A Phase 2 Trial Comparing Antiviral Treatments in Early Symptomatic Influenza

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)

Overview

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

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.

Interventions

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

Primary outcome measures

• Rate of viral clearance for currently available drugs and those with potential activity [Time frame: Days 0 - 5]

Secondary outcome measures (3)

• Rate of viral clearance in early influenza infection [Time frame: Days 0 - 5]
• Rate of viral clearance for drugs shown to have considerable antiviral activity [Time frame: Days 0 - 5]
• Time to symptom alleviation and fever duration [Time frame: Days 0 - 14]

Eligibility criteria

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 60 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

• Haemoglobin <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

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

Brazil · 1 center

• Universidade Federal de Minas Gerais — Minas Gerais

Laos · 1 center

• Laos-Oxford-Mahosot Wellcome Trust Research unit — Vientiane

Nepal · 1 center

• Sukraraj Tropical & Infectious Disease Hospital — Kathmandu

Thailand · 1 center

• Faculty of Tropical Medicine, Mahidol University — Bangkok

Publications

• Jittamala P, Schilling WHK, Leopold SJ, Watson JA, Kotchum K, Wongnak P, Seers T, Asawasriworanan T, Singh S, Beer E, Ngernseng T, Suwannasin K, Madmanee W, Phommasone K, Shrestha S, de Aguiar RS, Batty EM, Teixeira MM, Karkey A, Ashley EA, Intalapaporn P, Luvira V, Phumratanaprapin W, Chotivanich K, Imwong M, White NJ; AD ASTRA Collaborative Group. Baloxavir marboxil, favipiravir, or oseltamivir PMID 42520824

Identifiers

NCT: NCT05648448 · VIR22003

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗