler (Ox)• Johanna Cook (Ox)• Alike van der Velden (U)• Theo Verheij (U)• Additional staff when needed (Ox/U)

National networkCoordinatorSupporting staf

National networkCoordinatorSupporting staff


Local laboratory Local laboratory Local laboratory

Health centres Health centres Health centres


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’ CaptJannsens Diagnostics


Organisation primary care networkCentral 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 networkCoordinatorSupporting staf



Local laboratory Local laboratory Local laboratory

Health centres Health centres Health centres


Network development paper

funded by the european union wellcome! antivirals for influenza like illness? a rct of clinical and...

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