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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
3,000
Oral oseltamivir 75mg BD for 5/7
Oral favipiravir 1800mg BD D0 and 800mg BD for a further 4/7
Inhaled zanamivir 10mg BD for 5/7
Oral baloxavir: * \<80kg- single dose of 40mg on D0 * ≥80kg- single dose of 80mg on D0
Oral molnupiravir 800mg BD for 5/7
Intravenous peramivir 600mg once only
Inhaled laninamivir 40mg once only
Oseltamivir 75mg BD for 5/7 and Baloxavir: * \<80kg- single dose of 40mg on D0 * ≥80kg- single dose of 80mg on D0
Oseltamivir 75mg BD for 5/7 and favipiravir 1800mg BD D0 and 800mg BD for a further 4/7
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
Universidade Federal de Minas Gerais
Minas Gerais, Brazil
RECRUITINGLaos-Oxford-Mahosot Wellcome Trust Research unit
Vientiane, Laos
RECRUITINGSukraraj Tropical & Infectious Disease Hospital
Kathmandu, Nepal
RECRUITINGFaculty of Tropical Medicine, Mahidol University
Bangkok, Thailand
RECRUITINGRate of viral clearance for currently available drugs and those with potential activity
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
Time frame: Days 0 - 5
Rate of viral clearance in early influenza infection
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
Time frame: Days 0 - 5
Rate of viral clearance for drugs shown to have considerable antiviral activity
Rate of viral clearance for drugs to determine optimal dosing regimens for drugs shown to have considerable antiviral activity
Time frame: Days 0 - 5
Time to symptom alleviation and fever duration
Assessment of time to symptom alleviation and fever duration to compare time to symptom resolution and fever duration between interventions
Time frame: Days 0 - 14
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