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)
Phase: PHASE2
Conditions: Influenza, Influenza, Human
Sponsor: University of Oxford

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CONFIDENTIAL 
Master Protocol: 
 
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) 
 
Short title: A phase 2 trial comparing antiviral treatments in early symptomatic influenza  
 
Acronym: AD ASTRA 
 
OxTREC Ref: 
6-23  
Trial Registration Number: 
 
NCT05648448 
Protocol number: 
 
VIR22003 
Date and Version No: 
 
Version 7.0 dated 18 November 2025 
Co-Principal Investigators: 
Dr. William Schilling (william@tropmedres.ac) 
Mahidol Oxford Tropical Medicine Research Unit,  
Faculty of Tropical Medicine, Mahidol University  
420/6 Ratchawithi Road, Ratchathewi, Bangkok 10400 Thailand 
 
Professor Sir Nicholas J White (nickw@tropmedres.ac)  
Mahidol Oxford Tropical Medicine Research Unit,  
Faculty of Tropical Medicine, Mahidol University  
420/6 Ratchawithi Road, Ratchathewi, Bangkok 10400 Thailand 
 
Co-Investigators: 
 
Dr. Stije J Leopold 
Mahidol Oxford Tropical Medicine Research Unit, 
Faculty of Tropical Medicine, Mahidol University 
420/6 Ratchawithi Road, Ratchathewi, Bangkok 10400 Thailand 
 
Associate Professor Weerapong Phumratanaprapin  
Department of Clinical Tropical Medicine,  
Faculty of Tropical Medicine, Mahidol University  
420/6 Ratchawithi Road, Ratchathewi, Bangkok 10400 Thailand  
 
 
Professor Elizabeth Ashley 
Director of Lao-Oxford-Mahosot Hospital- Wellcome Trust Research Unit, 
Vientiane, Laos  
 
Professor Mauro Teixeria 
Universidade Federal de Minas Gerais, Av. Pres. Antônio Carlos, 6627 – 
Pampulha, Belo Horizonte, Minas Gerais, 31270-901, Brazil 
 
Associate Professor Abhilasha Karkey  
Director of Oxford University Clinical Research Unit Nepal,  
Kathmandu, Nepal 
 
 
Dr. James A Watson 
Statistician 
Mahidol Oxford Tropical Medicine Research Unit,  
Faculty of Tropical Medicine, Mahidol University  
420/6 Ratchawithi Road, Ratchathewi, Bangkok, Thailand 

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CONFIDENTIAL 
Professor Arjen M Dondorp 
Deputy Director and Head of Malaria & Critical Illness, 
Mahidol Oxford Tropical Medicine Research Unit,  
Faculty of Tropical Medicine, Mahidol University  
420/6 Ratchawithi Road, Ratchathewi, Bangkok, Thailand 
 
Professor Nicholas PJ Day  
Mahidol Oxford Tropical Medicine Research Unit,  
Faculty of Tropical Medicine, Mahidol University 
420/6 Ratchawithi Road, Ratchathewi, Bangkok 10400 Thailand  
 
Professor Mallika Imwong  
Department of Molecular Tropical Medicine, 
Faculty of Tropical Medicine, Mahidol University 
420/6 Ratchawithi Road, Ratchathewi, Bangkok 10400 Thailand  
 
Sponsor: 
 
The University of Oxford 
Research Governance, Ethics and Assurance, Boundary Brook House, 
Churchill Drive, Oxford OX3 7GB United Kingdom 
 
Funder: 
 
Wellcome Trust Grant ref: 226933/Z/23/Z through the COVID-19 
Therapeutics Accelerator 
 
 
Investigator’s contributions: 
 
NJW conceived of the study and initiated the study design with other investigators.  
 
Confidentiality Statement 
 
This document contains confidential information that must not be disclosed to anyone other than the Sponsor, 
the Investigator Team, host organisation, and members of the Research Ethics Committee and Regulatory 
Authorities unless authorised to do so.  
 
 
Investigator Agreement and Declaration of Interests  
 
“The undersigned has read and understood the trial protocol detailed above and:  
 
- 
agrees to conduct the trial in compliance with the protocol. 
- 
agrees to comply with the principles of the International Conference on Harmonisation Tripartite 
Guideline on Good Clinical Practice. 
- 
declare no conflict of interest, according to the current version of the Declaration of Helsinki”  
 
Dr William Schilling  
…………………………………....…… 
………………………… 
……19 Nov 2025…… 
Co-Principal Investigator  
Signature 
Date 
Professor Sir Nicholas J White 
………………………………..…..…… 
……19 Nov 2025……… 
Co-Principal Investigator 
Signature 
Date 
 
 
 

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CONFIDENTIAL 
Table of Contents 
1. SYNOPSIS............................................................................................................................................................ 5 
2. ABBREVIATION ................................................................................................................................................... 7 
3. BACKGROUND AND RATIONALE ........................................................................................................................ 8 
3.1. Proposal .................................................................................................................................................... 10 
3.2. Pharmacodynamic Assessment ................................................................................................................ 11 
4. OBJECTIVES AND ENDPOINTS .......................................................................................................................... 12 
5. STUDY DESIGN ................................................................................................................................................. 12 
5.1. Interventions ............................................................................................................................................ 13 
5.2. Randomisation ......................................................................................................................................... 13 
6. PATIENT IDENTIFICATION AND RECRUITMENT ............................................................................................... 14 
6.1. Study Patients .......................................................................................................................................... 14 
6.2. Inclusion Criteria ...................................................................................................................................... 14 
6.3. Exclusion Criteria ...................................................................................................................................... 14 
7. STUDY ENROLMENT AND PROCEDURES .......................................................................................................... 14 
7.1. Virological Sampling ................................................................................................................................. 15 
7.2. Recruitment .............................................................................................................................................. 16 
7.3. Screening and Eligibility Assessment ....................................................................................................... 16 
7.4. Informed Consent .................................................................................................................................... 16 
7.5. Baseline Assessments* ............................................................................................................................. 16 
7.6. Days of Study ............................................................................................................................................ 17 
7.7. Intensive Pharmacokinetic Sampling: ...................................................................................................... 18 
7.8. Management of Patients Who Become Ill ............................................................................................... 18 
7.9. Sample Handling and Retention ............................................................................................................... 19 
8. DISCONTINUATION/WITHDRAWAL OF PATIENTS FROM STUDY ..................................................................... 19 
8.1. Definition of End of Study ........................................................................................................................ 19 
9. SAFETY REPORTING ......................................................................................................................................... 20 
9.1. Definitions ................................................................................................................................................ 20 
9.2. Causality ................................................................................................................................................... 20 
9.3. Procedures for Recording Adverse Events ............................................................................................... 21 
9.4. Grading of Laboratory Abnormalities....................................................................................................... 21 
9.5. Reporting Procedures for Serious Adverse Events................................................................................... 21 
9.6. Data Safety Monitoring Board (DSMB) .................................................................................................... 22 
10. STATISTICS AND ANALYSIS ............................................................................................................................. 22 
10.1. Overview of Adaptive Study Design and Overall Approach ................................................................... 22 
10.2. Bayesian Hierarchical Model of Viral Clearance .................................................................................... 23 
10.3. Time Varying Effects ............................................................................................................................... 23 

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10.4. Sample Size Estimation, Randomisation and Statistical Considerations for the Bayesian Group 
Sequential Design ............................................................................................................................................ 23 
10.5. Sample Size for the Intensive PK-PD Sub-study ..................................................................................... 24 
10.6. Final Analysis of Primary Outcome ........................................................................................................ 24 
11. DATA MANAGEMENT .................................................................................................................................... 25 
11.1. Access to Data ........................................................................................................................................ 25 
11.2. Data Handling and Record Keeping ........................................................................................................ 25 
12. QUALITY CONTROL AND QUALITY ASSURANCE PROCEDURES ...................................................................... 25 
13. ETHICAL AND REGULATORY CONSIDERATIONS ............................................................................................. 25 
13.1. Declaration of Helsinki ........................................................................................................................... 26 
13.2. Guidelines for Good Clinical Practice ..................................................................................................... 26 
13.3. Approvals ................................................................................................................................................ 26 
13.4. Patient Confidentiality ........................................................................................................................... 26 
13.5. Expenses ................................................................................................................................................. 26 
13.6. Risk ......................................................................................................................................................... 26 
13.7. Benefits .................................................................................................................................................. 26 
13.8. Reporting ................................................................................................................................................ 26 
13.9. Finance and Insurance ........................................................................................................................... 26 
13.10. Data Ownership .................................................................................................................................... 27 
13.11. Publication Policy ................................................................................................................................. 27 
14. REFERENCES ................................................................................................................................................... 28 
15. Appendix 1: Schedule of Activities ................................................................................................................. 30 
16. Appendix 2: Study Drugs ................................................................................................................................ 31 
16.1. Oseltamivir ............................................................................................................................................. 31 
16.2. Zanamivir ................................................................................................................................................ 35 
16.3. Peramivir ................................................................................................................................................ 38 
16.4. Laninamivir ............................................................................................................................................. 41 
16.5. Baloxavir ................................................................................................................................................. 43 
16.6. Favipiravir ............................................................................................................................................... 46 
16.7. Molnupiravir ........................................................................................................................................... 49 
16.8. Combination Therapies .......................................................................................................................... 51 
17. Appendix 3: Sample Size Simulations............................................................................................................. 54 
18. Appendix 4: Exclusion Criteria ....................................................................................................................... 60 
19. Appendix 5: Potential Participating Countries ............................................................................................... 62 
20. Appendix 6: Amendment History .................................................................................................................. 63 
 
 
 

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1. SYNOPSIS 
 
Study 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) 
Protocol no 
VIR22003 
Rationale 
Quantitative evidence and comparison of antiviral activity in patients with influenza 
is required to inform therapeutic guidelines, and prescribing and purchasing 
decisions 
Study design 
Randomised, open label, controlled, group sequential, adaptive platform trial 
Inclusion and 
Exclusion 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 
• 
Taking any concomitant medications or drugs which could interact with the study 
medications or have antiviral activity (see Appendix 4) 
• 
Presence of any chronic illness/condition requiring long term treatment or other 
significant comorbidity (see Appendix 4) 
• 
BMI ≥35 Kg/m2 
• 
Clinically relevant laboratory abnormalities discovered at screening 
o Haemoglobin <10g/dL 
o Platelet count <100,000/uL 
o ALT > 2x ULN 
o Total bilirubin >1.5 x ULN 
o eGFR <70mls/min/1.73m2 
• 
For females: pregnancy, actively trying to become pregnant or lactation (women 
on OCP are eligible to join) 
• 
Contraindication to taking, or known hypersensitivity reaction to any of the 
proposed therapeutics (see Appendix 4) 
• 
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 
Planned sample 
size 
Continuously running group sequential adaptive platform trial. There is no fixed 
sample size.  
 
This study aims to enrol 1500 patients. 
Planned study 
period 
3 years for total duration of trial and 7 days for individual patient’s involvement  

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Interventions 
The platform trial will assess available antiviral drugs currently licensed in different 
countries for treatment of influenza. These include: Oseltamivir, Peramivir, 
Zanamivir, Laninamivir, Baloxavir, Favipiravir, Oseltamivir PLUS Baloxavir, 
Oseltamivir PLUS Favipiravir, Favipiravir PLUS Baloxavir 
 
And those with antiviral activity against influenza demonstrated in pre-clinical 
studies e.g. Molnupiravir  
Control 
Controls will receive no antiviral treatment (although the current standard of care, 
local hospital supportive treatment will remain the same e.g. antipyretics, anti-
tussives, antihistamines etc as per the treating Physician’s judgement) 
Rationale 
Many antivirals are licensed for the treatment of influenza in patients at high risk of 
severe disease, oseltamivir being the most widely studied and used. However, there 
are insufficient direct comparisons of in vivo antiviral effect to inform prescribing and 
guidelines and assist National policies and purchasing 
 
Objectives 
Endpoint 
Primary 
1. To evaluate Influenza antiviral efficacy in-
vivo (accelerated viral clearance relative to 
the no study drug arm). This is a superiority 
comparison. 
2. 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. 
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 5 for each 
therapeutic arm compared with 
the contemporaneous no antiviral 
treatment control/ positive control 
Secondary 
To characterise the determinants of viral 
clearance in early influenza infection e.g. 
contribution of baseline serology, influenza 
type/subtype, prior vaccination, host genetics  
Rate of viral clearance 
To determine optimal dosing regimens for 
drugs with evidence of antiviral activity 
Rate of viral clearance 
To compare time to symptom resolution and 
fever duration with respect to no treatment 
The following comparisons will be 
made: 
• 
Time to resolution of fever  
• 
Area Under the Curve of 
recorded temperature 
• 
Time to resolution of 
symptoms 
To determine the effects of drugs on the 
development of drug resistant viral mutants 
between interventions and no treatment arm 
Number of mutations known to 
confer resistance in detectable 
virus at later timepoints 
Tertiary 
Characterise the relationship between viral 
clearance and hospitalisation for clinical 
reasons 
Hospitalisation for clinical reasons 
up to day 7 
Characterise the relationship between viral 
clearance and development of influenza 
complications including bronchitis, sinusitis, 
otitis media and pneumonia requiring 
antibiotics 
Development of influenza-related 
complications including bronchitis, 
sinusitis, otitis media and 
pneumonia requiring antibiotics, 
up to day 7 
 
 

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2. ABBREVIATION 
 
ADLs 
Activities of daily living 
AE 
Adverse event 
AR 
Adverse reaction 
ARI 
Acute Respiratory Infection 
COVID-19 
Coronavirus disease of 2019 
CRF 
Case Report Form 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTSG 
Clinical Trials Support Group 
DSMB 
Data Safety Monitoring Board 
EC 
Ethic Committee 
EDTA 
Ethylenediaminetetraacetic acid 
FBC 
Full blood count 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
IL 
Interleukin 
IM 
Intramuscular 
IMP 
Investigational Medicinal Product 
IV 
Intravenous 
LFT 
Liver function test 
MORU 
Mahidol Oxford Tropical Medicine Research Unit 
OxTREC 
Oxford Tropical Research Ethics Committee 
PD 
Pharmacodynamic 
PI 
Principle Investigator 
PK 
Pharmacokinetics 
PPE 
Personal Protective Equipment 
RT-qPCR 
Real-time quantitative polymerase chain reaction 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SAR 
Serious Adverse Reaction 
SARS-CoV-2 
Severe acute respiratory syndrome coronavirus 2  
SOP 
Standard Operating Procedure 
TNF 
Tumor Necrosis Factor 
U&E 
Urea and Electrolytes 
VTM 
Viral transport medium 
WHO 
World Health Organisation 
 
 
 
 

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3. BACKGROUND AND RATIONALE 
Epidemiology 
Before the COVID-19 pandemic, annual seasonal influenza epidemics (mainly associated with influenza A/H3N2, 
influenza A/H1N1 pandemic 2009 and influenza B strains), were estimated by the WHO to cause ~1 billion 
infections, 3-5million cases of severe illness and 290,000-650,000 deaths each year. Influenza is therefore a 
significant cause of global morbidity and mortality (1). Global influenza incidence was low in 2020 attributed to 
the implementation of COVID-19-associated non-pharmaceutical interventions (NPIs) such as travel 
restrictions, social distancing, mask-wearing and enhanced hand-hygiene. Late 2021 saw a resurgence in 
influenza cases as use of NPIs to reduce COVID-19 transmission declined (2). We now face a situation where 
both influenza and SARS-CoV-2 viruses can be expected to co-circulate for the foreseeable future. Upcoming 
influenza seasons may be compounded in severity as population-level immunity has waned in the face of 
reduced exposure. In this context, it remains essential to ensure we are well prepared to deal with future 
influenza outbreaks while resources and attention have been diverted to COVID-19. Each year influenza viruses 
with genetic origins in East Asia spread westwards across the world. In addition, sporadic zoonotic infections 
with novel influenza A viruses continue to pose a pandemic threat with potentially devastating consequences. 
Currently a highly pathogenic “bird-flu” H5N1 is causing large numbers of deaths in wild birds and poultry. 
Fortunately, human cases have been rare as the virus is currently not well adapted to human hosts. Since 1918, 
when the ‘Spanish Flu’ killed an estimated 25-50 million people (true figures may be as high as 60 million), new 
highly pathogenic influenza strains have posed a perennial threat. The conditions which allowed another 
respiratory illness, COVID-19, to spread across the world i.e., increased population density and travel, increase 
the risks of further pandemic acute respiratory illnesses, of which Influenza is the most likely candidate.  
Vaccines 
Vaccination is currently the most effective method for preventing and reducing the severity of influenza 
infection, but ongoing rapid mutation within the immunogenic haemagglutinin surface glycoprotein 
necessitates annual revaccination. When vaccines strains are well-matched to circulating strains, clinical 
efficacy reaches ~60% but is generally lower in high-risk groups for severe illness, and is variable from year to 
year with waning of the protective response (3). In addition, uncertainty regarding future seasonal influenza 
circulation due to COVID-19-associated disruptions to normal seasonal patterns and resultant difficulties in 
predicting circulating stains, will further challenge influenza vaccine efficacy (2). Since vaccine-induced 
immunity is suboptimal, short-lived and will not protect against pandemic strains, there is a strong rationale for 
identifying effective antiviral drugs with activity against a wide range of influenza subtypes and strains, for use 
in those at high-risk of severe illness.  
Influenza viral kinetics 
In most cases, influenza is a short-lived infection with an incubation period of approximately 2 days. Viral 
shedding data from volunteer challenge studies have formed the basis of the standard influenza virus kinetic 
model. For influenza A infection, this is characterised by an initial phase of rapid viral replication with a peak in 
viral load occurring 1-3 days post infection, followed by a non-linear decline to undetectable levels over the 
subsequent 3-5 days (4). The trajectory of symptoms largely correlates with these dynamics; abrupt onset of 
systemic and respiratory symptoms coincides with the peak in viral load followed by gradual clinical 
improvement as viral load decreases, with systemic symptoms subsiding first. In comparison, influenza B 
infections may result in a more prolonged period of viral shedding with a less prominent peak occurring prior 
to symptom onset (5). These viral kinetics are based on viral load data derived from viral culture, which is a less 
sensitive method of viral detection compared to RT-PCR (6). Recent studies of naturally acquired influenza 
infection using RT-PCR to quantify viral loads report symptom and viral shedding patterns consistent with the 
culture observations, the main difference being detection of virus for a longer period of time (up to 7 days post 
symptom onset) with RT-PCR (7,8). The elderly and those with comorbidities may experience even longer 
periods of active viral replication beyond those documented in healthy individuals (9).  
Analysis of cytokine responses in experimental influenza A infection demonstrated an early peak in IL-6 and 
INF-a levels, correlating with peak viral titres and symptom scores. This suggests a role for these cytokines in 
symptom formation and host defence in influenza. TNF-a responses peaked later in the course of infection 
when viral shedding and symptoms were subsiding (10).   
 

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Severe influenza 
Although the majority of influenza infections are uncomplicated, a minority of patients (particularly those >65 
years, children <5 years and those with comorbidities) will experience progression to severe disease including 
pneumonia (primary viral or secondary bacterial), acute respiratory distress syndrome (ARDS), multi-organ 
failure and sometimes death (3). In these later stages of disease ongoing deleterious inflammatory processes 
predominate, resulting in the immunopathology seen (11).  
Anti-influenza drugs 
Several classes of antiviral drugs are approved in different countries for the treatment of influenza infection in 
those at risk of severe disease: neuraminidase inhibitors (five days of oral oseltamivir, single dose of intravenous 
peramivir, five days of inhaled zanamivir, single dose of inhaled laninamivir), an endonuclease inhibitor (single 
dose of oral baloxavir), a polymerase inhibitor (five days of oral favipiravir) and a haemagglutinin inhibitor (five 
days of oral umifenovir) (3).  
The neuraminidase inhibitors (NAIs) are the most commonly used class of influenza antivirals, differing by 
availability and routes of administration. Of these, oseltamivir is the most widely studied, used and stockpiled 
in case of future pandemics. Early randomised controlled trials of oseltamivir versus placebo in both 
uncomplicated acute influenza and experimental influenza demonstrated that oseltamivir administered within 
48 hours reduces the duration and severity of symptoms (12-15). Three out of four of these licensing trials 
showed statistically significant reductions in viral titres (12,13,15) with oseltamivir, although one study did not 
demonstrate any difference in viral shedding at any time point (14). A recent re-analysis of median viral 
shedding curves from experimental influenza infection trials showed that, in addition to reducing peak viral 
loads, oseltamivir increases the rate of viral clearance after the peak. However, this study showed that 20-40% 
of oseltamivir treated volunteers continued shedding virus as did placebo-treated controls, suggesting 
treatment failure. This study also demonstrated that in the oseltamivir treated group, the rate of viral clearance 
was slower for influenza B than influenza A infections (16). This is supported by other studies which have shown 
reduced clinical efficacy (in reducing fever duration) of oseltamivir in treating influenza B infection compared 
with influenza A infections (16-18). Inhaled zanamivir has demonstrated superior efficacy with regards to this 
endpoint in treating influenza B infections (18,19). Thus, although there is evidence for antiviral efficacy of 
oseltamivir, the data are variable and there are clear differences in efficacy in treating different influenza 
subtypes.  
The clinical effectiveness of oseltamivir in ameliorating symptoms and possibly in reducing complications is 
considered greatest when the drug is started as soon as possible after illness onset, preferably within 48 hours 
(20,21) i.e., when viral replication is at its peak. This suggests that accelerating viral clearance reduces 
subsequent pathology, a hypothesis supported by studies demonstrating that viral clearance correlates with 
symptom resolution and may be associated with a shorter duration of hospitalisation (22,23). A 48 hour window 
for treatment initiation, which is recommended for some anti-influenza drugs, is based on the trials which 
recruited healthy, non-hospitalised individuals. Viral replication patterns and the efficacy of antiviral drugs in 
severe influenza have not been adequately studied so evidence supporting antiviral use in later stages of the 
disease is lacking. However, one study of hospitalised patients with influenza infection found high viral RNA 
concentrations even beyond the first two days of illness. In this context, oseltamivir started within 4 days of 
symptom onset was associated with accelerated viral clearance when compared with no treatment, and viral 
RNA clearance was associated with a shorter duration of hospitalisation (9). This suggests there may be antiviral 
and clinical efficacy of oseltamivir even beyond the recommended 48 hour window, where there is evidence of 
prolonged viral replication. 
Data regarding oseltamivir’s effectiveness in reducing mortality and viral complications is not robust, as studies 
involved previously healthy individuals in whom complication and mortality rates are low (23). Oseltamivir is 
currently the only antiviral recommended by WHO for the treatment of individuals at high-risk of severe 
influenza illness. It is acknowledged this advice is based on evidence considered low-quality for critical 
outcomes.  
Several other neuraminidase inhibitors have been developed and all have been individually compared with 
oseltamivir in clinical trials. However, no trial has compared all of the neuraminidase inhibitors together. A 
recent network meta-analysis of RCTs compared the relative efficacy of all NAIs in reducing the duration of 
influenza symptoms using surface under the cumulative ranking curve (SUCRA); in adults and children, 

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peramivir (SUCRA = 82.6%), zanamivir (SUCRA = 64%) and oseltamivir (SUCRA = 55.1%) were the three top-
ranking drugs for this endpoint (24). Direct high quality RCTs with head-to-head comparisons of all NAIs are 
required to establish relative antiviral efficacies.  
Baloxavir is a newer influenza antiviral which, in phase 3 trials of healthy and high-risk outpatients, has shown 
superior virological efficacy compared with oseltamivir (significantly faster declines in viral titres) but similar 
efficacy to oseltamivir in ameliorating symptoms (25). Efficacy with regards to other clinical outcomes including 
reducing complications is unclear.  
Favipiravir, currently only licensed in Japan for the treatment of novel or re-emerging influenza viruses, has 
demonstrated significant reductions in viral titres and shortened duration of viral shedding in two phase 3 
randomised placebo-controlled trials of uncomplicated influenza, but evidence regarding symptom alleviation 
was inconsistent. This was attributed to considerable inter-subject variability in pre- and post-dose favipiravir 
plasma concentrations over time. Optimal dose regimens for favipiravir require further study. These trials did 
not compare the antiviral or clinical efficacy of favipiravir to other influenza antivirals (26).  
Despite the availability of a large number of antivirals to treat influenza, only one of these is recommended by 
the WHO and this recommendation is based on low-quality evidence for clinical outcomes. Although some 
clinical trials of new antivirals have included oseltamivir as a comparator arm, direct comparisons of antiviral 
and clinical efficacy between the multiple available antivirals are lacking. This comparative information is 
important for guideline development and aiding purchasing and prioritisation decisions when several options 
are available. In addition, in vivo synergy testing of combinations of antivirals will also be important when 
considering the potential for development of antiviral resistance, particularly in those patients with prolonged 
viral replication and in the circumstances that more virulent strains appear. Combination antiviral therapies can 
offer synergistic, and therefore more effective, rapid and multi-mechanistic inhibition of viral replication and 
thus accelerated viral clearance, with implications for improved clinical outcomes, transmission dynamics as 
well as reducing risk of development of resistance. 
More data regarding antiviral efficacy against different influenza types and subtypes is required, allowing for 
development of alternative treatment regimens. However large sample sizes would be required for a platform 
study comparing the impact of multiple antivirals on clinically meaningful outcomes in patients with early 
uncomplicated influenza. A study comparing the impact of different antivirals on in vivo viral clearance is an 
efficient method for rapidly comparing antiviral efficacy, as demonstrated for anti-SARS-CoV-2 drugs by the 
ongoing PLATCOV trial (27). 
Assessing viral clearance 
PLATCOV is an ongoing multi-country platform adaptive trial currently being conducted in Thailand, Brazil, Laos 
and Nepal through which we have developed and validated a platform for rapid quantitative and comparative 
in vivo assessment of antiviral effects in low-risk patients with uncomplicated COVID-19 and high viral burdens. 
The primary outcome of this trial is the rate of viral clearance measured as the slope of the log10 oropharyngeal 
viral clearance curve. This was shown to be a uniformly better endpoint in terms of increased study power 
compared to the widely used and reported time to viral clearance. The assessment is of the antiviral effect in 
vivo, as distinct from the outcome on the clinical course of the infection. The results are applicable to all stages 
of disease where viral replication occurs. This trial has so far shown that remdesivir accelerates the rate of viral 
clearance in early symptomatic COVID-19 and that ivermectin does not have measurable antiviral activity.  
This validated platform is being adapted for in vivo assessment of antiviral activity in other acute respiratory 
viruses, including seasonal and pandemic influenza.  
3.1. Proposal 
In this randomised, open-label, controlled, group sequential adaptive platform trial, we will 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 

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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 prioritisation decisions.  
The key metric assessed is the rate of viral clearance.  
3.2. Pharmacodynamic Assessment  
For the PLATCOV trial, we used prospectively collected serial viral load data from 46 individuals infected with 
SARS-CoV-2 and an accompanying pharmacodynamic model to simulate different trial designs for putative 
antiviral drugs using either time-to-clearance or rate-of-clearance as the primary trial endpoint. This model was 
then tested on data from a small pilot study of 24 patients with early symptomatic COVID-19 who were 
randomised to either ivermectin or placebo. Rate-of-clearance was shown to be a uniformly better endpoint in 
terms of type 2 error (i.e., results in increased power) than the widely used and reported time-to-clearance. 
Rate of decline in oropharyngeal qPCR estimates of viral density measured daily also allows shorter and more 
efficient evaluation of viral clearance. These simulations showed that this trial design could identify an effective 
therapy rapidly in the setting of a platform trial and quickly discard ineffective therapies. The available data 
suggests that the elimination kinetics of influenza virus from the pharynx are very similar to those for SARS-
CoV-2. The initial results of the PLATCOV study demonstrated that regular oropharyngeal swabbing from day 0 
to day 7 well-characterised the rate of viral clearance, and was well-tolerated. Although some previously 
published influenza studies with virologic endpoints have suggested a shorter duration of shedding for influenza 
viruses compared to SARS-CoV-2, when RT-PCR has been used instead of viral culture, influenza RNA has been 
detected up until day 7 (7,8). Without data to change the sampling schedule used for PLATCOV (SARS-CoV-2), 
we initially opted for the same sampling schedule and methodology for AD ASTRA (Influenza viruses), to be 
reviewed and updated after the first interim analysis of 50 patients recruited. A review of the qPCR data for the 
first 17 patients, with assignment concealed, indicated that oropharyngeal swabbing from day 0 to day 5 would 
be optimal to characterise viral clearance (as many were undetectable at D6 and D7). Swabbing on day7 was 
maintained considering secondary outcomes to measure emergence of viral mutations (see section 4). 
 
 
 

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4. OBJECTIVES AND ENDPOINTS 
 
Objectives 
Endpoint 
Timepoint(s) of 
the evaluation 
of this endpoint 
(if applicable) 
Primary  
1. To evaluate Influenza antiviral 
efficacy in-vivo (accelerated viral 
clearance relative to the no study 
drug arm). This is a superiority 
comparison. 
2. 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. 
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 5 for each 
therapeutic arm compared with 
the contemporaneous no antiviral 
treatment control/positive 
control. 
Days 0-5 
Secondary To characterise the determinants of 
viral clearance in early influenza 
infection e.g. contribution of 
baseline serology, influenza 
type/subtype, prior vaccination, 
host genetics  
Rate of viral clearance 
Days 0-5 
To determine optimal dosing 
regimens for drugs with evidence of 
antiviral activity 
Rate of viral clearance 
Days 0-5 
To compare time to symptom 
resolution and fever duration with 
respect to no treatment 
The following comparisons will be 
made: 
• Time to resolution of fever  
• Area Under the Curve of 
recorded temperature 
• Time to resolution of symptoms 
Days 0-7 
 
To determine the effects of drugs on 
the development of drug resistant 
viral mutants between interventions 
and no treatment arm 
Number of mutations known to 
confer resistance in detectable 
virus at later timepoints 
Days 0-7 
Tertiary 
Characterise the relationship 
between viral clearance and 
hospitalisation for clinical reasons 
Hospitalisation for clinical reasons 
up to day 7 
Days 0-7 
Characterise the relationship 
between viral clearance and 
development of influenza 
complications including bronchitis, 
sinusitis, otitis media and 
pneumonia requiring antibiotics 
Development of influenza-related 
complications including bronchitis, 
sinusitis, otitis media and 
pneumonia requiring antibiotics, 
up to day 7 
Days 0-7 
 
5. STUDY DESIGN 
The study is a randomised, open label, controlled, adaptive platform trial that will be conducted in low-risk 
patients with influenza, recruited from outpatient acute respiratory infection clinics (ARIs) or through other 
approved facilities, or by patient self-referral to the study site. These will be adults 18-60 years old with early 
symptomatic influenza and without co-morbidities.  
After obtaining fully informed consent, we will recruit adult patients with early symptomatic influenza (within 
4 days (96 hours) since the reported onset of symptoms), who are positive by an influenza rapid antigen test 

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OR a positive RT-PCR test for influenza within the last 24 hours with a Ct value less than 30. Patients will be 
included who can be followed up reliably for 7 days.  
The primary pharmacodynamic measure in this study is the rate of viral clearance (expressed as the slope of a 
fitted regression to the linear segment of the serial standardised oropharyngeal sample qPCR densities from 0 
to day 5) following treatment. Each site will include a no antiviral treatment control arm consisting of patients 
not receiving any antiviral treatment, although local hospital supportive treatment will remain unchanged for 
the patients including antipyretics, antitussives, antihistamines and other required medications, in the clinical 
judgement of the treating physician.  
5.1. Interventions 
• 
The list of intervention influenza antivirals is Oseltamivir, Peramivir, Zanamivir, Laninamivir, Baloxavir, 
Favipiravir, a combination of Oseltamivir PLUS Baloxavir, and combination of Oseltamivir PLUS 
Favipiravir and a combination of Favipiravir PLUS Baloxavir. The interventions will be chosen in order 
of priority as well as local feasibility at sites (availability of drugs, local EC and regulatory approvals) 
• 
Antivirals with in vitro activity against influenza viruses/activity in early clinical trials: Molnupiravir 
At any given time in the study, it is possible that not all intervention arms are available. Randomisation ratios 
will be uniform across all available treatments and the control arm in each site, although the no study drug arm 
will have a minimum randomisation of 20%.  
Randomisation will be continuously monitored by MORU. A positive influenza rapid antigen test will be used as 
the main inclusion criteria in patients with symptoms of influenza illness. Viral load is proportional to the 
severity of symptoms (8). In order to assess viral clearance dynamics accurately over time initial high viral 
densities are required.  
Initially we aim to identify interventions that accelerate viral clearance by a minimum of 20% for the 
futility/success assessments relative to the no study drug arm, as in the current PLATCOV study (see section 
10.4 and appendix 3). This threshold and the sampling schedule will be reviewed at the first interim analysis of 
50 participants. This analysis will be open - thereafter the investigators will be blinded to the viral clearance 
results and interim analyses will be conducted as described in appendix 3.  
Any intervention that shows an acceleration of viral clearance, defined as a greater than 90% probability of 
accelerating viral clearance by more than 20%, or if there is evidence of accelerated viral clearance from other 
studies, may be selected for inclusion in a nested pharmacokinetic-pharmacodynamic study. In this nested 
study, frequent blood sampling will allow assessment of the relationship between plasma drug concentrations 
and viral clearance. The design of the pharmacokinetic study depends on the known pharmacokinetic 
properties of each drug. In each case, no more than 10 blood samples (20ml) will be taken. Any intervention 
that meets the futility endpoint (less than 10% probability of accelerating viral clearance by more than 20%) 
will be dropped from the study. New arms can be added at any time during the trial. Decisions concerning 
success and futility will be made sequentially, first at the pre-specified interim analysis to be conducted after 
50 patients are enrolled, and thereafter (blinded to the investigators) interim analysis will be conducted as 
described in appendix 3. The nested intensive PK-PD substudy may be triggered if the probability that viral 
clearance is accelerated by more than 20% goes above 90% or if there is evidence of accelerated viral clearance 
from other studies (e.g. oseltamivir). 
5.2. Randomisation 
Randomisation involves randomising the participants once. All drugs currently available and being used in the 
study may be included in this i.e.,: 
Oseltamivir OR Peramivir OR Zanamivir OR Laninamivir OR Baloxavir OR Favipiravir OR Molnupiravir OR 
Oseltamivir PLUS Baloxavir OR Oseltamivir PLUS Favipiravir OR Favipiravir PLUS Baloxavir OR no study drug. 

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6. PATIENT IDENTIFICATION AND RECRUITMENT  
6.1. Study Patients  
Adult patients with early symptomatic influenza. The subject population includes those at low risk for 
complications and morbidity from influenza (as defined by WHO).  
6.2. 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 
6.3. 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 (see Appendix 4) 
• 
Presence of any chronic illness/condition requiring long term treatment or other significant comorbidity 
(see Appendix 4) 
• 
BMI ≥35 Kg/m2 
• 
Clinically relevant laboratory abnormalities discovered at screening  
o Haemoglobin <10g/dL 
o Platelet count <100,000/uL 
o ALT > 2x ULN 
o Total bilirubin >1.5 x ULN 
o eGFR <70mls/min/1.73m2 
• 
For females: pregnancy, actively trying to become pregnant or lactation (women on OCP are eligible to 
join) 
• 
Contraindication to taking, or known hypersensitivity reaction to any of the proposed therapeutics (see 
Appendix 4) 
• 
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 
7. STUDY ENROLMENT AND PROCEDURES  
Recruitment of patients will be from outpatient influenza/ARI clinics or through other approved facilities, or by 
patient self-referral to the study site.  
Patients with a positive influenza rapid antigen-detection test OR a positive PCR test for influenza within the 
last 24 hours with a Ct value of less than 30 will be enrolled in the study after providing fully informed written 
consent. In each study site there will be a designated research ward for study procedures. In accordance with 
local and national infection control guidelines the initial assessments will be conducted in a designated research 
ward set-up to manage influenza patients. Patients will receive care in either an inpatient or outpatient setting, 
in accordance with local and national guidelines.  
All recruited patients will be visited at their home or place of residence, or be seen in the designated clinical 
trials unit or hospital ward. All staff will wear appropriate personal protective equipment (PPE), in accordance 

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with local hospital guidelines. For home visits a trained member of staff will perform the swabbing (and may 
ask the patient to give a saliva sample).  
Participants will be asked if they have been in the study before.  
The patient will undergo a physical examination and blood sampling for routine haematology and biochemistry 
and other baseline investigations.  
After enrolment into the study, the patient will be randomised to one of the study arms. Further details of 
randomisation process will be provided.  
An oropharyngeal swab will be obtained initially 1 time in duplicate (i.e. total 2 swabs, one from the left tonsil, 
one from the right tonsil) (baseline) by the study team using a standard operating procedure (SOP) after a full 
explanation is provided to the patient and before receiving the first dose of the study drug. An optional set of 
swabs may also be collected at this time (baseline). Swabs will be taken in duplicate again 1 hour after receiving 
the study drug, or 1 hour after the first swabs for those who be randomised to no study drug. To minimise 
patient discomfort, all influenza qPCRs will be performed on eluates from standard oropharyngeal swabs taken 
in duplicate as opposed to nasopharyngeal sampling.  
In addition, some patients may be asked to have an extra set of swabs taken between day 0 – day 5 either by 
study personnel or self-swabbing following standardised study self-swab instructions and/or give a sample of 
saliva (see section 7.1).  
For oral and inhaled study drugs, the first dose will be administered and observed at the research ward/hospital. 
In the case of inhaled study drugs, training will be provided on proper inhaler technique. Subsequent doses will 
be administered on the research ward in cases of patients admitted. In the case of outpatients, either 
participants will self-administer the medication at their home/current residence and record the timing of this 
in a diary card, or they will administer the medication under the supervision of study staff when they attend 
the research facility for daily oropharyngeal swabbing, or in some cases they may be supervised administering 
the medication at their home/current residence (if multiple doses, then one of the doses per day will be 
confirmed in this case). In case a study drug requires parenteral administration, this will be provided under 
supervision by the study personnel in the research ward, or hospital, or the patient’s home.  
7.1. Virological Sampling 
On Day 0, oropharyngeal swabs will be taken initially 1 time in duplicate (one swab each tonsil) before receiving 
the first dose of the study drug (baseline). An optional set of swabs may also be collected at this time (baseline). 
Swabs will be taken in duplicate again 1 hour after receiving the study drug, or 1 hour after the first swabs for 
those who be randomised to no study drug.  
From Day 1 to Day 5, and again on Day 7, serial oropharyngeal swabs will be taken in duplicate (one swab each 
tonsil) according to the sample schedule. The swabs will be taken from the back of the throat (oropharynx; 
tonsillar fossa) by trained study personnel according to the SOP abiding by PPE measures. Each swab will be 
placed in 3ml of viral transport medium (VTM) (e.g. Copan UTM® 330C), snapped off and sealed. 
In addition, the study team may ask some participants to have an extra set of swabs taken between day 0 – day 
5. Either the study personnel will be asked to take this extra set, or the participant will be asked to take it 
themselves as a self-swab, according to a set of given instructions. The purpose of this extra swab set (between 
day 0 – 5) is to assess whether an additional set of values would be beneficial for analysis of viral clearance. The 
purpose of self-swabs is to assess and validate whether self-swabbing will provide qPCR data of comparable 
quality to that carried out by study personnel, if standardised instructions are provided and adhered to. If the 
result is positive, this could reduce inconvenience to participants and reduce loss to follow up. 
In addition, some patients may be asked to give a sample of saliva between day 0 and 5, either by spitting in a 
tube, or by sucking on a swab tip until it is saturated. The volume of saliva will be standardised. The purpose of 
saliva collection is to assess and validate a method of determining the viral density in the oropharynx in a less 
invasive manner, or supplement the results of the oropharyngeal swabs to improve the characterisation of viral 
clearance.  

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Swabs scheduled for days 6 and 14 will be removed, while those on days 7 will be retained to better characterise 
potential viral rebound. Consequently, the study will assess viral clearance rates up to day 5, rather than day 7 
as previously done. The inclusion of additional early samples is expected to enhance the characterisation of the 
initial viral decline. At least once daily sampling will be performed by the study personnel who will place the 
swabs in the transport medium, and document the time. The samples will be kept cool, and subsequently stored 
at -80°C as detailed in the SOP. Transport times will be recorded, as well as the time at which the swab is frozen 
at -80°C. Viral genomes from the throat swabs will be quantitated by RT-qPCR, according to published methods 
(28). Each observed value will be recorded along with the RNAseP log10 density (representing human cell 
numbers), if available. The measurements for the patient over time will be used to estimate the rate of viral 
clearance under a Bayesian hierarchical linear mixed effects model.  
The concentration of urea in the VTM will also be measured and compared with the serum urea concentration 
in the baseline biochemistry sample. This comparison enables determination of the extracellular fluid content 
in the eluate volume of the oropharyngeal samples. The urea concentration in throat fluid is the same as in 
serum, so that the dilution factor of the throat sample in the VTM fluid can be easily calculated (29).  
All samples positive for influenza will be typed and subtyped to determine the effect of type/subtype on viral 
load and response to treatment. This will be done using whole genome sequencing technology or specific PCRs 
to determine subvariants.  
7.2. Recruitment 
Potential patients with a positive influenza test obtained during routine screening, or those with symptoms in 
keeping with influenza even if they do not have the results of their influenza test or have not been tested yet 
may be contacted by the research group. Alternatively, they may contact the research group for participation 
in the study. Each will be provided with a written participant information sheet.  
7.3. Screening and Eligibility Assessment  
Eligibility assessment will occur at the point of screening. If, based on the inclusion and exclusion criteria, the 
patient is eligible and willing to complete the full study, they will be included into the study after informed 
consent is obtained.  
7.4. Informed Consent 
Written and verbal versions of the participant information and informed consent will be presented to the 
patients detailing the exact nature of the study; what it will involve for the patient; the implications and 
constraints of the protocol; and the known side effects of the medicines under evaluation and any risks involved 
in taking part. It will be stated clearly that the patient is free to withdraw from the study at any time for any 
reason without prejudice to future care, and with no obligation to give the reason for withdrawal.  
The patient will be allowed as much time as required to consider the information as long as they remain eligible 
and within the time-frame for recruitment into the study, and the opportunity to question the investigator or 
other independent parties to decide whether they will participate.  
Written informed consent will then be documented by a patient with the dated signature of the person who 
presented and obtained the informed consent. The person who obtained the consent must be suitably qualified 
and experienced and have been authorised to do so by the site PI. A copy of the signed informed consent will 
be given to the patient. The original signed form will be retained at the study site.  
7.5. Baseline Assessments* 
A physical exam, vital signs, oxygen saturation, symptom review and basic demographics will be recorded. 
Oropharyngeal viral swabs will be taken by the study personnel 1 time in duplicate (a left sided and right sided 
swab i.e., two swabs in total) at baseline. An optional set of swabs may also be collected at this time (baseline). 
Some participants will be asked if they agree to have saliva (see section 7.1) collected in addition to 
oropharyngeal swabs. If they agree, they will have a saliva specimen taken at this point.  
A total of 16ml of venous blood for study testing will be taken at this point.  

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Administration of the therapeutic may be delayed until the results of the FBC and biochemistry will be available 
(although these will ideally be available within 1 hour of sample collection i.e., before randomisation), to 
determine if there is any contraindication.  
If these bloods are not available in this timeframe, then the patient can be safely enrolled, randomised and 
given their first dose, and can be excluded prior to their next dose if laboratory abnormalities resulting in a 
contraindication are present.  
If an FBC and biochemistry has been taken in the previous 24hrs, the results of these can be used to determine 
whether there is a contraindication.  
One of the baseline blood tests will be used for host genetic tests. This will allow investigation of potential 
genetic signatures associated with differential immune responses to influenza infection. Additionally, in those 
antivirals shown to accelerate viral clearance, genetic determinants of drug response (pharmacogenomics) may 
prove essential to optimised dosing of drugs and thus management of early influenza.  
Laboratory tests at baseline 
• 
Blood sample for 
o FBC and differential count  
o Biochemistry (including U&Es, creatinine, LFTs) 
o Serology (antibody responses)  
o Drug level  
o Host genotyping to assess determinants of the therapeutic response  
• 
Oropharyngeal swab in duplicate, up to 2 times and possibly a saliva sample (see 
section 7.1). 
*See appendix 1 for detailed schedule of activities 
7.6. Days of Study 
             7.6.1. Randomisation D0  
After enrolment, the patient will be randomised to one of the study arms using an online randomisation 
application which is managed by the trial statistician. The number of arms at a site can be limited by the 
approval and availability of the study drug at that site - there will be a minimum of 2 arms per site. The 
randomisation ratios will be uniform for all available interventions (e.g. 1:1:1) but randomisation to the no 
antiviral treatment control arm (no antiviral treatment arm) will be fixed at a minimum of 20% throughout the 
study. The study team will use a web-app to randomise as different sites may have different drugs. Only 
designated study staff will be authorised to access the web-app for patient allocation and it will be password 
protected. The drug allocations are not blinded for the patient for practical reasons. For patients randomised 
to an active drug, the first treatment dose (hour 0) will be supervised by study team after viral swabs (and 
possibly a saliva sample see section 7.1) are taken for qPCR (taken in duplicate) (see appendix 1 for schedule of 
activities). The patient will then be observed for a minimum of 1 hour in the ward. Oropharyngeal swabs will be 
taken again by the study personnel in duplicate at hour 1 (H1) for all participants.  
For the therapeutic arms for which intensive PK has been triggered, allocated patients will stay for extra blood 
tests for drug monitoring levels, according to the schedule in the drug-specific appendix 2.  
Body temperature recorded up to two times daily by study staff or participant (information collected in a diary 
and reviewed by the study personnel).              
 
7.6.2.   Day 1-Day 5 and Day 7* 
The following variables will be assessed daily:  
• 
Vital signs, eligibility check, and assessment of treatment (taking of medications will be confirmed by 
the study personnel and the time recorded. In participants who are outpatients, for medications taken 
more than once daily, the patient will record the time non-observed doses are taken in a diary card). 
• 
Oropharyngeal swab for qPCR taken from each tonsil (two swabs) and possibly a saliva sample (see 
section 7.1) once a day by the study personnel (time taken recorded).  

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• 
Temperature recorded up to two times daily by study staff or participant (information collected in a 
diary and reviewed by the study personnel daily).  
• 
Study personnel completes a brief symptom checklist each day.  
• 
Blood samples will be taken (Day 3 and Day 7) for later pharmacokinetic analyses and FBC and 
biochemistry, to assess potential drug adverse effects. Blood samples for serology testing will be taken 
on Day 7. 
Remark: In addition, some participant if agreeable will be asked to take an extra set of swab (two swabs, 
one from each tonsil) between day 0 – day 5 either by study personnel or self-swab at home according 
to a set of given instructions. The purpose of this extra swab set (between day 0 – 5) is to assess whether 
an additional set of values would be beneficial for analysis of viral clearance. The purpose of self-swabs 
is to assess and validate whether self-swabbing will provide qPCR data of comparable quality to that 
carried out by study personnel, if standardised instructions are provided and adhered to. If the result is 
positive, this could reduce inconvenience to participants and reduce loss to follow up. 
*See appendix 1 for detailed schedule of activities 
7.7. Intensive Pharmacokinetic Sampling: 
For those study drugs that are shown to be effective antivirals in other studies or meet the success criteria of 
the study (defined as greater than 90% probability of accelerating viral clearance by more than 20% relative to 
the no study drug arm), we will then conduct intensive pharmacokinetic (PK) sampling for further patients who 
are enrolled into that arm. The exact sampling schedule will depend on the study drug characteristics (see 
appendix 2), but in general the patient will stay at the ward for the remainder of the day to have further blood 
tests performed. A cannula will be inserted so that blood can be drawn without the need for repeated 
venepuncture. A further blood test will be performed the next day, either at the ward or at their home if 
feasible. The volume of blood from this will not exceed 20 mls.  
7.8. Management of Patients Who Become Ill 
During the study, although this is unlikely, the patient may deteriorate clinically from their influenza or may 
develop a new intercurrent illness or potentially a side-effect related to the study medication.  
All patients who develop difficulty with activities of daily living, shortness of breath or worsening of other 
symptoms, will be assessed initially by the study personnel. All of their vital signs will be measured, including 
oxygen saturations. They will be brought to the clinic research physician for further assessment. Clinical 
deterioration in this study may be due to several factors including progression of influenza illness, development 
of complications e.g. pneumonia, co-infection with other respiratory viruses, adverse reaction to medications, 
amongst others. Thus, a thorough clinical assessment will be performed by the study physician and we will take 
advice from infectious diseases experts. Based on this assessment, they may be referred to hospital, re-
examined the next day, or asked to update the research team by mobile phone frequently on their well-being. 
The Physician may decide to repeat study oropharyngeal swabs in duplicate if symptoms of influenza recur, for 
the duration of the illness, to characterise symptomatic viral rebound or lack of response to treatment. 
If a patient is referred to hospital, a clinical assessment will be made by the hospital physician and a diagnosis 
made. The decision to stop study drug will depend on that diagnosis and be made between the hospital team 
and the study PI.  
The hospital physicians will have the responsibility for patient care but the research team will continue to follow 
the progress of the patients in hospital. Treatment for influenza severe enough to warrant hospitalisation will 
follow national guidelines. For those patients where treatment is changed (i.e., a new treatment is started for 
clinical reasons) an extra set of swabs in duplicate (and possibly a saliva sample see section 7.1) should be 
collected prior to the initiation of the new treatment (i.e. 2 sets of swabs will be taken in duplicate). This will 
only occur if the patient is within the first 7 days of the study.  
The D0, D3, and D7 blood samples will be tested for FBC and biochemistry (e.g. U&Es, LFTs) to assess for drug-
related adverse effects or abnormalities which require a potential dose adjustment or stopping the therapeutic 
or clinical intervention. The responsibility for evaluating and acting upon the results of blood tests will belong 
to the study team at the local site. They will use their clinical judgement in the assessment of the patient, further 

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tests and onwards referral. At any point of the study, extra laboratory tests may be conducted on the patient if 
felt to be clinically indicated by the research team, based on symptoms or previous laboratory abnormalities.  
7.9. Sample Handling and Retention 
Samples will be transferred to designated testing facilities, where they will undergo testing in accordance with 
best practice laboratory measures and safety procedures.  
Oropharyngeal swabs (and possibly a saliva sample see section 7.1) will be processed using validated 
quantitative Real-Time quantitative Polymerase Chain Reaction (qPCR) to detect influenza, according to the 
study SOP. A urea measurement will be measured on each and compared to the baseline blood concentration. 
Swabs will be tested in duplicate.  
The samples will be retained as per University of Oxford and local site regulations. Consenting patients may 
rescind their consent up until the completion of the study. Unless requested the samples collected prior to date 
of withdrawal will be retained for study analysis.  
Samples, including those for PK, may be transferred to MORU or other designated testing facilities outside the 
site country, with appropriate material transfer agreements (MTA) and associated approvals prior to shipment.  
Some of the leftover blood samples will be stored and may be used for further studies in the scope related to 
susceptibility or response to the influenza infection, and treatments. Blood samples will be labelled with a 
unique number and initials but not with the patient name. Any additional testing apart from what indicated in 
this study will be tested only after permission by the IRB/IEC. 
8. DISCONTINUATION/WITHDRAWAL OF PATIENTS FROM STUDY 
Patients may choose to stop treatment and/or study assessments but may remain on study follow-up. Patients 
may also withdraw their consent, meaning that they wish to withdraw from the study completely. In the case 
of withdrawal from both treatment and active follow up the following options for a tiered withdrawal from the 
study would apply:  
a) Patients withdraw from the study but permit data and samples obtained up until the point of 
withdrawal to be retained for use in the study analysis. No further data or samples would be collected 
after withdrawal;  
b) Patients withdraw from active follow-up and further communication but allow the trial team to 
continue to access their medical records and any relevant hospital data that is recorded as part of 
routine standard of care; i.e., CT-Scans, blood results and disease progression data etc.  
c) Patients withdraw but do not allow data and samples collected to be used.  
In addition, the Investigator may discontinue a patient from the trial treatment at any time if the Investigator 
considers it necessary for any reason including, but not limited to:  
• 
Pregnancy  
• 
Ineligibility (either arising during the study or retrospectively having been overlooked at screening)  
• 
Significant protocol deviation  
• 
Significant non-compliance with treatment regimen or trial requirements  
• 
An adverse event which requires discontinuation of the trial medication or results in inability to 
continue to comply with trial procedures  
• 
Disease progression which requires discontinuation of the trial medication or results in inability to 
continue to comply with trial procedures  
The reason for discontinuation and/or withdrawal will be recorded in the Case Report Form. qPCR data from 
patients withdrawn from the study will still be analysed if at least three distinct timepoints are available for the 
estimation of a clearance slope. The sample size is adaptive so there is no need to replace withdrawn patients.  
Consenting patients may rescind their consent up until the completion of the study. Unless requested, data and 
samples collected prior to the date of withdrawal will be retained in the study database and analysis.  
8.1. Definition of End of Study 
The end of study is the date of the 7 day follow up visit of the last enrolled patient.  

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9. SAFETY REPORTING  
9.1. Definitions  
Adverse 
Event (AE)  
Any untoward medical occurrence in a patient to whom a medicinal product has been 
administered, including occurrences which are not necessarily caused by or related to that 
product.  
Adverse 
Reaction 
(AR)  
An untoward and unintended response in a patient to an investigational medicinal product which 
is related to any dose administered to that patient.  
The phrase "response to an investigational medicinal product" means that a causal relationship 
between a trial medication and an AE is at least a reasonable possibility, i.e., the relationship 
cannot be ruled out.  
All cases judged by either the reporting medically qualified professional or the Sponsor as having 
a reasonable suspected causal relationship to the trial medication qualify as adverse reactions.  
Serious 
Adverse 
Event (SAE) 
A serious adverse event is any untoward medical occurrence that:  
• 
results in death  
• 
is life-threatening  
• 
requires inpatient hospitalisation or prolongation of existing hospitalisationş  
• 
results in persistent or significant disability/incapacity 
• 
consists of a congenital anomaly or birth defect.  
Other ‘important medical events’ may also be considered serious if they jeopardise the patient or 
require an intervention to prevent one of the above consequences.  
NOTE: The term "life-threatening" in the definition of "serious" refers to an event in which the 
patient was at risk of death at the time of the event; it does not refer to an event which 
hypothetically might have caused death if it were more severe.  
Hospitalisation is defined as an unplanned, formal inpatient admission, even if the hospitalisation 
is a precautionary measure for continued observation. The patient must be admitted overnight, 
a short stay of several hours to receive treatment is not considered hospitalisation. If a patient is 
admitted overnight or longer for social/economic or isolation reasons and is otherwise medically 
stable, this does not constitute a SAE. Other examples of visits to a hospital facility that are not 
considered hospitalisation are: Emergency room visits, outpatient surgery, pre-planned or 
elective procedures for a pre-existing condition (as long as that condition has not deteriorated 
while on trial treatment or brought forward because of worsening symptoms) and for the purpose 
of this study, being hospitalised for isolation.  
Serious 
Adverse 
Reaction 
(SAR) 
An adverse event that is both serious and, in the opinion of the reporting Investigator, believed 
with reasonable probability to be due to one of the trial treatments, based on the information 
provided.  
NB: to avoid confusion or misunderstanding of the difference between the terms “serious” and “severe”, the 
following note of clarification is provided: “Severe” is often used to describe intensity of a specific event, which 
may be of relatively minor medical significance. “Seriousness” is the regulatory definition supplied above.  
Any pregnancy occurring during the clinical trial and the outcome of the pregnancy should be recorded and 
followed up for congenital abnormality or birth defect, at which point it would fall within the definition of 
“serious”.  
9.2. Causality 
The relationship of each adverse event to the trial medication must be determined by a medically qualified 
individual according to the following definitions:  
Definitely related: 
There is clear evidence to suggest a causal relationship and other possible 
contributing factors can be ruled out.  
 

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Probably related: 
There is evidence to suggest a causal relationship and the influence of other 
factors is unlikely.  
 
Possibly related: 
There is some evidence to suggest a causal relationship (e.g., because the event 
occurs within a reasonable time after administration of the trial medication). 
However, the influence of other factors may have contributed to the event (e.g., 
the patient’s clinical condition, other concomitant treatments).  
Unlikely to be related: 
There is little evidence to suggest there is a causal relationship (e.g., the event 
did not occur within a reasonable time after administration of the trial 
medication), or there is another reasonable explanation for the event (e.g., the 
patient’s clinical condition, other concomitant treatment). 
 
Not related: 
There is no evidence of any causal relationship. 
 
9.3. Procedures for Recording Adverse Events 
A symptom checklist will be performed daily from D0 until D5 with a final follow-up assessment on D7 to aid in 
the identification of adverse events. The severity of adverse events will be assessed following the Common 
Terminology Criteria for Adverse Events (CTCAE) v5.0:  
1 = mild, 2 = moderate, 3 = severe, 4 = life-threatening, 5 = fatal.  
AEs occurring in patients from enrolment and during trial participation that are observed by the Investigator or 
reported by the patient with severity grade of 3 (severe) or higher will be recorded on the CRF, whether or not 
attributed to trial medication.  
If drug combinations are assessed, the team will record all clinical AEs of severe grade (grade 3 or higher) for 
those arms which have been previously assessed in humans and shown to be safe and well-tolerated e.g., 
Oseltamivir PLUS Favipiravir, Oseltamivir PLUS Baloxavir. All clinical AEs for other combinations e.g., Favipiravir 
PLUS Baloxavir will be recorded grade of 1 or higher. This will be important to monitor the safety and tolerability 
of combinations in direct comparison to the individual drugs.  
The following information will be recorded: description, date of onset and end date, severity, assessment of 
relatedness to trial medication, other suspect drug or device and action taken. Follow-up information should 
be provided as necessary.  
AEs considered related to the trial medication as judged by a medically qualified investigator or the Sponsor 
will be followed either until resolution, or the event is considered stable.  
It will be left to the Investigator’s clinical judgment to decide whether or not an AE is of sufficient severity to 
require the patient’s removal from treatment. A patient may also voluntarily withdraw from treatment due to 
what he or she perceives as an intolerable AE. If either of these occurs, the patient must undergo an end of trial 
assessment and be given appropriate care under medical supervision until symptoms cease, or the condition 
becomes stable.  
9.4. Grading of Laboratory Abnormalities 
Abnormal laboratory findings detected during the study or are present at baseline and worsen following the 
taking of study medication will be reported as AEs or SAEs. If found to be abnormal the values will be graded 
according to the CTCAE v5.0. AEs and SAEs of severity grade 3 or higher will be recorded in the CRF and will be 
followed up until grade 2 or below, returned to baseline, or deemed to be permanent. For laboratory results 
that are not available in the CTCAE v5.0, the site investigator should make a determination as to whether or not 
the laboratory abnormality is clinically significant. If the site investigator believes a laboratory abnormality is 
clinically significant, it should be reported as an adverse event and a grade should be identified to the best of 
their ability.  
9.5. Reporting Procedures for Serious Adverse Events 
All SAEs detected by the site investigator must be reported to the AD ASTRA safety team within 24 hours of site 
awareness. The Serious Adverse Event CRF documenting the SAE should be emailed to AD ASTRA safety team. 

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The AD ASTRA safety team will inform the DSMB within 10 days of initial notification of the SAE and keep the 
DSMB updated as needed.  
Further follow-up reports should be submitted, if required, until the SAE is resolved, is deemed stable/ 
permanent or results in death. A final status should be determined for any SAEs ongoing at the study end date.  
The site PI must also report the SAEs to the local ethics committee and the regulatory authority in accordance 
with local requirements. 
               9.5.1    Expectedness 
Expectedness will be determined according to the Investigators’ Brochure/Summary of Product Characteristics.  
9.6. Data Safety Monitoring Board (DSMB) 
An independent Data Safety and Monitoring Board (DSMB) will be set up consisting of qualified volunteers with 
the necessary knowledge of clinical trials. The DSMB will receive summary reports from MORU as defined per 
charter or per ad-hoc request, prior to each meeting. All data reviewed by the DSMB will be in the strictest 
confidence. A DSMB charter will outline its responsibilities and how it will operate.  
An interim report will be prepared by the Trial Statistician for the pre-specified interim analysis. In case of safety 
concerns, additional information or formal interim analyses can be requested by the DSMB.  
The DSMB will meet formally at the following timepoints:  
• 
after the first 50 patients have been accrued into the study  
• 
At additional time-points as indicated by the DSMB after their review, if deemed necessary  
All DSMB recommendations will be communicated to site PIs. The site PI will be responsible for submitting the 
written DSMB summary reports with recommendations as applicable to local/ national ethics committees and 
other applicable groups.  
10. STATISTICS AND ANALYSIS  
10.1. Overview of Adaptive Study Design and Overall Approach  
The statistical plan for AD ASTRA is based on our COVID-19 platform trial, PLATCOV. The final statistical analysis 
of the AD ASTRA data will be according to the most recent signed version of the Statistical Analysis Plan (SAP). 
Below is a description of the general principles of the statistical method and analysis, with current examples 
from the SAP. 
The initial results of the PLATCOV study demonstrated that regular oropharyngeal swabbing from day 0 to day 
7 well-characterised the rate of viral clearance. Although some previously published influenza studies with 
virologic endpoints have suggested a shorter duration of shedding for influenza viruses compared to SARS-CoV-
2, when RT-PCR has been used instead of viral culture, influenza RNA has been detected up until day 7 (7,8). As 
such, without data to justify a change to the PLATCOV (SARS-CoV-2) methodology, we opted for the same 
sampling schedule, methodology and thus power calculations for AD ASTRA (Influenza viruses), with a plan to 
review and update after the first interim analysis of 50 patients recruited.  
An analysis of the PCR data for the first 400 patients with concealed assignment indicated a day 0 to 5 sampling 
schedule would be optimal to characterise viral clearance. However, patients will continue to be swabbed from 
D0-D5 and again D7 to allow for detection of viral mutants conferring resistance, and for closer follow-up of 
patients from a clinical perspective. 
Clinical trials with adaptive designs are increasingly being used in research, including in such successful and 
prominent COVID-19 studies as the RECOVERY study. In addition, the FDA and EMA supply guidance on studies 
with these designs. They do not have fixed sample sizes as conventional RCTs. The number of patients recruited 
depends on the results (i.e., they are adaptive). The benefits of an adaptive sample size are increased efficiency 
and ethical considerations (i.e., they can both stop ineffective arms, and identify effective arms earlier, thereby 
limiting numbers in ineffective arms compared to fixed sample number studies). Because of these advantages 
this type of study is likely to become more prevalent, but it is important that the study is well-designed in 
advance, that the adaptive design is appropriate for the overall study design, and has mechanisms in place to 
control type I error.  

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As in the PLATCOV trial, the main pharmacodynamic endpoint is the rate of viral clearance, estimated from 
serial qPCR measurements in each patient. The measured end point is the slope of the initial log linear decline 
in qPCR estimated viral densities. The clearance rate will be correlated with the presence of symptoms and 
possibly other clinical endpoints such as duration of hospitalisation. As this is a multi-centre trial, populations 
may differ between sites with respect to key covariates. Therefore, the main analytic approach will be to fit a 
hierarchical Bayesian model to the serial qPCR measurements (using default weakly informative Bayesian priors 
to aid model fitting), whereby the baseline viral loads (intercept) and the first-order clearance rates (slope of 
initial decline) can vary between sites and between individuals. The viral clearance slope is also dependent on 
the randomised study arm. Stopping an intervention arm for futility or triggering an intensive PK-PD nested sub-
study will be decided using the posterior probabilities that the arm results in an increased slope. The PK-PD 
nested sub-study will be also triggered if there is evidence of accelerated viral clearance from other studies.  
10.2. Bayesian Hierarchical Model of Viral Clearance 
At each interim analysis we will fit a series of Bayesian hierarchical (mixed effects) model to the serial viral load 
measurements (modelled directly on the Ct scale). The main linear model will take the following form: 
yk,i,t ~ Student(α0 + αk + αi + (β0 + βi + βk + βT(i))t , sigma2, dof) 
where yk,i,t is the observed log10 viral load for individual i at time t from site k (two values per timepoint), and 
T(i) is the randomised arm assigned to individual i. Sigma2 is the measurement error (residual error). The error 
model is a t-distribution with degrees of freedom inferred from the data (dof). The slope of viral clearance 
decomposes into 4 terms: the population mean slope β0; the site random effect βk; the individual random effect 
βi; and the treatment effect (fixed across sites and individuals) βT(i). The intercept term (baseline viral load) 
decomposes into 3 terms: the population intercept α0; the site random effect αk; and the individual random 
effect αi. All comparisons are made relative to the no antiviral treatment control arm, so we set βcontrol = 0. 
Adjustment will be made for human RNaseP concentration. The model will treat viral load corresponding to Ct 
values of 40 as left censored. An equivalent non-linear model (allowing for an initial increase in viral load, 
followed by a linear decrease) will also be fitted to the data as a sensitivity analysis. 
10.3. Time Varying Effects  
Characterising and identifying time varying effects not specified in the main model is important:  
• 
Interventions which are added later on during the trial cannot be compared directly to all data from the 
control arm without accounting for possible differences in population over time (as an epidemic 
evolves, included populations may differ in a single site over time).  
We will use descriptive approaches to detect time-varying effects (residual plots over time, mean slopes in 
control individuals over time). If substantial time-varying effects are observed, we will add a smooth time 
varying spline component to the linear model. The base model will not include this for simplicity.  
10.4. Sample Size Estimation, Randomisation and Statistical Considerations for the Bayesian Group 
Sequential Design 
The platform study has two main objectives: 
• 
Characterise antiviral efficacy of interventions relative to the no study drug arm to demonstrate that 
this methodology works in identifying active compounds 
• 
Identify the antiviral with the best virological efficacy in head-to-head comparisons  
The sample size is adaptive. For each intervention, the required sample size is based on pre-specified stopping 
rules, which use 1) a futility/success margin λ1 for comparisons with the no-study drug arm, and 2) a non-
inferiority margin λ2 for comparisons with the positive control arm, defined as the intervention with the highest 
virological efficacy upon interim analyses. Each intervention arm will be stopped when it meets the stopping 
rules in the interim analyses, as laid out in the most recent signed version of the Statistical Analysis Plan. See 
below example: 
1. Meets the futility criteria: if Probability[βT < λ1 * β0] > 0.9; 
2. Meets the success criteria: if Probability[βT > λ1 * β0] > 0.9 relative to the no-study drug arm AND meets 
the non-inferiority criteria or the inferiority criteria: if Probability[βT > -λ2 * β0] > 0.9 or Probability[βT < 
-λ2 * β0] > 0.9 relative to the positive control arm, respectively. 

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The flow of interim analyses and decision rules for removing an arm from the platform or designating an arm 
as the new positive control is described in Appendix 3. While the negative control arm (no-study drug arm) and 
the positive control arm are required as contemporaneous control arms to adjust for potential temporal bias in 
estimating antiviral efficacies, the required sample size for these arms depends on the duration of the trial and 
the number of concurrent intervention arms.  
The trial is continuously running group sequential adaptive platform trial. Therefore, there is no fixed sample 
size. If the trial starts with 5 intervention arms (one of which becomes the positive control, and one is the 
negative control arm - the ‘no study drug’ arm), all starting recruitment simultaneously, the expected maximum 
sample size would be approximately 1000 participants. If all intervention arms start at different time points, 
additional participants are required as contemporaneous negative and positive controls (enrolment is 
competitive). In other words, the resulting in the expected maximum patient number could exceed 1000 
participants.  
Therefore, across all study sites, the trial is expected to enrol approximately 1500 participants in total, 
depending on the number, timing, and duration of active intervention arms. Further recruitment can occur after 
consultation with the DSMB or TSC, if it is felt that more precision of the result is beneficial. Different arms may 
be assessed in different sites in the multinational platform study. Recruitment will be competitive between the 
sites in an adaptive manner without pre-defined numbers per site. 
The most recent determinations of the futility/success margin λ1 and the non-inferiority margin λ2 were 
informed by insights gained from simulations using data from the first 500 participants enrolled in the PLATCOV 
trial, which has a similar study design for assessing the efficacies of SARS-CoV-2 antivirals. Details of the 
simulations are described in Appendix 3. The results suggested that choosing the futility/success margin λ1 = 
1.2 (20%) minimized the false positive rate to 1% in interventions with no antiviral effect, with a median sample 
size of 30 participants per arm (for futility/success decision). It also minimised false negative rates to less than 
1% in interventions with antiviral effects of 40% and 60%, with median sample sizes of 50 and 20 participants 
per arm (for futility/success decision), respectively. Additional participants are required for the non-inferiority 
assessment. 
For the non-inferiority assessment, the simulations described in Appendix 3 suggested that choosing a stringent 
non-inferiority margin (λ2 = 0.9; -10%) results in earlier stopping of interventions which are clearly less effective 
than the positive control and later stopping for interventions with an effect close to the positive control.  
This study is open label and so a centralized server-based randomization system will be used. Only designated 
study staff will be authorised to access the webapp for patient allocation. The webapp will be password 
protected. All randomisation activities will be traced within the webapp and attributed to a timestamp along 
with the anonymised patient study code, age and sex.  
10.5. Sample Size for the Intensive PK-PD Sub-study 
Any drugs with evidence of accelerated viral clearance from other studies or which meet the success endpoint 
(>90% probability that clearance is accelerated by more than 20% relative to control) will be included in an 
intensive PK-PD study. The sample size calculation for each sub-study will be drug dependent and will use the 
information regarding the variability in clearance in the intervention arm versus the variability in clearance in 
the control arm (i.e., it will be determined by the results), but based on previous experience with PLATCOV, 
would be capped at approximately 40 participants per arm. Larger observed variability in the intervention arm 
would be expected if an active intervention had variation in exposures that corresponded to variation around 
the near maximal effect concentration (e.g., EC95).  
We will use a PK simulation-based approach where we will simulate predicted drug AUC values for patients 
given the characteristics of the patients in each site (weight and sex) and use the observed variability in viral 
clearance rates to estimate the necessary sample size to infer a dose-response relationship whereby a 10% 
increase in AUC resulted in a 10% increase in the slope of viral clearance with 80% power and 5% type 1 error.  
10.6. Final Analysis of Primary Outcome  
As for PLATCOV, the final analysis will fit a series Bayesian hierarchical linear and non-linear models to the serial 
log10 viral load measurements (copies per mL) as determined in the most recent signed version of the SAP. The 

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primary estimates of interest are the relative changes in the rate of viral clearance for the intervention arms 
compared to the no study drug arm. These will be reported as their mean posterior estimates along with 
credible intervals. All analyses will be done using R using the package RStan along with bespoke software. All 
analysis code for AD ASTRA is openly available via a GitHub repository: https://github.com/jwatowatson/AD 
ASTRA-SAP. Anonymised viral load data and key meta data (e.g., site, strata, randomised allocation) will be 
made available at publication of results. 
 11. DATA MANAGEMENT  
11.1. Access to Data  
Direct access will be granted to authorised representatives from the University of Oxford, local ethics 
committees and regulatory authorities, and any host institution for monitoring and/or audit of the study to 
ensure compliance with regulations. Outcome data and treatment assignment data will be made available for 
analysis in real time.  
11.2. Data Handling and Record Keeping 
Clinical study data will be recorded on CRFs and entered on to a password-protected database by the local study 
PI, research nurse or designee. The study database will be built in MACRO EDC, a clinical data management 
system that is compliant with ICH GCP and FDA 21 CFR Part 11 and will be hosted in a secure, access-restricted 
server in MORU. The study database will include internal quality checks to identify data that appear 
inconsistent, incomplete, or inaccurate.  
Measures will be taken to ensure non-disclosure of information that is potentially harmful to patients. Paper 
records (for example, patient identifiable information for the purposes of follow-up, the screening logs and 
signed ICFs) will be kept in locked cabinets; electronic data will only be accessible to staff with user accounts 
and passwords. The database contains an audit trail that keeps record of changes to data and user activity 
within the database. All electronic data will be stored on secure servers that are backed up daily, with weekly 
off-site storage.  
Patient records at site will, taking into account the ability of the sites, be stored in binders in the secured access-
limited room or scanned and stored electronically. The records will be retained for at least five years following 
completion of the study, or according to local site regulation. The study database will be retained indefinitely.  
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. 
(www.tropmedres.ac/units/moru-bangkok/bioethics-engagement/data-sharing/moru-tropical-network-
policy-on-sharing-data-and-other-outputs).  
12. QUALITY CONTROL AND QUALITY ASSURANCE PROCEDURES 
The study will be conducted in accordance with relevant regulations and standard operating procedures.  
The study will be conducted in compliance with this protocol, International Conference on Harmonization (ICH) 
Guidelines for Good Clinical Practice (GCP) and any applicable regulatory requirement(s). Monitoring will be 
overseen by the MORU Clinical Trials Support Group (CTSG) according to a prespecified risk-based monitoring 
plan to ensure compliance to the study protocol and applicable guidelines and regulations. Biological specimens 
will be processed, stored and shipped in accordance with MORU SOPs.  
Data validation will be performed to identify errors or discrepancies and thus ensure completeness, validity and 
accuracy of data.  
13. ETHICAL AND REGULATORY CONSIDERATIONS 
This study will be conducted in patients who would be unlikely to progress to severe illness. The investigated 
medications may benefit the patient; i.e., shorten the duration of symptoms or decrease their severity, but are 
unlikely to have a significant adverse effect on the patient’s illness and subsequent health.  
Funds will be set aside to cover hospital costs in the unlikely event of a drug adverse reaction.  

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Women who are pregnant, actively trying to become pregnant, or breast feeding will be excluded from this 
study as it is not known if any of the treatments being tested will have additional benefits that would outweigh 
any risks associated with pregnancy/breast feeding.  
13.1. Declaration of Helsinki 
The Investigator will ensure that this study is conducted in accordance with the current revision of the 
Declaration of Helsinki.  
13.2. Guidelines for Good Clinical Practice 
The Investigator will ensure that this study is conducted in accordance with relevant regulations and with Good 
Clinical Practice.  
13.3. Approvals 
The protocol, informed consent form, participant information sheet and any proposed advertising material will 
be submitted to OxTREC and local ethics committees for written approval.  
The Investigator will submit and, where necessary, obtain approval from the above parties for all amendments 
to the original approved documents.  
13.4. Patient Confidentiality 
The study staff will ensure that the patients’ anonymity is maintained. The patients will be identified only by a 
patient ID number on all study documents and any electronic database. All documents will be stored securely 
and only accessible by study staff and authorised personnel. The study will comply with GDPR, which requires 
that personal data must not be kept as identifiable data for longer than necessary for the purposes concerned.  
13.5. Expenses 
Patients will be financially compensated for their time in the study, in accordance with local EC guidance and 
approval.  
13.6. Risk 
All of the treatments being tested initially (see Appendix 2 for study drugs) are generally well-tolerated with 
the main adverse effects related to gastrointestinal symptoms (diarrhoea, nausea and vomiting). Further 
information regarding specific side effects for each of the drugs used in the study can be found in Appendix 2. 
These are usually mild and settle without the need for medical intervention. In the case of intravenously 
administered treatments, there may be discomfort, bleeding or bruising of the skin at the site of needle 
puncture.  
The risks associated with blood withdrawal during the study include local discomfort, occasional bleeding or 
bruising at the site of needle puncture and very rarely, infection. The risks associated with oropharyngeal 
swabbing are limited to slight local discomfort.  
13.7. Benefits 
There may be earlier resolution of symptoms in those who are randomised to certain active treatment arms, 
but benefit is not guaranteed. Although an individual patient may not personally benefit, this study should help 
future influenza patients by identifying treatments that have the best antiviral effect in early disease. 
Remuneration will be provided to the patients for the period they are enrolled in the study. Patients will be 
reimbursed for costs associated with traveling to the study site and loss of work time. The amount will be 
determined per local allowed guidelines and ethics committee policies.  
13.8. Reporting 
The PI shall submit an Annual Progress Report to OxTREC and local EC on the anniversary of the date of approval 
of the study. In addition, the PI shall submit an End of Study Report to OxTREC and local EC of upon the 
completion of the study.  
13.9. Finance and Insurance 
13.9.1 Funding  
The trial is funded by Wellcome Trust Grant ref: 226933/Z/23/Z through the COVID-19 Therapeutics 
Accelerator. 

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13.9.2 Insurance 
The University of Oxford has a specialist insurance policy in place which would operate in the event of any 
patient suffering harm as a result of their involvement in the research (Newline Underwriting Management Ltd, 
at Lloyd’s of London).  
13.10. Data Ownership 
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. The criteria for authorship will be 
consistent with the international guidelines (http://www.icmje.org/#author).  
13.11. Publication Policy 
The Investigators will be involved in reviewing drafts of the manuscripts, abstracts, press releases and any other 
publications arising from the study. Authors will acknowledge that the study was funded by Wellcome Trust. 
Authorship will be determined in accordance with the International Committee of Medical Journal Editors 
(ICMJE) guidelines and other contributors will be acknowledged.  
The results of the study will be summarised in lay language, in both English and the language(s) commonly 
spoken at the study sites, and disseminated to key stakeholders, user communities and patients.  

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17. Kawai N et al. Longer virus shedding in influenza B than in influenza A among outpatients treated with 
oseltamivir. Journal of Infection. 2007;55:267-72 
18. Kawai N et al. A comparison of the effectiveness of zanamivir and oseltamivir for the treatment of influenza 
A and B. Journal of Infection. 2008;56:51-7 
19. Kawai N et al. Comparison of the Effectiveness of Zanamivir and Oseltamivir against influenza A/H1N1, 
A/H3N2, and B. Clinical Infectious Diseases. 2009;48:996-997 
20. Dobson et al. Oseltamivir treatment for influenza in adults: a meta-analysis of randomised controlled trials. 
The Lancet. 2015;385 (9979):1729-1737. 
https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(14)62449-1/fulltext 
21. Aoki FY et al;IMPACT Study Group. Early administration of oral oseltamivir increases the benefits of 
influenza treatment. Journal of Antimicrobial Chemotherapy. 2003;51:123-9. 
https://pubmed.ncbi.nlm.nih.gov/12493796/ 
22. Leekha S. Duration of influenza A virus shedding in hospitalized patients and implications for infection 
control. Infection Control & Hospital Epidemiology. 2007;28:1071-6. 

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https://www.cambridge.org/core/journals/infection-control-and-hospital-
epidemiology/article/abs/duration-of-influenza-a-virus-shedding-in-hospitalized-patients-and-
implications-for-infection-control/DEA5B2FE41800BA25CBA92322377E0D7 
23. Jefferson T. Neuraminidase inhibitors for preventing and treating influenza in adults and children. Cochrane 
Database of Systematic Reviews. 2014(4):CD008965. 
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6464969/ 
24. Su HC et al. Comparative effectiveness of neuraminidase inhibitors in patients with influenza: A systematic 
review and network meta-analysis. Journal of Infection and Chemotherapy. 2022;28:158-169. 
https://www.jiac-j.com/article/S1341-321X(21)00325-1/fulltext 
25. Hayden F et al. Baloxavir Marboxil for Uncomplicated Influenza in Adults and Adolescents. New England 
Journal of Medicine. 2018;379(10):913-23. https://www.nejm.org/doi/full/10.1056/nejmoa1716197 
26. Hayden F. Favipiravir Treatment of Uncomplicated Influenza in Adults: Results of Two Phase 3, Randomised, 
Double-Blind, 
Placebo-Controlled 
Trials. 
The 
Journal 
of 
Infectious 
Diseases. 
2022;jiac135. 
https://doi.org/10.1093/infdis/jiac135 
27. Jittamala P et al. Clinical antiviral efficacy of remdesivir and casirivimab/imdevimab against the SARS-CoV-
2 Delta and Omicron variants. medRxiv (preprint). 2022; 10.17.2228116. https://doi.org/10.1101/2022 
28. WHO. WHO information for the molecular detection of influenza viruses. 2021. 
https://cdn.who.int/media/docs/default-source/influenza/molecular-detention-of-influenza-
viruses/protocols_influenza_virus_detection_feb_2021.pdf?sfvrsn=df7d268a_5 
29. Kaulbach HC, White MV, Igarashi Y, Hahn BK, Kaliner MA. Estimation of nasal epithelial lining fluid using 
urea as a marker. J Allergy Clin Immunol. 1993;92(3):457-65.  
 
 
 

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Appendices 
15. Appendix 1: Schedule of Activities 
 
Procedures 
D0 
D1 
D2 
D3 
D4 
D5 
D7 
If new Tx/ 
symptoms 
Pre-1st 
dose 
H0 
H1 
Screening incl. lateral flow Ag test  
X 
 
 
 
 
 
 
 
 
 
Urine pregnancy test (female of 
childbearing age) 
X 
 
 
 
 
 
 
 
 
 
Eligibility assessment 
X 
 
 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
Randomisation 
X 
 
 
 
 
 
 
 
 
 
Baseline information including basic 
demographics, symptoms, physical exam, 
vital signs, oxygen saturation 
X 
 
 
 
 
 
 
 
 
 
Vital sign 
X 
 
 
X 
X 
X 
X 
X 
X 
 
Symptom checklist 
 
 
X 
X 
X 
X 
X 
X 
X 
 
Observed/ confirmed dose  
 
X1 
 
X1 
X1 
X1 
X1 
 
 
 
Observation post dose  
 
 
X1 
 
 
 
 
 
 
 
Temperature 2 
X 
X 
X 
X 
X 
X 
X 
 
Virology 
 
Oropharyngeal swabs 3, 4, 5 
X6 
 
X 
X 
X 
X 
X 
X 
X 
X 
Bloods 
 
FBC+diff 
X7 
 
 
 
 
X 
 
 
X 
 
Biochemistry (including U&Es, creatinine, 
LFTs) 
X7 
 
 
 
 
X 
 
 
X 
 
Serology  
X 
 
 
 
 
 
 
 
X 
 
Drug level 
X 
 
 
 
 
X 
 
 
X 
 
Host genotyping  
X 
 
 
 
 
 
 
 
 
 
1 Depends on dosing schedule of the drug. The first dose will be given at the designated trial facility. For drugs where 
further doses are required, at least one dose per day will be confirmed by the study team. The time the drug is taken 
will be recorded by the study team.  
2 Performed up to two times a day and self-recorded  in a temperature card if non-observed.  
3 Swabbing will be conducted in different locations within the study site depending on whether the participant is an 
inpatient or outpatient.  
4 Taken at least once daily in duplicate by the study team (right and left tonsillar fossa). The time is recorded when swabs 
were taken 
5 Some participants may be asked for an additional set of bilateral swabs (two swabs: one swab from each tonsil) to be 
collected between day 0 to 5 either by study personnel, or by patient self-swabbing, following study standardised self-
swabbing instructions, and/or a saliva sample, between the same period (day 0-5) 
6 Taken at least 1 time, up to 2 times in duplicate (up to four swabs, two from each of the right and left tonsillar fossa). 
The time is recorded when swabs were taken.  
7 Results will be used to detect laboratory abnormalities included in the exclusion criteria 
 
 

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16. Appendix 2: Study Drugs  
 
16.1. Oseltamivir  
 
16.1.1. Rationale 
Neuraminidase inhibitors are a class of antivirals that were developed in the 1990s as a novel approach to 
prophylaxis and treatment of influenza. By selective binding to the active site of influenza neuraminidase, 
neuraminidase inhibitors block the enzyme’s ability to cleave sialic acid residues on the cell surface, thus 
blocking release of progeny virions from infected respiratory epithelial cells and reducing viral spread in the 
respiratory tract.  
The use of neuraminidase inhibitors, oseltamivir and zanamivir in particular, has increased dramatically since 
the outbreak of A/H1N1 in April 2009, partly because of the rise in amantadine/rimantadine resistance, and in 
the early stages of the outbreak, the lack of a vaccine.  
Of the four neuraminidase inhibitors developed, oseltamivir is the most widely studied and used. It is 
considered the standard of care in many countries for treatment of suspected or proven influenza in seriously 
ill or hospitalised patients, as well as in ambulatory patients with underlying conditions associated with higher 
risks of influenza complications.  
Oseltamivir carboxylate is the active metabolite of the pro-drug oseltamivir phosphate (Tamiflu©). Oseltamivir 
phosphate dissociates in the gastrointestinal tract to form oseltamivir, which is absorbed and metabolised into 
oseltamivir carboxylate by hepatic carboxylesterase.  
Oseltamivir carboxylate inhibits influenza A and B neuraminidases in vitro. Neuraminidase enzyme IC50 (the half 
maximal inhibitory concentration) values for oseltamivir for clinically isolated influenza A ranged from 0.1nM 
to 1.3nM, and for influenza B was 2.6nM. Higher IC50 values for influenza B, up to a median of 8.5nM have been 
observed in published studies1. This is reflected in clinical data where oseltamivir has shown to be less effective 
in treating influenza B viral infections compared with influenza A infections2,3.  
Prospective, placebo-controlled data supporting the use of oseltamivir in the treatment of adult influenza 
comes from 4 published studies4,5,6,7. Two of these enrolled previously healthy individuals with acute 
uncomplicated influenza presenting within 36 hours of onset, and the other two evaluated experimentally 
induced influenza (one influenza A study and one influenza B study) with oseltamivir administered 24-28 hours 
post-inoculation. These trials consistently showed that oseltamivir reduces the duration of illness by 
approximately 24 hours. Three out of the four trials demonstrated statistically significant reductions in viral 
titers (measured as area under the curve) with oseltamivir but one study did not demonstrate a significant 
difference in viral shedding at any time point. A recent re-analysis of median viral shedding curves from early 
experimental influenza infection trials8 showed that in addition to reducing peak viral loads, oseltamivir 
increases the rate of viral clearance after the peak, although more slowly in influenza B than influenza A 
infection; however, analysis of individual shedding curves did not reveal an impact of oseltamivir on viral decline 
rates. In addition, this study showed that 20-40% of oseltamivir treated volunteers continued shedding virus 
similarly as placebo-treated controls, suggesting treatment failure. Thus, although there is evidence for antiviral 
efficacy of oseltamivir, data is somewhat variable.  
Clinical effectiveness in symptom alleviation is greatest when administered within 48 hours thus it is licensed 
for use within this time-frame. A Cochrane meta-analysis of 20 treatment trials demonstrated considerable 
variation in the reduction of clinical symptoms after oseltamivir treatment, ranging from 8.4 to 25.1 hours9.  
Data on the effectiveness of oseltamivir in the prevention of influenza-related complications are variable. A 
2014 Cochrane review, which analysed data in the intention-to-treat (ITT) group without accounting for 
confirmed infection, found no decrease in the risk of hospital admission or serious complications with 
oseltamivir treatment10. A subsequent meta-analysis by Dobson and colleagues divided individuals into an ITT 
group and an ITT-infected (ITT-I) group, in which influenza infection was confirmed by testing. This study 
estimated a 44% risk reduction (relative risk 0.56 [95% CI 0.42-0.75]; p=0.0001) in lower respiratory tract 
complications and a 63% risk reduction (0.37 [0.17-0.81]; p=0.013) in hospital stay for the ITT-I group that 
received oseltamivir11.  

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No RCTs of oseltamivir versus placebo have been conducted in patients hospitalised with influenza meaning 
evidence for its efficacy in patients with severe disease is uncertain.  
Oseltamivir is the only antiviral currently recommended by the WHO for the treatment of influenza. However, 
evidence for these recommendations is largely based on observational studies and is acknowledged to be based 
on evidence considered low quality for critical outcomes including mortality12.   
During the 2007-2008 influenza season, substantial resistance to oseltamivir emerged in influenza A H1N1 
viruses through a histidine to tyrosine substitution (H275Y) in the neuraminidase protein. Since the emergence 
of the 2009 pandemic H1N1 (H1N1pdm09) influenza A viruses and their establishment as circulating epidemic 
strains, resistance to neuraminidase inhibitors including oseltamivir has been uncommon. As of March 2016, 
5% of influenza A H1N1pdm09 isolates were resistant to oseltamivir. Rates of oseltamivir resistance were lower 
than 5% in the European union, with resistance observed in less than 1% of influenza A H1N1pdm09 isolates13.  
16.1.2. Composition and dose 
Each Tamiflu® 75mg hard capsule contains oseltamivir phosphate equivalent to 75mg oseltamivir  
The recommended dosing schedule is 75mg of oseltamivir twice daily for five days  
Tamiflu® may be taken with or without food but when taken with food, tolerability may be enhanced in some 
patients 
We will use Tamiflu® or a high-quality generic alternative in the study. 
16.1.3. Pharmacokinetic characteristics  
Oseltamivir phosphate is an oral pro-drug which is cleaved by esterases in the liver, gastrointestinal tract and 
blood to the active oseltamivir carboxylate with good bioavailability estimated ~80%. Administration with food 
may delay absorption slightly but does not decrease overall bioavailability1.  
Following oral administration of oseltamivir, the time to maximum concentration of oseltamivir carboxylate is 
3-4 hours and the plasma half-life (t1/2) averages 7 to 9 hours.  
Both the prodrug and parent are eliminated primarily unchanged through the kidney. Distribution is not well 
characterised in humans, but peak bronchoalveolar lavage levels are similar to plasma levels in humans. In 
humans, concentrations in sinus and middle ear fluid aspirates are similar to those in plasma1.  
No dose adjustment is required for treatment in patients with hepatic dysfunction.  
Dose adjustment is recommended for adults and adolescents (13-17 years) with moderate or severe renal 
impairment (creatinine clearance <60ml/minute)1. In this study, patients with creatinine clearance 
<60ml/minute will not be eligible for randomisation.  
Pharmacokinetic sampling schedule (only if there is evidence of accelerated viral clearance): 
All patients will need to be admitted for 12 hours for intense sampling 
The timings are: 
• 
Pre-dose D0H0, then 
• 
1,2,3,4,6,9,12 and 24h post dose  
Note that blood will be taken on D3, and D7 for routine haematology and biochemistry. The EDTA sample will 
be used to measure the drug concentrations  
16.1.4. Toxicity 
Oral oseltamivir is generally well tolerated and no serious end-organ toxicity has been found1.  
The overall safety profile of Tamiflu is based on data from 6049 adult/adolescent and 1473 patients treated 
with Tamiflu or placebo for influenza. In adults and adolescents, the most commonly reported adverse reactions 
were nausea, vomiting and diarrhoea in the treatment studies. The majority of these ARs were reported on a 
single occasion on either the first or second treatment day and resolved spontaneously within 1-2 days1.  
Animal studies do not indicate reproductive toxicity. Data on oseltamivir exposure of pregnant women from 
post-marketing reports and observational studies (more than 1000 exposed outcomes during the first 

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trimester) indicate no malformative nor feto/neonatal toxicity by oseltamivir. The use of Tamiflu may be 
considered during pregnancy if necessary1.  
16.1.5. Contraindications1 
• 
Hypersensitivity to the active substance, oseltamivir carboxylate 
• 
Hypersensitivity to any excipient:  
o Capsule contents: pregelatinised starch, talc, povidone, croscarmellose sodium and sodium stearyl 
fumarate  
o Capsule shell: gelatin, yellow iron oxide (E172), red iron oxide (E172), black iron oxide (E172) and 
titanium dioxide (E171)  
o Printing ink: shellac (E904), titanium dioxide (E171) FD and C Blue 2 (indigo carmine E132). 
16.1.6. Cautions 
The following serious adverse reactions have been rarely reported since oseltamivir has been marketed 
(<1/1000): anaphylactic and anaphylactoid reactions, thrombocytopenia, hepatic disorders (fulminant 
hepatitis, hepatic function disorder and jaundice), angioneurotic oedema, Steven-Johnson syndrome and toxic 
epidermal necrolysis, gastrointestinal bleeding and neuropsychiatric disorders1.  
There have been postmarketing reports, mostly from Japan, of neuropsychiatric events including abnormal 
behaviour, self-injury and delirium during administration of Tamiflu in patients with influenza. These reports 
were primarily among paediatric patients and these events have also been experienced by patients with 
influenza without oseltamivir treatment1. Estimates of frequency cannot be made but these events appear to 
be uncommon based on Tamiflu usage data. The FDA package insert for Tamiflu advises monitoring for signs of 
abnormal behaviour.  
16.1.7. Drug interactions  
No clinically significant drug interactions have been recognised for either drug. Neither oseltamivir or 
oseltamivir carboxylate interact with human cytochrome P450 enzymes which suggests that drug interactions 
as a result of competition with this pathway are unlikely. Oseltamivir also has low protein binding and 
metabolism independent of the glucuronidase systems again suggesting that clinically significant drug 
interactions are unlikely1.  
The FDA package insert for Tamiflu advises against administration of Tamiflu until 2 weeks following 
administration of the live attenuated influenza vaccine.  
16.1.8. References 
1. Electronic medicines compendium. Tamiflu 75mg Hard Capsules summary of product characteristics. 
https://www.medicines.org.uk/emc/product/1194/smpc#PHARMACODYNAMIC_PROPS 
2. Sugaya N et al. Lower clinical effectiveness of oseltamivir against influenza B contrasted with influenza A 
infection in children. Clinical Infectious Diseases. 2007;44:197-202.  
3. Burnham AJ et al. Neuraminidase inhibitors for influenza B virus infection: efficacy and resistance. Antiviral 
Research. 2013; 100:520-34.  
4. Hayden F et al. Oral oseltamivir in human experimental influenza B infection. Antiviral therapy. 2000;5:205-
213.  
5. Hayden F et al. Use of the oral neuraminidase inhibitor oseltamivir in experimental human influenza. JAMA. 
1999;282(13):1240-6.  
6. Treanor JJ et al. Efficacy and safety of the oral neuraminidase inhibitor oseltamivir in treating acute 
influenza: a randomised controlled trial. JAMA. 2000;283:1016-24.  
7. Nicholson KG et al. Efficacy and safety of oseltamivir in treatment of acute influenza: a randomised 
controlled trial. The Lancet. 2000;355:1845-50.  
8. Hooker et al. Impact of Oseltamivir Treatment on influenza A and B virus dynamics in Human Volunteers. 
Frontiers in Microbiology. 2021; 12:631211 
9. Jefferson T et al. Oseltamivir for influenza in adults and children: a systematic review of clinical study reports 
and summary of regulatory comments. The BMJ. 2014; 348:g2545.  
10. Jefferson T et al. Neuraminidase inhibitors for preventing and treating influenza in adults and children. 
Cochrane Database of Systematic Reviews. 2014(4):CD008965. 

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11. Dobson et al. Oseltamivir treatment for influenza in adults: a meta-analysis of randomised controlled trials. 
The Lancet. 2015;385 (9979):1729-1737. 
12. World Health Organisation. Guidelines for the management of severe illness from influenza virus infections. 
2022. 
https://apps.who.int/iris/bitstream/handle/10665/352453/9789240040816-
eng.pdf?sequence=1&isAllowed=y 
13. Paules C et al. Influenza. The Lancet. 2017;390:697-708 
14. Li L, Liu J, Qin K. Comparison of double-dose vs standard-dose oseltamivir in the treatment of influenza: A 
systematic review and meta-analysis. Journal of Clinical Pharmacy and Therapeutics. 2020;45(5):918-26. 
15. South East Asia Infectious Disease Clinical Research Network. "Effect of double dose oseltamivir on clinical 
and virological outcomes in children and adults admitted to hospital with severe influenza: double blind 
randomised controlled trial." BMJ. 2013. 346: f3039. 
 
 
 
 

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16.2. Zanamivir 
 
16.2.1. Rationale 
Zanamivir is a potent, selective inhibitor of influenza A and B neuraminidase, including some influenza virus 
variants with NA substitutions conferring loss of susceptibility to other NAIs.  
The inhibition of this enzyme is reflected in both in vitro and in vivo activity against influenza A and B virus 
replication, and encompasses all of the known neuraminidase subtypes of influenza A viruses. Neuraminidase 
inhibition occurs in vitro at very low zanamivir concentrations; the concentrations of zanamivir required to 
inhibit in vitro plaque formation of influenza A and B viruses by 50% in Madin-Darby canine kidney cells (MDCK) 
were 0.002 to 16umol/L in assays of clinical isolates1.  
In one study, the respective reported mean values of inhibitory concentrations of 50% of zanamivir and 
oseltamivir were 1.14 and 0.9 nmol/L for influenza A/H1N1, 2.09 and 0.73nmol/L for influenza A/H3N2, and 
4.15 and 11.53 nmol/L for influenza B2 i.e. oseltamivir exhibits less potent inhibition of influenza B virus than 
zanamivir in vitro.  
Consistent with in vitro findings, results from mouse and ferret models demonstrate the antiviral activity of 
intranasal zanamivir in vivo with relatively low doses of the drug (as low as 0.05mg/kg) inhibiting viral 
replication1.  
Pooled data from four randomised, controlled trials of intranasal zanamivir versus placebo in experimental 
influenza A (H1N1) infection indicated that early treatment (zanamivir 16mg nasal drops two or six times daily 
beginning 26 or 32 hours after viral inoculation and continuing for 4 days) significantly reduced peak viral titres 
by 2log10 TCID50/ml and the median duration of viral shedding by 3 days compared with placebo. Early treatment 
was also associated with statistically significant reductions in the incidence of febrile illness3.  
In phase 3 studies involving otherwise healthy adults with laboratory-confirmed influenza A or B infection, 
zanamivir (10mg by inhalation twice daily for 5 days) significantly reduced the duration of symptoms of 
influenza by a median of 1.5 days (range 1-2.5 days). Efficacy was demonstrated when treatment is initiated 
within 48 hours4,5,6,7.  
Several studies in both children and adults have demonstrated superior efficacy of inhaled zanamivir compared 
to oral oseltamivir in reducing the duration of fever in those with influenza B infection8,9,10. In an observational 
study enrolling adults aged 9-94 years with laboratory confirmed influenza, similar efficacy of zanamivir 
compared to oseltamivir in reducing fever duration was reported for influenza A/H1N1 infections whereas 
superior efficacy of oseltamivir compared to zanamivir was seen for influenza A/H3N2 infections9, reflecting in 
vitro data. These data suggest that zanamivir therapy may be more effective than oseltamivir for the treatment 
of influenza B infection and oseltamivir may be more effective than zanamivir for treatment of A/H3N2 
infections.  
In a network meta-analysis comparing the clinical effects of all four neuraminidase inhibitors as monotherapy 
and oseltamivir and zanamivir combination therapy, zanamivir was higher ranked (as measured by surface 
under the cumulative ranking, SUCRA) than oseltamivir with regards to effectiveness in reducing time to 
symptom alleviation compared with placebo. Based on SUCRA, zanamivir therapy was associated with the 
lowest risk of nausea and vomiting among the four regimens11.   
16.2.2. Composition and dose 
Each pre-dispensed quantity of Relenza® inhalation powder (one blister) contains 5mg zanamivir. Zanamivir is 
administered directly to the respiratory tract by oral inhalation via DISKHALER®.  
The recommended dose of Zanamivir for treatment of influenza in adults and children from the age of 5 years 
is two inhalations (2x 5mg) twice daily for five days, providing a total daily inhaled dose of 20mg12. 
Training will be provided on Diskhaler technique 
16.2.3. Pharmacokinetic characteristics 
Studies of orally inhaled zanamivir indicate that approximately 4-17% of the dose is systemically absorbed, with 
serum concentrations generally peaking within 1-2 hours. The poor absorption of the drug results in low 
systemic concentrations and therefore there is no significant systemic exposure to zanamivir after oral 

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inhalation12. Lung scintigraphy in healthy adult volunteers (n=11) showed that the main deposition site for 
inhaled zanamivir (10mg) was the oropharynx (mean 77.6%), with other lesser sites of deposition being the 
bronchi and lungs (mean 13.2%) and the trachea (mean 1.2%)1. 
The serum half-life of zanamivir following administration by oral inhalation ranges from 2.6 to 5.05 hours. At 
12 and 24 hours post-dose, inhaled zanamivir (10mg) is retained in tracheal and bronchial epithelia at 
concentrations which exceed those inhibitory for influenza A and B neuraminidases. Dose proportionality of 
Cmax values indicate linear pharmacokinetics1.  
Although elimination of the drug takes place largely via renal excretion, the bioavailability of a therapeutic dose 
of inhaled zanamivir is low and as a result there is no significant systemic exposure. Therefore, dosage 
adjustments in patients with renal dysfunction are not necessary with administration of zanamivir via oral 
inhalation12.  
Zanamivir does not inhibit the cytochrome P450 enzymes. 
No dose modification is required with hepatic dysfunction12.  
16.2.4. Toxicity 
General toxicity studies did not indicate any significant toxicity of zanamivir.  
The tolerability of inhaled zanamivir is similar to that of placebo in otherwise healthy adults, high-risk and 
elderly patients, and children. In phase II and III trials of therapeutic efficacy, 33% of patients receiving zanamivir 
(inhaled or intranasal) and 38% of those receiving placebo reported adverse events during treatment1. Adverse 
events that occurred with an incidence ≥1.5% in treatment studies include headaches, diarrhoea, nausea, 
vomiting, nasal signs and symptoms, bronchitis, cough, sinusitis and dizziness13.  
No drug-related malformations, maternal toxicity or embryotoxicity were observed in pregnant rats or rabbits 
or their foetuses following intravenous administration of zanamivir at doses up to 90mg/kg/day.  
16.2.5. Contraindications12  
• 
Hypersensitivity to the active substance, zanamivir 
• 
Hypersensitivity to any of the excipients 
o lactose monohydrate (which contains milk protein) 
• 
Milk protein allergy  
• 
Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-
galactose malabsorption should not take this medicine 
16.2.6. Cautions 
There have been rare reports of patients with previous history of respiratory disease (asthma, COPD) and very 
rare reports of patients without previous history of respiratory disease, who have experienced acute 
bronchospasm and/or serious decline in respiratory function after use of zanamivir. Many of these cases were 
reported during postmarketing and causality was difficult to assess. Thus, zanamivir is not recommended in 
individuals with underlying airways disease. Any patients experiencing such reactions should discontinue 
zanamivir and medical evaluation should be provided. Should zanamivir be considered appropriate for patients 
with asthma or COPD, the patient should be informed of the potential risk of bronchospasm and should have a 
fast-acting bronchodilator available12.  
Allergic-like reactions, including oropharyngeal oedema, serious skin reactions (erythema multiforme, Stevens-
Johnson syndrome, Toxic epidermal necrolysis) and anaphylaxis have been reported in postmarketing 
experience with Relenza.  
There have been postmarketing reports, mostly from Japan, of neuropsychiatric events during administration 
of zanamivir in patients with influenza, mainly in children and adolescents12. The contribution of Relenza to 
these events has not been established. It is advised to monitor for signs of abnormal behaviour during zanamivir 
treatment.  
16.2.7. Drug interactions 
Zanamivir is not a substrate nor does it affect cytochrome P450 enzymes. There are currently no known 
reported drug interactions with zanamivir and no clinically significant drug interactions are likely12.  

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Because of potential interference with the live attenuated influenza vaccine (LAIV), LAIV should not be 
administered within 2 weeks before or 48 hours after administration of Relenza13.  
16.2.8. References 
1.Cheer S et al. Zanamivir: An Update of its Use in Influenza. Adis Drug Evaluation. 2002; 62(1):71-106.  
2. Boivin G et al. Susceptibility of recent Canadian influenza A and B virus isolates to different neuraminidase 
inhibitors. Antiviral Research. 2002; 54: 143-7. 
3.Hayden F et al. Safety and efficacy of the neuraminidase inhibitor GG167 in experimental human influenza. 
JAMA. 1996; 275(4):295-9.  
4. Hayden F et al. Efficacy and safety of the neuraminidase inhibitor zanamivir in the treatment of influenza 
virus infections. New England Journal of Medicine. 1997;337:874-80.  
5.MIST (Management of Influenza in the Southern Hemisphere Trialists) Study Group. Randomised trial of 
efficacy and safety of inhaled zanamivir in treatment of influenza A and B virus infections. The Lancet. 
1998;352:1877-81.  
6.Lalezari J et al. The efficacy and safety of inhaled zanamivir in the treatment of influenza in otherwise healthy 
and high risk individuals in North America. Journal of Antimicrobial Chemotherapy. 1999; 44 Suppl.A:42 
7.Monto AS et al. Randomised, placebo-controlled studies of inhaled zanamivir in the treatment of influenza A 
and B: pooled efficacy analysis. Journal of Antimicrobial Chemotherapy. 1999; 44 Suppl. B:23-9.  
8. Kawai N et al. A comparison of the effectiveness of zanamivir and oseltamivir for the treatment of influenza 
A and B. Journal of Infection. 2008;56:51-57 
9. Kawai N et al. Comparison of the Effectiveness of Zanamivir and Oseltamivir against Influenza A/H1N1, 
A/H3N2, and B.  Clinical Infectious Diseases. 2009;48(7):996-997.  
10.Sugaya N et al. Lower clinical effectiveness of oseltamivir against influenza B contrasted with influenza A 
infection in children. Clinical Infectious Diseases. 2007;44:197-202 
11. Su HC et al. Comparative effectiveness of neuraminidase inhibitors in patients with influenza: A systematic 
review and network meta-analysis. Journal of Infection and Chemotherapy. 2022;28:158-169.  
12. 
European 
Medicines 
Compendium. 
Relenza 
5mg/dose 
inhalation 
powder. 
https://www.medicines.org.uk/emc/product/3809/smpc#gref 
13. 
GSK. 
RELENZA 
(zanamivir) 
inhalation 
powder, 
for 
oral 
inhalation. 
2010. 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/021036s025lbl.pdf 
 
 

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16.3. Peramivir  
 
16.3.1. Rationale 
Peramivir is a novel neuraminidase inhibitor of influenza virus. It was approved by the Food and Drug 
administration in December 2014 for treatment of acute uncomplicated influenza in patients 18 years and 
older. It was approved for treatment of influenza in Japan in 2010. Peramivir is administered intravenously, 
providing an alternative access to patients unable to take medication via the oral or inhalation routes.  
Peramivir is a novel cyclopentane (five vs six-membered ring structure of oseltamivir and zanamivir) with side 
chain substitutions (a carboxyl group, a guanidine group and lipophilic side chains), allowing higher affinity 
interactions between peramivir and the neuraminidase catalytic site compared to oseltamivir and zanamivir1.  
In vitro activity of peramivir has been investigated against human and avian influenza A and B viruses. These 
studies have shown that peramivir possesses similar or more potent in vitro activity against influenza A and B 
viruses than oseltamivir, zanamivir and laninamivir2. Peramivir shows improved in vitro activity against influenza 
B isolates compared to oseltamivir or zanamivir; the IC50 values of peramivir against influenza B were reported 
to be several folds lower than those of the rest of the NAIs3,4. Peramivir has been also demonstrated to have in 
vitro activity against emerging avian influenza viruses of pandemic potential including H5N1, H7N9 and H9N25,6.  
Despite well-established efficacy of oral peramivir in animal studies, human clinical trials resulted in less success 
due to low oral bioavailability. Thus, further efforts were focused on exploring the parenteral route. Studies in 
non-human primates, ferrets and mice showed that a single IV administration of peramivir significantly reduced 
viral titers and clinical symptoms2.  
The efficacy of the approved peramivir regimen (600mg dose given as a single 15-30 minutes infusion) for the 
treatment of uncomplicated influenza within 48 hours of symptoms in otherwise healthy adults was evaluated 
in two large, randomised, controlled, double-blind trials7,8. Relative to placebo, peramivir 600mg significantly 
reduced the median time to alleviation of influenza symptoms (hazard ratio 0.666, adjusted p value, 0.0092). 
When stratifying by influenza A infection subtype, there was no significant difference in median time to 
alleviation of symptoms between the peramivir 600mg group and placebo in those infected with A/H1 although 
the median time for this outcome was shorter in those infected with A/H3 (HR 0.326, p=0.0008). The proportion 
of virus-positive subjects (50% tissue culture infective dose) by day 3 was significantly decreased in the 
peramivir 600mg group compared with placebo (25.8% versus 51.5%, p=0.0003)7.  
A single dose of peramivir was noninferior to 5 days of oseltamivir 75mg twice daily for the median time to 
alleviation of symptoms. Significantly more peramivir 600mg than oseltamivir recipients were afebrile 24h after 
treatment8.  
Available data do not support a conclusion that peramivir is effective in patients with influenza B or in those 
with complicated influenza.  
For peramivir, less than 1% of influenza clinical isolates (including A/H1N1, A/H3N2, B/Victoria lineage and 
B/Yamagata-lineage) analysed by WHO Global Influenza Surveillance and Response System (GISRS), exhibited 
reduced inhibition or highly reduced inhibition, with this percentage being relatively consistent for each 
influenza season since 20091.  
16.3.2. Composition and dose 
RAPIVAB® has been approved for intravenous use by FDA since 2014.  
Each vial of RAPIVAB® injection contains 200mg per 20ml (10mg per ml) as a clear, colourless solution.  
In this study, participants will be given 600mg IV peramivir administered once via IV infusion for 15-30 minutes 
in accordance with FDA license9 
16.3.3. Pharmacokinetics 
Plasma concentrations of IV peramivir peak immediately after administration.  
In healthy adult volunteers, after a single 600mg dose, peak concentrations of peramivir in pharyngeal and 
bronchial epithelial lining fluid exceeded the IC50 value for influenza. The elimination half-life of peramivir 
following a single IV administration of 600mg to healthy subjects is approximately 20h. Together with the slow 
neuraminidase dissociation rate, the prolonged half-life allows for infrequent dosing regimens.  

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The pharmacokinetic parameters following IV administration of peramivir showed a linear relationship between 
dose and exposure parameters (Cmax and AUC). Peramivir exhibits low (<30%) binding to human plasma proteins 
in vitro1.  
Peramivir is not significantly metabolised by the liver in humans. Thus, dose adjustment is unnecessary in 
hepatic impairment1.  
The drug is not a substrate for CYP enzymes, does not affect glucuronidation and is not a substrate or inhibitor 
of P-glycoprotein mediated transport2.  
Peramivir is almost entirely eliminated by renal excretion with 90% of the drug excreted unchanged. In patients 
with moderate and severe renal impairment, exposure to peramivir upon IV administration is expected to be 
increased by 3.4- and 6-fold, respectively, compared to those with normal renal function. Therefore, dose 
adjustment based on renal function (creatinine clearance <50 ml/min) in patients with renal impairment is 
required.1,9 In this study, individuals with creatinine clearance <60ml/min will be excluded.  
No difference in PK has been observed by gender, and the effects of age and body weight on peramivir clearance 
are negligible1.  
Pharmacokinetic sampling schedule (only if there is evidence of accelerated viral clearance): 
All patients will need to be admitted for 12 hours for intense sampling 
The timings are: 
• 
Pre-dose D0H0, then 
• 
1,2,3,4,6,9,12 and 24h post dose  
Note that blood will be taken on D3, and D7 for routine haematology and biochemistry. The EDTA sample will 
be used to measure the drug concentrations  
16.3.4. Toxicity 
A single dose of IV peramivir was generally well tolerated in adults and paediatric patients with uncomplicated 
influenza participating in clinical trials.   
In five randomised, double-blind, controlled trials, 1399 subjects with acute uncomplicated influenza received 
a single dose of RAPIVAB, administered intravenously at doses up to 600mg. Among the 664 subjects receiving 
RAPIVAB 600mg, the most commonly observed adverse reaction was diarrhoea occurring at a rate of 8% versus 
7% in subjects receiving placebo. No subject receiving RAPIVAB experienced a serious adverse event9.  
Laboratory abnormalities occurring in ≥2% of subjects treated with RAPIVAB 600mg included low neutrophils, 
ALT >2.5x ULN, creatinine phosphokinase >6x ULN. 
In rats, no treatment-related maternal and fetal toxicities were observed when RAPIVAB was given by IV bolus 
at the maximum feasible dose of 600mg/kg, representing exposures approximately 8-fold that in humans at the 
recommended dose. There are no adequate and well-controlled trials of RAPIVAB in pregnant women. Because 
animal reproduction studies are not always predictive of human response, and peramivir has been shown to 
cross the placenta in animal studies, RAPIVAB should only be used during pregnancy if clearly needed9.  
16.3.5. Contraindications 
• 
Hypersensitivity to the active substance, peramivir 
16.3.6. Cautions 
Post-marketing evaluations under routine clinical settings mirrored the clinical trials in terms of safety in adults 
and paediatrics.  
However, rare cases of anaphylactic reactions and serious skin reactions (including erythema multiforme, toxic 
epidermal necrolysis and Stevens-Johnson syndrome) have been reported with peramivir treatment1.  
There have been postmarketing reports (from Japan) of delirium and abnormal behaviour leading to injury in 
patients with influenza (mainly paediatric patients) who were receiving neuraminidase inhibitors, including 
RAPIVAB. These events appear uncommon9.  

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16.3.7. Drug interactions  
Given the known elimination route of peramivir, there is a low potential for interactions between peramivir and 
other drugs1.  
The use of live attenuated influenza vaccines is not recommended within 2 weeks before or until 48h after 
peramivir administration due to the theoretical risk that peramivir could reduce the immunogenicity of the 
vaccine1. 
16.3.8. References 
1.Scott LJ. Peramivir: A Review in Uncomplicated Influenza. ADIS Drug Evaluation. 2018;78:1363-1370 
2. Alame MM. Peramivir: A Novel Intravenous Neuraminidase Inhibitor for Treatment of Acute Influenza 
Infections. Frontiers in Microbiology. 2016;7:450.  
3. Dapat C et al. Rare influenza A (H3N2) variants with reduced sensitivity to antiviral drugs. Emerging Infectious 
Diseases. 2010; 16: 493–496. doi: 10.3201/eid1603.091321  
4. Ikematsu H et al.  (2014). In vitro neuraminidase inhibitory activity of four neuraminidase inhibitors against 
influenza virus isolates in the 2011-2012 season in Japan. Journal of Infection and Chemotherapy.2014; 20: 77–
80. doi: 10.1016/j.jiac.2013.07.002  
5. Govorkova E. et al. (2001). Comparison of efficacies of RWJ-270201, zanamivir, and oseltamivir against H5N1, 
H9N2, and Other avian influenza viruses. Antimicrobial Agents and Chemotherapy. 2001;45:2723–2732. doi: 
10.1128/AAC.45.10.2723-2732.2001  
6. Zhang X et al. (2014). Drug susceptibility profile and pathogenicity of H7N9 influenza virus (Anhui1 lineage) 
with R292K substitution. Emerging Microbes and Infection. 2014; 3(11):e78. doi: 10.1038/emi.2014.80  
7. Kohno S et al. Efficacy and safety of intravenous peramivir for treatment of seasonal influenza virus infection. 
Antimicrobial Agents and Chemotherapy. 2010;54(11):4568–74.  
8. Kohno S et al. Phase III randomized, double-blind study comparing single-dose intravenous peramivir with 
oral oseltamivir in patients with seasonal influenza virus infection. Antimicrobial Agents and Chemotherapy. 
2011;55(11):5267–76.  
9. 
Food 
and 
Drug 
Administration. 
RAPIVABTM 
(peramivir 
injection). 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/206426lbl.pdf 
 
 
 
 
 

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16.4. Laninamivir  
 
16.4.1. Rationale  
Laninamivir octanoate is the orally inhaled octanyl ester prodrug of laninamivir, the 7-methyoxy derivative of 
zanamivir. Laninamivir shares zanamivir’s mechanism of action and antiviral spectrum of activity against 
influenza A and B viruses1. In vitro studies showed potent inhibitory activity to NAs of various influenza viruses, 
such as the seasonal H1N1, pandemic H1N1, H3N2, H5N1 and influenza B viruses, although potency was less 
against NA of H3N2 and influenza B viruses compared with zanamivir and oseltamivir2.  It retains inhibitory 
activity against some NA variants with reduced oseltamivir susceptibility (e.g. H275Y, R293K or E119V)1.  
Laninamivir octanoate is a long-acting NAI because of its pharmacokinetic properties in the respiratory tract 
and its slower dissociation from influenza NAs compared to other NAIs. It is thus administered as a single 
intranasal dose1.  
In mice and ferret influenza infection models, a single intranasal dose of laninamivir octanoate significantly 
reduced virus titers compared with oral oseltamivir and placebo3. After a single intranasal administration of 
laninamivir octanoate in a mouse model of influenza infection, lung laninamivir concentrations increased soon 
after administration and retained a half-life of as long as 41.4h. Even at 120h post-dose, laninamivir remained 
in the lungs at concentrations considerably higher than the IC50 of laninamivir against the NA activities of various 
influenza viruses4.  
One phase 2 double-blind, placebo-controlled RCT compared the safety and efficacy of single inhaled 40mg and 
80mg doses of laniamivir octanoate, enrolling 248 influenza-positive adult outpatients across 12 countries. 
Despite showing more rapid antiviral effects, neither the 40mg nor 80mg group significantly reduced the 
median time to alleviation of influenza symptoms compared to placebo1.  
A phase three study of adults, the Multinational Asian Clinical Research for Influenza Virus Extermination on 
Long-acting Neuraminidase-Inhibitor Study, was performed as a randomised double-blinded study in order to 
confirm the efficacy and safety of Laninamivir Octanoate administered as a single inhaled dose of 20 or 40mg 
compared with oral oseltamivir 75mg administered twice daily for 5 days in adult patients with influenza A or 
B virus infection. Non-inferiority to oseltamivir was confirmed in both the 20mg and 40mg group of laninamivir 
octanoate in terms of the primary endpoint which was time to alleviation of influenza illness5.  
A meta-analysis of treatment studies that had oseltamivir as a comparator arm found comparable duration of 
fever and symptoms between laninamivir and oseltamivir. However, laninamivir was associated with a 
significantly longer fever duration in those with A/H3N2 virus infection6.  
In analysing four observational studies that compared the clinical effectiveness of inhaled laninamivir to inhaled 
zanamivir in children, no differences were found in fever duration7.  
In Japan, this drug has been approved for influenza treatment by a single inhalation since 2010 and for 
prophylaxis since 2013 (commercially available as Inavir – Daichi Sankyo Co., Ltd, Tokyo) but remains 
investigational in other countries.  
16.4.2. Composition and dose 
Inavir© dry powder inhaler 20mg is manufactured by Daiichi Sankyo. It contains 20.76mg of Laninamivir 
Octanoate Hydrate (equivalent to 20mg of laninamivir octanoate).  
In adults, Inavir© is administered as a single dose of 40mg laninamivir octanoate by inhalation (two devices)8. 
Training will be provided on inhaler technique.  
 
16.4.3. Pharmacokinetic characteristics  
In an ascending single-dose study involving healthy, male volunteers, inhaled laninamivir octoneate was 
administered as a single dose of 5, 10, 20, 40, 80 or 120mg. The time to maximum concentration of the 
pharmacologically active form of Laninamivir octoneate, laninamivir, was 4 hours. Laninamivir was slowly 
eliminated from the body, lasting for up to 144h after administration with a half-life of approximately 3 days. 
The maximum concentration of the prodrug and laninamivir after a single inhaled dose increased almost linearly 
with the doses tested.  
Laninamivir octeonate was well tolerated by all the subjects even with high exposures attained9.  

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16.4.4. Toxicity 
Laninamivir octanoeate has been generally well tolerated.  
In a large RCT, the most common adverse events included asthma exacerbation (5.9%), diarrhoea (3.9%) and 
bronchitis (3.9%), and occurred in similar proportions to oseltamivir1.  
 
16.4.5. Contraindications 
• 
Hypersensitivity to the active substance, laninamivir 
• 
Hypersensitivity to excipients 
o Lactose monohydrate 
• 
Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-
galactose malabsorption should not take this medicine 
 
16.4.6. Cautions 
In 2017, the pharmaceuticals and medical devices agency reported 8 cases of bronchial spasm and dyspnoea 
(including 3 cases for which a causal relationship with the product could not be ruled out) associated with 
Inavir©use over the preceding 3 years in Japan; the package insert was updated in view of this information10.   
 
16.4.7. Drug interactions  
No significant drug interactions are mentioned in the literature.  
 
16.4.8. References 
1.Beigel JH et al. Influenza Therapeutics in Clinical Practice- Challenges and Recent Advances. Cold Spring Harbor 
Perspectives in Medicine. 2021;11:a038463.  
2. Yamashita M. Laninamivir and its prodrug, CS-8958: long-acting neuraminidase inhibitors for the treatment 
of influenza. Antiviral Chemistry and Chemotherapy. 2010;21:71-84.  
3. Kubo S et al. Laninamivir prodrug CS-8958, a long-acting neuraminidase inhibitor, shows superior anti-
influenza virus activity after a single administration. Antimicrobial agents and Chemotherapy. 2010; 54:1256–
1264.  
4. Koyama K et al. CS-8958, a prodrug of the novel neuraminidase inhibitor R-125489, demonstrates a favorable 
long retention profile in the mouse respiratory tract. Antimicrobial agents and Chemotherapy. 2009; 53:4845–
4851.  
5. Watanabe A, Chang SC, Kim MJ, et al. Long-acting neuraminidase inhibitor laninamivir octanoate versus 
oseltamivir for treatment of influenza: a double-blind, randomized, noninferiority clinical trial. Clin Infect Dis 
2010; 51:1167-1175.  
6. Higashiguchi M et al. A meta-analysis of laninamivir octanoate for treatment and prophylaxis of influenza. 
Antiviral Therapy. 2018;23(2):157-165 
7. Koseki et al. Comparison of the clinical effectiveness of zanamivir and laninamivir octanoate for children with 
influenza A(H3N2) and B in the 2011-2012 season. Influenza and Other Respiratory Viruses. 2014;8(2):151-158 
8. Evaluation and Licensing Division, Pharmaceutical and Food Safety Bureau. Report on the Deliberation 
Results: Inavir Dry Powder Inhaler 20mg. https://www.pmda.go.jp/files/000211431.pdf 
9. Ishizuka H et al. Clinical pharmacokinetics of laninamivir, a novel long-acting neuraminidase inhibitor, after 
single and multiple inhaled doses of its prodrug, CS-8958, in healthy male volunteers. Journal of Clinical 
Pharmacology. 2010; 50(11):1319-29.  
10.Pharmaceuticals and Medical Devices Agency. Summary of Investigation Results Laninamivir octanoate 
hydrate. 2017. https://www.pmda.go.jp/files/000219291.pdf 
 
 
 

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16.5. Baloxavir  
 
16.5.1. Rationale 
Baloxavir marboxil selectively inhibits the cap-dependent endonuclease activity of the polymerase acid protein 
(PA) subunit of the highly conserved influenza polymerase complex, thus preventing viral mRNA transcription. 
It is an oral prodrug that is rapidly converted to its active form, baloxavir acid1.  
The 50% inhibition concentration (IC50) of baloxavir was 1.4-3.1nmol/L for influenza viruses and 4.5-8.9nmol/L 
for influenza B viruses in an enzyme inhibition assay2. 
In cell culture, baloxavir acid inhibits replication of representative seasonal influenza A and B viruses, including 
strains resistant to neuraminidase inhibitors, and avian influenza viruses, at low nanomolar concentrations3;  
In a MDCK cell culture assay, the median 50% effective concentration (EC50) values of baloxavir were 0.73nmol/L 
for H1N1 strains, 0.83nmol/L for H3N2 strains and 5.97nmol/L for type B strains. EC90 values were between 
0.80-3.16nmol/L for avian subtype H5N1 and H7N9 viruses2.  
Oral baloxavir’s prolonged half-life enables the use of a single dose in the treatment of uncomplicated influenza.  
CAPSTONE -1 was a phase 3, placebo and oseltamivir-controlled RCT testing single, weight-based baloxavir 
doses (40 or 80mg) administered within 48 hours of symptoms to patients aged 12-64 years with uncomplicated 
influenza4. The study found that the median time to alleviation of influenza symptoms was 53.7 hours in 
baloxavir recipients compared to 80.2 hours in placebo recipients (p<0.0001). The median time to alleviation of 
influenza symptoms was similar between baloxavir and oseltamivir groups. By 1 day after initiating treatment, 
the reductions in nasal virus titers compared to baseline were >100 fold and >1000-fold greater in the baloxavir 
groups compared to the oseltamivir and placebo groups, respectively. The median duration of infectious virus 
detection was shorter in the baloxavir group (24 hours) than in the oseltamivir group (72 hours, p<0.001) and 
the placebo group (96 hours, p<0.001). In this study, therapeutic use was associated with relatively high 
frequencies of emergence of variants with PA substitutions (PA I38T and I38M) conferring reduced 
susceptibility- resistant viruses emerged in 9.7% of 370 baloxavir recipients (all infected with H3N2) within five 
days, associated with prolonged virus shedding and longer median time to alleviation of symptoms. The 
transmission fitness and pathogenicity of these variants requires assessment.  
Baloxavir was approved by the FDA in 2018 for treatment of uncomplicated influenza following CAPSTONE-1. It 
was approved by the European Commission in 2021.  
CAPSTONE-25 was a phase 3 oseltamivir and placebo-controlled trial of single weight-based baloxavir treatment 
(40 or 80mg) administered within 48 hours of symptoms in outpatients with at least one risk factor for severe 
disease. This RCT again showed the superior efficacy of baloxavir compared to placebo in shortening duration 
of symptoms. Baloxavir was associated with a significantly faster decline in infectious virus titres than were 
placebo and oseltamivir, a finding also observed for subgroups infected with influenza A/H3N2 or influenza B. 
Median time to alleviation of symptoms was similar between oseltamivir and baloxavir in analysis of all patients 
and those infected with influenza A H3N2 virus but was significantly shorter in the baloxavir group compared 
to the oseltamivir group in those with influenza B virus.  
16.5.2. Composition and dose 
The following information is taken from the European Medicines Compendium (EMC) summary of product 
characteristics for Xofluza©, 2.  
Xofluza© 20mg film-coated tablets contains 20mg baloxavir marboxil.  
Xofluza© 40mg film-coated tablets contains 40mg baloxavir marboxil.  
The approved doses for adults and adolescents (>/= 12 years of age) are: 
• 
Patients <80kg take a single dose of 40mg (taken as 2x20mg tablets at the same time) 
• 
Patients >/=80kg take a single dose of 80mg (taken as 2x40mg tablets at the same time).  
 
A single dose of baloxavir marboxil should be taken as soon as possible within 48 hours of symptom onset.  
Xofluza© may be taken with or without food. It should not be taken with products that contain polyvalent 
cations such as laxatives, antacids or oral supplements containing iron, zinc, selenium, calcium or magnesium.  

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16.5.3. Pharmacokinetic characteristics 
After oral administration of baloxavir marboxil, the drug is extensively converted to its active constituent, 
baloxavir.  Following a single oral administration of 80mg of baloxavir marboxil, the time to achieve peak plasma 
concentrations is approximately 4 hours in the fasted stage. The absolute bioavailability of baloxavir after oral 
dosing has not been established2.  
In an ascending single-dose study involving healthy volunteers, baloxavir was administered up to the highest 
dose tested (80mg) without evident safety concerns, and it showed linear pharmacokinetic characteristics and 
a long plasma elimination half-life (range 49-91 hours)1. The prolonged plasma half-life enables the use of a 
single dose in the treatment of uncomplicated influenza.   
In clinical studies, there were no clinically relevant differences in efficacy when baloxavir was taken with or 
without food5.  
Body weight is a significant covariate for baloxavir pharmacokinetics based on the population pharmacokinetic 
analysis. Dosing recommendations for baloxavir marboxil are thus based on body weight2.  
The effects of renal impairment on the pharmacokinetics of baloxavir marboxil or baloxavir have not been 
evaluated. Renal impairment is not expected to alter the elimination of baloxavir5.  
No clinically meaningful differences in the pharmacokinetics of baloxavir were observed in patients with mild 
or moderate hepatic impairment (Child-Pugh class A and B) compared with healthy controls with normal hepatic 
function. The pharmacokinetics in patients with severe hepatic impairment have not been evaluated.2  
Based on human mass balance studies the metabolism of baloxavir is predominantly via glucuronidation (via 
UGT1A3 enzyme). Oxidation to sulfoxide metabolites are mediated via CYP3A4. Baloxavir was found to inhibit 
CYP2B6, CYP2C8, and CYP3A4 enzymes in human liver microsomes. Baloxavir has some induction potential 
for CYP1A2, CYP2B6, and CYP3A4, although with lesser potency (<20% effect of positive controls), thus the 
potential for inducible effects of baloxavir is low. In a DDI study considering the predominance of 
glucuronidation, plasma exposure of baloxavir was decreased in the presence of the pan-UGT inhibitor 
probenecid. This reduction of 21-25% suggests there is an unexplained effect.2 
Baloxavir was detected in breast milk of nursing rats up to 8 hours and was undetected at 24 hours.2 
Pharmacokinetic sampling schedule (only if there is evidence of accelerated viral clearance): 
All patients will need to be admitted for 12 hours for intense sampling 
The timings are: 
• 
Pre-dose D0H0, then 
• 
1,2,3,4,6,9,12 and 24h post dose  
Note that blood will be taken on D3, and D7 for routine haematology and biochemistry. The EDTA sample will 
be used to measure the drug concentrations  
16.5.4. Toxicity 
Nonclinical data reveal no special hazards for humans.2  
The safety of Xofluza in adults and adolescents is based on data from 3 placebo-controlled trials in which a total 
of 1640 subjects received Xofluza. No specific drug-related adverse events have been identified in baloxavir 
studies to date1. Adverse events reported in at least 1% of adults and adolescents treated with Xofluza included 
diarrhoea, bronchitis, nausea, sinusitis and headache6.  
Baloxavir marboxil had no effects on fertility when given orally to male and female rats at doses providing 
exposure equivalent to 5-times the human exposure based on AUC0-24hr.. There are no or limited data from the 
use of baloxavir marboxil in pregnant women. As a precautionary measure, it is preferable to avoid the use of 
Xofluza during pregnancy. 2 
 
 

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16.5.5. Contraindications5 
• 
Hypersensitivity to the active substance, baloxavir 
• 
Hypersensitivity to any of the following excipients: 
o Tablet core: Lactose monohydrate, Croscarmellose sodium (E468), Povidone (K25), 
Microcrystalline cellulose (E460), Sodium stearyl fumarate 
o Film-Coating: Hypromellose, Talc (E553b), Titanium dioxide (E171) 
• 
Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-
galactose malabsorption should not take this medicine 
 
16.5.6. Cautions 
Cases of anaphylaxis, urticaria, angioedema, and erythema multiforme have been reported in postmarketing 
experience with Xofluza6.  
 
16.5.7. Drug interactions 
Based on in vitro and in vivo drug-drug interaction studies, baloxavir marboxil and baloxavir had low potential 
to inhibit isoenzymes of the CYP (CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4) or UGT 
families or cause relevant induction of CYP enzymes5.  
Baloxavir marboxil and baloxavir are substrates of P-glycoprotein (P-gp). A clinical DDI study confirmed that 
baloxavir marboxil minimally altered PK of P-gp and BCRP substrates to a degree that is not considered to have 
an effect on drugs that are substrates for these transporters.2 
Avoid coadministration with dairy products, polyvalent cation-containing laxatives, antacids or oral 
supplements (e.g. calcium, iron, magnesium, selenium or zinc).  
16.5.8. References 
1. Beigel JH et al. Influenza Therapeutics in Clinical Practice- Challenges and Recent Advances. Cold Spring 
Harbor Perspectives in Medicine. 2021;11:a038463.  
2. European Medicines Compendium. Xofluza 20mg and 40mg film coated tablets summary of product 
characteristics. https://www.medicines.org.uk/emc/product/12879/smpc#gref 
3. Omoto S et al. Characterisation of influenza virus variants induced by treatment with the endonuclease 
inhibitor baloxavir marboxil. Scientific Reports. 2018;8:9633. https://doi.org/10.1038/s41598-018-27890-4 
4. Hayden F et al. Baloxavir Marboxil for Uncomplicated Influenza in Adults and Adolescents. New England 
Journal of Medicine. 2018;379:913-923 
5. Ison MG et al. Early treatment with baloxavir marboxil in high-risk adolescent and adult outpatients with 
uncomplicated influenza (CAPSTONE-2): a randomised, placebo-controlled, phase 3 trial. The Lancet Infectious 
Diseases. 2020;20:1204-14 
6.Food 
and 
Drug 
Administration. 
XOFLUZA 
(baloxavir 
marboxil). 
2020. 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/214410s000,210854s004s010lbl.pdf 
 
 
 
 

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16.6. Favipiravir  
 
16.6.1. Rationale 
Favipiravir is a substituted pyrazine derivative that inhibits the replication of many RNA viruses, including 
influenza A, B and C viruses. Once metabolised intracellularly, favipiravir acts as a purine nucleoside analogue 
which functions as a competitive substrate inhibitor of the RNA-dependent RNA polymerase of RNA viruses, 
leading to chain termination. In addition, another mechanism of antiviral action is lethal mutagenesis caused 
by increased guanosine to adenine mutation frequency, causing non-viable progeny viruses1.  
Favipiravir was first reported to inhibit influenza virus replication in vitro and in mice in 2002. Favipiravir inhibits 
seasonal influenza A and B viruses, including those resistant to adamantanes and NAIs and avian A/H5N1 and 
A/H7N9 viruses. It has broad spectrum RNA virus activity in vitro and inhibits a range of RNA viruses in animal 
models1.  
The 50% inhibitory concentration (IC50) of Favipiravir in inhibiting RdRp of influenza virus has been reported as 
0.34uM. Plaque reduction experiments in MDCK cells showed the 50% effective concentration ranges from 
0.013 to 3.53 ug/ml2.  
Favipiravir has shown better efficacy compared to oseltamivir in an animal model of severe lethal influenza 
infection where initial viral titres are high; this model corresponds to pandemic influenza in humans. In a mouse 
model of nonlethal influenza infection, corresponding to human seasonal influenza infection, oseltamivir and 
favipiravir have shown similar efficacy3. 
Clinical studies of various dose regimens have been conducted mainly in adults with acute, uncomplicated 
influenza. One RCT enrolling influenza-infected participants found that a twice-daily dosing regimen (1800mg 
BD on day 1 and 800mg BD on days 2-5) gave better antiviral and clinical effects than a thrice-daily regimen. 
The favipiravir 1800mg/800mg BD group demonstrated significantly faster median time to alleviation of 
influenza symptoms (difference of 15 hours) and viral load reductions compared with the placebo group4.  
Two placebo-controlled phase 3 RCTs tested a favipiravir regimen consisting of two separate 1800mg loading 
doses on day 1 followed by 800mg BD on days 2-5 in adults with uncomplicated influenza presenting within 48 
hours of symptoms5. Both showed significant reductions in nasal infectious virus titers (as measured by RNA 
load area under the curve over days 1-5, and median time to cessation of virus detection) compared to placebo. 
One study found a significant difference of 14.4h in median time to alleviation of symptoms in the favipiravir 
recipients compared to placebo, whereas the other study found a non-significant difference of 6.1h. The 
inconsistent clinical outcomes despite significant antiviral activity is unclear. However, considerable 
intersubject variability in both pre-dose and postdose favipiravir concentration was seen over time so that some 
participants had relatively low favipiravir exposures and trough concentrations below the target of 20ug/ml, a 
concentration above which has been associated with clinical and antiviral effect in prior phase 2 trials. The 
optimal dose regimes for favipiravir need further study.  
Favipiravir was approved in Japan in 2014 with an indication limited to the treatment of novel or re-emerging 
influenza virus infections unresponsive or insufficiently responsive to current agents. It remains investigational 
for influenza elsewhere. The dose regimen approved in Japan (1600mg BD for 1 day followed by 600mg BD for 
4 days) is lower than that tested in the above trials.  
16.6.2. Composition and dose 
In this study, patients will be given 1800mg of favipiravir (nine 200mg tablets) at H0 and 1800mg of favipiravir 
(nine 200mg tablets) at H12. Thereafter the patient will take 800mg BD (four 200mg tablets) for a further 4 
days.  
16.6.3. Pharmacokinetics  
Oral favipiravir reaches maximal concentrations at 2 hours post oral administration and has a half-life of 2.5-5 
hours. Protein binding occurs at 54%. The active parent drug is metabolised to the inactive metabolite T-705M1 
mainly by aldehyde oxidase and partially by xanthine oxidase. PK analysis of continuous doses of favipiravir in 
nonhuman primate models exhibit nonlinear pharmacokinetics over time, with decreasing trough levels at D4, 
relative to D2.  

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Pharmacokinetic schedule: only if there is evidence of accelerated viral clearance 
All patients will be admitted for 12 hours for intense sampling. The timings are: 
• 
Pre-dose D0, H0, then 
• 
1,2,3,4,6,9,12 and 24h 
Note that blood will be taken on D3, and D7 for routine haematology and biochemistry. The EDTA sample will 
be used to measure the drug concentration. 
Favipiravir is mainly metabolised by aldehyde oxidase, leading to the inactive metabolite T705M1, and 
marginally by xanthine oxidase. Most metabolites are excreted under hydroxylated forms via the kidney.6 
16.6.4. Toxicity 
A review of the safety of favipiravir from 29 studies demonstrates a favourable safety profile.  
Side-effects which tend to be mild, include diarrhoea, as well as blood abnormalities including raised uric acid 
levels, raised liver function tests and uncommonly, decreased neutrophil counts. Early concerns regarding QTc 
prolongation were not born out in a study of healthy Japanese individuals using moxifloxacin as a positive 
control, where favipiravir showed no effect on QT intervals.  
Animal models have demonstrated teratogenicity and no human studies on pregnant or lactating women have 
been conducted.  
16.6.5. Contraindications7 
• 
Women known or suspected to be pregnant and in lactating women 
• 
Hypersensitivity to the active substance, favipiravir  
• 
Hypersensitivity to any excipient  
o Povidone, colloidal silicon dioxide, low-substituted hydroxypropyl cellulose, crospovidone, sodium 
stearyl fumarate, hydroxypropyl methylcellulose, titanium dioxide, talcum, yellow iron oxide 
16.6.6. Cautions  
Because favipiravir is associated with dose-related increases in serum uric levels, it should be used with care in 
patients with gout or a history of gout, and in those with hyperuricaemia2  
When administrating favipiravir to women of child-bearing potential, confirm a negative pregnancy test before 
starting the treatment. Instruct to use most effective contraceptive methods with her partner during and for 7 
days after the end of the treatment6  
Because favipiravir is distributed in sperm, men should use the most effective contraception methods during 
treatment and for 7 days afterwards2.  
16.6.7. Drug interactions  
Favipiravir is not metabolised by cytochrome P-450 (CYP). The drug inhibits AO and CYP2C8 but does not induce 
CYP.  
Favipiravir inhibits the formation of acetaminophen sulphate in vitro and in vivo, resulting in a small magnitude 
increase in acetaminophen levels. As a result, daily acetaminophen (paracetamol) should not exceed 3g/day.  
16.6.8. References 
1. Beigel JH et al. Influenza Therapeutics in Clinical Practice- Challenges and Recent Advances. Cold 
Spring Harbor Perspectives in Medicine. 2021;11:a038463.  
2. Fang et al. Advance researches on the inhibition of influenza virus by Favipiravir and Baloxavir. 
Biosafety and Health. 2020; 2(2):64-70 
3. Shiraki J and Daikoku T. Favipiravir, an anti-influenza drug against life-threatening RNA virus 
infections. Pharmacology and Therapeutics. 2020;209:107512.  
4. McKimm-Breschkin JL, Fry AM. Meeting report: 4th ISIRV antiviral group conference: novel antiviral 
therapies for influenza and other respiratory viruses. Antiviral Research. 2016; 129:21–38. 
5. Hayden F et al. Favipiravir Treatment of Uncomplicated Influenza in Adults: Results of Two Phase 3, 
Randomised, Double-Blind, Placebo-Controlled Trials. The Journal of Infectious Diseases.  
2022;jiac135. https://doi.org/10.1093/infdis/jiac135  

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6. Madelain V, Nguyen TH, Olivo A, de Lamballerie X, Guedj J, Taburet AM, et al. Ebola Virus Infection: 
Review of the Pharmacokinetic and Pharmacodynamic Properties of Drugs Considered for Testing in 
Human Efficacy Trials. Clin Pharmacokinet. 2016;55(8):907-23. 
7. Avigan Tablets 200mg. November 2017 (4th version). https://www.cdc.gov.tw/File/Get/ht8jUiB_MI-
aKnlwstwzvw 
 
 
 

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16.7. Molnupiravir  
 
16.7.1. Rationale 
Molnupiravir is a small molecular ribonucleoside prodrug of N-hydroxycytidine (NHC). It is phosphorylated 
intracellularly into NHC triphosphate (NHC-TP). NHC-TP incorporates into viral RNA by viral RNA polymerase 
causing an accumulation of deleterious errors into the viral genome. This causes “error catastrophe” by 
increasing the rate of mutation in the viral genome to a level lethal to the virus and causing extinction1.  
Molnupiravir was originally intended to treat alphavirus infections and at the beginning of the COVID-19 
pandemic it was in pre-clinical testing for seasonal influenza. After the spread of COVID-19, the molnupiravir 
development program moved to the treatment of COVID-192.   
Molnupiravir has demonstrated potent anti-influenza activity and good oral bioavailability in 
mice/ferrets/nonhuman primates. In a ferret model of influenza infection (either intranasally infected with 
pandemic 2009 H1N1 or H3N2), molnupiravir administered 24 hours post-infection reduced shed viral titers by 
≥4 orders of magnitude within 24 hours of the first dose and compared favourably to prophylactically 
administered oseltamivir phosphate which had no significant effect on shed virus titer. Duration of fever was 
significantly shortened in molnupiravir treated ferrets (H1N1-infected group). This study also highlighted that 
molnupiravir shows antiviral effects because of its mutagenic property towards influenza viruses and suggested 
further clinical studies of molnupiravir for influenza treatment3.  
A phase 1 safety trial of doses up to 1600mg per day found molnupiravir was well tolerated with the incidence 
of adverse effects being highest in the placebo arm4. Another phase 1 trial also concluded molnupiravir was 
safe and well tolerated and advised 800mg BD for 5 days for the treatment of SARS-COV2 infection5. 
Molnupiravir has been licensed for treatment of mild-moderate COVID-19 in patients at risk of severe disease 
at a dose of 800mg BD for 5 days based on phase 2 and 3 trials. No phase 2 studies of molnupiravir treatment 
have occurred in patients with influenza.  
16.7.2. Composition and dose 
Each Lagevrio© capsule contains 200mg of molnupiravir.  
The recommended dose for treatment of mild to moderate COVID-19 is 800mg (4 capsules) taken orally every 
12 hours for 5 days.  
Molnupiravir is being manufactured by Merck, Sharpe & Dohme.  
We will use Lagevrio© or a high-quality generic alternative. 
 
16.7.3. Pharmacokinetics 
Molnupiravir is a prodrug metabolised to the ribonucleoside analogue N-hydroxyxytidine (NHC) and 
phosphorylated to the active rinonucleoside triphosphate (NHC-TP). Following twice daily oral administration 
of 800mg molnupiravir, median time to peak plasma NHC concentrations is 1.5 hours. The effective half-life of 
NHC is 3.3. hours. It can be taken with or without food.  
Pharmacokinetic schedule: only if there is evidence of accelerated viral clearance 
All patients will be admitted for 12 hours for intense sampling. The timings are: 
• 
Pre-dose D0, H0, then 
• 
1,2,3,4,6,9,12 and 24h 
Note that blood will be taken on D3, and D7 for routine haematology and biochemistry. The EDTA sample will 
be used to measure the drug concentration.  
16.7.4. Toxicity 
Highest dose tested in safety trials was 800mg BD, found to have a 0.9% probability of having 30% excess toxicity 
compared to control therefore considered safe5.  
Studies in animals have shown reproductive toxicity.  
In an interim analysis of a phase 3 trial of subjects with mild to moderate COVID-19 treated with molnupiravir 
(n=386), the most common adverse reactions (>/=1% of subjects) reported during treatment and during 14 days 

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after the last dose were diarrhoea (3%), nausea (2%), dizziness (1%) and headache (1%) all of which were Grade 
1 (mild) or Grade 2 (moderate).  
16.7.5. Contraindications 
• 
Hypersensitivity to the active substance, molnupiravir 
• 
Hypersensitivity to any of the excipients: 
o Capsules contents: Croscarmellose sodium (E468), Hydroxypropyl cellulose (E463), Magnesium 
stearate (E470b), Microcrystalline cellulose (E460) 
o Capsule shell: Hypromellose (E464), Titanium dioxide (E171), Red iron oxide (E172) 
o Printing ink: Butyl alcohol, Dehydrated alcohol, Isopropyl alcohol, Potassium hydroxide, Propylene 
glycol (E1520), Purified water, Shellac, Strong ammonia solution, Titanium dioxide (E171) 
 
16.7.6. Cautions  
No dose adjustment needed for renal impairment however the pharmacokinetics have not been evaluated with 
eGFR <30ml/min, also not evaluated with hepatic impairment.  
As per US FDA advice, those on molnupiravir need to be aware of avoiding pregnancy. Females of child bearing 
potential need to use a reliable method of contraception for the duration of the treatment, and also for 4 days 
after the final doe of molnupiravir. Males of reproductive potential, if they are sexually active with females of 
child bearing potential, should use a reliable form of contraception during the treatment and at least 3 months 
after the final dose.  
Breast-feeding is not recommended during treatment and for 4 days after the last dose of Lagevrio.  
16.7.7. Drug interactions  
None identified. Molnupiravir and its metabolites are not substrates of the CYP enzymes, and are broken down 
into uridine and cytidine through the normal intracellular pyrimidine catabolism pathways.  
Based on in vitro studies, neither molnupiravir or NHC are inhibitors or inducers of major drug metabolising 
enzymes or inhibitors of major drug transporters. Therefore, the potential for molnupiravir or NHC to interact 
with concomitant medications is considered unlikely.  
 
16.7.8. References 
1.Singh AK, Singh A, Singh R, Misra A. Molnupiravir in COVID-19: A systematic review of literature. Diabetes & 
Metabolic Syndrome: Clinical Research & Reviews. 2021;15(6):102329.  
2. Imran M et al. Discovery, Development, and Patent Trends on Molnupiravir: A Prospective Oral Treatment 
for COVID-19. Molecules. 2021;26(19):5795.  
3. Toots M et al. Characterization of orally efficacious influenza drug with high resistance barrier in ferrets and 
human airway epithelia. Science Translational Medicine. 2019; 11(515): doi:10.1126/scitranslmed.aax5866  
4. Painter WP et al. Human safety, tolerability, and pharmacokinetics of molnupiravir, a novel broad-spectrum 
oral antiviral agent with activity against SARS-CoV-2. Antimicrobial Agents and Chemotherapy. 
2021;65(5):e02428-20.  
5. Khoo SH et al. Optimal dose and safety of molnupiravir in patients with early SARS-CoV-2: a Phase I, open-
label, dose-escalating, randomized controlled study. Journal of Antimicrobial Chemotherapy. 2021;76(12):3286-
95  
 
 

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16.8. Combination Therapies 
Rationale 
Combination antiviral therapies can offer synergistic, and therefore more effective, rapid and multi-mechanistic 
inhibition of viral replication and thus accelerated viral clearance, with implications for improved clinical 
outcomes, transmission dynamics as well as reducing risk of development of resistance. 
Pre-clinical in-vitro studies have shown synergy between neuraminidase inhibitors Oseltamivir, Zanamivir and 
Peramivir when combined with cap-dependent endonuclease inhibitor Baloxavir. Synergy was also seen 
between Baloxavir and RdRp inhibitor Favipiravir when used together against two strains of influenza A. (1) 
16.8.1. Oseltamivir PLUS Baloxavir 
16.8.1.1. Rationale 
In-vitro synergy has been shown with a weighted combination index (CIwt) of 0.48 A(H1N1) 0.49 A(H3N2), as 
well as in mice (2, 3). Note if CIwt <1 there is synergy. In humans, a randomised parallel group double blind 
superiority trial of neuraminidase inhibitors (any of oseltamivir, peramivir and zanamivir) versus neuraminidase 
inhibitor PLUS Baloxavir was conducted, called the FLAGSTONE study. In 366 hospitalised patients >12 years 
with severe influenza (NEWS2 or above at baseline) no difference in time to clinical improvement (defined as 
median time to NEWS2) was shown between the combination arm (n=241) and the single therapy arm (n=128) 
(4). However, median time to negative RT-PCR was 23.9 hours for combination therapy versus 63.7 NAI 
suggesting added antiviral benefits not captured by the clinical endpoint. Combination therapy resulted in a 
rapid reduction of viral titre compared to NAI alone in hospitalised patients. Notably the sample was skewed 
towards late presentation (only 39% in the Baloxavir group started treatment within 48 hours of symptom 
onset), otherwise subjects were recruited up until day 4 after symptom onset. Around 85% of patients in each 
group had started NAI treatment prior to enrollment. Delineation between combination types and associated 
results was not carried out, making it difficult to understand any differences between each of the NAI-Baloxavir 
combinations and possible superiority. Another trial comparing oseltamivir monotherapy with oseltamivir PLUS 
Baloxavir in hospitalised patients is underway pending results (COMBO Trial 1 2020-2023) (5), although plans 
to recruit only 60 with the imprecise measure of time to viral clearance.  
16.8.1.2. Drug-to-Drug interactions 
There are no known drug-to-drug interactions. Safety data for Oseltamivir-Baloxavir combination therapy used 
in FLAGSTONE does not delineate between each of the neuraminidase inhibitor-Baloxavir combinations, 
however there was no meaningful difference in the rate of adverse events between arms. In addition, no 
meaningful drug to drug interactions were observed between Oseltamivir and Baloxavir in a phase I open label 
DDI study of 18 healthy subjects (6), and it is not expected that there would be any interactions based on 
pharmacokinetic properties. 
16.8.1.3. Pharmacokinetic characteristics  
Pharmacokinetic sampling schedule (only if there is evidence of accelerated viral clearance): 
All patients will need to be admitted for 12 hours for intense sampling 
The timings are: 
• 
Pre-dose D0H0, then 
• 
1,2,3,4,6,9,12 and 24h post dose  
Note that blood will be taken on D3, and D7 for routine haematology and biochemistry. The EDTA sample will 
be used to measure the drug concentrations  
16.8.1.4. Toxicity 
Baloxavir plus Neuraminidase Inhibitors were well-tolerated in FLAGSTONE and no new safety signals were 
observed; serious adverse events occurred in 29 (12%) of 239 patients in the Baloxavir group versus 19 (15%) 
of 124 patients in the control group, of which one was considered related to treatment (orthostatic hypotension 
in a patient in the control group). Overall, four deaths (2%) occurred in the Baloxavir group and seven (6%) in 
the control group; none were considered related to treatment (4). 
 

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16.8.2. Oseltamivir PLUS Favipiravir 
16.8.2.1. Rationale 
In-vitro studies have demonstrated combination effectiveness against neuraminidase inhibitor resistant 
influenza strains of this combination in-vitro (1, 7) and superiority against severe influenza in 
immunosuppressed mice, but did not prevent emergence of oseltamivir resistant strains. (8) 
Data from 2 separate prospective studies compared combination oseltamivir and favipiravir (n=40) to 
oseltamivir only (n=138) in critically ill adults with A(H1N1)pdm09 and A(H3N2) influenza. The combination arm 
was part of a phase 2a combination therapy trial comparing combinations 2018-2019 but with two dose 
regimens of favipiravir. The control arm was made up of patients enrolled to a different study 2016-19. showed 
better cumulative clinical improvement for combination, with lower proportion of patients with severe 
outcomes on day 7 (60.0% combination vs 63.3% P=0.0257) and day 14 (30% combination vs 48.5%, P=0.0069). 
(9) 62.5% had improved by day 14 in the combination group vs 42.2% in monotherapy, P=0.025, but no 
differences were found on day 7 or day 28, or in mortality. Clinical improvement was defined as a decline in 2 
categories on the 7-category ordinal scale. The proportion of patients with negative RT-PCRs was significantly 
lower in the combination group on days 2 (10% vs 0.8%), 5 (30% vs 5.5%), 7 (45.0% vs 15.6%) and 10 (67.5% vs 
21.9%, P<0.01 for all) (9). Resistance development wasn’t monitored across both groups. 53% of the control 
group received corticosteroids, whilst the PLUS Favipiravir group did not. 
16.8.2.2. Drug to Drug interactions 
No theoretical interactions, no known overlap in metabolism pathways. 
16.8.2.3. Pharmacokinetic characteristics  
Pharmacokinetic sampling schedule (only if there is evidence of accelerated viral clearance): 
All patients will need to be admitted for 12 hours for intense sampling 
The timings are: 
• 
Pre-dose D0H0, then 
• 
1,2,3,4,6,9,12 and 24h post dose  
Note that blood will be taken on D3, and D7 for routine haematology and biochemistry. The EDTA sample will 
be used to measure the drug concentrations  
Favipiravir is mainly metabolised by aldehyde oxidase, leading to the inactive metabolite T705M1, and 
marginally by xanthine oxidase. Most metabolites are excreted under hydroxylated forms via the kidney.6 
16.8.2.4. Toxicity 
Combination well-tolerated in human study (n=128 received combination therapy for severe influenza), no 
severe adverse events occurred, 3 reversible increases in ALT occurred.(9) 
16.8.3. Favipiravir PLUS Baloxavir 
16.8.3.1. Rationale 
Synergy with CIwt’s of 0.54 A(H1N1) 0.16 A(H3N2) have been shown in-vitro. (2) To our knowledge, the 
combination of favipiravir plus Baloxavir has only been tested in vitro. 
16.8.3.2. Drug Interactions 
There are no theoretical DDIs between Oseltamivir and Baloxavir. 
16.8.3.4. Pharmacokinetic characteristics  
Pharmacokinetic sampling schedule (only if there is evidence of accelerated viral clearance): 
All patients will need to be admitted for 12 hours for intense sampling 
The timings are: 
• 
Pre-dose D0H0, then 
• 
1,2,3,4,6,9,12 and 24h post dose  
Note that blood will be taken on D3, and D7  for routine haematology and biochemistry. The EDTA sample will 
be used to measure the drug concentrations  

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Favipiravir is mainly metabolised by aldehyde oxidase, leading to the inactive metabolite T705M1, and 
marginally by xanthine oxidase. Most metabolites are excreted under hydroxylated forms via the kidney.6 
16.8.3.5. Toxicity 
No human data are available 
16.8.4. References for combination therapies 
1. 
Tarbet EB, Vollmer AH, Hurst BL, Barnard DL, Furuta Y, Smee DF. In vitro activity of favipiravir and 
neuraminidase inhibitor combinations against oseltamivir-sensitive and oseltamivir-resistant pandemic 
influenza A (H1N1) virus. Arch Virol. 2014;159(6):1279-91. 
2. 
Checkmahomed L, Padey B, Pizzorno A, Terrier O, Rosa-Calatrava M, Abed Y, et al. In Vitro Combinations 
of Baloxavir Acid and Other Inhibitors against Seasonal Influenza A Viruses. Viruses. 2020;12(10). 
3. 
Fukao K, Noshi T, Yamamoto A, Kitano M, Ando Y, Noda T, et al. Combination treatment with the cap-
dependent endonuclease inhibitor baloxavir marboxil and a neuraminidase inhibitor in a mouse model of 
influenza A virus infection. J Antimicrob Chemother. 2019;74(3):654-62. 
4. 
Kumar D, Ison MG, Mira J-P, Welte T, Hwan Ha J, Hui DS, et al. Combining baloxavir marboxil with 
standard-of-care neuraminidase inhibitor in patients hospitalised with severe influenza (FLAGSTONE): a 
randomised, parallel-group, double-blind, placebo-controlled, superiority trial. The Lancet Infectious Diseases. 
2022;22(5):718-30. 
5. 
ClinicalTrials.gov. COmbination Therapy With Baloxavir and Oseltamivir 1 for Hospitalized Patients With 
Influenza 
(The 
COMBO 
Trial 
1) 
(COMBO 
1) 
NCT04327791 
2020 
[Available 
from: 
https://classic.clinicaltrials.gov/ct2/show/NCT04327791. 
6. 
Kawaguchi N, Koshimichi H, Ishibashi T, Wajima T. Evaluation of Drug-Drug Interaction Potential 
between Baloxavir Marboxil and Oseltamivir in Healthy Subjects. Clin Drug Investig. 2018;38(11):1053-60. 
7. 
Marathe BM, Wong SS, Vogel P, Garcia-Alcalde F, Webster RG, Webby RJ, et al. Combinations of 
Oseltamivir and T-705 Extend the Treatment Window for Highly Pathogenic Influenza A(H5N1) Virus Infection 
in Mice. Sci Rep. 2016;6:26742. 
8. 
Baz M, Carbonneau J, Rhéaume C, Cavanagh MH, Boivin G. Combination Therapy with Oseltamivir and 
Favipiravir Delays Mortality but Does Not Prevent Oseltamivir Resistance in Immunodeficient Mice Infected 
with Pandemic A(H1N1) Influenza Virus. Viruses. 2018;10(11). 
9. 
Wang Y, Fan G, Salam A, Horby P, Hayden FG, Chen C, et al. Comparative Effectiveness of Combined 
Favipiravir and Oseltamivir Therapy Versus Oseltamivir Monotherapy in Critically Ill Patients With Influenza 
Virus Infection. J Infect Dis. 2020;221(10):1688-98. 
 
 
 

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17. Appendix 3: Sample Size Simulations  
 
Planned interim analyses 
Figure 1 describes the decision flow for interim analyses. At the start of the study we planned to have an 
unblinded interim analysis at the point we have PCR data for the first 50 participants enrolled. The aim of this 
is analysis is to assess the methodology as relates to the influenza virus and inform the statistical analysis plan, 
and not to stop arms. The interim analysis for an intervention arm begins with a minimum sample size of 20 
participants (relative to 20 concurrent negative control arm). If the arm meets the futility criteria, it is removed 
from the platform. If interim results are ambiguous, the arm continues with an additional 10 participants in 
both the intervention and concurrent negative control arms until the next analysis. 
Once an arm meets success criteria, the analysis shifts to non-inferiority, comparing antiviral efficacies to the 
positive control arm. The non-inferiority interim analysis begins with a minimum sample size of 40 participants 
in the intervention arm (with 40 concurrent positive control arm). If the antiviral efficacy is inferior to the 
positive control arm, recruitment stops, and the arm is removed. If it's superior, the arm becomes the new 
positive control. Ambiguous results prompt continuation with an additional 10 participants in both arms until 
the next analysis. If antiviral efficacy falls within the non-inferiority margin, decisions depend on context, such 
as drug tolerability. 
Figure 1 A flowchart describes planned interim analyses and decision rules for removing an arm from 
the platform or making an arm the new positive control.  
During interim analyses the study will not be stopped. The pre-defined stopping rules are based in-vivo antiviral 
efficacy and not safety (which is reviewed on a continuous basis- see section 9. Safety Reporting). It is not 
possible to infer individual benefit, or harm, to a participant based on a relative change in viral clearance, so 
continued recruitment during analysis does not pose any disadvantage, and allows for further precision on the 
clearance estimate. This is in line with other adaptive studies (e.g. RECOVERY).  
The determinations of the futility/success margin λ1 and the non-inferiority margin λ2 were informed by insights 
gained from simulations using data from the first 500 participants enrolled in the PLATCOV trial, which has a 
similar study design for assessing the efficacies of SARS-CoV-2 antivirals. The simulations assessed thresholds 
λ1 ∈ {1.125, 1.15, 1.2} (i.e. 12.5%, 15% or 20%) for the futility/success assessments relative to the no study drug 

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arm; and thresholds λ2 ∈ {0.905, 0.875, 0.85} (i.e. -9.5%, -12.5%, or -15%) for the non-inferiority assessments 
relative to the positive control arm. 100 iterations were simulated for each permutation of λ1, λ2 and for three 
hypothesised effect sizes (0%, 40% and 60% increase relative to no study drug), i.e. 2700 simulations in total. 
The first interim analysis is triggered at 20 participants per arm, with subsequent analyses for each additional 
10 per arm. For the non-inferiority comparisons, they start when there are at least 40 participants per arm, and 
only if the success criteria have been met. 
• 
Choosing futility/success margin λ1 The results of the simulations for the success and futility stopping 
rules are shown in Figures 2-3.  
For λ1 = 1.125 (12.5%) and an intervention that had no effect, the median sample size was 40 
participants per arm with 4% false positive results and 28% of inconclusive trials at 120 participants per 
arm. Increasing λ1 to 1.2 (20%) would reduce the median sample size to 30 participants per arm and 
result in approximately 1% false positive results and 18% of inconclusive trials at 120 participants per 
arm. 
For an intervention with an effect of 40%, the median sample size was 30 participants per arm for a 
threshold of 12.5% and 50 participants per arm for a threshold of 20%. In all cases, false negative results 
were less than 3% of simulations, and inconclusive results increased from 14% for a threshold of 12.5% 
to 34% for a threshold of 20%. 
For an intervention with an effect of 60%, the median sample size was 20 participants per arm, 
regardless of the λ1 threshold. False negative results were less than 1% of simulations, and inconclusive 
results increased from 1% for a threshold of 12.5% to 9% for a threshold of 20%. 
Following discussion with the trial steering committee for the PLATCOV trial, it was decided to increase 
the λ1 threshold to 20% in order to stop poorly performing arms earlier (this reflects how the 
therapeutic priorities of the trial have changed as the pandemic has progressed). 
• 
Choosing non-inferiority margin λ2 The results of the simulations for the non-inferiority stopping rules 
are shown in Figures 4-5. 
In simulations which met the stopping rule for success, stopping for non-inferiority or inferiority was 
then assessed for each of the three threshold values. Only in 1 simulation with an effect of 0% was the 
non-inferiority threshold met (<0.3% false positive result). 
An effect of 40% relative to no study drug arm is very close to/on the boundaries defined by the λ2 
values, assuming that the positive control has an effect of 60% relative to the no study drug. For all 
three boundary values, around half the simulations met the non-inferiority criterion, 10% were 
inconclusive and 40% met the inferiority criterion. 
For an effect of 60% relative to the no study drug arm (i.e. same as the positive control), 70% to 78% of 
simulations met the non-inferiority criterion for the -9.5% (i.e. most stringent) to the -15% (least 
stringent) thresholds, respectively. Around 6% of simulations were inconclusive at 120 participants, and 
24 to 17% resulted in a false inferiority result for the -9.5% (i.e. most stringent) to the -15% (least 
stringent) thresholds, respectively. 
Following discussion with the trial steering committee, it was decided to initially set the λ2 threshold at 
-10%. This results in earlier stopping of interventions which are clearly less effective than the positive 
control and later stopping for interventions with an effect close to the positive control. 

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Figure 2 Waffle plots showing the proportion of each outcome (success: blue; futility: orange; no result by 120 
participants: green) for the success versus futility stopping rule. 100 simulations were run for each permutation 
of the effect size and λ1 threshold. 
 

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Figure 3 Histogram of sample size until stopping rule is met (success: blue; futility: orange; no result by 120 
participants: green). 
 

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Figure 4 Waffle plots showing the proportion of each outcome (non-inferiority: blue; inferiority: orange; no 
result by 120 participants: green) for the non-inferiority stopping rule. 100 simulations were run for each 
permutation of the effect size and λ2 threshold. 
 

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Figure 5 Histogram of sample size until stopping rule is met (non-inferiority: blue; inferiority: orange; no result 
by 120 participants: green). 
 
 

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18. Appendix 4: Exclusion Criteria  
 
The exclusion criteria in the Master Protocol are expanded upon here. The exclusion criteria in bold below have 
a corresponding section in this appendix where more details are given.  
 
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  
o Haemoglobin <10g/dL 
o Platelet count <100,000/uL 
o ALT > 2x ULN 
o Total bilirubin >1.5 x ULN 
o eGFR <70mls/min/1.73m2 
• 
For females: pregnancy, actively trying to become pregnant or lactation (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 
 
1. Taking any concomitant medications or drugs which could interact with the study medications or have 
antiviral activity 
 
The study will exclude all patients taking regular drugs including herbal drugs, but some patients may take over 
the counter drugs or other vitamin and herbal supplements if considered safe in the judgement of the site 
investigator upon screening assessment. Patients should be counselled to end and avoid all non-essential 
medications during study participation. In certain circumstances where a patient is on regular medication, 
which does not reflect an excluded underlying illness and in the opinion of the study PI is not likely to interfere 
with the study outcomes, or predispose that patient to any increased risk, a decision can be made to enrol. In 
all cases, the risks/benefits of this decision should be documented, as well as the person(s) making the decision.  
 
If any doubt about drug interactions, please refer to some of the websites below: 
 
https://crediblemeds.org/healthcare-providers 
 
https://compendium.ch/fr/account/logon?returnUrl=%2Ffr%2FPatient – this is a Swiss website dealing with 
drug interactions  
 
https://www.bnf.org/products/bnf-online/ - available only in the UK 
 
https://www.uptodate.com/content-not-available#di-druglist 
 
https://www.covid19-druginteractions.org/checker - This can be used for checking drug interactions for 
Favipiravir and Molnupiravir  
 
Contraindication to taking, or known hypersensitivity reaction to any of the proposed therapeutics  
 
 

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Oseltamivir 
No additional contraindications 
 
Zanamivir  
• 
Milk protein allergy  
 
Peramivir 
No additional contraindications 
 
Laninamivir 
No additional contraindications 
 
Baloxavir 
No additional contraindications 
 
Favipiravir 
• 
Gout or history of gout 
• 
For females of childbearing age, they should use effective contraception during the study and for 7 days 
after the last dose. For males, contraception should be used during the study and for 7 days post last dose and 
they should abstain from sex with females of child bearing potential 
 
Molnupiravir 
• 
As per US FDA advice, those on molnupiravir need to be aware of avoiding pregnancy. Females of child 
bearing potential need to use a reliable method of contraception for the duration of the treatment, and also 
for 4 days after the final dose of molnupiravir. Males of reproductive potential, if they are sexually active with 
females of child bearing potential, should use a reliable form of contraception during the treatment and at least 
3 months after the final dose 
 
Oseltamivir PLUS Favipiravir 
• 
Gout or history of gout 
• 
For females of childbearing age, they should use effective contraception during the study and for 7 days 
after the last dose. For males, contraception should be used during the study and for 7 days post last dose and 
they should abstain from sex with females of child bearing potential 
 
Oseltamivir PLUS Baloxavir 
No additional contraindications 
 
Favipiravir PLUS Baloxavir  
• 
Gout or history of gout 
• 
For females of childbearing age, they should use effective contraception during the study and for 7 days 
after the last dose. For males, contraception should be used during the study and for 7 days post last dose and 
they should abstain from sex with females of child bearing potential 
 
2. Prescence of any chronic illness/condition requiring long term treatment, or other significant comorbidity 
 
The protocol excludes almost all individuals with a chronic illness of any severity and those with an illness that 
requires long term treatment.  
In addition, the following are considered significant comorbidities associated with severe illness or 
complications according to US centers for Disease Control and Prevention and WHO: 
• 
Age 65 years of age or older 
• 
Asthma 
• 
Neurological and neuro-developmental conditions (including disorders of the brain, spinal cord, peripheral 
nerve, and muscle such as cerebral palsy, epilepsy [seizure disorders], stroke, moderate to severe 
developmental delay, muscular dystrophy or spinal cord injury) 
• 
Chronic lung disease (including COPD and asthma) 

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• 
Chronic heart disease (such as coronary heart disease, congenital heart disease, congestive heart failure) 
• 
Haematological disorders (such as sickle cell disease) 
• 
Endocrine disorders (such as diabetes mellitus) 
• 
Chronic renal disease including known end stage renal function or reduced kidney function - creatinine 
clearance <60ml/min/1.73m2 
• 
Liver disorders  
• 
Metabolic disorders (such as inherited metabolic disorders and mitochondrial disorders) 
• 
Individuals with immunosuppression due to disease or medication (such as people with HIV/AIDS, or cancer, 
chronic steroids or other medications causing immune suppression) 
• 
Pregnant or 2 weeks postpartum 
• 
BMI ≥40 kg/m2 
 
*eGFR for males is calculated based on the Chronic Kidney Disease Epidemiology Collaboration (Andrew S 
Levey, Lesley A Stevens et al. 2009) 
https://qxmd.com/calculate/calculator_251/egfr-using-ckd-epi 
 
19. Appendix 5: Potential Participating Countries  
 
Thailand 
Laos 
Brazil  
Nepal 
 
 
 

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20. Appendix 6: Amendment History  
 
Amendment 
No. 
Protocol 
Version 
No. 
Date 
issued 
Author(s) of 
changes 
Details of Changes made 
1 
V4.0 
24 Feb 23 
Dr William Schilling • 
Include host genetic test on day 3, 7 and 14.  
• 
Include serology test on day 3 and 7.  
2 
V4.2 
06 Nov 23 
Dr William Schilling, 
Dr Ellen Beer 
1. Updated co-investigators. 
2. Upper limit inclusion age extended from 50 to 
60 years old. 
3. Viral clearance analysis changed from day 0-7 to 
day 0-5 
4. Primary objective to compare antiviral efficacy 
amended to clarify that a superiority 
comparison will be done comparing study drug 
to no study drug arm and the current best 
available treatment i.e. positive control. 
5. Secondary objective ‘time to symptom 
resolution’ clarified to indicate comparison 
between study drug arm and no treatment arm 
6. Secondary objective endpoint amended to 
specify each  
endpoint e.g. Area Under the Curve of recorded 
temperature 
7. Objective to determine viral mutant 
development by looking at number of 
mutations in detectable virus added. 
8. Tertiary objective to characterise the 
relationship between viral clearance, study 
arms, and the development of persistent post-
acute symptoms added. 
9. Tertiary endpoint recording the occurrence of 
persistent symptoms of post-acute influenza 
using the Modified Influenza Yorkshire 
Rehabilitation Scale (Flu-YRSm), adapted from 
the Modified COVID-19 Yorkshire Rehabilitation 
Scale  
10. The follow up period of the participant has 
extended from 28 days to 120 days   
11. Sample size increased to 1500 participants. 
12. Addition option to ask some patients to have 
one extra set bilateral swabs taken on any day 
between day 0 and day 5 by study personnel or 
by self-swab. 
13. Clarified saliva collection can be done between 
day 0 and day 5 
14. Updated intervention arms to include 
combination therapies. 
15. Formatting to insert section hyperlinks, minor 
grammatical corrections where identified, 
clarity added to order of asterisk typography in 
appendix 1. 
16. Study duration extended by one year. 

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3 
V6.0 
15 Sep 25 
Dr William Schilling, 
Dr Stije J Leopold 
1. Updated list of co-investigators: some co-
investigators have been removed and two new 
co-investigators have been added, Dr Stije J 
Leopold and Dr Abhilasha Karkey. 
2. Removed a tertiary objective regarding 
monitoring symptoms associated with post-
acute symptoms. 
3. Removed all activities on day 6, day 14, day 28, 
and day 120, thereby shortening individual 
participants’ involvement to 7 days and the 
total blood volume was decreased.  
4. Removed blood collection for cytokine analysis 
(TNF/IL-6/IL-1) on day 0 (baseline), day 3, day 7, 
and day 14 
5. Removed blood collection for host genetic test 
on day 3, day 7, and day 14.  
6. Removed blood collection for serology analysis 
and stored blood samples on day 3 and day 14. 
7. Added oropharyngeal swabs at hour 1 (H1) time 
point on day 0 
8. Changed D0 pre-dose swab requirement from 
two sets (4 swabs) to one required set, with the 
second set be optional. 
9. Updated the procedure for observation of 
multiple doses of drug administration from 
'observe' to 'confirm' 
10. Administrative changes, including updated 
grant reference (funder), revised wording from 
observed to confirmed, changed the brand of 
VTM, formatting adjustments, and correction of 
typographical errors, updated web site for data 
sharing etc. 
4 
V7.0 
18 Nov 25 
Dr William Schilling, 
Dr Stije J Leopold 
1. Updated section 10: statistics and analysis, 
including the sample size estimation, 
determinations of the futility/success margin (from 
12.5% to 20%) and the non-inferiority margin, a link 
to access AD ASTRA statistical analysis plan (SAP) on 
GitHub.  
2. Revised the interim analysis plan and sample size 
simulation on appendix3. 
3. Updated the wording and structure in Section 7 
regarding the oropharyngeal swab schedule to 
improve clarity and understanding.