Clinical trial NCT05507567
Conditions: Influenza Viral Infections
Keywords: Influenza Human Challenge Prophylaxis
Sponsor: Pneumagen Ltd.
Start date: 2022-08-12; Completion date: 2023-05-04
Enrollment: 104 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Study to assess the efficacy and safety of a multiple dose regimen and a single dose regimen of intranasal Neumifil, administered prior to challenge with Influenza virus in healthy adult participants

Detailed description:
This is a single-centre, randomized, double-blind, placebo-controlled study in healthy adult participants to assess the pre-exposure prophylactic antiviral activity of Neumifil via a human viral challenge model.

Participants will enter the quarantine unit on Day -4.

Participants will be randomized to receive either active (single dose), active (multiple dose) or placebo in a 3:3:4 ratio followed by influenza viral challenge on Day 0.

Participants will leave the unit on Day 8, provided that no virus is detected by a qualitative virus antigen test and the participant has no clinically significant symptoms. A final follow-up will be performed on Day 28.

Arms: arm 1: Neumifil intranasal spray administered as 3 single daily doses prior to viral challenge arm 2: Neumifil intranasal spray administered as a single dose and blinded by placebo administered as two single daily doses. All administrations completed prior to viral challenge arm 3: Intranasal spray administered as 3 single daily doses prior to viral challenge
Interventions: intervention 1: Neumifil intervention 2: Placebo
Intervention descriptions: intervention 1: Liquid for intranasal spray administration intervention 2: Liquid for intranasal spray administration

Protocol documents:
Prot_SAP_000.pdf: 
Protocol number: 
/PNG-NMF-201 
 
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CLINICAL STUDY PROTOCOL 
A Randomised, Double-blind, Placebo-controlled, Phase 2 Study to Assess the Safety, 
Tolerability, and Prophylactic Antiviral Activity against Influenza of Neumifil via a Human Viral 
Challenge Model in Healthy Adult Participants 
 
Short Title: 
Phase 2 study of the prophylactic antiviral activity of 
Neumifil in an influenza challenge model in healthy 
adult participants 
Version and Date of Protocol: 
Final Version 3.0, 12Feb2023 
Sponsor: 
Pneumagen Limited 
Kinburn Castle, 
Doubledykes Road, St. Andrews, Fife, 
Scotland, KY16 9DR 
Sponsor Protocol Number: 
PNG-NMF-201 
hVIVO Protocol Number: 
 
Compound: 
Neumifil 
EudraCT Number: 
2022-001853-22 
 
Confidentiality and Protections Statement: 
This document contains confidential information of hVIVO and Pneumagen Limited. This document 
must not be disclosed to anyone other than the study staff and members of the Independent Ethics 
Committee/Institutional Review Board or Competent Authorities. The information in this document 
cannot be used for any purpose other than the conduct or evaluation of the clinical investigation without 
the prior written consent of hVIVO and Pneumagen Limited. 
Personal data included in the protocol is subject to General Data Protection Regulation (European 
Union 2016/679) considerations and protections. 
 
 


Protocol number: 
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Sponsor Statement 
 
This protocol was subjected to critical review. The information it contains is consistent with current 
knowledge of the risks and benefits of the study intervention, and with the moral, ethical, and scientific 
principles governing clinical research as set out in the current Declaration of Helsinki and the principles 
of International Council for Harmonisation (ICH) Good Clinical Practice (GCP). 
 
Sponsor Signatory: 
 
 
 
 
Douglas Thomson 
Sponsor Representative, Pneumagen Limited 
 
Date 
(DD MMM YYYY) 
 
 
 
 
 
Geoff Kitson 
Sponsor’s Medical Expert 
 
Date 
(DD MMM YYYY) 
 
 
 
 


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Investigator Agreement: 
I have read the protocol and agree to conduct the study in accordance with the approved protocol and 
any future amendments, the Declaration of Helsinki, the principles of ICH GCP, the current regulatory 
requirements as detailed in the Medicines for Human Use (Clinical Trial) Regulations (Statutory 
Instrument 2004/1031) and all subsequent amendments, the United Kingdom (UK) Data Protection Act 
2018, any other applicable laws, and guidance. 
I agree to conduct the procedures described in this protocol according to these guidelines and to 
appropriately direct and assist the study staff under my control. 
 
Principal Investigator Signatory: 
Name (typed or printed): 
 
 
 
Signature: 
 
Date: 
 
 
 
 
(DD MMM YYYY) 
 
 
 
 
 
Note: In this protocol, the terms hVIVO and ‘investigator’ distinguish between the principal investigator’s 
(PI’s) responsibility, and actions required by the organisation (hVIVO). The term ‘investigator’ includes 
appropriately qualified persons to whom the PI has formally delegated his/her investigator roles and 
responsibilities. 
 
 




Protocol number: 
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Table of Contents 
Table of Contents .................................................................................................................................... 5 
List of Tables ........................................................................................................................................... 8 
List of Figures .......................................................................................................................................... 8 
1. 
Protocol Synopsis ...................................................................................................................... 9 
1.1. 
Study Schematic: On-study Participant Progression ............................................................. 18 
1.2. 
Schedule of Events ................................................................................................................ 19 
2. 
Introduction ............................................................................................................................... 26 
2.1. 
Background ............................................................................................................................ 26 
2.1.1. 
Influenza ........................................................................................................................... 26 
2.1.2. 
Neumifil ............................................................................................................................. 27 
2.1.2.1. 
Nonclinical Studies ...................................................................................................... 28 
2.1.2.2. 
Clinical Studies ............................................................................................................ 30 
2.2. 
Study Rationale ..................................................................................................................... 30 
2.3. 
Benefit/Risk Assessment ....................................................................................................... 31 
2.3.1. 
Risk Assessment .............................................................................................................. 31 
2.3.1.1. 
Vulnerable Persons ..................................................................................................... 35 
2.3.1.2. 
Risk Associated with Coronavirus Disease 2019 Pandemic ....................................... 35 
2.3.2. 
Benefit Assessment .......................................................................................................... 36 
2.3.3. 
Overall Benefit: Risk Conclusion ...................................................................................... 36 
3. 
Objectives and Endpoints ........................................................................................................ 37 
4. 
Study Design ............................................................................................................................. 42 
4.1. 
Overall Design ....................................................................................................................... 42 
4.2. 
Scientific Rationale for Study Design .................................................................................... 43 
4.3. 
Justification for Dose ............................................................................................................. 43 
4.4. 
Population to be Studied........................................................................................................ 44 
4.5. 
Rationale for Trial Endpoints ................................................................................................. 44 
4.6. 
End of Study Definition .......................................................................................................... 44 
5. 
Study Population ...................................................................................................................... 45 
5.1. 
Inclusion Criteria .................................................................................................................... 45 
5.2. 
Exclusion Criteria ................................................................................................................... 47 
5.3. 
Lifestyle Considerations......................................................................................................... 50 
5.3.1. 
Meals and Dietary Restrictions ......................................................................................... 50 
5.3.2. 
Caffeine, Alcohol, and Tobacco ........................................................................................ 50 
5.3.3. 
Activity .............................................................................................................................. 50 
5.3.4. 
Other Restrictions ............................................................................................................. 50 
5.4. 
Screen Failures ...................................................................................................................... 51 
6. 
Study Intervention .................................................................................................................... 52 
6.1. 
Study Intervention(s) Administered ....................................................................................... 52 
6.2. 
Preparation/Handling/Storage/Accountability ........................................................................ 53 
6.2.1. 
Investigational Product ..................................................................................................... 53 
6.2.2. 
Challenge Agent ............................................................................................................... 54 
6.2.3. 
All Study Interventions ...................................................................................................... 54 
6.3. 
Randomisation and Blinding .................................................................................................. 55 
6.4. 
Study Intervention Compliance .............................................................................................. 56 
6.5. 
Concomitant Therapy ............................................................................................................ 56 
6.6. 
Dose Modification .................................................................................................................. 58 
6.7. 
Treatment of Overdose .......................................................................................................... 58 
7. 
Discontinuation of Study Intervention/Withdrawal ............................................................... 59 


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7.1. 
Participant Withdrawal ........................................................................................................... 59 
7.2. 
Participant Discontinuation .................................................................................................... 59 
7.2.1. 
Temporary Discontinuation/Temporary Delay in Enrolment ............................................ 60 
7.3. 
Lost to Follow-up ................................................................................................................... 60 
7.4. 
Participant Replacement Strategy ......................................................................................... 60 
7.5. 
Stopping Rules ...................................................................................................................... 60 
7.6. 
Features ................................................................................................................................. 61 
8. 
Study Assessments and Procedures ..................................................................................... 63 
8.1. 
Demographics and Baseline Characteristics ......................................................................... 63 
8.1.1. 
Demographics ................................................................................................................... 63 
8.1.2. 
Height, Body Weight, and Body Mass Index .................................................................... 63 
8.1.3. 
Medical and Medication History ........................................................................................ 63 
8.1.4. 
Challenge Agent Serology Samples ................................................................................. 64 
8.1.5. 
Patient Health Questionnaire-9 (PHQ-9) and Generalised Anxiety Disorder-7 (GAD-7) 
Questionnaire ................................................................................................................... 64 
8.2. 
Respiratory Samples ............................................................................................................. 64 
8.2.1. 
Nasosorption ..................................................................................................................... 64 
8.2.2. 
Nasopharyngeal Swab ..................................................................................................... 64 
8.2.2.1. 
Respiratory Pathogen Screen ..................................................................................... 65 
8.2.2.2. 
Influenza Discharge Test/Rapid Viral Antigen Test ..................................................... 65 
8.2.3. 
Viral Sequencing............................................................................................................... 65 
8.3. 
Efficacy Assessments ............................................................................................................ 65 
8.3.1. 
Viral Shedding/Load Assessment..................................................................................... 65 
8.3.2. 
Participant Diary Cards ..................................................................................................... 65 
8.3.3. 
Nasal Discharge Collection from Paper Tissues .............................................................. 67 
8.3.4. 
Exploratory Assessments ................................................................................................. 67 
8.4. 
Safety Assessments .............................................................................................................. 67 
8.4.1. 
Complete Physical Examination ....................................................................................... 67 
8.4.2. 
Symptom-directed Physical Examination ......................................................................... 67 
8.4.3. 
Vital Signs and Tympanic Temperature ........................................................................... 67 
8.4.4. 
Electrocardiogram............................................................................................................. 68 
8.4.5. 
Clinical Safety Laboratory Assessments .......................................................................... 69 
8.4.5.1. 
Urinalysis ..................................................................................................................... 69 
8.4.5.2. 
Drugs of Misuse and Cotinine ..................................................................................... 69 
8.4.5.3. 
Alcohol Breath Testing ................................................................................................ 69 
8.4.5.4. 
Safety Blood Analysis and Assessments .................................................................... 69 
8.4.6. 
Pregnancy Tests and Follicle-stimulating Hormone ......................................................... 69 
8.4.7. 
Lung Function ................................................................................................................... 70 
8.5. 
Recording of Adverse Events/Serious Adverse Events ........................................................ 70 
8.5.1. 
Time Period and Frequency for Collecting Adverse Event and Serious Adverse Event 
Information ........................................................................................................................ 70 
8.5.2. 
Method of Detecting Adverse Events/Serious Adverse Events ....................................... 71 
8.5.3. 
Follow-up of Adverse Events/Serious Adverse Events .................................................... 71 
8.5.4. 
Regulatory Reporting Requirements for Serious Adverse Events ................................... 71 
8.5.5. 
Pregnancy ......................................................................................................................... 71 
8.6. 
Bioanalysis/Pharmacokinetics ............................................................................................... 72 
8.6.1. 
Pharmacokinetic Blood Samples ...................................................................................... 72 
8.6.2. 
Pharmacokinetic Parameters ........................................................................................... 72 
8.6.3. 
Anti-drug Antibodies ......................................................................................................... 73 
8.7. 
Pharmacodynamics ............................................................................................................... 73 
8.8. 
Immunogenicity Assessments ............................................................................................... 73 
8.9. 
Genetics ................................................................................................................................. 73 
8.10. 
Biomarkers ............................................................................................................................. 73 


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8.10.1. 
Immunology Biomarker Evaluations ................................................................................. 73 
9. 
Statistical Considerations ........................................................................................................ 75 
9.1. 
Statistical Hypothesis ............................................................................................................. 75 
9.2. 
Sample Size Determination ................................................................................................... 75 
9.3. 
Populations for Analyses ....................................................................................................... 76 
9.4. 
Statistical Analyses ................................................................................................................ 77 
9.4.1. 
Statistical Analysis Plan .................................................................................................... 77 
9.4.2. 
General Considerations .................................................................................................... 77 
9.4.2.1. 
Descriptive Statistics ................................................................................................... 77 
9.4.2.2. 
Inferential Statistics and Significance Testing ............................................................. 77 
9.4.3. 
Planned Analysis .............................................................................................................. 78 
9.4.3.1. 
Participant Accountability ............................................................................................ 78 
9.4.3.2. 
Protocol Deviations...................................................................................................... 78 
9.4.3.3. 
Demographic and Baseline Characteristics ................................................................ 78 
9.4.3.4. 
Compliance to Study Intervention ............................................................................... 78 
9.4.4. 
Primary Efficacy Analysis ................................................................................................. 78 
9.4.5. 
Secondary Efficacy Analysis ............................................................................................ 79 
9.4.6. 
Tertiary/Exploratory Analysis ............................................................................................ 81 
9.4.7. 
Safety Analyses ................................................................................................................ 81 
9.4.8. 
Bioanalysis/Plasma Concentrations ................................................................................. 81 
9.5. 
Interim Analysis ..................................................................................................................... 82 
9.6. 
Data Monitoring Committee ................................................................................................... 82 
10. 
Supporting Documentation and Operational Considerations.............................................. 83 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations ................................ 83 
10.1.1. 
Regulatory and Ethical Considerations ............................................................................ 83 
10.1.2. 
Financial Disclosure ......................................................................................................... 83 
10.1.3. 
Confidentiality ................................................................................................................... 83 
10.1.4. 
Informed Consent Process ............................................................................................... 84 
10.1.5. 
Data Protection ................................................................................................................. 84 
10.1.6. 
Committee(s) Structure .................................................................................................... 85 
10.1.7. 
Dissemination of Clinical Study Data ............................................................................... 85 
10.1.8. 
Data Quality Assurance .................................................................................................... 85 
10.1.9. 
Source Documents ........................................................................................................... 86 
10.1.10. 
Study Discontinuation ....................................................................................................... 86 
10.1.11. 
Publication Policy.............................................................................................................. 86 
10.2. 
Appendix 2: Clinical Laboratory Tests ................................................................................... 87 
10.3. 
Appendix 3: Adverse Events: Definitions and Procedures for Recording, Evaluating, Follow-
up, and Reporting .................................................................................................................. 89 
10.3.1. 
Adverse Event .................................................................................................................. 89 
10.3.2. 
Adverse Drug Reaction .................................................................................................... 90 
10.3.3. 
Unexpected Adverse (Drug) Reaction .............................................................................. 91 
10.3.4. 
Serious Adverse Event ..................................................................................................... 91 
10.3.5. 
Suspected Unexpected Serious Adverse Reaction.......................................................... 92 
10.3.6. 
Recording, Assessment, and Follow-up of Adverse Events/Serious Adverse Events ..... 92 
10.3.6.1. 
Adverse Event/Serious Adverse Event Recording ...................................................... 92 
10.3.6.2. 
Assessment ................................................................................................................. 93 
10.3.6.3. 
Assessment of Intensity .............................................................................................. 95 
10.3.6.4. 
Frequency .................................................................................................................... 96 
10.3.6.5. 
Assessment of Causality ............................................................................................. 96 
10.3.6.6. 
Action Taken ................................................................................................................ 97 
10.3.6.7. 
Outcome ...................................................................................................................... 98 
10.3.6.8. 
Follow-up ..................................................................................................................... 98 


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10.3.7. 
Reporting of Serious Adverse Events .............................................................................. 99 
10.3.8. 
Reporting of Suspected Unexpected Serious Adverse Reaction ................................... 100 
10.3.9. 
Adverse Reactions to Non-investigational Medicinal Products ...................................... 100 
10.3.10. 
Post-study Adverse Events and Serious Adverse Events .............................................. 100 
10.3.11. 
Pregnancy ....................................................................................................................... 101 
10.4. 
Appendix 4: Normal Ranges ................................................................................................ 102 
10.5. 
Appendix 5: Genetics ........................................................................................................... 103 
10.6. 
Appendix 6: Abbreviations ................................................................................................... 104 
10.7. 
Appendix 7: Definitions ........................................................................................................ 106 
10.7.1. 
General ........................................................................................................................... 106 
10.7.2. 
Study Definition of Infection and Illness ......................................................................... 107 
10.7.3. 
Study Definition of a Postmenopausal Woman .............................................................. 108 
10.8. 
Appendix 8: Protocol Amendment History ........................................................................... 109 
11. 
References ............................................................................................................................... 110 
 
List of Tables 
Table 2-1: 
Risk Assessment .............................................................................................................. 32 
Table 6-1: 
Study Interventions ........................................................................................................... 52 
Table 6-2: 
Prohibited Medication ....................................................................................................... 56 
Table 6-3: 
Permitted Medication ........................................................................................................ 57 
Table 7-1: 
Study Stopping Rules ....................................................................................................... 61 
Table 7-2: 
Features ............................................................................................................................ 62 
Table 9-1: 
Study Populations ............................................................................................................. 76 
Table 9-2: 
Methods for Analysis of Secondary Efficacy Endpoints ................................................... 79 
Table 10-1: 
Protocol-required Safety Laboratory Assessments ..................................................... 87 
Table 10-2: 
Classification of Adverse Events Severity ................................................................... 96 
Table 10-3: 
Classification of Adverse Events Relationship ............................................................ 97 
Table 10-4: 
Classification of Adverse Events Outcome ................................................................. 98 
Table 10-5: 
Contact Details for Reporting All Serious Adverse Events.......................................... 99 
 List of Figures 
Figure 1-1: 
HEX17 hexavalent structure ........................................................................................ 27 
Figure 1-2: 
Modifications made in the construction of HEX17 from parent CBM Sp2CBMTD ...... 28 
 
 


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1. 
Protocol Synopsis 
Protocol title 
A randomised, double-blind, placebo-controlled, Phase 2 study to 
assess the safety, tolerability, and prophylactic antiviral activity against 
influenza of Neumifil via a human viral challenge model in healthy adult 
participants. 
Short title 
Phase 2 study of the prophylactic antiviral activity of Neumifil in an 
influenza challenge model in healthy adult participants 
Protocol number 
 (PNG-NMF-201) 
Sponsor 
Pneumagen Limited 
Clinical phase 
2 
Study site(s) 
hVIVO Services Limited, 
Queen Mary BioEnterprises Innovation Centre, 
42 New Road, London, E1 2AX, United Kingdom (UK) 
hVIVO Services Limited 
The Whitechapel Clinic (formerly The Whitechapel Hotel) 
43-53 New Road, London, E1 1HH, United Kingdom (UK) 
Study type 
Interventional 
Indication 
Prevention of seasonal and pandemic influenza 
Design 
This is a proof-of-concept study to assess the efficacy and safety of a 
multiple dosing regimen (once daily for 3 days) and of a single dose of 
intranasal Neumifil, administered to healthy adults, initiated prior to being 
challenged with influenza A/Perth/16/2009 (H3N2) virus 
Objectives and endpoints 
 
Objective(s) 
Related Endpoints/Outcome Measure(s) 
Primary: 
Efficacy 
To evaluate the effect of 
Neumifil in 1) reducing the 
incidence of symptomatic 
influenza infection and/or 
2) reducing the severity of 
symptoms after influenza 
viral challenge, compared 
to placebo. 
The study has 2 primary endpoints: 
1) Reducing the incidence of symptomatic 
influenza infection: 
• 
Reverse transcriptase polymerase chain 
reaction 
(RT-PCR)-confirmed 
symptomatic influenza infection, defined 
as: 
o 
RT-PCR-confirmed 
influenza 
infection defined as 2 detectable (≥ 
lower limit of detection [LLOD]) RT-
PCR measurements (reported on 2 or 
more independent nasal samples 


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over 2 days), starting from Day 1 (pm) 
up 
to 
planned 
discharge 
from 
quarantine (Day 8, am), 
AND 
o 
Any symptoms of grade ≥2 at a single 
time point. 
2) Reducing the severity of symptoms: 
• 
Peak symptoms diary card score: peak 
total symptoms score (TSS) as measured 
by graded symptom scoring system 
collected 3 times daily, starting from 
Day 1 (am) up to planned discharge from 
quarantine (Day 8, am). 
Secondary: 
Efficacy 
To evaluate the effect of 
Neumifil 
in 
reducing 
clinical symptoms due to 
influenza viral challenge, 
compared to placebo. 
• 
Area under the curve over time of total 
symptoms 
score 
(TSS-AUC) 
as 
measured by graded symptom scoring 
system collected 3 times daily, starting 
from Day 1 (am) up to planned discharge 
from quarantine (Day 8, am). 
• 
Peak daily symptom score: individual 
maximum daily sum of symptom score, 
starting from Day 1 (am) up to planned 
discharge from quarantine (Day 8, am). 
• 
Number (%) of participants with grade 2 
or higher symptoms, starting from Day 1 
(am) up to planned discharge from 
quarantine (Day 8, am). 
• 
Duration of clinical symptoms: 1) any 
symptoms, 2) TSS of 2 or more (with at 
least 2 systems), and 3) grade 2 or higher 
symptoms, starting from Day 1 (am) up to 
planned 
discharge 
from 
quarantine 
(Day 8, am). 
• 
Time to resolution from peak clinical 
symptoms as measured by graded 
symptom 
scoring 
system 
collected 
3 times daily. Time to resolution is defined 
as the time (hours) from peak clinical 
symptoms until first time with TSS = 0 
after which no further increase above 0 is 
observed. 
To evaluate the effect of 
Neumifil in reducing or 
shortening viral shedding 
after 
influenza 
viral 
challenge, compared to 
placebo. 
• 
Area under the viral load-time curve 
(VL-AUC) of influenza challenge virus as 
determined by quantitative RT-PCR (qRT-
PCR) on nasal samples, starting from 
Day 1 (pm) up to planned discharge from 
quarantine (Day 8, am). 
• 
VL-AUC of influenza challenge virus as 
determined by tissue culture on nasal 
samples, starting from Day 1 (pm) up to 


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planned 
discharge 
from 
quarantine 
(Day 8, am). 
• 
Peak viral load (VLPEAK) of influenza as 
defined by the maximum viral load 
determined by qRT-PCR measurements 
in nasal samples, starting from Day 1 
(pm) up to planned discharge from 
quarantine (Day 8, am). 
• 
VLPEAK as defined by the maximum viral 
load determined by quantitative viral 
culture measurements in nasal samples, 
starting from Day 1 (pm) up to planned 
discharge from quarantine (Day 8, am). 
• 
Duration 
of 
quantifiable 
influenza, 
assessed by qRT-PCR measurements in 
nasal samples, starting from Day 1 (pm) 
up to planned discharge from quarantine 
(Day 8, am). Duration is defined as the 
time (hours) from first quantifiable until 
first confirmed unquantifiable assessment 
after their peak measure (after which no 
further virus is quantified). 
• 
Duration 
of 
detectable 
influenza, 
assessed by qRT-PCR measurements in 
nasal samples, starting from Day 1 (pm) 
up to planned discharge from quarantine 
(Day 8, am). Duration is defined as the 
time (hours) from first detectable until first 
confirmed undetectable assessment after 
their peak measure (after which no further 
virus is detected). 
• 
Duration of quantifiable influenza viral 
culture measurements in nasal samples, 
starting from Day 1 (pm) up to planned 
discharge from quarantine (Day 8, am). 
Duration is defined as the time (hours) 
from first quantifiable until first confirmed 
unquantifiable assessment after their 
peak measure (after which no further virus 
is quantified). 
• 
Duration of detectable influenza viral 
culture measurements in nasal samples, 
starting from Day 1 (pm) up to planned 
discharge from quarantine (Day 8, am). 
Duration is defined as the time (hours) 
from first detectable until first confirmed 
undetectable assessment after their peak 
measure (after which no further virus is 
detected). 
• 
Time to resolution from VLPEAK as 
defined by the maximum viral load 
determined by qRT-PCR measurements 
in nasal samples. Time to resolution is 
defined as the time (hours) from VLPEAK 
until 
first 
confirmed 
undetectable 


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assessment (after which no further virus is 
detected). 
• 
Time to resolution from VLPEAK as 
defined by the maximum viral load 
determined by qRT-PCR measurements 
in nasal samples. Time to resolution is 
defined as the time (hours) from VLPEAK 
until 
first 
confirmed 
unquantifiable 
assessment (after which no further virus is 
quantified). 
• 
Time to resolution from VLPEAK as 
defined by the maximum viral load 
determined by viral culture measurements 
in nasal samples. Time to resolution is 
defined as the time (hours) from VLPEAK 
until 
first 
confirmed 
undetectable 
assessment (after which no further virus is 
detected). 
• 
Time to resolution from VLPEAK as 
defined by the maximum viral load 
determined by viral culture measurements 
in nasal samples. Time to resolution is 
defined as the time (hours) from VLPEAK 
until 
first 
confirmed 
unquantifiable 
assessment (after which no further virus is 
quantified). 
To evaluate the effect of 
Neumifil in reducing nasal 
discharge, compared to 
placebo. 
• 
Total weight of mucus produced, starting 
from Day 1 (am) up to planned discharge 
from quarantine (Day 8, am). 
• 
Total 
number 
of 
tissues 
used 
by 
participants, starting from Day 1 (am) up 
to planned discharge from quarantine 
(Day 8, am). 
To evaluate the effect of 
Neumifil in reducing the 
incidence 
of 
influenza 
infection due to influenza 
viral challenge, compared 
to placebo. 
• 
RT-PCR-confirmed influenza infection, 
defined as 2 quantifiable (≥ lower limit of 
quantification 
[LLOQ]) 
qRT-PCR 
measurements (reported on 2 or more 
independent nasal samples over 2 days), 
starting from Day 1 (pm) up to planned 
discharge from quarantine (Day 8, am). 
• 
Occurrence 
of 
at 
least 
1 
positive 
quantitative 
(≥ LLOQ) 
cell 
culture 
measurement in nasal samples, starting 
from Day 1 (pm) up to planned discharge 
from quarantine (Day 8, am).  
• 
Culture 
lab-confirmed 
symptomatic 
influenza infection, defined as: 
o 
Lab-confirmed culturable influenza 
infection (1 quantifiable [≥ LLOQ] cell 
culture measurement, starting from 
Day 1 [pm] up to planned discharge 
from quarantine [Day 8, am]), 


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AND 
o 
Any symptoms of grade ≥2 at a single 
time point.  
Further sensitivity analysis may be performed 
on the above qRT-PCR-related endpoints 
where detection by qRT-PCR is reported 
above the LLOD instead of the LLOQ and/or 
using other definitions for the symptomatic 
component. Details will be provided in the 
statistical analysis plan (SAP). 
• 
Number (%) of participants with lab-
confirmed infection and fever (≥37.9°C). 
Safety 
To evaluate the safety of 
intranasal 
doses 
of 
Neumifil, 
compared 
to 
placebo. 
• 
Occurrence of adverse events (AEs) 
(solicited and unsolicited) up to the 
Day 28 (±3 days) follow-up visit, including 
any serious adverse events (SAEs). 
• 
Occurrence of unsolicited AEs of special 
interest (AESIs) up to the Day 28 
(±3 days) follow-up visit. AESIs are: 
clinically significant reduction in forced 
expiratory volume in 1 second (FEV1) and 
forced vital capacity (FVC). 
To monitor the safety of 
the challenge virus. 
• 
Occurrence of unsolicited AEs related to 
virus challenge from Day 0 up to planned 
discharge from quarantine (Day 8, am). 
• 
Occurrence of unsolicited SAEs related to 
virus challenge from Day 0 up to planned 
discharge from quarantine (Day 8, am). 
• 
Use of concomitant medications from 
Day 0 up to the Day 28 (±3 days) follow-
up visit. 
Tertiary / 
Exploratory*: 
To 
explore 
Neumifil 
concentrations in blood 
(single 
and 
multiple 
doses). 
Neumifil concentrations will be explored in 
blood. 
To 
evaluate 
antibody 
(immunoglobulin [Ig] A 
[IgA] 
and 
G 
[IgG]) 
development in Neumifil-
treated 
participants 
(single 
and 
multiple 
doses), 
compared 
to 
placebo. 
Development of antibodies (IgA, IgG) against 
the virus will be evaluated in serum samples. 


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To evaluate antibody (IgA 
and IgG) response to the 
virus. 
Anti-drug 
antibody 
(ADA) 
(IgA, 
IgG) 
development will be evaluated in serum 
samples. 
To evaluate cytokine and 
chemokine responses in 
nasal 
samples 
in 
Neumifil-treated 
participants (single and 
multiple 
doses), 
compared to placebo. 
Cytokines and chemokines will be assayed in 
nasal samples. 
* Note that tertiary/exploratory objectives and endpoints are optional and might be assessed only if 
needed; therefore, not all testing might be performed and reported. 
Hypothesis 
The primary statistical hypothesis is that prophylactic treatment with 
Neumifil will significantly reduce the incidence and/or the severity of 
symptomatic influenza infection after influenza viral challenge when 
compared to placebo. 
Investigational medicinal 
product (IMP) 
• 
Neumifil, liquid for intranasal spray administration (active) 
• 
Liquid for intranasal spray administration (placebo) 
Challenge agent 
Influenza A/Perth/16/2009 (H3N2) virus 
Challenge agent route 
Intranasally, 
 
Challenge agent titre 
~105.5 tissue culture infective dose (50%) (TCID50) 
Study population 
Healthy adult male or female participants aged between 18 and 55 years 
old, inclusive, with a total body weight ≥50 kg and body mass index (BMI) 
≥18 kg/m2 and ≤35kg/m2, who have been determined to be serosuitable 
with regard to pre-existing antibody levels to the influenza challenge 
virus. 
Summary of study design 
This is a single-centre, randomised, double-blind, placebo-controlled, 
proof-of-concept Phase 2 study in healthy adult male or female 
participants aged between 18 and 55 years old, inclusive. The primary 
goal of this Phase 2 study is to assess the pre-exposure prophylactic 
antiviral activity against influenza, safety, and tolerability of Neumifil via 
a human viral challenge model.  
Each participant will receive one of 3 treatments: 
• 
Neumifil once daily for 3 days on Days -3 to -1 (multiple dose active 
treatment). 
• 
A single dose of Neumifil on Day -3 and placebo once daily on 
Days -2 and -1 (single dose active treatment). 
• 
Placebo once daily for 3 days on Days -3 to -1. 


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A total of up to 100 evaluable participants is planned to be enrolled in 
this study: 30 participants on multiple dose active treatment, 30 
participants on single dose active treatment, and 40 participants on 
placebo. 
The study is divided into the following phases: 
Screening phase: 
From Day -93 to Day -5 (prior to quarantine admission). Historical 
generic screening data collected through the hVIVO generic screening 
process may be transferred to this study after the study-specific consent 
form has been signed by the participant. 
Inpatient phase: 
Participants will be resident in the quarantine unit for approximately 
13 days (from Day -4 to Day 8). Procedures will include: 
• 
Pre-human viral challenge: 
o 
Admission to quarantine unit on Day -4. 
o 
Baseline assessments and randomisation will be 
conducted as per Schedule of Events (SoE) up to Day -3, 
predose. 
o 
Administration of Neumifil and/or placebo once daily on  
Days -3 to -1, according to randomisation. 
• 
Human viral challenge: 
o 
Influenza virus inoculation on Day 0. 
• 
Post-human viral challenge: 
o 
Day 1 onwards and each day – study assessments will be 
conducted as per SoE. 
o 
Discharge from the quarantine unit on Day 8 (participants 
may remain longer, at the principal investigator’s [PI’s] 
discretion, if they are still shedding the influenza 
A/Perth/16/2009 (H3N2) virus challenge strain or have 
symptoms of influenza). 
Outpatient phase: 
• 
Final follow-up visit: Day 28 (±3 days). 
Study assessments will be conducted as per SoE. 
Randomisation 
3:3:4 to Neumifil multiple dose active treatment, Neumifil single dose 
active treatment, or placebo 
Participant replacement 
strategy 
Participants may be replaced in this study. 
 
 
 
 


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Expected duration of 
participation per 
participant 
Approximately 4 months from screening to the participant’s last 
scheduled visit. 
Overall duration of 
clinical phase 
The length of the clinical phase is expected to be approximately 
7 months from the first participants planned first study visit (screening 
visit) to the last participants last scheduled study visit. 
End of study 
The end of the study is defined as the date of the last visit of the last 
participant in the study. 
Sample size 
determination 
The number of 40 participants in the placebo arm and 60 (30 in each 
dose arm) in the pooled Neumifil group selected for this study will provide 
a power of at least 80% to detect a significant reduction in the primary 
endpoints: 
• 
of 70% compared to the placebo arm in symptomatic influenza 
infection rate, assuming a symptomatic infection rate of 27.8% 
in the placebo arm,  
• 
of 65% compared to the placebo arm in peak TSS, assuming a 
coefficient of variation (CV) of 125%, 
using a 1-sided 0.05 type-one error rate for each of the 2 comparisons, 
without adjustment for multiple testing.  
The table below summarises the power achieved with 40 versus 
60 participants (for the placebo and pooled active treatment arms, 
respectively) for the 2 primary endpoints and some secondary 
endpoints. 
Endpoint 
Assumption 
(placebo arm) 
Relative 
reduction 
Power (*) 
Symptomatic infection 
rate 
rate=27.8% 
70% 
81.5% 
Peak TSS 
CV=125% 
65% 
81.2% 
VL-AUC 
CV=91% 
50% 
84.8% 
VLPEAK 
CV=63.5 
40% 
92.2% 
TSS-AUC 
CV=155% 
80% 
80.7% 
(*) Power achieved with placebo and 60 Neumifil participants  
(alpha 0.05 1-sided). 
CV = coefficient of variation. 


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Statistics 
Primary Efficacy Analysis 
The primary efficacy analysis will be conducted on the per protocol (PP) 
analysis set. 
The PP analysis set will consist of all participants randomised, having 
received the planned dose of IMP (Neumifil 3 doses on Days -3 to -1, or 
1 single dose of Neumifil on Day -3 followed by 2 doses of placebo on 
Days -2 and -1, or placebo 3 doses on Days -3 to -1, according to 
randomisation) and challenged with the study virus, who complete the 
quarantine period up to its planned final day (Day 8) and present no 
major deviation likely to impact the evaluation of the primary efficacy 
endpoint. 
For the symptomatic infection rate, the estimator with its 2-sided 90% 
and 95% confidence intervals (CIs) will be presented by treatment arm. 
The differences between the pooled active treatment arms and the 
placebo arm, and between each active treatment dose arm and the 
placebo arm, will be computed with their 2-sided 90% and 95% CIs. The 
3 pairwise comparisons will use the Pearson Chi-square test, or the 
Fisher exact test if the assumptions for the Chi-square test are not met. 
Each test will use a nominal 1-sided type-one error of 0.05 without 
adjustment for multiplicity. In addition, the difference between the 
2 Neumifil dose arms will be computed with its 90% and 95% CIs but no 
formal statistical test will be computed. 
For the peak TSS, the mean and median and the 2-sided 90% and 95% 
CIs for the mean will be presented by treatment arm. The differences 
between the pooled active treatment arms and the placebo arm, and 
between each active treatment dose arm and the placebo arm, will be 
computed with their 2-sided 90% and 95% CIs. The 3 pairwise 
comparisons will use the Wilcoxon rank-sum test. Each test will use a 
nominal 1-sided type-one error of 0.05 without adjustment for multiplicity. 
In addition, the difference between the 2 Neumifil dose arms will be 
computed with its 90% and 95% CIs but no formal statistical test will be 
computed. 
Further details on the primary efficacy analysis, secondary efficacy 
analyses, and safety analyses will be provided in the SAP. 
 
 












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KEY NOTES FOR TIME AND EVENTS SCHEDULE 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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2. 
Introduction 
Neumifil™ is a first-in-class carbohydrate binding module (CBM) 40 and is being developed for the universal 
treatment of influenza virus, respiratory syncytial virus (RSV), human rhinovirus, and Coronavirus 
Disease 2019 (COVID19). 
2.1. 
Background 
2.1.1. 
Influenza 
Influenza viruses are associated with significant human disease and cause annual epidemics during 
autumn and winter. Although most people recover within 1 to 2 weeks without requiring medical attention, 
seasonal influenza yearly results in approximately 3 to 5 million cases of severe illness and up to 
500,000 deaths worldwide, particularly among the very young, elderly, and chronically ill. Influenza caused 
an estimated yearly average of 23,600 deaths between seasons 1976 and 2007 and more than 
200,000 hospitalisations in the United States. Comparable mortality and morbidity rates have been reported 
for European countries. Currently, the influenza type A viruses H1N1 and H3N2 are circulating in humans, 
along with influenza type B viruses. H3N2 viruses have been predominant in most seasons and have 
caused a higher number of deaths and hospitalisations than H1N1 and influenza B viruses (Nunes et al, 
2011; Thompson et al, 2004; Zucs et al, 2005). 
The neuraminidase inhibitors zanamivir and oseltamivir are currently recommended for the treatment and/or 
(post-exposure) prophylaxis of influenza A and B virus infections (Weinstock and Zuccotti, 2009; Fiore et 
al, 2011). However, new drugs are now required as there have been reports of the emergence of resistance 
after oseltamivir treatment (Dharan et al, 2009; Poland et al, 2009; Stephenson et al, 2009), and the 
increasing use of zanamivir monotherapy may lead to the development of zanamivir resistance. Xocluza 
(baloxavir marboxil) was subsequently developed and is available in several countries for treatment and 
post-exposure prophylaxis for influenza A and B. However, there remains a need to develop better vaccines 
(demonstrating high efficacy, with longer or broader protection, or with faster manufacturing) as well as 
additional antivirals and immunomodulators to manage infection, transmission, and disease. 
Progress towards a medicinal agent that provides protection against a broad range of influenza strains with 
a longer duration of protection, otherwise known as a “universal vaccine”, has been disappointing. The 
monoclonal antibody therapeutics developed to date have suffered from limited spectrum and commercial 
limitations due to high dosing requirements and/or the need for multiple antibody cocktails to achieve a 
desired spectrum and efficacy. Thus, a significant unmet need exists for long-acting universal protective 
agents. 
The influenza human challenge model was established to not only aid understanding of influenza disease 
and transmission, but to also assess the efficacy of antivirals, immunomodulators, and vaccines (as 
reviewed by Lambkin-Williams et al, 2018; Yogaratnam et al, 2019; Bueno de Mesquita et al, 2021; Nguyen-
Van-Tam et al, 2020; Ramos-Sevillano et al, 2019). hVIVO has given different influenza strains to over 
1,300 volunteers over the last 20 years. The influenza A/Perth/16/2009 (H3N2) virus challenge strain used 
in the majority of studies to date has been given to over 400 volunteers by hVIVO. The virus has been well 
tolerated with no virus-related serious adverse events (SAEs) occurring in any of the participants inoculated 
to date. Furthermore, the challenge virus has been shown to induce measurable disease profiles with clear 




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CBM = carbohydrate binding module; TD = trimerisation domain. 
Figure 1-2: 
Modifications made in the construction of HEX17 from parent CBM Sp2CBMTD 
2.1.2.1. 
Nonclinical Studies 
2.1.2.1.1. 
In Vitro And In Vivo Pharmacology 
 
 
 
 
 
 
 
 
 
2.1.2.1.2. 
Safety Pharmacology 
A functional observation battery was used to assess neurotoxicity of Neumifil in a 28-day study in rats. 
No neurotoxicity was observed after repeated doses up to 1,040 µg/animal/day, although a slight increase 
in the presence of pinna reflex was seen in both male and female treated animals. In a functional 
observation battery in primates Neumifil had no significant central nervous system effects at repeated doses 
up to 1.65 mg/kg/day for 28 days. 
Cardiovascular safety of Neumifil was tested in a 28-day repeat dose study in Cynomolgus monkeys. 
Animals received repeated doses up to 1.25 mg/kg/day, and there were no changes in electrocardiogram 
(ECG), or in diastolic and systolic blood pressure (SBP, DBP). 
The pharmacology of Neumifil does not suggest any respiratory risk, and no significant lung pathology has 
been noted in efficacy studies in mice and rats, or in dose-finding studies. Specific respiratory observations 
were made during the 28-day repeat dose study in primates. There were no changes in respiratory signs 
(rhinorrhoea, sneezing, coughing, abnormal breath sounds, respiratory rate, and breathing depth). 


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2.1.2.1.3. 
Pharmacokinetics 
The absorption and pharmacokinetics (PK) of Neumifil have been studied after single intravenous and 
intranasal doses in rats. Neumifil 0.5 mg/kg given intravenously yielded a mean maximum observed 
concentration (Cmax) of 1,240 ng/mL, area under the concentration-time curve from time zero to infinity 
(AUC0-∞) of 2,360 ng.h/mL, and a terminal half-life (t1/2) 24.1 hours (range 9.29–46.0 hours). 
Pharmacokinetic parameters could not be calculated after intranasal administration of 4 mg/kg Neumifil, 
because plasma concentrations were above lower limit of quantification (LLOQ: 25.0 ng/mL) in only a single 
sample at 2 hours postdose (plasma concentration 42.8 ng/mL). Bioavailability of intranasal Neumifil was 
therefore considered to be <5%. 
Very low plasma concentrations of Neumifil were detected during the 28-day repeated dose study in rats. 
The paucity of samples with quantifiable concentrations of Neumifil precluded any calculation of PK 
parameters, but systemic exposure was clearly minimal after repeated intranasal administration of doses 
up to 1,040 µg/day. Given the low plasma concentrations of Neumifil after intranasal dosing, its distribution 
has not been studied. 
It is anticipated that intranasal Neumifil (a protein) will be broken down in the nasal mucosa by local 
peptidases to yield oligopeptides and free amino acids. Thus, further investigation of Neumifil metabolism 
is deemed unnecessary. 
2.1.2.1.4. 
Toxicology 
In the rat dose-range finding study, rats received intranasal doses up to 1,000 µg/day for 7 days, and there 
were no treatment-related deaths or significant clinical observations. However, some female rats had a 
slight decrease in body weight gain (average 3%), attributed to decreased food consumption. The maximum 
tolerated dose was 1000 µg/animal/day. 
In the pivotal Good Laboratory Practice (GLP) 28-day repeated dose toxicity study in rats, animals received 
intranasal doses of 520, 780, and 1,040 µg/animal/day, but few samples had plasma Neumifil 
concentrations above LLOQ. The following PK parameters were estimated for Day 28: Cmax 123 ng/mL; 
time to maximum concentration (tmax) 2 hours; and AUC0-∞ 381 ng.h/mL. No animal died, but significant 
weight loss occurred at the 2 highest dose levels (6% in males and 7% in females). That adverse effect 
was reversible after 2 weeks of recovery. Abnormal respiratory sounds (loud breathing and/or respiratory 
crackles) were observed at all dose levels but remitted after dosing was stopped. Mild to moderate 
inflammatory and reactive changes in the nasal mucosa, associated with polymorphonuclear cell infiltration 
and goblet cell proliferation, were found in all treatment groups but were considered adverse only the at the 
mid and top dose levels. Inflammatory changes were noted also in respiratory tissues (larynx, trachea, 
bronchi, and bronchioles) at the 2 highest dose levels of Neumifil, but animals recovered fully after 2 weeks. 
The no observed adverse effect level (NOAEL) in rats after 4 weeks of dosing was 2.5 mg/kg/day. 
In a non-GLP dose-range finding study, Cynomolgus monkeys received doses up to 1.25 mg/kg/day for 
7 days. There were no treatment-related deaths or significant clinical findings. 
Doses of 0.8, 1.20 and 1.65 mg/kg/day were tested in a GLP 28-day repeated dose Cynomolgus monkey 
toxicity study. All plasma concentrations of Neumifil were below LLOQ. There were no deaths and no effects 
related to the test item. Anti-drug antibody (ADA) analysis showed weak seroconversion in 4 animals, but 
ADA titres were similar to those in untreated animals so Neumifil was of low immunogenicity. The NOAEL 
in Cynomolgus monkeys after 28 days of dosing was 1.65 mg/kg/day. 


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2.1.2.1.5. 
Pharmacodynamics 
Doses of up to 100 µg Sp2CBMTD were administered to BALB/c mice to investigate the potential 
mechanism of action of the parent family of HEX17, and its efficacy in preventing and treating infection with 
the influenza virus. Sp2CBMTD was either administered prophylactically to mice that were then challenged 
with a lethal dose of the virus or administered after the viral challenge. As well as promoting animal survival 
(80–100% when administered prophylactically, or 40% after exposure to the virus), cytokine analysis 
revealed that Sp2CBMTD stimulated a proinflammatory response when given as a prophylactic.
 
 
 
 
 
 
2.1.2.2. 
Clinical Studies 
A first-in-human, single ascending and multiple ascending dose study has been conducted, is clinically 
complete, but has not yet been fully analysed. 
 
 No SAEs and no deaths occurred. 
In the single dose groups adverse events (AEs) were related to short-lived nasal irritation, desire to sneeze, 
unpleasant taste, and changes in taste and smell. In the multiple dose groups, the participants reported the 
same effects on nasal irritation and desire to sneeze. Change in taste and smell lasted for up to 4 days. 
Two participants reported short-lived nose bleeds sometime after administration of study intervention and 
these short-lived events were not considered related to the study intervention but could be related to the 
instrumentation of the nose. 
One participant experienced a fall in forced expiratory volume in 1 second (FEV1) and forced vital capacity 
(FVC) 8 hours after the first dose, spirometry was normal at 4 hours postdose and had returned to baseline 
at 12 hours postdose. The participant met the protocol criteria for withdrawal from the study and was 
withdrawn. The participant was asymptomatic throughout the event. The timing of changes in spirometry 
are temporally related to the administration of study intervention but are of an unusual time-course for an 
effect of the study intervention on respiratory function. This one-off event is not considered a reason to stop 
development. 
Overall Neumifil was well tolerated in the healthy population under study, when administered as single or 
multiple (up to 7) doses and further investigation is warranted. 
In summary, Neumifil is a novel candidate for the pre-exposure prophylaxis of viral respiratory tract 
infections. Neumifil has low to minimal risk of generating viral resistance because of its host- and viral-
targeting modes of action. Neumifil’s in vitro and in vivo animal data, clinical data, potential pan-viral 
efficacy, and toxicology profile makes it suitable for progression to a viral challenge study. 
2.2. 
Study Rationale 
The purpose of this Phase 2 study is to assess the efficacy, safety, and tolerability of a multiple dosing 
regimen (once daily for 3 days) and of a single dose of intranasal Neumifil, administered to healthy adults, 
initiated prior to being challenged with the influenza A/Perth/16/2009 (H3N2) virus. The main comparison 
will be between both dosing regimens pooled and the placebo arm. The comparison of each dose arm to 


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the placebo arm is not expected to elicit statistically significant difference, but will provide estimates of the 
relative efficacy of the 2 dosing regimens. 
The anticipated use of Neumifil is to prevent viral infection in patients with underlying pulmonary disease 
(e.g., chronic obstructive pulmonary disease, bronchiectasis), in whom viral infections induce exacerbations 
of the underlying pulmonary disease. Neumifil will be administered on a regular basis (daily or possibly 
weekly) to prevent viral respiratory infections. 
Influenza challenge strains have been used for over 20 years by both hVIVO and others and have helped 
assess numerous antiviral, immunomodulating, and vaccine therapies. Specifically, hVIVO has safely and 
successfully used the influenza A/Perth/16/2009 (H3N2) virus challenge strain in over 400 healthy 
participants (18 to 64 years of age). 
2.3. 
Benefit/Risk Assessment 
2.3.1. 
Risk Assessment 
The known risks to participants are detailed in Table 2-1. However, there may also be risks that are 
unforeseen and unanticipated (e.g., unknown allergies). Every effort will be made to monitor the health of 
the participants to ensure that such risks are minimised. Trained medical staff and appropriate facilities will 
be available to provide medical emergency care. 
More detailed information about the known and expected benefits and risks and reasonably expected AEs 
of Neumifil be found in the Investigator’s Brochure. 
 




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Potential Risk of 
Clinical Significance 
Description of Risk 
Mitigation Strategy 
Nasal sampling 
Collection of respiratory (nasal) samples may cause 
discomfort, sneezing, watery eyes, irritated nose, or 
nose bleeding. 
Sample collection will be performed by appropriately 
qualified and trained study staff to minimise the 
discomfort 
Influenza A/Perth/16/2009 (H3N2) virus infection from inoculation 
influenza 
A/Perth/16/2009 
(H3N2) 
virus 
infection & severe 
complications 
Approximately 60% to 75% chance of becoming infected 
with influenza (influenza A/Perth/16/2009 [H3N2] virus). 
Typical influenza illness: abrupt onset of rhinitis, nasal 
stuffiness, fever, malaise, myalgia (muscle aches), and 
sore throat. 
Severe complications are not expected as these tend to 
occur almost exclusively in infants, elderly, and persons of 
any age with chronic comorbidities and significant immune 
compromise and not in healthy adults with no comorbidities 
of coinfections. 
The safety profile of the influenza A/Perth/16/2009 (H3N2) 
virus is well characterised in healthy adults as this has 
been used for over 20 years by hVIVO. At hVIVO more 
than 400 healthy participants aged 18 to 64 years have 
been challenged with influenza A/Perth/16/2009 (H3N2) 
virus. 
Influenza infection in healthy adults usually resolves 
without any treatment, with relief of symptoms occurring 
naturally within 3 to 5 days. 
Strict inclusion and exclusion criteria will apply to ensure 
only healthy adults are enrolled in this study. 
There will be a daily medical monitoring in a quarantine 
unit for at least 8 days post-human viral challenge. 
Qualified medical and nursing staff in the quarantine unit 
will monitor for and manage any symptoms. 
Transmission 
of 
influenza 
A/Perth/16/2009 
(H3N2) 
virus 
to 
participants’ 
close 
contacts 
Influenza A/Perth/16/2009 (H3N2) virus presence in 
nasal secretions can cause infection in close contacts. 
The duration of the quarantine has been designed to 
allow for resolution of infectious virus (culturable) before 
discharge. This is based on experience to date with 
more than 400 inoculations. As appropriate, the 
PI/delegate may request additional testing of nasal 
swab samples using a qualitative virus antigen test to 
assist in determining participants’ suitability for 
departure. 
As an additional precaution, participants will be 
instructed to avoid close contact with vulnerable 
individuals as described in Section 2.3.1.1, Vulnerable 
Persons, for 2 weeks after they leave the quarantine 
unit. 


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Potential Risk of 
Clinical Significance 
Description of Risk 
Mitigation Strategy 
Risk of reactivation of 
herpes infection 
If a participant ever had a herpes infection (e.g., cold 
sores, genital herpes, or shingles), there is a small 
possibility that this infection could return after challenge. 
Participants will be instructed to inform the study staff if 
they currently have an active herpes infection or have 
had one during the 30 days before enrolment. 
In case the participants develop any cold sore, herpes 
or shingles; they may be treated symptomatically while 
at the quarantine unit. If it continues, they will be 
followed up until resolved or, if necessary, dependent 
on medical history, will be referred to their GP or any 
specific department at hospital, as required. 
Consult the Investigator’s Brochure for detailed information on Neumfil. 


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2.3.1.1. 
Vulnerable Persons 
For the purposes of possible contact after leaving the quarantine unit, the participant should avoid close 
contact with vulnerable individuals for 2 weeks after they leave the quarantine unit. A vulnerable individual 
is a person including but not limited to: 
• 
Persons ≥65 years of age. 
• 
Children ≤2 years of age. 
• 
Residents of nursing homes. 
• 
Women who are pregnant or who are trying to become pregnant. 
• 
Persons of any age with significant chronic medical conditions such as: 
o 
 
 
 
 
 
 
 
 
 
 
 
 
 
2.3.1.2. 
Risk Associated with Coronavirus Disease 2019 Pandemic 
hVIVO has implemented enhanced infection control measures during the pandemic to minimise risks of 
COVID-19 infection. 
Risk of Increased Severity of COVID-19 Infection if Contracted After Challenge Agent Inoculation: 
 
 
 
 
 
Risk of Increased Severity of COVID-19 Infection After Study Intervention Administration: 
 
 
 
 
. 


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2.3.2. 
Benefit Assessment 
Healthy participants will not receive direct benefit from treatment during their participation in this clinical 
study. 
Participants may develop some immunity to influenza A/Perth/16/2009 (H3N2) virus and benefit from a 
general health check at screening. Benefit may also be derived from the medical evaluations and 
assessments associated with study procedures. In addition, participants are contributing to the process of 
developing new therapies in an area of unmet medical need. 
2.3.3. 
Overall Benefit: Risk Conclusion 
Considering the measures taken to minimise risk to participants in this study, the potential risks identified 
in association with Neumifil treatment and influenza A/Perth/16/2009 (H3N2) virus infection are justified by 
the anticipated benefits linked to the evaluation of the antiviral activity of Neumifil in the viral challenge 
model which will contribute to the development of a new therapy for the prevention of seasonal and 
pandemic influenza. 
 


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3. 
Objectives and Endpoints 
 
Objective(s) 
Related Endpoints/Outcome Measure(s) 
Primary: 
Efficacy 
To evaluate the effect of 
Neumifil in 1) reducing the 
incidence of symptomatic 
influenza infection and/or 
2) reducing the severity of 
symptoms after influenza 
viral challenge, compared 
to placebo. 
The study has 2 primary endpoints: 
1) Reducing the incidence of symptomatic 
influenza infection: 
• 
Reverse 
transcriptase 
polymerase 
chain 
reaction 
(RT-PCR)-confirmed 
symptomatic 
influenza infection, defined as: 
o 
RT-PCR-confirmed 
influenza 
infection 
defined as 2 detectable (≥ lower limit of 
detection [LLOD]) RT-PCR measurements 
(reported on 2 or more independent nasal 
samples over 2 days), starting from Day 1 
(pm) up to planned discharge from 
quarantine (Day 8, am), 
AND 
o 
Any symptoms of grade ≥2 at a single time 
point. 
2) Reducing the severity of symptoms: 
• 
Peak symptoms diary card score: peak total 
symptoms score (TSS) as measured by graded 
symptom scoring system collected 3 times 
daily, starting from Day 1 (am) up to planned 
discharge from quarantine (Day 8, am). 
Secondary: 
Efficacy 
To evaluate the effect of 
Neumifil 
in 
reducing 
clinical symptoms due to 
influenza viral challenge, 
compared to placebo. 
• 
Area under the curve over time of total clinical 
symptoms score (TSS-AUC) as measured by 
graded symptom scoring system collected 
3 times daily, starting from Day 1 (am) up to 
planned discharge from quarantine (Day 8, 
am). 
• 
Peak daily symptom score: individual maximum 
daily sum of symptom score, starting from 
Day 1 (am) up to planned discharge from 
quarantine (Day 8, am). 
• 
Number (%) of participants with grade 2 or 
higher symptoms, starting from Day 1 (am) up 
to planned discharge from quarantine (Day 8, 
am). 


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Objective(s) 
Related Endpoints/Outcome Measure(s) 
• 
Duration 
of 
clinical 
symptoms: 
1) any 
symptoms, 2) TSS of 2 or more (with at least 
2 systems), 
and 
3) grade 
2 
or 
higher 
symptoms, starting from Day 1 (am) up to 
planned discharge from quarantine (Day 8, 
am). 
• 
Time to resolution from peak clinical symptoms 
as measured by graded symptom scoring 
system collected 3 times daily. Time to 
resolution is defined as the time (hours) from 
peak clinical symptoms until first time with 
TSS = 0 after which no further increase above 
0 is observed. 
To evaluate the effect of 
Neumifil in reducing or 
shortening viral shedding 
after 
influenza 
viral 
challenge, compared to 
placebo. 
• 
Area under the viral load-time curve (VL-AUC) 
of influenza challenge virus as determined by 
quantitative RT-PCR (qRT-PCR) on nasal 
samples, starting from Day 1 (pm) up to 
planned discharge from quarantine (Day 8, 
am). 
• 
VL-AUC of influenza challenge virus as 
determined by tissue culture on nasal samples, 
starting from Day 1 (pm) up to planned 
discharge from quarantine (Day 8, am). 
• 
Peak viral load (VLPEAK) of influenza as 
defined by the maximum viral load determined 
by qRT-PCR measurements in nasal samples, 
starting from Day 1 (pm) up to planned 
discharge from quarantine (Day 8, am). 
• 
VLPEAK as defined by the maximum viral load 
determined 
by 
quantitative 
viral 
culture 
measurements in nasal samples, starting from 
Day 1 (pm) up to planned discharge from 
quarantine (Day 8, am). 
• 
Duration of quantifiable influenza, assessed by 
qRT-PCR measurements in nasal samples, 
starting from Day 1 (pm) up to planned 
discharge 
from 
quarantine 
(Day 8, 
am). 
Duration is defined as the time (hours) from first 
quantifiable until first confirmed unquantifiable 
assessment after their peak measure (after 
which no further virus is quantified). 
• 
Duration of detectable influenza, assessed by 
qRT-PCR measurements in nasal samples, 
starting from Day 1 (pm) up to planned 
discharge 
from 
quarantine 
(Day 8, 
am). 
Duration is defined as the time (hours) from first 
detectable until first confirmed undetectable 


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Objective(s) 
Related Endpoints/Outcome Measure(s) 
assessment after their peak measure (after 
which no further virus is detected). 
• 
Duration of quantifiable influenza viral culture 
measurements in nasal samples, starting from 
Day 1 (pm) up to planned discharge from 
quarantine (Day 8, am). Duration is defined as 
the time (hours) from first quantifiable until first 
confirmed unquantifiable assessment after their 
peak measure (after which no further virus is 
quantified). 
• 
Duration of detectable influenza viral culture 
measurements in nasal samples, starting from 
Day 1 (pm) up to planned discharge from 
quarantine (Day 8, am). Duration is defined as 
the time (hours) from first detectable until first 
confirmed undetectable assessment after their 
peak measure (after which no further virus is 
detected). 
• 
Time to resolution from VLPEAK as defined by 
the maximum viral load determined by qRT-
PCR measurements in nasal samples. Time to 
resolution is defined as the time (hours) from 
VLPEAK until first confirmed undetectable 
assessment (after which no further virus is 
detected). 
• 
Time to resolution from VLPEAK as defined by 
the maximum viral load determined by qRT-
PCR measurements in nasal samples. Time to 
resolution is defined as the time (hours) from 
VLPEAK until first confirmed unquantifiable 
assessment (after which no further virus is 
quantified). 
• 
Time to resolution from VLPEAK as defined by 
the maximum viral load determined by viral 
culture measurements in nasal samples. Time 
to resolution is defined as the time (hours) from 
VLPEAK until first confirmed undetectable 
assessment (after which no further virus is 
detected). 
• 
Time to resolution from VLPEAK as defined by 
the maximum viral load determined by viral 
culture measurements in nasal samples. Time 
to resolution is defined as the time (hours) from 
VLPEAK until first confirmed unquantifiable 
assessment (after which no further virus is 
quantified). 


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Objective(s) 
Related Endpoints/Outcome Measure(s) 
To evaluate the effect of 
Neumifil in reducing nasal 
discharge, compared to 
placebo. 
• 
Total weight of mucus produced, starting from 
Day 1 (am) up to planned discharge from 
quarantine (Day 8, am). 
• 
Total number of tissues used by participants, 
starting from Day 1 (am) up to planned 
discharge from quarantine (Day 8, am). 
To evaluate the effect of 
Neumifil in reducing the 
incidence 
of 
influenza 
infection due to influenza 
viral challenge, compared 
to placebo. 
• 
RT-PCR-confirmed influenza infection, defined 
as 2 quantifiable (≥ lower limit of quantification 
[LLOQ]) qRT-PCR measurements (reported on 
2 or more independent nasal samples over 
2 days), starting from Day 1 (pm) up to planned 
discharge from quarantine (Day 8, am). 
• 
Occurrence of at least 1 positive quantitative 
(≥ LLOQ) cell culture measurement in nasal 
samples, starting from Day 1 (pm) up to 
planned discharge from quarantine (Day 8, 
am).  
• 
Culture lab-confirmed symptomatic influenza 
infection, defined as: 
o 
Lab-confirmed 
culturable 
influenza 
infection 
(1 quantifiable 
[≥ LLOQ] 
cell 
culture measurement, starting from Day 1 
[pm] up to planned discharge from 
quarantine [Day 8, am]), 
AND 
o 
Any symptoms of grade ≥2 at a single time 
point. 
Further sensitivity analysis may be performed on 
the above qRT-PCR-related endpoints where 
detection by qRT-PCR is reported above the LLOD 
instead of the LLOQ and/or using other definitions 
for the symptomatic component. Details will be 
provided in the statistical analysis plan (SAP). 
• 
Number (%) of participants with lab-confirmed 
infection and fever (≥37.9°C). 
Safety 
To evaluate the safety of 
intranasal 
doses 
of 
Neumifil, 
compared 
to 
placebo. 
• 
Occurrence of AEs (solicited and unsolicited) 
up to the Day 28 (±3 days) follow-up visit, 
including any SAEs. 
• 
Occurrence of unsolicited AEs of special 
interest (AESIs) up to the Day 28 (±3 days) 
follow-up visit. AESIs are: clinically significant 
reduction in FEV1 and FVC.  


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Objective(s) 
Related Endpoints/Outcome Measure(s) 
To monitor the safety of 
the challenge virus. 
• 
Occurrence of unsolicited AEs related to virus 
challenge from Day 0 up to planned discharge 
from quarantine (Day 8, am). 
• 
Occurrence of unsolicited SAEs related to virus 
challenge from Day 0 up to planned discharge 
from quarantine (Day 8, am). 
• 
Use of concomitant medications from Day 0 up 
to the Day 28 (±3 days) follow-up visit. 
Tertiary / 
Exploratory*: 
To 
explore 
Neumifil 
concentrations in blood 
(single 
and 
multiple 
doses). 
Neumifil concentrations will be explored in blood. 
To 
evaluate 
antibody 
(immunoglobulin 
[Ig] 
A 
[IgA] 
and 
G 
[IgG]) 
development in Neumifil-
treated participants (single 
and 
multiple 
doses), 
compared to placebo. 
Development of antibodies (IgA, IgG) against the 
virus will be evaluated in serum samples. 
To evaluate antibody (IgA 
and IgG) response to the 
virus. 
Anti-drug antibody (ADA) (IgA, IgG) development 
will be evaluated in serum samples. 
To evaluate cytokine and 
chemokine responses in 
nasal samples in Neumifil-
treated participants (single 
and 
multiple 
doses), 
compared to placebo. 
Cytokines and chemokines will be assayed in nasal 
samples. 
* Note that tertiary/exploratory objectives and endpoints are optional and might be assessed only if needed; 
therefore, not all testing might be performed and reported. 
 




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o 
Post-human viral challenge: 
▪ 
Day 1 onwards and each day – study assessments will be conducted as per 
SoE. 
▪ 
Discharge from the quarantine unit on Day 8 
 
 
 
• 
Outpatient phase: 
o 
Final follow-up visit: Day 28 (±3 days). 
Study assessments will be conducted as per SoE 
The Study Schematic, showing participant progression through the study, is presented in Section 1.1, Study 
Schematic: On-study Participant Progression. The SoE is presented in Section 1.2, Schedule of Events. 
4.2. 
Scientific Rationale for Study Design 
The study will be conducted by hVIVO Services Limited, which has extensive experience with influenza 
challenge studies. Numerous studies have been performed using experimental influenza infection in human 
participants. To date, in hVIVO’s studies, over 400 participants have been successfully and safely 
inoculated with influenza A/Perth/16/2009 (H3N2) virus. These studies demonstrated that adults could be 
infected by nasal inoculation and that experimental infection was safe. This influenza strain has been shown 
to cause symptoms and virus shedding that closely match natural infection. 
Administration of IMP and challenge with influenza A/Perth/16/2009 (H3N2) virus will take place in hVIVO’s 
specialised clinical facilities, in a quarantine unit. Standard study procedures (including collection of blood, 
urine, and nasopharyngeal secretions for assessment of safety and efficacy) have been employed in 
previous studies conducted by hVIVO. 
Blinding, Control, and Randomisation 
The placebo control will be used to establish the frequency and magnitude of changes in endpoints that 
may occur in the absence of active treatment. It will allow a comparative evaluation of the efficacy of 
Neumifil. 
Blinding will prevent the occurrence of conscious and unconscious bias in the conduct and interpretation of 
the study. 
Randomisation will be used to prevent bias in the assignment of participants to treatment arms, to increase 
the likelihood that known and unknown participant characteristics (e.g., demographic and baseline 
characteristics) are equally balanced across treatment arms, and to enhance the validity of statistical 
comparisons across treatment arms. 
4.3. 
Justification for Dose 
All doses administered in the first-in-human study were well tolerated. In the multiple dose part of the study 
Neumifil was administered as a single daily dose of 
 
 Based on the safety profile and 
tolerability of Neumifil seen to date 3
 
 
 would be appropriate. 


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An inoculum titre of approximately 105.5 TCID50 of the influenza A/Perth/16/2009 (H3N2) virus strain has 
been shown to cause disease profiles that are consistent with the mild to moderate disease profiles 
expected with wild-type challenge viruses in healthy adult participants. 
4.4. 
Population to be Studied 
Healthy adult participants. 
4.5. 
Rationale for Trial Endpoints 
The measures for evaluation of the safety and tolerability profile of Neumifil are standard for most clinical 
studies and follow the recommendations in the International Council for Harmonisation (ICH) guidelines. 
The measures for evaluation of the pre-exposure prophylactic antiviral activity of Neumifil against influenza 
have been employed in previous studies conducted by hVIVO and are appropriate to characterise the 
efficacy of Neumifil, considering the Neumifil mode of action. 
Biomarkers (cytokine and chemokine) and ADAs are exploratory in nature and do not have predefined 
endpoints. 
4.6. 
End of Study Definition 
A participant is considered to have completed the study if he/she has completed all phases of the study 
including the last scheduled study visit or the last unscheduled study visit, as applicable. If a safety visit is 
required after the last scheduled study visit, this will be at the discretion of the PI/investigator as a duty of 
care, e.g., repeat spirometry or laboratory tests. These discretionary follow-up visits will not be considered 
part of the study data unless they represent follow-up and closure on an AE or SAE identified during the 
study period. 
The end of the study is defined as the date of the last visit of the last participant in the study. 


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5. 
Study Population 
Prospective approval of protocol deviations to recruitment and enrolment criteria, also known as protocol 
waivers or exemptions, is not permitted. 
5.1. 
Inclusion Criteria 
No. 
hVIVO APPROVED STANDARD INCLUSION CRITERIA 
(Viral Challenge Volunteer Studies) 
Final v11.0, 08FEB2022 
To be eligible for the study, participants must meet all the following inclusion criteria: 
1. 
Written informed consent signed and dated by the participant and the investigator obtained 
before any assessment is performed. 
2. 
Adult male or female aged between 18 and 55 years old, inclusive, on the day prior to signing 
the consent form. 
3. 
A total body weight ≥50 kg and body mass index (BMI) ≥18 kg/m2 and ≤35kg/m2. 
4. 
In good health with no history, or current evidence, of clinically significant medical conditions, 
 
 
. 
5. 
Participants will have a documented medical history either prior to entering the study or 
following medical history review with the study physician at screening. 
6. 
The following criteria are applicable to female participants participating in the study. 
a) Females of childbearing potential must have a negative pregnancy test prior to 
enrolment. 
b) Females of non-childbearing potential: 
a. Postmenopausal females defined 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
b. Documented status as being surgically sterile 
 
 
7. 
The following criteria apply to female and male participants: 
a) Female participants of childbearing potential must use 1 form of highly effective 
contraception. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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No. 
hVIVO APPROVED STANDARD INCLUSION CRITERIA 
(Viral Challenge Volunteer Studies) 
Final v11.0, 08FEB2022 
1. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
b) Male participants must agree to the contraceptive requirements 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
c)  In addition to the contraceptive requirements above, male participants must agree 
not to donate sperm 
 
 
8. 
Serosuitable for the challenge virus 
• 
The serology result obtained from the influenza antibody assay suggests that the 
participant is sensitive to influenza infection (i.e., likely to be infected following 
inoculation with the challenge virus; he/she must have no or low pre-existing serum 
levels of antibodies specific to the challenge agent). 


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5.2. 
Exclusion Criteria 
NO 
hVIVO APPROVED STANDARD EXCLUSION CRITERIA 
(Viral Challenge Volunteer Studies) 
Final v11.0, 08FEB2022 
Participants who meet any of the following exclusion criteria will not be included in the study. 
Medical History 
1. 
History of, or currently active, symptoms or signs suggestive of upper or lower respiratory 
tract (URT, LRT) infection within 4 weeks prior to the first study visit. 
2. 
Any history or evidence of any clinically significant or currently active cardiovascular, 
respiratory, dermatological, gastrointestinal, endocrinological, haematological, hepatic, 
immunological (including immunosuppression), metabolic, urological, renal, neurological, or 
psychiatric disease and/or other major disease that, in the opinion of the investigator, may 
interfere with a participant completing the study and necessary investigations. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
e) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
3. 
Any participants who have smoked ≥10 pack years at any time (10 pack years is equivalent 
to 1 pack of 20 cigarettes a day for 10 years). 




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NO 
hVIVO APPROVED STANDARD EXCLUSION CRITERIA 
(Viral Challenge Volunteer Studies) 
Final v11.0, 08FEB2022 
c) Prior inoculation with a virus from the same virus-family as the challenge virus. 
d) Prior participation in another human viral challenge study with a respiratory virus in 
the preceding 3 months, taken from the date of viral challenge in the previous study 
to the date of expected viral challenge in this study. 
11. 
Use or anticipated use during the conduct of the study of concomitant medications 
(prescription and/or non-prescription), including vitamins or herbal and dietary supplements 
within the specified windows, unless in the opinion of the PI/investigator, the medication will 
not interfere with the study procedures or compromise participant safety. Specifically, the 
following are excluded: 
a) Herbal supplements, any medication or product (prescription or over the counter) 
for symptoms of nasal congestion, or short or long-acting histamines, within 7 days 
prior to the planned date of first dosing with IMP. 
b) Chronically used medications, vitamins, or dietary supplements, including any 
medications known to be moderate/potent inducers or inhibitors of cytochrome 
P450 (CYP) enzymes, within 21 days prior to the planned date of first dosing with 
IMP. 
c) Over the counter medications (e.g., paracetamol or ibuprofen) where the dose 
taken over the preceding 7 days prior to the planned date of first dosing with IMP 
has exceeded the maximum permissible daily dose (e.g., ≥4 g paracetamol or ≥1.2 
g ibuprofen over the preceding week). 
d) Systemic (oral and parenteral) antiviral drugs, within 4 weeks prior to the planned 
date of first dosing with IMP. 
e) Use of any intranasal medication, including saline douches, within the 30 days prior 
to admission. 
12. 
a) Confirmed positive test for drugs of misuse and cotinine on first study visit. 
 
b) Recent history or presence of alcohol addiction, or excessive use of alcohol (weekly 
intake in excess of 28 units alcohol; 1 unit being a half glass of beer, a small glass 
of wine, or a measure of spirits), or excessive consumption of xanthine-containing 
substances (e.g., daily intake in excess of 5 cups of caffeinated drinks, e.g., coffee, 
tea, cola). 
13. 
A FEV1 <
%, a FVC <
, or an FEV1/FVC ratio <
 
14. 
Positive HIV, hepatitis B virus, or hepatitis C virus test. 
15. 
Presence of fever,
 
on Day -4 
 


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NO 
hVIVO APPROVED STANDARD EXCLUSION CRITERIA 
(Viral Challenge Volunteer Studies) 
Final v11.0, 08FEB2022 
Other 
16. 
Those employed or immediate relatives of those employed at hVIVO or the sponsor. 
17. 
Any other finding that, in the opinion of the investigator, deems the participant unsuitable for 
the study. 
5.3. 
Lifestyle Considerations 
5.3.1. 
Meals and Dietary Restrictions 
 
 
 
 
5.3.2. 
Caffeine, Alcohol, and Tobacco 
 
 
 
 
 
 
 
 
 
5.3.3. 
Activity 
Participants must refrain from strenuous exercise 
 
 
 
 
5.3.4. 
Other Restrictions 
Participants will be instructed to avoid close contact with vulnerable people as described in Section 2.3.1.1, 
Vulnerable Population, for 2 weeks after they leave the quarantine unit. 


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5.4. 
Screen Failures 
 
 
 
 
 
 
. 


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6. 
Study Intervention 
Study intervention is defined as any investigational intervention(s), marketed product(s), placebo, or 
medical device(s) intended to be administered to a study participant according to the study protocol. 
Study interventions administered to participants are described in Table 6-1. 
6.1. 
Study Intervention(s) Administered 
Table 6-1: 
Study Interventions 
Intervention 
Name 
Neumifil 
Placebo 
Influenza 
A/Perth/16/2009 (H3N2) 
Virus 
Type 
Drug 
Other 
Virus 
Dose 
Formulation 
Liquid for intranasal spray 
administration 
Liquid for intranasal spray 
administration 
Capped vial, liquid for 
internasal 
drops 
administration 
Unit Dose 
Strength(s) 
 
Not applicable 
The challenge agent titre 
is 
determined 
in 
an 
infectivity assay. The dose 
is 
approximately 
105.5 
TCID50 
Dosage 
Level(s) 
Multiple dose active treatment: 
A single dose of challenge 
agent will be delivered 
3-day once daily dosing 
regimen 
of 
 
 
 (Days -3 to -1), 
divided between left and 
right nostrils 
 
 
Not applicable 
Single dose active treatment: 
 (Day -3) 
divided between left and 
right nostrils 
 
  
2-day once daily dosing 
regimen 
of 
0.28 mL 
(Days -2 and -1), divided 
between left and right 
nostrils 
 
 
Placebo treatment: 


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Not applicable 
3-day once daily dosing 
regimen 
 
 
(Days -3 to -1),
 
 
 
 
 
 
 
Route of 
Administration 
Intranasal 
Intranasal 
Intranasal 
Use 
Experimental 
Placebo 
Infectious challenge agent 
Sourcing 
Provided by Pneumagen 
Provided by Pneumagen 
Provided 
centrally 
by 
hVIVO  
Packaging and 
Labelling 
The 
details 
of 
the 
packaging and labelling 
will be provided in the 
study-specific 
pharmacy 
manual 
The 
details 
of 
the 
packaging and labelling 
will be provided in the 
study-specific 
pharmacy 
manual 
Influenza challenge agent 
will be provided in vials. 
The 
details 
of 
the 
challenge agent provision 
will be provided in the 
analytical plan (AP) 
Current/Former 
Name(s) or 
Alias(es) 
Not applicable 
Not applicable 
Not applicable 
 
6.2. 
Preparation/Handling/Storage/Accountability 
6.2.1. 
Investigational Product 
Neumifil and placebo (IMP) will be supplied in prefilled nasal spray pump devices for intranasal 
administration. Details on dose preparation and administration are provided in the study-specific pharmacy 
manual. 
hVIVO will receive supplies of IMP after the supply has received qualified person sign off by the Good 
Manufacturing Practice (GMP) sponsor’s representative/pharmacy provider and has been released for 
shipment. All IMP supplies will be used only for this protocol and for no other purpose. 
Ready-to-dispense IMP will be supplied at the beginning of the study. Once received at hVIVO, hVIVO 
study staff will perform stock level accountability and the IMP will be stored securely, according to the 
directions on the IMP labels. IMP accountability will be controlled by hVIVO and monitored by the study 
monitor throughout the study and at study close-out. 
The PI/investigator will ensure that all supplies are received by a responsible person, all deliveries and 
returns are documented and signed for, and the condition of the IMP is monitored. Accurate records will be 


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kept of when and how much IMP is dispensed and used in the study. Any reasons for departure from the 
protocol dispensing regimen will be recorded. 
Accountability records will be available for verification by the study monitor at each monitoring visit. At the 
completion of the study, there will be a final reconciliation of all IMP. 
6.2.2. 
Challenge Agent 
The challenge agent used in this study is influenza A/Perth/16/2009 (H3N2) virus. 
The challenge agent stock was manufactured under current good manufacturing practices (cGMP). The 
challenge agent stock has undergone quality testing performed during manufacturing (identity, appearance, 
sterility, infectivity, and contaminants) according to pre-determined specifications, and has subsequently 
also passed an extensive panel of adventitious agent testing. The challenge agent is stored in a secure -
80oC freezer (normal temperature range -60°C to -90°C). 
Each participant will be allocated a unique vial containing the challenge agent and will receive the inoculum 
intranasally. The inoculum will be prepared and/or provided according to the hVIVO Analytical Plan (AP) 
and administered in accordance with hVIVO standard operating procedure (SOPs). 
All administrations will be made by a member of the study staff and witnessed by a second study staff 
member. The exact time of challenge agent inoculation will be recorded in the administration log. Accurate 
records will be kept of when and how much inoculum is prepared and/or provided and used. The oversight 
process will be signed off prior to administration of the challenge agent. Any noncompliance or problems 
with the inoculation will be recorded in the participant’s source notes and reported to the PI/investigator. 
 
 
 
. 
6.2.3. 
All Study Interventions 
The PI/investigator or designee must confirm appropriate temperature conditions have been maintained 
during transit for all study intervention received and that any discrepancies are reported and resolved before 
use of the study intervention. 
Only participants enrolled in the study may receive study intervention and only authorised investigator site 
staff may supply or administer study intervention. All study intervention must be stored in a secure, 
environmentally controlled area, and monitored (manual or automated) in accordance with the labelled 
storage conditions with access limited to the PI/investigator and authorised investigator site staff. 
The PI/investigator, institution, or the head of the medical institution (where applicable) is responsible for 
study intervention accountability, reconciliation, and record maintenance (i.e., receipt, reconciliation, and 
final disposition records) 
Further guidance and information for the final disposition of unused study interventions are provided in the 
pharmacy manual. 


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6.3. 
Randomisation and Blinding 
 
 
 
 The randomisation number 
encodes the participant’s assignment to one of 3 study arms (Neumifil multiple dose active treatment, 
Neumifil single dose active treatment, or placebo) in a 3:3:4 ratio. 
Randomisation numbers will be assigned sequentially in ascending order; and once assigned, that 
randomisation number shall not be reassigned. The study site will keep a log of the randomisation number 
assigned to each participant. 
A designated unblinded statistician, separate from the conduct or analysis of the study, will be responsible 
for the computer-generated randomisation schedule. Sealed copies of the randomisation code will be stored 
in a secure location. 
Randomisation numbers will follow a 3-digit format e.g., [001]. If participants are replaced as per 
Section 7.4, Participant Replacement Strategy, the replacement participant will be assigned a new, unique 
randomisation number equalling the randomisation number of the replaced participant, plus 100. This will 
ensure that the replacement participant receives the same allocated, blinded treatment as the participant 
who is being replaced. 
A copy of the randomisation code list will be sent to the unblinded pharmacist preparing the IMP, so that 
IMP (Neumifil/placebo) can be prepared for each participant as appropriate. An independent statistician 
prepares the randomisation schedule, and the GMP pharmacy provider ’s pharmacist/designee will prepare 
the participant level IMP doses in line with the randomisation schedule. 
Each participant will be dispensed blinded IMP (Neumifil/placebo), labelled with his/her unique 
randomisation number, throughout the study. With the exception of the unblinded pharmacist, the unblinded 
statistician preparing the randomisation code list, and the quality assurance auditors where necessary, the 
PI/investigator and all other clinical and nonclinical staff, (including the study statistician, data management 
staff), and the participants will remain blinded to the treatment allocation until after the database has been 
locked and approval for study unblinding has been given. 
Following database lock, on receipt of authorisation from the sponsor, a copy of the randomisation code list 
will be provided to the study statistician to conduct study unblinding prior to analysis. 
Individual access to a secured Interactive Web Response System (IWRS) will be provided to the 
investigator. The website, compliant with 21CFR part 11 guidelines, will be used if unblinding is necessary. 
In case of an emergency, the investigator has the sole responsibility for determining if unblinding of a 
participant’s intervention assignment is warranted. The blind should only be broken where knowledge of 
the IMP received is required to provide appropriate patient care. Participant safety must always be the first 
consideration in making such a determination. If the investigator decides that unblinding is warranted, the 
investigator should make every effort to contact the sponsor prior to unblinding a participant’s intervention 
assignment unless this could delay emergency treatment of the participant. When the investigator breaks 
the code, he/she will have to indicate on the web site the reason of unblinding. The person who performed 
the unblinding and the date of time of code breaking will be automatically recorded. After confirmation the 
nature of treatment will appear on the screen. A notification with the nature of treatment will also be provided 




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Prohibited medication 
Washout 
the study procedures or compromise participant 
safety. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vaccines. 
 
 
 
Any IMP used in another study. 
 
 
 
Any concomitant medication required for the participant’s welfare may be given by the PI/investigator. 
However, it is the responsibility of the PI/investigator to ensure that details regarding the medication and 
the reason for its use are recorded appropriately in the source notes to permit their transfer to the clinical 
database. 
 
 
 
 
 
 
Table 6-3: 
Permitted Medication 
Permitted medication 
Time period 
Paracetamol 
 
 
Ibuprofen 
 
 
Oral contraceptives 
Allowed at any time during the study. 
 
. 


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Permitted medication 
Time period 
If, e.g., in an outbreak or pandemic, a newly instated national vaccination programme is applicable to an 
individual participant, the PI/investigator and sponsor will discuss on an individual basis if concomitant 
vaccination may be allowed, study dosing/viral challenge postponed, or the participant withdrawn from 
the study. 
6.6. 
Dose Modification 
This is not applicable in this study. 
6.7. 
Treatment of Overdose 
For this study, any dose of any drug administered as part of the study greater than the dose prescribed by 
the protocol will be considered an overdose. 
In the event of an overdose, the PI/investigator should: 
1. Contact the medical monitor immediately. 
2. Closely monitor the participant for any AE/SAE and laboratory abnormalities possibly associated 
with overdose and the participant will be clinically followed up until any AE/SAE has resolved. 
3. Obtain a plasma sample for measurement of plasma concentrations of Neumifil within 2 hours of 
the overdose of study intervention if requested by the medical monitor (determined on a case-by-
case basis). 
4. Document the quantity of the excess dose as well as the duration of the overdose in the eCRF. 
The sponsor is responsible for notifying the MHRA and Research Ethics Committee (REC) of the potential 
serious breach within 7 days of becoming aware of it. 


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7. 
Discontinuation of Study Intervention/Withdrawal 
7.1. 
Participant Withdrawal 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
7.2. 
Participant Discontinuation 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Participants who are withdrawn from the study will be requested to attend an early withdrawal visit, with 
assessments as detailed in the SoE. 
7.2.1. 
Temporary Discontinuation/Temporary Delay in Enrolment 
 
 
 
 
7.3. 
Lost to Follow-up 
A participant will be considered lost to follow-up if he/she repeatedly fails to return for scheduled visits and 
is unable to be contacted by the study site. 
The following actions must be taken if a participant fails to return to the study site for a required study visit: 
• 
The site must attempt to contact the participant and reschedule the missed visit as soon as possible 
and counsel the participant on the importance of maintaining the assigned visit schedule and 
ascertain whether the participant wishes to and/or should continue in the study. 
• 
Before a participant is deemed lost to follow-up, the PI/investigator or designee must make every 
effort to regain contact with the participant (where possible, 3 telephone calls and, if necessary, a 
follow-up letter to the participant’s last known mailing address or local equivalent methods). These 
contact attempts should be documented in the participant’s medical record. 
• 
Should the participant continue to be unreachable, he/she will be considered to have withdrawn 
from the study. 
Discontinuation of specific sites or of the study are handled as part of Appendix 1, Regulatory, Ethical, and 
Study Oversight Considerations. 
7.4. 
Participant Replacement Strategy 
Participants may be replaced in this study. 
 
 
 
. 
7.5. 
Stopping Rules 
The PI/investigator and the SME will perform safety reviews on available clinical and virology data as 
appropriate during the quarantine period. 
Three clinical scenarios relating to the incidence of SAEs/suspected unexpected serious adverse reactions 
(SUSARs) during the study and the procedures that should be performed in each case are presented in 
Table 7-1. 


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Table 7-1: 
Study Stopping Rules 
Status 
Criterion 
Procedure 
1 
A report has been received of one (or 
more) SUSAR(s) in any, one (or more) 
participant(s). 
If such a status occurs at any point during the 
study, then further administration of the IMP will 
not take place. The PI/investigator and the SME 
will review the data and decide on whether it is 
appropriate 
to 
recommence 
IMP 
dosing 
(approval of a substantial amendment from the 
Competent Authorities is required) or terminate 
the study. 
2 
No SUSAR(s) have been reported but an 
overall pattern of clinical changes or 
symptoms exists, attributed to the IMP, 
which may appear minor or moderate in 
terms of individual AEs or SAEs but which 
collectively represent a concern for safety. 
If such a status occurs at any point during the 
study, then further administration of IMP will not 
take place. The PI/investigator and the SME will 
review the data and decide on whether it is 
appropriate 
to 
recommence 
IMP 
dosing 
(approval of a substantial amendment from the 
Competent Authorities is required) or terminate 
the study. 
3 
Unexpected 
virus-related 
SAE(s) 
or 
unexpected virus-related AE(s) of clinical 
concern have been reported following viral 
challenge. 
If such a status occurs at any point during the 
study, then the PI/investigator and the SME will 
review the data and decide based on 
expectedness* of the viral event. 
If the event is unexpected, further administration 
of 
the 
virus 
will 
not 
take 
place. 
The 
PI/investigator and the SME will review the data 
and decide on whether it is appropriate to 
recommence 
inoculation 
(approval 
of 
a 
substantial amendment from the Competent 
Authorities is required) or terminate the study. 
* Expectedness will be assessed by referring to the challenge virus dossier. 
A final follow-up visit will be performed on Day 28 (±3 days). Follow-up of any event should continue until 
resolution (return to normal or baseline values), stabilisation, it is judged by the PI/investigator to be no 
longer clinically significant, the participant is lost to follow-up (as defined in Section 7.3, Lost to Follow-up), 
or an alternative explanation has been provided (see Section 10.3.6.8., Follow-up) 
Further enrolment into the study may be either temporarily or permanently discontinued if: 
• 
An unacceptable number of severe or life-threatening exacerbations of AEs take place (as 
determined by the PI/investigator). 
• 
Any clinically significant life-threatening AEs, considered related to the study intervention as 
determined by the PI/investigator, occur. 
7.6. 
Features 
This study is designed to be able to utilise features to enhance study safety, efficiency, and efficacy. These 
design elements are predefined in their scope and limit, as detailed in Table 7-2. 
The implementation of study-specific features will be documented in a non-substantial amendment. Generic 
features may be implemented at any time at the discretion of the PI/investigator. 


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Table 7-2: 
Features 
Design Category 
Feature 
Limit 
Generic 
Cohort(s) 
1. Participants 
who 
have 
been 
withdrawn (for any reason) may be 
replaced 
(sponsor 
and/or 
PI/investigator discretion). 
2. Participants who are replacing a 
withdrawn 
participant 
may 
be 
randomised 
for 
inclusion, 
and 
dosed/challenged: 
a. In an ongoing cohort 
b. In a new cohort 
c. Separately. 
3. Any study cohort may run at the 
same time 
4. The number of participants enrolled 
in each cohort may be reduced or 
increased 
(sponsor 
and/or 
PI/investigator discretion) to best 
meet the study objectives. 
1. The stopping rules of the study 
must be always adhered to, and 
replacement participants may not 
be enrolled to replace participants 
who have been withdrawn from the 
trial due to the meeting of stopping 
rules. 
2. The 
total 
number 
of 
study 
participants will not exceed 100 
evaluable participants. 
3. Replacement participants will be 
given replacement randomisation 
numbers 
(see 
Section 7.4, 
Participant Replacement Strategy). 
4. All 
protocol-defined 
rules 
and 
safety criteria must be met before 
any participant commences the 
study. 
Sample/Specimen 1. The PI/investigator may perform 
additional safety assessments, at 
any time, if they believe them to be 
clinically required. 
2. Where clinically required (sponsor 
and/or PI/investigator discretion), 
participants may be referred for 
consultation(s) 
and/or 
investigation(s) under the care of a 
specialist physician. 
1. The maximum blood volume will not 
be exceeded. 
2. Any required 
additional safety 
assessments, 
or 
specialist 
referrals, will be conducted on a 
case-by-case basis. As such the 
maximum number needed cannot 
be prospectively defined. 
Duration 
of 
Inpatient Stay 
1. A participant’s inpatient stay may be 
prolonged if discharge criteria of 
minimal infectiousness is not met 
(sponsor 
and/or 
PI/investigator 
discretion). 
1. Must meet the terms and criteria as 
detailed 
in 
the 
participant 
information sheet. 
2. Participants must always be able to 
leave the study site unhindered if 
they wish to do so. 
3. The additional stay is triggered 
based 
on 
the 
minimal 
infectiousness discharge criteria 
not being met (as detailed in this 
protocol), and the participant’s 
suitability for residential stay will be 
assessed on a case-by-case basis. 
As such, a maximum length of stay 
cannot be prospectively defined. 
 
 


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8. 
Study Assessments and Procedures 
Unless otherwise stated, study assessments will be performed according to hVIVO SOPs. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
8.1. 
Demographics and Baseline Characteristics 
8.1.1. 
Demographics 
Demographic data will be recorded at the screening visit. 
8.1.2. 
Height, Body Weight, and Body Mass Index 
Height and body weight measurements will be recorded in compliance with hVIVO’s standard procedures. 
Body mass index will be calculated as: BMI (kg/m2) = Body weight (kg) 
 
 
 
 
 
 
 
 
 
 
 
Height (m)2 
8.1.3. 
Medical and Medication History 
Medical and medication histories will be recorded at screening, including, but not limited to, detailed 
histories on current contraception, and allergies (e.g., rhinitis, dermatitis, food, aspirin/non-steroidal 
anti-inflammatory drugs and asthma). 


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8.1.4. 
Challenge Agent Serology Samples 
A participant must be serosuitable to take part in the study, i.e., he/she must have no or low pre-existing 
serum levels of antibodies specific to the challenge agent. This antibody titre cut-off for serosuitability will 
be described in the applicable hVIVO policy. 
Serum levels of pre-existing influenza-specific antibodies will be determined using haemagglutination 
inhibition (HAI) influenza. Participants with results of HAI of 10 or less are eligible. 
8.1.5. 
Patient Health Questionnaire-9 (PHQ-9) and Generalised Anxiety 
Disorder-7 (GAD-7) Questionnaire 
 
 
8.2. 
Respiratory Samples 
The following exploratory nasal sampling procedures will be performed during the study and are detailed in 
the sections below: 
• 
Nasosorption (nasal wick). 
• 
Nasopharyngeal swab. 
Where any nasal sampling time points occur together, the order of sampling will typically be 
(1) nasosorption followed by (2) nasopharyngeal swab, with appropriate time between sampling. 
8.2.1. 
Nasosorption 
A nasosorption (Class 1 Device) procedure will be used to collect samples of epithelial lining fluid for: 
• 
Inflammatory markers (e.g., cytokines/chemokines). 
• 
Other protein biomarkers, e.g., antibodies. 
• 
Exploratory purposes (see Section 8.3.4, Exploratory Assessments). 
Remaining epithelial lining fluid may be stored and used for exploratory purposes. 
8.2.2. 
Nasopharyngeal Swab 
Nasopharyngeal swabs will be performed to collect samples of nasal material for: 
• 
Respiratory pathogen screen. 
• 
Viral discharge test. 
• 
Virology, i.e., viral shedding/load assessments (see Section 8.3.1, Viral Shedding/Load 
assessment). 
Remaining material from the nasopharyngeal swabs may be stored and used for exploratory purposes. 


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8.2.2.1. 
Respiratory Pathogen Screen 
On entry to quarantine, a nasopharyngeal swab will be collected and tested to detect the presence of a set 
of respiratory pathogens that could potentially contraindicate a person’s participation in the study. The 
methodology to be used to conduct the respiratory pathogen screen will be documented in the AP. 
 
 
 
 
8.2.2.2. 
Influenza Discharge Test/Rapid Viral Antigen Test 
Where required, a rapid viral antigen test (RVAT) will be used to determine the presence of influenza in a 
nasopharyngeal swab sample taken prior to discharge from the quarantine unit. A polymerase chain 
reaction (PCR) test may be used as an alternative test for this purpose, details of which will be documented 
in the AP. An RVAT/PCR test will be performed at the discretion of the PI/investigator and only if indicated 
for a clinical or other reason. 
8.2.3. 
Viral Sequencing 
 
 
 
8.3. 
Efficacy Assessments 
8.3.1. 
Viral Shedding/Load Assessment 
Viral titre will be determined by quantitative reverse transcription polymerase chain reaction (qRT-PCR) 
and/or a viral culture assay to investigate the following parameters: 
• 
Viral load. 
• 
Infectivity status and rate. 
• 
Viral dynamics (e.g., duration, peak, time to resolution). 
8.3.2. 
Participant Diary Cards 
Solicited IMP Self-assessment Diary Card 
On Days -3, -2, and -1, the solicited IMP self-assessment diary card will be completed twice daily, at 1 hour 
(±15 mins) and 12 hours (±30 minutes) postdose, to report the participant’s experience following intranasal 
administration of IMP (Neumifil/placebo). 


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Symptom Diary Card (Categorical) 
Participants will report and assess the severity of any challenge agent-related signs and symptoms 3 times 
per day starting from Day -1 (am) up to planned discharge from quarantine (Day 8, am), at the same time 
each day (±1 hour), using the hVIVO symptom diary card. This information will be collected using a paper 
form. 
The following symptoms in the 11-item symptom questionnaire will be graded on a scale of 0-3 (grade 0: 
no symptoms; grade 1: just noticeable; grade 2: clearly bothersome from time to time but does not interfere 
with me doing my normal daily activities; grade 3: quite bothersome most or all of the time, and it stops me 
participating in activities); shortness of breath has an additional grade, i.e., grade 4: symptoms at rest. 
• 
Runny nose 
• 
Stuffy nose 
• 
Sneezing 
• 
Sore throat 
• 
Earache 
• 
Malaise/tiredness 
• 
Headache 
• 
Muscle and/or joint ache 
• 
Chilliness/feverishness 
• 
Cough 
• 
Shortness of breath 
Participant Common Cold Perception Questions 
Two additional common cold-related questions will be answered by the participant each morning. The first 
question asks the participant’s perception of whether they have a cold or not, the second asks the 
participant’s perception of improvement/worsening of the cold. 
1. Do you have a cold: Yes/No 
If the participant selects Yes to having a cold, then the second 7-point Likert scale “global change since 
yesterday” question is completed by the participant, as below: 
2. Compared to yesterday, I feel that my cold is: 
o 
Very much better 
o 
Somewhat better 
o 
A little better 
o 
The same 
o 
A little worse 
o 
Somewhat worse 
o 
Very much worse 


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8.3.3. 
Nasal Discharge Collection from Paper Tissues 
Each participant will be given pre-weighed packets of paper tissues. Participants will be asked to place 
single tissues used for nose blowing or sneezing into a specified collection bag (for that participant only). 
A daily 24-hour paper tissue collection will take place throughout the quarantine period. Distribution of paper 
tissues and collection bags will start in the morning on Day -1, with the first collection on Day 0. Thereafter, 
distribution and collection of tissues will occur daily, at the same time point (±1 hour) in the morning ,with 
tissues distributed 24 hours ahead, until discharge from quarantine. 
24-hour paper tissue collections will be analysed to determine the following over the quarantine period: 
• 
24-hour nasal discharge weight. 
• 
The number of paper tissues used for nose blowing or sneezing over each 24-hour period. 
8.3.4. 
Exploratory Assessments 
Cytokine and chemokine proteomic profile and/or messenger RNA profile will be assessed for associations 
with Neumifil response, and other endpoints. 
8.4. 
Safety Assessments 
8.4.1. 
Complete Physical Examination 
A complete physical examination to include a full systemic assessment. 
8.4.2. 
Symptom-directed Physical Examination 
Symptom-directed physical examinations will be conducted as deemed appropriate by the PI/investigator 
and may include (as applicable) examination of the eyes, ears, nose, throat, and respiratory system/chest. 
Based upon the presence or absence of clinical signs and symptoms, PI/investigator discretion will be used 
to determine the requirement to perform certain ongoing assessments. 
 
 
 
 
 
 
 
 
. 
8.4.3. 
Vital Signs and Tympanic Temperature 
Vital signs assessments will be recorded 
 


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• 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study-specific normal ranges for vital signs and tympanic temperature are provided in Appendix 4, Normal 
Ranges. 
If a result is out of the normal range and meets the criteria for an AE, the severity of the AE will be guided 
by sponsor requirements using the Food and Drug Administration (FDA) toxicity grading scale (FDA 
Guidance document for Industry, 2007). 
 
 
 
 
 
 
 
 
 
 
 
 
8.4.4. 
Electrocardiogram 
Study-specific normal ranges are provided in Appendix 4, Normal Ranges. 
 
 
 
 
 
 
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8.4.5. 
Clinical Safety Laboratory Assessments 
8.4.5.1. 
Urinalysis 
Clinical urine safety analysis will be undertaken using commercially available urine test strips (i.e., dipsticks) 
that provide an instant result, which will be documented in the source data. 
Urinalysis will be performed to evaluate the parameters described in Appendix 2, Clinical Laboratory Tests. 
 
 
 
 
 
 
8.4.5.2. 
Drugs of Misuse and Cotinine 
 
 
 
 
8.4.5.3. 
Alcohol Breath Testing 
 
 
 
8.4.5.4. 
Safety Blood Analysis and Assessments 
 
 
 
8.4.6. 
Pregnancy Tests and Follicle-stimulating Hormone 
 
 
 
 
 
 


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8.4.7. 
Lung Function 
Spirometry 
 
 
 
 
 
 
 
 
 
 
 
 
 
. 
8.5. 
Recording of Adverse Events/Serious Adverse Events 
The PI/investigator is responsible for ensuring that all AEs/SAEs and pregnancies are identified, evaluated, 
recorded, and reported in a timely manner as per regulatory requirements, hVIVO SOPs, and the study-
specific protocol. The PI/investigator is also responsible for ensuring that the medical management 
(including follow-up) of AEs/SAEs and, where appropriate, pregnancy symptoms/complications is provided 
by competent investigator site staff. 
The sponsor of the study will also perform an evaluation of seriousness, causality, and expectedness of all 
SAEs. 
The definitions of an AE/SAE, as well as the method of recording, evaluating, and assessing causality of 
AE and SAE and the procedures for completing and transmitting AE/SAE, and other reportable safety event 
reports can be found in Appendix 3, Adverse Events: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting. 
8.5.1. 
Time Period and Frequency for Collecting Adverse Event and Serious 
Adverse Event Information 
All AEs/SAEs will be collected from signing of the study-specific ICF until the last scheduled follow-up visit. 
Investigators are not obligated to actively seek AEs/SAEs after conclusion of study participation. However, 
if the PI/investigator learns of any SAE, including a death, at any time after a participant has been 
discharged from the study, and he/she considers the event to be reasonably related to the study intervention 
or study participation, the PI/investigator must promptly notify the sponsor. 


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8.5.2. 
Method of Detecting Adverse Events/Serious Adverse Events 
The method of recording, evaluating, and assessing causality of AEs/SAEs and the procedures for 
completing and transmitting SAE reports are provided in Appendix 3, Adverse Events: Definitions and 
Procedures for Recording, Evaluating, Follow-up, and Reporting. 
Care will be taken not to introduce bias when detecting AEs/SAEs. Open-ended and non-leading verbal 
questioning of the participant is the preferred method to inquire about AE occurrences. 
8.5.3. 
Follow-up of Adverse Events/Serious Adverse Events 
 
 
 
 
 
 
8.5.4. 
Regulatory Reporting Requirements for Serious Adverse Events 
Any SAE will be reported immediately by the PI/investigator to the sponsor and the SME or sponsor’s 
pharmacovigilance vendor (in practice reporting within 24 hours of the PI/investigator’s knowledge of the 
event). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
8.5.5. 
Pregnancy 
 
 
 
 
 


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8.6. 
Bioanalysis/Pharmacokinetics 
Blood samples will be collected for measurement of plasma concentrations of Neumifil as specified in the 
SoE. 
A maximum of 2 samples may be collected at additional time points during the study if warranted and 
agreed upon between the PI/investigator and the sponsor. The timing of sampling may be altered during 
the study based on newly available data (e.g., to obtain data closer to the time of peak plasma 
concentrations) to ensure appropriate monitoring. 
Instructions for the collection and handling of biological samples will be provided by the sponsor. The actual 
date and time (24-hour clock time) of each sample will be recorded. 
Samples will be used to evaluate the plasma concentrations of Neumifil. Samples collected for analyses of 
Neumifil plasma concentration may also be used to evaluate safety or efficacy aspects related to concerns 
arising during or after the study. 
Genetic analyses will not be performed on these plasma samples. Participant confidentiality will be 
maintained. 
Drug concentration information that may unblind the study will not be reported to investigative sites or 
blinded study staff until the study has been unblinded. 
8.6.1. 
Pharmacokinetic Blood Samples 
Neumifil plasma concentrations will be measured and may be used to assist in evaluating the efficacy of 
Neumifil. A full PK investigation is not planned for this study. Blood samples for measurement of plasma 
concentrations of Neumifil will be collected in accordance to the SoE and plasma will be sent to sponsor’s 
PK vendor according to the AP. 
Blood samples for measurement of plasma concentrations of Neumifil will be collected on Days -3, -2, and 
-1 at the following time points: predose (within 2 hours before IMP administration) and 1, 2, and 3 hours 
(±15 mins) postdose. 
8.6.2. 
Pharmacokinetic Parameters 
Pharmacokinetic parameters of interest may include: 
AUC0-t, AUC0-∞, Cmax, tmax, t1/2 
Pharmacokinetic parameters will be calculated using non-compartmental methods. Parameters will be 
summarised descriptively. 
A full PK investigation is not planned for this study. Neumifil plasma concentrations will be measured and 
may be used to assist in evaluating the efficacy of Neumifil. 


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8.6.3. 
Anti-drug Antibodies 
Serum samples will be collected to measure the incidence of anti-drug antibodies (ADAs) to Neumifil during 
the study. 
8.7. 
Pharmacodynamics 
Pharmacodynamic parameters are not evaluated in this study. 
8.8. 
Immunogenicity Assessments 
Blood will be collected for immunological analysis. 
Humoral immune responses, e.g., haemagglutination inhibition (HAI) will be evaluated in serum samples 
collected from all participants according to the SoE.  
 
 
 
 
 
8.9. 
Genetics 
 
8.10. 
Biomarkers 
Collection of samples for biomarker research is also part of this study. The following samples for biomarker 
research are required and will be collected from all participants in this study as specified in the SoE: 
• 
Nasosorption 
• 
Serum 
 
 
 
 
 
 
8.10.1. 
Immunology Biomarker Evaluations 
Blood will be taken for exploratory immunology and genomic analysis related to viral infection/study 
intervention(s), including but not limited to: 
• 
Influenza antibodies 


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• 
Immunoglobulin [Ig] A [IgA] and G [IgG] antibodies 
• 
PAXgene RNA 
Sample processing, storage, and assessments will be detailed in the AP. 


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9. 
Statistical Considerations 
9.1. 
Statistical Hypothesis 
The primary statistical hypothesis is that prophylactic treatment with Neumifil will significantly reduce the 
incidence and/or the severity of symptomatic influenza infection after influenza viral challenge when 
compared to placebo. Individual comparisons of each Neumifil dose arm to the placebo arm will be 
performed with an exploratory purpose. No adjustment for multiple comparisons will be performed. 
9.2. 
Sample Size Determination 
The sample size is based on the primary comparison of the 2 active treatment arms pooled to the placebo 
arm. The study has not been powered for the comparisons between each active treatment arm to the 
placebo arm and these comparisons will be presented for exploratory purposes. Nevertheless, for some of 
the endpoints, a power above 80% is achieved for these comparisons. 
The number of 40 participants in the placebo arm and 60 (30 in each dose arm) in the pooled Neumifil 
group selected for this study will provide a power of at least 80% to detect a significant reduction in the 
primary endpoints: 
• 
of 70% compared to the placebo arm in symptomatic influenza infection rate, assuming a 
symptomatic infection rate of 27.8% in the placebo arm,  
• 
of 65% compared to the placebo arm in peak TSS, assuming a coefficient of variation (CV) of 
125%, 
using a 1-sided 0.05 type-one error rate for each of the 2 comparisons, without adjustment for multiple 
testing.  
The table below summarises the power achieved with 40 versus 60 participants (for the placebo and 
pooled active treatment arms, respectively) for the 2 primary endpoints and some secondary endpoints. 
 
Endpoint 
Assumption 
(placebo arm) 
Relative reduction 
Power (*) 
Symptomatic infection rate 
rate=27.8% 
70% 
81.5% 
Peak TSS 
CV=125% 
65% 
81.2% 
VL-AUC 
CV=91% 
50% 
84.8% 
VLPEAK 
CV=63.5% 
40% 
92.2% 
TSS-AUC 
CV=155% 
80% 
80.7% 
(*) Power achieved with placebo and 60 Neumifil participants (alpha 0.05 1-sided). 
CV = coefficient of variation. 
 
Corresponding power calculations for the comparison of the placebo arm (40 participants) to one of the 
2 Neumifil dose arms (30 participants) are provided below: 


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Endpoint 
Assumption (placebo 
arm) 
Relative reduction 
Power (*) 
Symptomatic infection rate 
rate=27.8% 
70% 
66.6% 
Peak TSS 
CV=125% 
65% 
68.7% 
VL-AUC 
CV=91% 
50% 
72.8% 
VLPEAK 
CV=63.5% 
40% 
82.6% 
TSS-AUC 
CV=155% 
80% 
68.1% 
(*) Power achieved with placebo and 30 Neumifil participants (alpha 0.05 1-sided). 
CV = coefficient of variation. 
9.3. 
Populations for Analyses 
The study populations are defined in Table 9-1. 
Table 9-1: 
Study Populations 
Population 
Description 
Enrolled  
All participants who have been randomised. 
Potential participants who are screened for the purpose of determining 
suitability for the study, but do not participate in the study, are not 
considered enrolled, unless otherwise specified by the protocol.  
Intent-to-treat (ITT) analysis 
set 
All participants randomised, having received at least 1 dose of IMP, and 
challenged with the study virus. 
Intent-to-treat infected (ITT-I) 
analysis set 
All participants randomised, having received at least 1 dose of IMP, and 
challenged with the challenge virus, and who were infected with 
challenge virus as per the definition of laboratory-confirmed infection. 
Per protocol (PP) analysis set 
All participants randomised, having received the planned dose of IMP 
(Neumifil 3 doses on Days -3 to -1, 1 single dose of Neumifil on Day -3 
followed by 2 doses of placebo on Days -2 and -1; or placebo 3 doses 
on Days -3 to -1, according to randomisation) and challenged with the 
study virus, who complete the quarantine period up to its planned final 
day (Day 8) and present no major deviation likely to impact the 
evaluation of the primary efficacy endpoint. 
Safety analysis set 
All participants randomised having received at least 1 dose of IMP. 
Participants will be analysed according to the intervention (multiple dose 
Neumifil, single dose Neumifil, placebo) they received. 
PK analysis set 
All participants randomised having received at least 1 dose of IMP, with 
at least 1 postdose PK result. 
Membership of participants in each analysis set will be determined at a planned data review meeting, prior 
to any analysis and database lock. 
The primary efficacy analysis will be on the PP analysis set. The ITT analysis set will be used for supportive 
analyses on all or part of the primary and secondary efficacy endpoints, as defined in the statistical analysis 


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plan (SAP). The safety evaluation will be performed on the safety analysis set. Additional analysis sets may 
be defined in the SAP. 
9.4. 
Statistical Analyses 
This section is a summary of the planned statistical analyses of the most important endpoints including 
primary and key secondary endpoints. 
Data will be analysed and reported using SAS® version 9.4 or later. 
9.4.1. 
Statistical Analysis Plan 
The SAP will be developed and finalised prior to database lock for the study. The finalised SAP will be 
signed prior to unblinding the study data. The SAP will provide a more technical, detailed, and 
comprehensive description of the statistical analyses that will be computed, expanding on the 
protocol-specified analysis. 
Any deviation(s) from the original statistical plan outlined in the protocol will be described and justified in an 
amendment to the protocol and/or SAP, as appropriate, and referenced in the final clinical study report. 
Further post-hoc evaluations of any exploratory endpoints may be conducted and reported separately. 
9.4.2. 
General Considerations 
9.4.2.1. 
Descriptive Statistics 
Continuous variables will be summarised using number of available data, number of missing data, mean 
(and/or geometric mean, where applicable), standard deviation, median, lower quartile, upper quartile, 
minimum, and maximum values. When relevant, confidence intervals (CIs) will be computed for the mean 
and/or the median. 
Categorical variables will be summarised using number of available data, number of missing values, 
frequency counts for each category and corresponding percentage. Percentages will be calculated using 
the number of available data as the denominator (i.e., not including missing values). When relevant, CIs 
will be computed. If not otherwise specified in the SAP, the Wilson Score Method will be used to compute 
CIs for proportions. 
9.4.2.2. 
Inferential Statistics and Significance Testing 
Between-arm comparisons will be performed using appropriate hypothesis tests at the 5% 1-sided 
significance level, except if otherwise specified. No adjustment for multiple testing will be performed (see 
Section 9.1, Statistical Hypothesis). 
The main analyses will be the ones comparing the 2 active treatment arms pooled to the placebo arm. 
These analyses will be repeated with an exploratory purpose to the comparison of each Neumifil arm to the 
placebo. 
For continuous variables (either raw data or log-transformed data) the difference in means, the standard 
error and the 90% and 95% 2-sided CIs will be presented. In case of log-transformed variables, in addition 
to the previous statistics on the log-transformed data, the geometric means and geometric mean ratio and 


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its 90% and 95% 2-sided CIs for the original variable will be presented. The Wilcoxon rank sum test, t-test, 
or analysis of covariance will be used, depending on whether the endpoints are normally distributed. Details 
on the method used for each endpoint will be provided in the SAP. Methods for checking statistical model 
assumptions and alternative methods of analysis if the assumptions are not fulfilled will be described in the 
SAP. 
For categorical variables, differences in absolute frequency and/or relative risks will be presented, with their 
90% and 95% 2-sided CIs. Except otherwise specified in the SAP, the Chi-square test (or Fisher exact test) 
will be used to compare frequencies between study intervention arms. 
9.4.3. 
Planned Analysis 
9.4.3.1. 
Participant Accountability 
The number of participants receiving challenge agent, receiving IMP (Neumifil/placebo), withdrawing from 
(also split by reason for withdrawal), and completing the study, and the numbers in each analysis set, will 
be summarised. 
9.4.3.2. 
Protocol Deviations 
Participant’s data will be reviewed for major protocol deviations prior to database lock at a planned data 
review meeting, and decisions will be documented within the meeting minutes. At this meeting, participants 
will be reviewed for their inclusion/exclusion from the analysis sets. 
9.4.3.3. 
Demographic and Baseline Characteristics 
Descriptive statistics of demographics (age, sex, height, body weight, BMI, and ethnicity) will be presented 
by study intervention arm (each individual dose arm, the pooled Neumifil arms, and the placebo arm) and 
across all participants. Medical history information will be listed. Other baseline characteristics will be 
defined in the SAP. 
9.4.3.4. 
Compliance to Study Intervention 
For each participant, the proportion of the planned dose actually received will be computed. 
Compliance with IMP (Neumifil/placebo) will be computed for each study intervention arm as the proportion 
of participants actually receiving IMP as prescribed (i.e., 100% of the planned dose has been received). 
9.4.4. 
Primary Efficacy Analysis 
The primary efficacy analysis will be conducted on the per protocol (PP) analysis set (Section 9.3, 
Populations for Analyses). 
For the symptomatic infection rate, the estimator with its 2-sided 90% and 95% CIs will be presented by 
treatment arm. The differences between the pooled active treatment arms and the placebo arm, and 
between each active treatment dose arm and the placebo arm, will be computed with their 2-sided 90% 
and 95% CIs. The 3 pairwise comparisons will use the Pearson Chi-square test, or the Fisher exact test if 
the assumptions for the Chi-square test are not met. Each test will use a nominal 1-sided type-one error of 


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0.05 without adjustment for multiplicity. In addition, the difference between the 2 Neumifil dose arms will be 
computed with its 90% and 95% CIs but no formal statistical test will be computed. 
For the peak TSS, the mean and median and the 2-sided 90% and 95% CIs for the mean will be presented 
by treatment arm. The differences between the pooled active treatment arms and the placebo arm, and 
between each active treatment dose arm and the placebo arm, will be computed with their 2-sided 90% 
and 95% CIs. The 3 pairwise comparisons will use the Wilcoxon rank-sum test. Each test will use a nominal 
1-sided type-one error of 0.05 without adjustment for multiplicity. In addition, the difference between the 
2 Neumifil dose arms will be computed with its 90% and 95% CIs but no formal statistical test will be 
computed. 
Further details on the primary efficacy analysis will be provided in the SAP. 
9.4.5. 
Secondary Efficacy Analysis 
Secondary endpoints as outlined in Section 3, Objectives and Endpoints, will be summarised by study 
intervention arm as described in Table 9-2. Further details on the secondary efficacy analysis will be 
provided in the SAP. 
Table 9-2: 
Methods for Analysis of Secondary Efficacy Endpoints 
Endpoint 
Analysis 
TSS-AUC 
Descriptive statistics for continuous variables by treatment arm 
(Section 9.4.2, General Considerations). 
Inferential analysis: pairwise t-tests or Wilcoxon rank sum tests. 
Peak viral load by qRT-PCR 
Descriptive statistics for continuous variables (Section 9.4.2, 
General Considerations).Inferential analysis: Wilcoxon rank sum 
test. 
Peak daily symptom score 
Descriptive statistics for continuous variables (Section 9.4.2, 
General Considerations). 
No inferential analysis. 
Number (%) of participants with 
grade 2 or higher symptoms, starting 
from Day 1 (am) up to planned 
discharge from quarantine (Day 8, 
am) 
Descriptive statistics for categorical variable variables 
(Section 9.4.2, General Considerations). 
Inferential analysis: pairwise Chi-square tests (or Fisher exact 
tests). 
Duration 
of 
clinical 
symptoms: 
1) any symptoms. 
Descriptive statistics for continuous variables (Section 9.4.2, 
General Considerations). 
No inferential analysis. 
Duration 
of 
clinical 
symptoms: 
2) TSS of 2 or more (with at least 
2 systems) 


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Duration 
of 
clinical 
symptoms: 
3) grade 2 or higher symptoms 
Time to resolution from peak clinical 
symptoms 
Descriptive statistics for continuous variables (Section 9.4.2, 
General Considerations). 
Kaplan Meier curves will be prepared. 
No inferential analysis. 
Area under the qRT-PCR viral load-
time curve (VL-AUC) 
Descriptive statistics for continuous variables by treatment arm 
(Section 9.4.2, General Considerations).Inferential analysis: 
pairwise t-tests or Wilcoxon rank sum tests. 
Area under the tissue culture viral 
load-time curve (VL-AUC) 
VLPEAK (qRT-PCR) 
VLPEAK (tissue culture) 
Duration of quantifiable influenza 
(qRT-PCR) 
Descriptive statistics for continuous variables (Section 9.4.2, 
General Considerations). 
No inferential analysis. 
Duration of quantifiable influenza 
(tissue culture) 
Duration of detectable influenza 
(tissue culture) 
Time to resolution from VLPEAK by 
qRT-PCR 
Descriptive statistics for continuous variables (Section 9.4.2, 
General Considerations). 
Kaplan Meier curves will be prepared. 
No inferential analysis. 
Time to resolution from VLPEAK by 
quantitative viral culture 
Total weight of mucus produced 
Descriptive statistics for continuous variables (Section 9.4.2, 
General Considerations). 
No inferential analysis. 
Total number of tissues used 
Incidence 
of 
RT-PCR-confirmed 
influenza 
infection, 
defined 
as 
2 quantifiable (≥ LLOQ) qRT-PCR 
measurements (reported on 2 or 
more independent nasal samples 
over 2 days)* 
Descriptive statistics for categorical variable variables 
(Section 9.4.2, General Considerations). 
Inferential analysis: pairwise Chi-square tests (or Fisher exact 
tests). 
Occurrence of at least 1 positive 
quantitative (≥ LLOQ) cell culture 
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Incidence of cell culture-confirmed 
symptomatic influenza infection 
Number (%) of participants with lab-
confirmed 
infection 
and 
fever 
(≥37.9°C) 
LLOQ = lower limit of quantification; (q)RT-PCR = (quantitative) reverse transcriptase polymerase chain reaction; 
TSS = total symptoms score; TSS-AUC = area under the curve over time of total symptoms score; VL-AUC = area 
under the viral load-time curve; VLPEAK = peak viral load. 
* Additional sensitivity analyses using alternative definitions for symptomatic infections may be added in the 
Statistical Analysis Plan (SAP). 
9.4.6. 
Tertiary/Exploratory Analysis 
Tertiary/exploratory endpoints as outlined in Section 3, Objectives and Endpoints, will be summarised by 
study intervention arm. Further details are described in the SAP. 
9.4.7. 
Safety Analyses 
All safety analyses will be computed on the safety analysis set. 
Unless otherwise stated, safety endpoints will be presented in terms of descriptive statistics only. 
Adverse events will be coded using the most current version of the Medical Dictionary for Regulatory 
Activities (MedDRA) and summarised descriptively by system organ class, preferred term, and study 
intervention arm for the number of AEs reported and the number and percentage of participants reporting 
each AE. 
 
 
 
 
 
Further details on the safety analyses will be provided in the SAP. 
9.4.8. 
Bioanalysis/Plasma Concentrations 
Descriptive statistics will be calculated for the plasma concentrations of Neumifil at each applicable time 
point and for the derived plasma PK parameters. Statistics include sample size (n), mean, standard 
deviation, coefficient of variation (CV), geometric mean, median, minimum, and maximum. 
For each participant, plasma concentration-time data of Neumifil will be graphically presented. Similarly, 
graphs of the mean plasma concentration-time profiles and overlay graphs with combined individual plasma 
concentration-time profiles will be produced. 
Additional PK analyses may be performed as deemed necessary. 
The details of the PK analyses will be provided in a separate PK analysis plan. 


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9.5. 
Interim Analysis 
No interim analyses are planned for this study. 
9.6. 
Data Monitoring Committee 
Not applicable. 


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10. 
Supporting Documentation and Operational Considerations 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations 
10.1.1. 
Regulatory and Ethical Considerations 
This study will be conducted in accordance with the protocol and with the following: 
• 
Consensus ethical principles derived from international guidelines including the Declaration of 
Helsinki and Council for International Organisations of Medical Sciences International Ethical 
Guidelines. 
• 
Applicable ICH Good Clinical Practice (GCP) guidelines. 
• 
Applicable laws and regulations. 
 
 
 
 
 
 
The PI/investigator will be responsible for the following: 
• 
Providing written summaries of the status of the study to the REC annually, or more frequently, in 
accordance with the requirements, policies, and procedures established by the REC. 
• 
Notifying the REC of SAEs or other significant safety findings as required by REC procedures. 
• 
Providing oversight of the conduct of the study at the site and adherence to requirements of ICH 
guidelines, the REC, the REC, UK SI 2004/1031 The Medicines for Human Use (Clinical Trials) 
Regulations, European regulation 536/2014 for clinical studies (if applicable), and all other 
applicable local regulations. 
10.1.2. 
Financial Disclosure 
 
 
 
 
10.1.3. 
Confidentiality 
The PI/investigator will preserve the confidentiality of participants taking part in the study and is registered 
under the Data Protection Act. 


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10.1.4. 
Informed Consent Process 
The trained and delegated study staff competent to perform the informed consent procedure will obtain a 
signed study-specific ICF from each participant before any study-specific procedures are performed. 
Historical screening data may be collected through the hVIVO generic screening process, which is a 
comprehensive assessment of health status including previous medical history. For assessments taken 
under the hVIVO generic screening, a separate informed consent is obtained. 
When historical screening data collected through the hVIVO generic screening process is used for 
screening, the study-specific ICF will be obtained at the first study-specific visit from each participant before 
any study-specific procedures are performed. 
Potential participants will typically be sent a copy of the REC approved study-specific ICF at the time of 
invite to the first study-specific visit and at least a day prior to the visit and will be encouraged to read it prior 
to their appointment. Upon arrival at the screening visit/quarantine admission visit (as applicable), the study-
specific ICF is discussed by the trained and delegated study staff competent to perform the informed 
consent procedure, and the participants will be given the opportunity to ask any questions and may take 
the information sheet away to consider their participation. 
All participants will be required to have a good understanding of English and the PI/investigator will be 
responsible for ensuring that the participant understands the information contained in the ICF. Once the 
PI/investigator has confirmed that the participant has capacity and has understood the study, including the 
benefits and risks of participation, the participant and the PI/investigator can sign and date the study-specific 
ICF. 
The study-specific ICF must be signed and dated by the participant and countersigned by the trained and 
delegated study staff competent to perform the informed consent procedure (whoever conducted the 
consent discussion). A copy of the study-specific ICF will be given to the participant, and the original will be 
held in the hVIVO TMF. 
Participants will be assured that they can withdraw from the study at any time and for any reason without 
prejudice to their future medical care, and that they will be informed in a timely manner if new information 
becomes available that may affect their willingness to continue their participation in the study. This 
information will be included within in the study-specific ICF. 
The study-specific ICF will contain a separate section that addresses the use of samples for future research. 
The PI/investigator or authorised designee will explain to each participant the objectives of the exploratory 
research. Participants will be told that they are free to refuse to participate (with no requirements to disclose 
the reason for withdrawal) and may withdraw their consent at any time and for any reason. 
10.1.5. 
Data Protection 
Participants will be assigned a unique identifier by hVIVO. Any participant records or datasets that are 
transferred to the sponsor will contain the identifier only; participant names or any information which would 
make the participant identifiable will not be transferred. 
The participant must be informed that his/her personal study-related data will be used by the sponsor in 
accordance with local data protection law. The level of disclosure must also be explained to the participant 
in the ICF. 


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The participant must be informed that his/her medical records may be examined by clinical quality 
assurance auditors or other authorised study staff appointed by the sponsor, by appropriate REC members, 
and by inspectors from regulatory authorities. 
10.1.6. 
Committee(s) Structure 
This study will not include an early safety data review. 
10.1.7. 
Dissemination of Clinical Study Data 
The key design elements of this protocol will be posted on publicly accessible registry. 
 
 
 
 
 
 
 
 
 
 
 
10.1.8. 
Data Quality Assurance 
Participant data will be collected at site using paper source casebooks which will then be data entered into 
the eCRF database unless transmitted to the sponsor or designee electronically (e.g., laboratory data). The 
PI/investigator is responsible for verifying that data entries are accurate and correct by physically or 
electronically signing the eCRF. 
The PI/investigator must maintain accurate documentation (source data) that supports the information 
entered in the eCRF. This can be paper source and/or eSource. 
The PI/investigator must permit study-related monitoring, audits, REC review, and regulatory agency 
inspections and provide direct access to source data documents. 
 
 
 
 
 
 
 
 
 
 
 
 
 


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10.1.9. 
Source Documents 
Source documents provide evidence for the existence of the participant and substantiate the integrity of the 
data collected. Source documents are filed at the investigator’s site. 
 
 
 
 
 
10.1.10. Study Discontinuation 
The sponsor reserves the right to temporarily suspend or terminate the study for any reason at any time. In 
addition, the study may be temporarily put on hold or terminated at any time if, in the opinion of the 
PI/investigator, the safety data suggest that the medical safety of participants is being compromised. 
 
 
 
 
 
 
 
Termination of the clinical study may also be initiated by the MHRA or the REC. 
10.1.11. Publication Policy 
By signing the study protocol, the PI/investigator agrees that the results of this study may be used for the 
purposes of national and international registration, for publication, and as information for medical and 
pharmaceutical professionals by the sponsor. 
If necessary, the authorities will be notified of the PI/investigator’s name, address, qualifications, and extent 
of involvement. To allow the use of the information derived from this clinical study, the PI/investigator 
understands that he/she has an obligation to provide complete test results and all data developed during 
this study to the sponsor. 
If the study is to be published, the sponsor and hVIVO may jointly prepare and co-author manuscript(s) that 
could result from the clinical study. In the case the sponsor acts as fully responsible for the publication, the 
sponsor agrees to allow the PI/investigator time to review all manuscripts and abstracts prior to submission 
for publication. The sponsor reserves the right to include the report of this study in any regulatory 
documentation or submission or in any informational materials. The sponsor also reserves the right to delete 
any confidential information from any proposed manuscripts prior to submission for publication. 
Confirmation of study-specific arrangements can be found in the clinical study agreement. 
 
 


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10.2. 
Appendix 2: Clinical Laboratory Tests 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
. 
 
 


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10.3. 
Appendix 3: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting 
10.3.1. 
Adverse Event 
Adverse Event Definition 
 
 
 
 
 
 
 
Solicited Adverse Events 
 
 
 
 
 
 
 
 
 
 
 
 
Unsolicited Adverse Events 
 
 
 
Events Meeting the Adverse Event Definition 
• 
 
 
 
 
 
 
 
 


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• 
 
 
Events NOT Meeting the Adverse Event Definition 
• 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
• 
 
 
 
 
10.3.2. 
Adverse Drug Reaction 
An adverse drug reaction is any untoward and unintended response in a participant to an IMP which is 
related to any dose administered to that participant. 
‘Response’ in this context means that a causal relationship between a medicinal product and an AE is at 
least a reasonable possibility. 


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All AEs assessed by either the reporting PI/investigator or the sponsor as having a reasonable causal 
relationship to an IMP qualify as adverse drug reactions. The expression ‘reasonable causal relationship’ 
means to convey in general that there is evidence or argument to suggest a causal relationship. 
10.3.3. 
Unexpected Adverse (Drug) Reaction 
An “Unexpected Adverse (Drug) Reaction” means an adverse reaction, the nature and severity of which is 
not consistent with the information about the medicinal product in question set out: 
a) In the case of a product with a marketing authorisation, in the Summary of Product Characteristics 
for that product, 
b) In the case of any other IMP, in the Investigator’s Brochure relating to the study in question. 
10.3.4. 
Serious Adverse Event 
Serious Adverse Event Definition  
A Serious Adverse Event is defined as any untoward medical occurrence that, at any dose: 
a. 
Results in death 
b. 
Is life-threatening 
 
 
 
c. 
Requires inpatient hospitalisation or prolongation of existing hospitalisation 
• 
 
 
 
 
 
 
 
 
 
d. 
Results in persistent disability/incapacity 
• 
 
 
 
 
 
 
 
e. 
Is a congenital anomaly/birth defect 


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f. 
Is an important medical event 
• 
 
 
 
 
 
 
 
 
 
10.3.5. 
Suspected Unexpected Serious Adverse Reaction 
A SUSAR is a serious adverse reaction, the nature and severity* of which is not consistent with the 
information about the medicinal product in question, as defined in the Investigator’s Brochure relating to the 
study in question. 
 
 
 
 
 
 
 
10.3.6. 
Recording, Assessment, and Follow-up of Adverse Events/Serious 
Adverse Events 
10.3.6.1. Adverse Event/Serious Adverse Event Recording 
All AEs/SAEs will be collected from the time of written study-specific informed consent until study 
completion/final study contact or until the resolution of the AE. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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The PI/investigator will record all relevant information regarding an AE/SAE in the source documents and 
evaluate AEs/SAEs using the following guidelines: 
• 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
10.3.6.2. Assessment 
Description 
 
 
Onset and end 
The dates and times of the onset and end of the event should be recorded. 


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Assessment 
Challenge Agent-related Symptoms 
 
 
 
 
 
 
 
 
Physical Examination 
 
 
Symptom-directed Physical Examination 
 
 
 
 
 
Vital Signs 
 
 
 
 
Temperature 
 
 
 
 
 
 
Spirometry 
 
 
 
 
 


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. 
Laboratory Values 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
10.3.6.3. Assessment of Intensity 
 
 
 
 
 
 


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Table 10-2: 
Classification of Adverse Events Severity 
Grade 
Classification 
Definition 
Grade 1 
Mild 
Mild level of discomfort, and does not interfere with regular activities 
Grade 2 
Moderate 
Moderate level of discomfort and significantly interferes with regular 
activities 
Grade 3 
Severe 
Significant level of discomfort and prevents regular activities 
Grade 4 
Life-threatening  
Extreme limitation in activity, significant assistance required; 
significant medical intervention/therapy required, hospitalisation or 
hospice care probable 
An event is defined as ‘serious’ when it meets at least one of the predefined outcomes as described in the 
definition of an SAE, NOT when it is rated as severe. 
10.3.6.4. Frequency 
 
 
 
 
 
 
 
10.3.6.5. Assessment of Causality 
• 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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• 
The PI/investigator may change his/her opinion of causality considering follow-up information and 
send an SAE follow-up report with the updated causality assessment. 
• 
The causality assessment is one of the criteria used when determining regulatory reporting 
requirements. 
The relationship of an AE to the IMP will be categorised as shown in Table 10-3. 
Table 10-3: 
Classification of Adverse Events Relationship 
Classification 
Definition 
Not related 
 
 
Unlikely to be related 
 
 
Definitely related 
 
 
Possibly related 
 
 
 
 
Probably related 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
10.3.6.6. Action Taken 
 
 
 
 
 
 
 
 


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• 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
10.3.6.7. Outcome 
 
 
Table 10-4: 
Classification of Adverse Events Outcome 
Classification 
Definition 
 
 
 
 
 
 
 
 
 
 
 
 
10.3.6.8. Follow-up 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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10.3.7. 
Reporting of Serious Adverse Events 
Serious AEs must be documented and reported as per hVIVO SOPs. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Table 10-5: 
Contact Details for Reporting All Serious Adverse Events 
Contact 
Details 
Name of sponsor’s medical expert (SME): 
 
SME SAE telephone number: 
 
Pharmacovigilance reporting email:  
 
Pharmacovigilance telephone reporting: 
 
SAE email address:  
pvservices@propharmagroup.com  
(cc to 
) 
 
 
 
 
 
 
 
 
 
 


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10.3.11. Pregnancy 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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10.4. 
Appendix 4: Normal Ranges 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
  
 
 


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10.5. 
Appendix 5: Genetics 
 
 


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10.6. 
Appendix 6: Abbreviations 
Abbreviation  
Term 
ADA 
Anti-drug antibody 
AE 
Adverse event 
AESI 
Adverse event of special interest 
AP 
Analytical plan 
AUC0-∞ 
Area under the concentration-time curve from time zero to infinity 
AUC0-t 
Area under the concentration-time curve from time zero to time t 
BD 
Twice daily 
β-hCG 
β-human chorionic gonadotrophin 
BMI 
Body mass index 
CBM 
Carbohydrate binding module 
(c)GMP 
(current) Good Manufacturing Practice 
CI 
Confidence interval 
Cmax 
Maximum observed concentration 
COVID19 
Coronavirus Disease 2019 
CRF 
Case report form 
CV 
Coefficient of variation 
CYP 
Cytochrome P450 
DBP 
Diastolic blood pressure 
DNA 
Deoxyribonucleic acid 
ECG 
Electrocardiogram  
eCRF 
Electronic case report form 
FDA 
Food and Drug Administration 
FEV(1) 
Forced expiratory volume (in 1 second) 
FSH 
Follicle-stimulating hormone 
FVC 
Forced vital capacity 
GAD 
Generalised Anxiety Disorder 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
GP 
General practitioner 
HAI 
Haemagglutination inhibition 
HIV 
Human immunodeficiency virus 
ICF 
Inform consent form 
ICH 
International Council for Harmonisation 
Ig 
Immunoglobulin 
IgA 
Immunoglobulin A 
IgG 
Immunoglobulin G 
IMP 
Investigational medicinal product 
ITT 
Intent-to-treat 
ITT-I 
Intent-to-treat infected 
IWRS 
Interactive Web Response System 
LLOD 
Lower limit of detection 
LLOQ 
Lower limit of quantification 
LRT 
Lower respiratory tract 
MedDRA 
Medical Dictionary for Regulatory Activities 
MHRA 
Medicines and Healthcare products Regulatory Agency 
NOAEL 
No observed adverse effect level 
PCR 
Polymerase chain reaction 
PHQ 
Patient Health Questionnaire 
PI 
Principal investigator 


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PK  
Pharmacokinetic 
PP 
Per protocol 
(q)RT-PCR 
(Quantitative) reverse transcriptase polymerase chain reaction 
REC 
Research Ethics Committee 
RNA 
Ribonucleic acid 
RSV 
Respiratory syncytial virus 
RVAT 
Rapid viral antigen test 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SARS-CoV-2 
severe acute respiratory syndrome coronavirus 2 
SBP 
Systolic blood pressure 
SME 
Sponsor’s medical expert 
SoE 
Schedule of events 
SOP 
Standard operating procedure  
SpO2 
Peripheral arterial oxygen saturation 
SUSAR 
Suspected unexpected adverse reaction 
T1/2 
Terminal half-life 
TCID50 
Tissue culture infective dose (50%) 
TD 
Trimerisation domain 
Tmax 
Time to maximum concentration  
TMF 
Trial master file 
TSS 
Total symptoms score 
TSS-AUC 
Area under the curve over time of total symptoms score 
UK 
United Kingdom 
URT 
Upper respiratory tract 
VL-AUC 
Area under the viral load-time curve 
VLPEAK 
Peak viral load 
WHO 
World Health Organisation 
 
 
 


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10.7. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 




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11. 
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