AD ASTRA: A Phase 2 Trial Comparing Antiviral Treatments in Early Symptomatic Influenza

Sponsor

University of Oxford (Other)

Overall Status

Not yet recruiting

CT.gov ID

NCT05648448

Collaborator

(none)

250

Enrollment

Location

Arms

23.3

Anticipated Duration (Months)

10.7

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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

Condition or Disease	Intervention/Treatment	Phase
Influenza Influenza, Human	Drug: Drug: Oseltamivir Drug: Drug: Favipiravir Drug: Drug: Zanamivir Drug: Drug: Baloxavir Drug: Drug: Molnupiravir Drug: Drug: Peramivir Drug: Drug: Laninamivir	Phase 2

Detailed Description

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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

250 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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)

Anticipated Study Start Date :

Jan 22, 2023

Anticipated Primary Completion Date :

Dec 1, 2024

Anticipated Study Completion Date :

Jan 1, 2025

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

Rate of viral clearance for currently available drugs and those with potential activity [Days 0 - 7]
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 Outcome Measures

Rate of viral clearance in early influenza infection [Days 0 - 7]
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 - 7]
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 - 7]
Assessment of time to symptom alleviation and fever duration to compare time to symptom resolution and fever duration between interventions

Other Outcome Measures

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

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 50 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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