European multi-centre platform, response-adaptive, open, randomised controlled interventional trial on Influenza-Like-Illness (ILI) in Primary Care (PC).

 ALIC4E: ‘Antivirals for influenza Like Illness? An rCt of Clinical and Cost effectiveness in primary CarE 


  • There have been many placebo controlled, efficacy trials of oseltamivir for influenza like illness (ILI), and systematic reviews of these trials have generated precise estimates for reductions in time to first alleviation of symptoms. These trials have almost all so far been funded by the pharmaceutical industry for regulatory and licensing purposes. Additional, similar placebo controlled studies that determine the advantage oseltamivir gives over placebo in terms of number of hours with fewer symptoms would be repetitive and largely uninformative for guiding routine primary care.  A critical outstanding question is not whether oseltamivir alleviates symptoms, but whether prescribing the drug in routine primary are is worth it in terms of helping people return to their usual activities, and if so, which patient characteristics are associated with greatest benefit?
  • ALIC4E will be the first publically funded, multi-country, pragmatic study determining whether antivirals should be routinely prescribed for (ILI) in primary care.
  • ALIC4E aims to go beyond determining the average treatment effect in a population to determining effects in patients with combinations of pre-specified characteristics (age, symptom duration, illness severity, and co-morbidities).
  • The platform design allows the study to remain relevant to evolving circumstances, with the ability to add treatments arms.
  • 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 intervention that will be most effective for them.
  • Because the possibility of taking a placebo influences participant expectations about their treatment and influences their future help-seeking behaviour, and determining effects of the interventions on patient behaviour in real-world care is critical to estimates of cost effectiveness, ALIC4E is an open-label trial.


Primary: To determine whether adding antiviral treatment to best usual primary care is effective in reducing time to return to usual daily activity

Secondary: To determine whether adding antiviral treatment to best usual primary care: Is cost effective; decreases the incidence of hospital admissions; decreases complications related to influenza like illness (ILI), especially pneumonia; decreases repeat attendance in primary care; 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 the transmission of infection within household; affects the self-management of ILI symptoms, and; benefits certain subgroups of patients more than others. 

Trial architecture

ALIC4E is an individually randomised trial of the clinical and cost effectiveness of adding antivirals into routine care.


The neuraminidase inhibitor, oseltamivir, is currently being evaluated in the trial, and the usual care will be compared to usual care with the addition of oseltamivir.

Sample size

The trial will seek to enrol over 2500 participants during three consecutive winters (2014/15; 2015/16; 2017/18) during times of confirmed, high influenza incidence.   2500 participants will provide over 99% power for comparing the primary end point in the overall study population where there is at least one day benefit of oseltamivir for participants with confirmed influenza. Analysis will be done for those with ILI and for the subgroup that had a nasopharyngeal swab that was positive for influenza virus. 


Male or Female, aged at least one year, presenting with ILI in primary care during a period of increased influenza activity. ILI is defined as the 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.

Assessment and follow up

Patients consulting with participating clinicians in ALIC4E primary care sites will be offered the chance to participate in the study. Those providing informed consent will be randomised to usual care or usual care with the addition of oseltamivir.  Baseline clinical data will be collected and a swab taken which will be analysed centrally for viral pathogens. Participants will be followed up for one month about their symptoms, resource use, health care utilisation, medication use, hospitalisations and complications. 


ALIC4E is being implemented in primary care networks the following countries: Belgium; Czech Republic; Denmark; France; Greece; Ireland; Lithuania; Netherlands; Norway; Poland; Hungary; Spain; Sweden; Switzerland; England and Wales.


1. Surveys and qualitative studies will evaluate participants’ experiences of the trial processes as well as their views on pandemic research.

2. ALIC4E will in addition evaluate the predictive values, sensitivity, specificity and added diagnostic performance characteristics of selected, novel POCTs. 


Key Objectives

  1. To inform evidence-based guidelines for primary healthcare management of patients presenting with influenza-like illness;
  2. To assess the most effective as well as cost-effective treatment of patients presenting to primary care with ILI, with specific attention for subgroup of patients (age, severity, comorbidity, high-risk).
  3. To assess the diagnostic performance of a novel point of care test (POCT) for diagnosing viral respiratory infections in PC;
  4. To make recommendations for safe, rapid, effective inter- and intra- pandemic clinical infections research in PC.

Key tasks

  1. Write protocol and design all associated patient-related, trial management and quality documents
  2. Set up adaptive design simulations
  3. Source and distribute medication
  4. Obtain ethical, all other required approvals in all countries WP4 will be working in
  5. Recruit and train network leads and staff in each country
  6. Enable recruitment of sites in each country
  7. Manage recruitment of all participants
  8. Manage the data
  9. Analyse the results
  10. Disseminate key findings

Team members

Chris Butler Co-ordinator
Theo Verheij Co-investigator
Johanna Cook Senior Trial Manager
Alike van der Velden Network Co-ordinator

Contact us


Herman Goossens

Deputy Coordinator:

Menno de Jong


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