A Phase 2 Trial Comparing Antiviral Treatments in Early Symptomatic Influenza

Several influenza antivirals are licensed, differing in availability and routes of administration. Direct comparisons of antiviral and clinical efficacy between the multiple available antivirals are lacking. This comparative information is important for guideline development and for aiding purchasing and prioritisation decisions with several options available.

The platform trial will assess the following interventions:

* Licensed influenza antiviral interventions: oseltamivir (TAMIFLU®), peramivir (RAPIVAB®), zanamivir (RELENZA®), laninamivir (INAVIR®), baloxavir (XOFLUZA®) and favipiravir alone and in combination. The interventions will be chosen in order of priority as well as local feasibility at sites (availability of drugs, local ethics committee and regulatory approvals)
* Interventions with antiviral activity against influenza demonstrated in pre-clinical studies: molnupiravir

Randomisation to the no antiviral treatment control arm (no intervention) will be fixed at a minimum of 20% throughout the study. The randomisation ratios will be uniform for all available interventions.

• Oseltamivir (Drug): Oral oseltamivir 75mg BD for 5/7
• Favipiravir (Drug): Oral favipiravir 1800mg BD D0 and 800mg BD for a further 4/7
• Zanamivir (Drug): Inhaled zanamivir 10mg BD for 5/7
• Baloxavir (Drug): Oral baloxavir: * <80kg- single dose of 40mg on D0 * ≥80kg- single dose of 80mg on D0
• Molnupiravir (Drug): Oral molnupiravir 800mg BD for 5/7
• Peramivir (Drug): Intravenous peramivir 600mg once only
• Laninamivir (Drug): Inhaled laninamivir 40mg once only
• Oseltamivir and Baloxavir (Drug): Oseltamivir 75mg BD for 5/7 and Baloxavir: * <80kg- single dose of 40mg on D0 * ≥80kg- single dose of 80mg on D0
• Oseltamivir and Favipiravir (Drug): Oseltamivir 75mg BD for 5/7 and favipiravir 1800mg BD D0 and 800mg BD for a further 4/7
• Favipiravir and Baloxavir (Drug): favipiravir 1800mg BD D0 and 800mg BD for a further 4/7 Baloxavir: * <80kg- single dose of 40mg on D0 * ≥80kg- single dose of 80mg on D0

Primary outcomes

• Rate of viral clearance for currently available drugs and those with potential activity [Days 0 - 5]: Rate of viral clearance- estimated from the log10 viral density derived from qPCR of standardised duplicate oropharyngeal swabs/saliva taken daily from baseline (day 0) to day 7 for each therapeutic arm compared with the no antiviral treatment control i.e. those not receiving study drug

Secondary outcomes

• Rate of viral clearance in early influenza infection [Days 0 - 5]: Rate of viral clearance in early influenza infection to characterise the determinants of viral clearance in early influenza infection e.g. contribution of baseline serology, influenza type/subtype, prior vaccination
• Rate of viral clearance for drugs shown to have considerable antiviral activity [Days 0 - 5]: Rate of viral clearance for drugs to determine optimal dosing regimens for drugs shown to have considerable antiviral activity
• Time to symptom alleviation and fever duration [Days 0 - 14]: Assessment of time to symptom alleviation and fever duration to compare time to symptom resolution and fever duration between interventions

Other outcomes

• Rates of hospitalisation for clinical trial reasons [Days 0 - 28]: Rates of hospitalisation for clinical reasons up to day 28
• Development of influenza-related complications [Days 0 - 28]: Development of influenza-related complications including bronchitis, sinusitis, otitis media and pneumonia requiring antibiotics, up to day 28
• 7. Relationship between viral clearance, randomisation arm and other measures (covariates) and development of symptoms or functional issues following illness with influenza. [Days 0-120]: This will be scored using the Modified Influenza Yorkshire Rehabilitation Scale (Flu-YRSm), adapted from the Modified COVID-19 Yorkshire Rehabilitation Scale (C19-YRSm).

Sex: All, ages: 18 Years to 60 Years

Inclusion Criteria:

* Patient understands the procedures and requirements and is willing and able to give informed consent for full participation in the study
* Adults, male or female, aged 18 to 60 years at time of consent.
* Early symptomatic Influenza (A or B); at least one reported symptom of influenza (including fever, history of fever, myalgias, headache, cough, fatigue, nasal congestion, rhinorrhoea and sore throat) within 4 days (96 hours)
* Influenza positive by rapid antigen test OR a positive RT-PCR test for influenza viruses within the last 24hrs with a Ct value of <30
* Able to walk unaided and unimpeded in activities of daily living (ADLs)
* Agrees and is able to adhere to all study procedures, including availability and contact information for follow-up visits

Exclusion Criteria:

The patient may not enter the study if ANY of the following apply:

* Taking any concomitant medications or drugs which could interact with the study medications or have antiviral activity
* Presence of any chronic illness/condition requiring long term treatment or other significant comorbidity
* BMI ≥35 Kg/m2
* Clinically relevant laboratory abnormalities discovered at screening

  * Haemoglobin <10g/dL
  * Platelet count <100,000/uL
  * ALT > 2x ULN
  * Total bilirubin >1.5 x ULN
  * eGFR <70mls/min/1.73m2
* For females: pregnancy, actively trying to become pregnant or lactation (healthy women on OCP are eligible to join)
* Contraindication to taking, or known hypersensitivity reaction to any of the proposed therapeutics
* Currently participating in another interventional influenza or COVID-19 therapeutic trial
* Clinical evidence of pneumonia- e.g. shortness of breath, hypoxaemia, crepitations (imaging not required)
* Known to be currently co-infected with SARS-CoV-2 (i.e. confirmed with positive ATK or RT-PCR)
* Received live attenuated influenza virus vaccine within 3 weeks prior to study entry

• Results publication: Jittamala P, Schilling WHK, Leopold SJ, Watson JA, Kotchum K, Wongnak P, Seers T, Asawasriworanan T, Singh S, Beer E, Ngernseng T, Suwannasin K, Madmanee W, Phommasone K, Shrestha S, de Aguiar RS, Batty EM, Teixeira MM, Karkey A, Ashley EA, Intalapaporn P, Luvira V, Phumratanaprapin W, Chotivanich K, Imwong M, White NJ; AD ASTRA Collaborative Group. Baloxavir marboxil, favipiravir, or oseltamivir in patients with non-severe symptomatic seasonal influenza (AD ASTRA): a phase 2, open-label, adaptive, randomised controlled trial. Lancet Infect Dis. 2026 Jul 28:S1473-3099(26)00255-0. doi: 10.1016/S1473-3099(26)00255-0. Online ahead of print. PMID 42520824

• Study Protocol (PDF, 2025-11-18)
• Statistical Analysis Plan (PDF, 2026-02-10)