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

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)

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

Study Overview

• Status: Recruiting
• Conditions: Influenza; Influenza, Human
• Intervention / Treatment: Drug: Drug: Oseltamivir; Drug: Drug: Favipiravir; Drug: Drug: Zanamivir; Drug: Drug: Baloxavir; Drug: Drug: Molnupiravir; Drug: Drug: Peramivir; Drug: Drug: Laninamivir

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 Type: Interventional
• Enrollment (Anticipated): 250
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: William Schilling, MD; Phone Number: +662 203 6333; Email: william@tropmedres.ac
• Study Contact Backup: Name: Nicholas J White, Prof; Phone Number: +662 203 6333; Email: nickw@tropmedres.ac

Study Locations

• Thailand
  • Bangkok, Thailand, 10400
    • Recruiting
    • Faculty of Tropical Medicine, Mahidol University
    • Contact: Weerapong Phumratanaprapin, MD; Email: weerapong.phu@mahidol.ac.th

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 50 years (Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

8

Arms and Interventions

Participant Group / 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)

What is the study measuring?

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Rates of hospitalisation for clinical trial reasons	Rates of hospitalisation for clinical reasons up to day 28	Days 0 - 28
Development of influenza-related complications	Development of influenza-related complications including bronchitis, sinusitis, otitis media and pneumonia requiring antibiotics, up to day 28	Days 0 - 28

Collaborators and Investigators

• Sponsor: University of Oxford

Study record dates

Study Major Dates

• Study Start (Actual): February 22, 2023
• Primary Completion (Anticipated): December 1, 2024
• Study Completion (Anticipated): January 1, 2025

Study Registration Dates

• First Submitted: December 5, 2022
• First Submitted That Met QC Criteria: December 5, 2022
• First Posted (Actual): December 13, 2022

Study Record Updates

• Last Update Posted (Estimate): May 11, 2023
• Last Update Submitted That Met QC Criteria: May 9, 2023
• Last Verified: April 1, 2023

More Information

Terms related to this study

• Keywords: Influenza; Phase 2; Antiviral Pharmacodynamics
• Additional Relevant MeSH Terms: RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Orthomyxoviridae Infections; Influenza, Human; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Enzyme Inhibitors; Favipiravir; Zanamivir; Oseltamivir; Baloxavir; Peramivir; Laninamivir
• Other Study ID Numbers: VIR22003

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

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.

• IPD Sharing Access Criteria: 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).

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No