A Phase 2 Trial Comparing Antiviral Treatments in Early Symptomatic Influenza

Influenza Clinical Trial

— AD ASTRA  

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)

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05648448
• Other study ID #: VIR22003
• Status: Recruiting
• Phase: Phase 2
• Start date: February 22, 2023
• Est. completion date: January 1, 2027

Study information

• Verified date: May 2024
• Source: University of Oxford
• Contact: William Schilling, MD
• Phone: +662 203 6333
• Email: william[@]tropmedres.ac
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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

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 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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 3000
• Est. completion date: January 1, 2027
• Est. primary completion date: January 1, 2027
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 60 Years

Eligibility

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

Related Conditions & MeSH terms

• Influenza
• Influenza, Human

Intervention

Drug:
• Oseltamivir
Oral oseltamivir 75mg BD for 5/7
• Favipiravir
Oral favipiravir 1800mg BD D0 and 800mg BD for a further 4/7
• Zanamivir
Inhaled zanamivir 10mg BD for 5/7
• Baloxavir
Oral baloxavir: <80kg- single dose of 40mg on D0 =80kg- single dose of 80mg on D0
• Molnupiravir
Oral molnupiravir 800mg BD for 5/7
• Peramivir
Intravenous peramivir 600mg once only
• Laninamivir
Inhaled laninamivir 40mg once only
• Oseltamivir and Baloxavir
Oseltamivir 75mg BD for 5/7 and Baloxavir: <80kg- single dose of 40mg on D0 =80kg- single dose of 80mg on D0
• Oseltamivir and Favipiravir
Oseltamivir 75mg BD for 5/7 and favipiravir 1800mg BD D0 and 800mg BD for a further 4/7
• Favipiravir and Baloxavir
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

Locations

Country	Name	City	State
Thailand	Faculty of Tropical Medicine, Mahidol University	Bangkok

Sponsors (1)

Lead Sponsor	Collaborator
University of Oxford

Country where clinical trial is conducted

Thailand, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Rates of hospitalisation for clinical trial reasons	Rates of hospitalisation for clinical reasons up to day 28	Days 0 - 28
Other	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
Other	7. Relationship between viral clearance, randomisation arm and other measures (covariates) and development of symptoms or functional issues following illness with influenza.	This will be scored using the Modified Influenza Yorkshire Rehabilitation Scale (Flu-YRSm), adapted from the Modified COVID-19 Yorkshire Rehabilitation Scale (C19-YRSm).	Days 0-120
Primary	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 - 5
Secondary	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 - 5
Secondary	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 - 5
Secondary	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 - 14