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)

Funders:
Wellcome Trust

Trial sites:
Thailand
Nepal
Brazil
Laos

Co-Principal Investigators:

Dr William Schilling
Mahidol Oxford Tropical Medicine Research Unit,
Faculty of Tropical Medicine, Mahidol University

Prof. Sir Nicholas J White
Mahidol Oxford Tropical Medicine Research Unit,
Faculty of Tropical Medicine, Mahidol University

Co-Investigators:

Associate Professor Abhilasha Karkey
Microbiologist
Director, Oxford University Clinical Research Unit Nepal

Associate Professor Buddha Basnyat
Chairperson, Oxford University Clinical Research Unit Nepal

Dr Yuba Nidhi Basaula
Consultant paediatrician
Director, Sukraraj Tropical and Infectious Disease Hospital (STIDH)

Dr Bimal Sharma Chalise
Consultant physician, Sukraraj Tropical and Infectious Disease Hospital (STIDH)

Dr Sulochana Manandhar
Molecular Microbiologist
Oxford University Clinical Research Unit Nepal

Dr Suchita Shrestha
Head of CTU
Oxford University Clinical Research Unit Nepal

Others involved in the project
Shristi Singh
Project Manager
Oxford University Clinical Research Unit Nepal

Alisha Pradhan
Research Coordinator
Oxford University Clinical Research Unit Nepal

Januka Khatri
Clinical Pharmacist
Oxford University Clinical Research Unit Nepal

This study is a randomized, open-label, controlled, group sequential adaptive platform trial, conducted in low-risk patients with Influenza, recruited from outpatient COVID-19/ Acute Respiratory Infection (ARI) clinics or through other approved facilities. Previously healthy patients 18 to 60 years old with early symptomatic Influenza and without co-morbidities are eligible for the study. Enrolled patients are followed up daily for 7 days and then on Day 14. Phone follow-up is conducted on Day 28 and Day 120. This study aims to quantitatively assess antiviral effects in low-risk patients with high viral burdens and uncomplicated influenza, to determine in-vivo antiviral activity. In this study, we will compare the performance of available influenza antivirals, and those with potential activity, relative to the control (no study drug) and each other. The study currently includes Oseltamivir, Baloxavir, Favipiravir and Molnupiravir in the treatment arms. The key metric to be assessed in this study is the viral clearance rate.

Background

In this study, we assess and compare the performance of currently licensed interventions with activity against influenza viruses, and those with potential activity demonstrated in pre-clinical and early clinical studies relative to each-other and the control (no antiviral treatment). Many antivirals for use against influenza are available but only oseltamivir is recommended by the WHO. Some clinical trials of antiviral drugs have used oseltamivir as a comparator arm and compared clinical and virological endpoints but direct, standardised comparison of in vivo antiviral effects between multiple available antivirals is lacking. There is also a lack of information regarding synergistic properties of antiviral combinations which may have relevance for those with prolonged viral replication. By comparing each intervention to the no study drug arm, we can demonstrate that the method does identify active compounds. We will then compare the antiviral effects across interventions. This information will aid prescribers, and guideline developers, and inform healthcare systems in making purchasing and prioritization decisions.

Primary Objectives:

To evaluate Influenza antiviral efficacy in-vivo (accelerated viral clearance relative to the no study drug arm). This is a superiority comparison.
To compare Influenza antiviral efficacy with current best antiviral treatment option (accelerated viral clearance relative to the positive control arm). This is a non-inferiority or superiority comparison.

Secondary Objectives:

To characterise the determinants of viral clearance in early influenza infection e.g. contribution of baseline serology, influenza type/subtype, prior vaccination, host genetics.
To determine optimal dosing regimens for drugs with evidence of antiviral activity
To compare time to symptom resolution and fever duration with respect to no treatment
To determine the effects of drugs on the development of drug-resistant viral mutants between interventions and no treatment arm

Tertiary Objectives:

To characterise the relationship between viral clearance and hospitalization for clinical reasons
To characterise the relationship between viral clearance and development of influenza complications including bronchitis, sinusitis, otitis media and pneumonia requiring antibiotics
To characterise the relationship between viral clearance, randomization arm and other measures (covariates) and development of post-acute symptoms in comparison to post-acute symptoms for other respiratory viral diseases (e.g. long-COVID)