A Phase 2 Trial Comparing Antiviral Treatments in Early Symptomatic Influenza

Study Overview
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Brief Summary
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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

Detailed Description
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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. 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.

Official Title
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ADaptive ASsessment of TReatments for influenzA: A Phase 2 Multi-centre Adaptive Randomised Platform Trial to Assess Antiviral Pharmacodynamics in Early Symptomatic Influenza Infection (AD ASTRA)

Conditions
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Influenza, Influenza, Human

Intervention / Treatment
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* Drug: Drug: Oseltamivir
* Drug: Drug: Favipiravir
* Drug: Drug: Zanamivir
* Drug: Drug: Baloxavir
* Drug: Drug: Molnupiravir
* Drug: Drug: Peramivir
* Drug: Drug: Laninamivir


Participation Criteria
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Eligibility Criteria
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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 50 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 Haemaglobin <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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 50 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Oseltamivir (TAMIFLU®)<br> | Drug: Drug: Oseltamivir<br>* Oral oseltamivir 75mg BD for 5/7<br>|
| Experimental: Favipiravir<br> | Drug: Drug: Favipiravir<br>* Oral favipiravir 1800mg BD D0 and 800mg BD for a further 4/7<br>|
| Experimental: Zanamivir (RELENZA®)<br> | Drug: Drug: Zanamivir<br>* Inhaled zanamivir 10mg BD for 5/7<br>|
| Experimental: Baloxavir (XOFLUZA®)<br> | Drug: Drug: Baloxavir<br>* Oral baloxavir: <80kg- single dose of 40mg on D0 ≥80kg- single dose of 80mg on D0<br>|
| Experimental: Molnupiravir<br> | Drug: Drug: Molnupiravir<br>* Oral molnupiravir 800mg BD for 5/7<br>|
| Experimental: Peramivir (RAPIVAB®)<br> | Drug: Drug: Peramivir<br>* Intravenous peramivir 600mg once only<br>|
| Experimental: Laninamivir (INAVIR®)<br> | Drug: Drug: Laninamivir<br>* Inhaled laninamivir 40mg once only<br>|
| No Intervention: Negative control group<br>No treatment (except antipyretics- paracetamol) | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate 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 | Days 0 - 7 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | Days 0 - 7 | 
| 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 | Days 0 - 7 | 
| 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 | Days 0 - 7 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Influenza, Phase 2, Antiviral Pharmacodynamics