This trial will use a previously validated platform, to quantitatively assess antiviral effects in low-risk patients with high viral burdens and uncomplicated influenza, to determine in-vivo antiviral activity. In this randomised, open-label, controlled, group sequential, adaptive, platform trial, we will compare the performance of available influenza antivirals, and those with potential activity, relative to the control (no treatment) and each other.

AD ASTRA study is supported by the Wellcome Trust Grant ref: 223195/Z/21/Z through the COVID-19 Therapeutics Accelerator

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.

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

With patient's consent, clinical data and results from blood analyses stored in the database may be shared according to the terms defined in the MORU data sharing policy with other researchers to use in the future. https://wellcome.ac.uk/press-release/statement-data-sharing-public-health-emergencies).

The data generated in this study belongs to the study group as a whole. The final database will be shared amongst the site PI and key members of the research team.

The database may be shared with researchers not directly involved in this study after the main paper has been published and in accordance with MORU guidelines on data sharing.

Refer to MORU data sharing policy with other researchers to use in the future. https://wellcome.ac.uk/press-release/statement-data-sharing-public-health-emergencies).