Clinical trial NCT06067191
Conditions: Respiratory Syncytial Virus (RSV)
Keywords: Anti-viral Challenge
Sponsor: Pfizer
Start date: 2022-08-08; Completion date: 2022-12-02
Enrollment: 82 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of the study is to learn about the safety, pharmacokinetics and antiviral activity of the study medicine (RV299) for the potential treatment of respiratory syncytial virus (RSV). RSV is a highly contagious virus that can lead to serious lung infections in patients with reduced ability to fight infection. Most vulnerable populations include babies, the elderly and patients that have received a bone marrow transplant.

Detailed description:
This study is seeking healthy participants who are:

Healthy adult male and female participants aged between 18 to 55 years, with a total body weight ≥50 kg and body mass index (BMI) ≥18 kg/m2 and ≤35kg/m2 and who have been screened to be sero-suitable for infection with the RSV-A Memphis 37b virus challenge virus.

A total of 80 participants is planned: 40 participants on RV299 and 40 participants on placebo.

The study is divided into 3 phases:

* Screening phase: from Day -90 to Day-3 pre-human viral challenge (HVC).
* Inpatient phase: Participants will be resident in the quarantine unit for approximately 15 days (from Day -2 to Day 12).

  * Post RSV-A Memphis 37b virus inoculation on Day 0, participants will be randomized to receive RV299 or matched placebo.
  * Administration of RV299 or placebo will be twice daily (\~12 hours interval) for 5 consecutive days and will start on confirmation of RSV infection.
* Outpatient phase: Day 28 (±3 days)

Arms: arm 1: spray-dried dispersion (SDD) for Oral Suspension arm 2: spray-dried dispersion (SDD) for Oral Suspension
Interventions: intervention 1: RV299 intervention 2: Placebo
Intervention descriptions: intervention 1: Oral Suspension intervention 2: matching placebo

Protocol documents:
Prot_000.pdf: 
Protocol number: REVD002/VIR-CST-001 
Version: final v3.0, 31Oct2022 
Confidential 
Page 1 of 109 
 
 
 
 
CLINICAL STUDY PROTOCOL 
A RANDOMISED, PHASE 1B, DOUBLE-BLIND, PLACEBO-CONTROLLED STUDY TO EVALUATE 
THE SAFETY, PHARMACOKINETICS, AND ANTIVIRAL ACTIVITY OF RV299 AGAINST 
RESPIRATORY SYNCYTIAL VIRUS IN THE VIRAL CHALLENGE MODEL 
 
 
 
Short Title: 
Safety, pharmacokinetics, and antiviral activity of 
RV299 against respiratory syncytial virus (RSV) 
Version and Date of Protocol: 
Final version 3.0, 31Oct2022 
Sponsor: 
ReViral Limited 
Stevenage Bioscience Catalyst 
Gunnels Wood Road 
Stevenage SG1 2FX United Kingdom (UK) 
Sponsor Protocol Number: 
REVD002 
hVIVO Protocol Number: 
VIR-CST-001 
Compound Number: 
RV299 
IRAS ID: 
1005624 
 
 
 
Confidentiality and Protections Statement: 
This document contains confidential information of hVIVO and ReViral 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 ReViral Limited. 
Personal data included in the protocol is subject to General Data Protection Regulation (European 
Union 2016/679) considerations and protections. 


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PPD 
PPD 
PPD 
 
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: 
 
 
 
 
 
 
November 3, 2022 
 
 
PPD 
 , MBBCh, MBA 
PPD 
 PPD 
 
Date 
(DD MMM YYYY) 
PPD 


Protocol number: REVD002/VIR-CST-001 
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PPD 
 
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):  Dr PPD 
 
 
 
 
 
 
 
 
Signature: 
Date: 04 NOV 2022 
 
 
(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. 


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P
PPD
PPD
 
Study Staff Contact Information 
 
CONTACT 
DETAILS 
Sponsor 
ReViral Limited 
Stevenage Bioscience Catalyst 
Gunnels Wood Road 
Stevenage SG1 2FX 
United Kingdom (UK) 
Sponsor’s representative 
PPD 
 
ReViral Inc. 
PPD 
 
Principal investigator and Clinical 
Study Unit 
Dr,PPPD 
 
PPD 
 
Sponsor's medical expert 
Dr PPD 
 
ReViral Limited 
PPD 
 
Medical monitor 
Dr PPD 
 
ReViral Limited 
PPD 
 
Key protocol contributors 
Refer to the local study contact list document 


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Table of Contents 
Protocol Amendment Summary of Changes Table ............................... 
. 
Table of Contents .................................................................................................................................... 5 
List of Tables ........................................................................................................................................... 8 
1. 
Protocol Synopsis ....................................................................................................................... 9 
1.1. 
Study Schematic: On-study Participant Progression .............................................................. 17 
1.2. 
Schedule(s) of Events (SoE) .................................................................................................. 18 
2. 
Introduction ............................................................................................................................... 24 
2.1. 
Respiratory Syncytial Virus .................................................................................................... 24 
2.2. 
RV299 .................................................................................................................................... 25 
2.2.1. 
Summary of Pre-clinical and Clinical Experience .............................................................. 25 
2.3. 
The Respiratory Syncytial Virus Human Challenge Model ..................................................... 27 
2.4. 
Study Rationale ...................................................................................................................... 27 
2.5. 
Benefit/Risk Assessment ........................................................................................................ 28 
2.5.1. 
Risk Assessment ............................................................................................................... 28 
2.5.1.1. 
Vulnerable Persons ...................................................................................................... 33 
2.5.1.2. 
Risk Associated with Coronavirus Disease 2019 Pandemic ........................................ 33 
2.5.2. 
Benefit Assessment .......................................................................................................... 34 
2.5.3. 
Overall Benefit: Risk Conclusion ....................................................................................... 34 
3. 
Objectives and Endpoints ........................................................................................................ 35 
4. 
Study Design ............................................................................................................................. 39 
4.1. 
Overall Design ........................................................................................................................ 39 
4.2. 
Scientific Rationale for Study Design ..................................................................................... 40 
4.3. 
Justification for Dose .............................................................................................................. 40 
4.4. 
Rationale for Trial Endpoints .................................................................................................. 41 
4.5. 
Population to be Studied ........................................................................................................ 41 
4.6. 
End of Study Definition ........................................................................................................... 41 
5. 
Study Population ....................................................................................................................... 42 
5.1. 
Inclusion Criteria..................................................................................................................... 42 
5.2. 
Exclusion Criteria ................................................................................................................... 45 
5.3. 
Lifestyle Considerations ......................................................................................................... 48 
5.3.1. 
Meals and Dietary Restrictions .......................................................................................... 48 
5.3.2. 
Caffeine, Alcohol, and Tobacco ........................................................................................ 49 
5.3.3. 
Activity ............................................................................................................................... 49 
5.4. 
Screen Failures ...................................................................................................................... 49 
6. 
Study Intervention ..................................................................................................................... 50 
6.1. 
Study Intervention(s) Administered ........................................................................................ 50 
6.2. 
Preparation/Handling/Storage/Accountability/Administration .................................................. 51 
6.2.1. 
Investigational Medicinal Product ...................................................................................... 51 
6.2.2. 
Challenge Agent ................................................................................................................ 52 
6.2.3. 
All Study Interventions ....................................................................................................... 52 
6.3. 
Randomisation and Blinding ................................................................................................... 52 
6.4. 
Study Intervention Compliance .............................................................................................. 54 
6.5. 
Concomitant Therapy ............................................................................................................. 54 
6.6. 
Dose Modification ................................................................................................................... 55 
6.7. 
Treatment of Overdose .......................................................................................................... 56 
7. 
Discontinuation of Study Intervention/Withdrawal................................................................. 57 


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7.1. 
Participant Withdrawal ............................................................................................................ 57 
7.2. 
Participant Discontinuation ..................................................................................................... 57 
7.2.1. 
Temporary Discontinuation/Temporary Delay in Enrolment .............................................. 58 
7.3. 
Lost to Follow-up .................................................................................................................... 58 
7.4. 
Participant Replacement Strategy .......................................................................................... 58 
7.5. 
Stopping Rules ....................................................................................................................... 58 
7.6. 
Adaptive Features .................................................................................................................. 60 
8. 
Study Assessments and Procedures ...................................................................................... 62 
8.1. 
Demographics and Baseline Characteristics .......................................................................... 62 
8.1.1. 
Demographics ................................................................................................................... 62 
8.1.2. 
Height, Body Weight, and Body Mass Index ..................................................................... 62 
8.1.3. 
Medical and Medication History ........................................................................................ 62 
8.1.4. 
Challenge Agent Serology Samples.................................................................................. 63 
8.1.5. 
Patient Health Questionnaire and Generalised Anxiety Disorder Questionnaire............... 63 
8.2. 
Respiratory Samples .............................................................................................................. 63 
8.2.1. 
Nasopharyngeal Swab ...................................................................................................... 63 
8.2.1.1. 
Respiratory Pathogen Screen ...................................................................................... 63 
8.2.1.2. 
RSV Discharge Test/Rapid Viral Antigen Test ............................................................. 64 
8.2.2. 
Nasal Wash ....................................................................................................................... 64 
8.2.3. 
Viral Shedding for Dosing ................................................................................................. 64 
8.2.4. 
Viral Sequencing ............................................................................................................... 64 
8.3. 
Efficacy Assessments ............................................................................................................ 64 
8.3.1. 
Viral Shedding Assessment .............................................................................................. 64 
8.3.2. 
Participant Diary Cards ..................................................................................................... 64 
8.3.3. 
Nasal Discharge Collection from Paper Tissues ............................................................... 65 
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8.4. 
Safety Assessments ............................................................................................................... 66 
8.4.1. 
Complete Physical Examination ........................................................................................ 66 
8.4.2. 
Symptom-directed Physical Examination .......................................................................... 66 
8.4.3. 
Vital Signs and Tympanic Temperature ............................................................................ 66 
8.4.4. 
Electrocardiogram ............................................................................................................. 67 
8.4.5. 
Clinical Safety Laboratory Assessments ........................................................................... 68 
8.4.5.1. 
Urinalysis ..................................................................................................................... 68 
8.4.5.2. 
Drugs of Misuse and Cotinine ...................................................................................... 68 
8.4.5.3. 
Alcohol Breath Testing ................................................................................................. 68 
8.4.5.4. 
Safety Blood Analysis and Assessments ..................................................................... 68 
8.4.6. 
Pregnancy Tests and Follicle-stimulating Hormone .......................................................... 68 
8.4.7. 
Lung Function ................................................................................................................... 69 
8.5. 
Recording of Adverse Events/Serious Adverse Events ......................................................... 69 
8.5.1. 
Time Period and Frequency for Collecting Adverse Event and Serious Adverse Event 
Information ........................................................................................................................ 69 
8.5.2. 
Method of Detecting Adverse Events/Serious Adverse Events ......................................... 70 
8.5.3. 
Follow-up of Adverse Events/Serious Adverse Events ..................................................... 70 
8.5.4. 
Regulatory Reporting Requirements for Serious Adverse Events .................................... 70 
8.5.5. 
Pregnancy ......................................................................................................................... 70 
8.6. 
Pharmacokinetics ................................................................................................................... 71 
8.6.1. 
Pharmacokinetic Blood Samples ...................................................................................... 71 
8.6.2. 
Pharmacokinetic Parameters ............................................................................................ 71 
 
 


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9. 
Statistical Considerations ........................................................................................................ 73 
9.1. 
Statistical Hypotheses ............................................................................................................ 73 
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9.3. 
Populations for Analyses ........................................................................................................ 73 
9.4. 
Statistical Analyses ................................................................................................................ 74 
9.4.1. 
Statistical Analysis Plan .................................................................................................... 74 
9.4.2. 
General Considerations ..................................................................................................... 74 
9.4.2.1. 
Descriptive Statistics .................................................................................................... 74 
9.4.2.2. 
Inferential Statistics and Significance Testing .............................................................. 75 
9.4.3. 
Planned Analysis ............................................................................................................... 75 
9.4.3.1. 
Participant Accountability ............................................................................................. 75 
9.4.3.2. 
Protocol Deviations ...................................................................................................... 75 
9.4.3.3. 
Demographic and Baseline Characteristics ................................................................. 75 
9.4.3.4. 
Compliance to Study Intervention ................................................................................ 76 
9.4.4. 
Primary Efficacy Analysis .................................................................................................. 76 
9.4.5. 
Secondary Efficacy Analysis ............................................................................................. 76 
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9.4.7. 
Safety Analyse(s) .............................................................................................................. 78 
9.4.8. 
Pharmacokinetic Analysis ................................................................................................. 78 
9.5. 
Interim Analysis ...................................................................................................................... 78 
9.6. 
Data Monitoring Committee .................................................................................................... 78 
10. 
Supporting Documentation and Operational Considerations ............................................... 79 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations .................................. 79 
10.1.1. 
Regulatory and Ethical Considerations ............................................................................. 79 
10.1.2. 
Financial Disclosure .......................................................................................................... 79 
10.1.3. 
Confidentiality .................................................................................................................... 79 
10.1.4. 
Informed Consent Process ................................................................................................ 80 
10.1.5. 
Data Protection ................................................................................................................. 80 
10.1.6. 
Committee(s) Structure ..................................................................................................... 81 
10.1.7. 
Dissemination of Clinical Study Data ................................................................................ 81 
10.1.8. 
Data Quality Assurance..................................................................................................... 81 
10.1.9. 
Source Documents ............................................................................................................ 82 
10.1.10. 
Study Discontinuation ........................................................................................................ 82 
10.1.11. 
Publication Policy .............................................................................................................. 82 
10.2. 
Appendix 2: Clinical Laboratory Tests .................................................................................... 84 
10.3. 
Appendix 3: Adverse Events: Definitions and Procedures for Recording, Evaluating, Follow- 
up, and Reporting ................................................................................................................... 86 
10.3.1. 
Adverse Event ................................................................................................................... 86 
10.3.2. 
Adverse Drug Reaction ..................................................................................................... 87 
10.3.3. 
Unexpected Adverse (Drug) Reaction .............................................................................. 87 
10.3.4. 
Serious Adverse Event ...................................................................................................... 88 
10.3.5. 
Suspected Unexpected Serious Adverse Reaction ........................................................... 89 
10.3.6. 
Recording, Assessment, and Follow-up of Adverse Events/Serious Adverse Events ...... 89 
10.3.6.1. 
Adverse Event/Serious Adverse Event Recording ....................................................... 89 
10.3.6.2. 
Assessment ................................................................................................................. 90 
10.3.6.3. 
Assessment of Intensity ............................................................................................... 92 
10.3.6.4. 
Frequency .................................................................................................................... 92 
10.3.6.5. 
Assessment of Causality .............................................................................................. 92 
10.3.6.6. 
Action Taken ................................................................................................................ 94 


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10.3.6.7. 
Outcome ...................................................................................................................... 94 
10.3.6.8. 
Follow-up ..................................................................................................................... 95 
10.3.7. 
Reporting of Serious Adverse Events ............................................................................... 95 
10.3.8. 
Reporting of Suspected Unexpected Serious Adverse Reaction ...................................... 96 
10.3.9. 
Adverse Reactions to Non-investigational Medicinal Products ......................................... 97 
10.3.10. 
Post-study Adverse Events and Serious Adverse Events ................................................. 97 
10.3.11. 
Pregnancy ......................................................................................................................... 97 
10.4. 
Appendix 4: Normal Ranges .................................................................................................. 99 
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10.6. 
Appendix 6: Abbreviations .................................................................................................... 101 
10.7. 
Appendix 7: Definitions ......................................................................................................... 103 
10.7.1. 
General ........................................................................................................................... 103 
10.7.2. 
Study Definition of Infection and Illness .......................................................................... 104 
10.8. 
Appendix 8: Protocol Amendment History ............................................................................ 106 
11. 
References ............................................................................................................................... 108 
 
 
List of Tables 
 
Table 2-1: 
Risk Assessment ............................................................................................................... 29 
Table 6-1: 
Study Interventions ............................................................................................................ 50 
Table 6-2: 
Prohibited Medication (Healthy Participants) ..................................................................... 54 
Table 6-3: 
Permitted Medication ........................................................................................................ 55 
Table 7-1: 
Study Stopping Rules ........................................................................................................ 59 
Table 7-2: 
Adaptive Features ............................................................................................................. 60 
Table 9-1: 
Study Populations ............................................................................................................. 73 
Table 9-2: 
Analysis of Secondary Efficacy Endpoints ........................................................................ 76 
Table 10-1: 
Protocol-Required Safety Laboratory Assessments .................................................... 84 
Table 10-2: 
Classification of Adverse Events Severity .................................................................... 92 
Table 10-3: 
Classification of Adverse Events Relationship ............................................................. 93 
Table 10-4: 
Classification of Adverse Events Outcome .................................................................. 94 
Table 10-5: 
Contact Details for Reporting All Serious Adverse Events ........................................... 96 


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1. 
Protocol Synopsis 
 
Protocol Title 
A randomised, Phase 1b, double-blind, placebo-controlled study to evaluate the 
safety, pharmacokinetics (PK), and antiviral activity of RV299 against respiratory 
syncytial virus (RSV) in the viral challenge model 
Short Title 
Safety, PK, and antiviral activity of RV299 against RSV 
Protocol number 
REVD002/VIR-CST-001 
Sponsor 
ReViral Limited 
Clinical phase 
1b 
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 UK 
Study type 
Interventional 
Indication 
Treatment of RSV infection 
Design 
This is a randomised, Phase 1b, double-blind, placebo-controlled proof-of-concept, 
study of orally administered RV299 in an RSV viral challenge model 
Objectives and Endpoints 
Objectives 
Endpoints 
Primary: 
Efficacy 
• 
To assess the antiviral activity of 
RV299 compared to placebo in healthy 
adult participants infected with RSV-A 
Memphis 37b. 
• 
The area under the curve (AUC) for RSV viral load 
measured in nasal washes by quantitative real 
time reverse transcription polymerase chain 
reaction (qRT-PCR) in participants inoculated 
with RSV-A Memphis 37b, starting at initial 
administration 
of 
investigational 
medicinal 
product (IMP) up to planned discharge from 
quarantine (Day 12, am). 
Secondary: 
Efficacy 
• 
To evaluate the effect of RV299 
compared to placebo in healthy adult 
Additional viral load endpoints relating to antiviral effect 
include, but are not limited to: 


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participants inoculated with RSV in 
terms of antiviral effect assessed by: 
o 
Viral-load related endpoints. 
• 
Peak viral load of RSV as defined by the 
maximum viral load determined by qRT-PCR 
measurements in nasal samples starting from 
initial administration of IMP up to planned 
discharge from quarantine (Day 12, am). 
• 
Time (days) to confirmed negative test by qRT- 
PCR measurements in nasal samples starting at 
initial administration of IMP to first confirmed 
undetectable assessment after peak measure. 
• 
Time (days) to confirmed negative test by qRT- 
PCR measurements in nasal samples starting 
from peak qRT-PCR after initial administration of 
IMP to first confirmed undetectable assessment 
after peak measure. 
• 
Time (days) to peak qRT-PCR in nasal samples, 
starting from initial administration of IMP. 
• 
Area under the viral load-time curve (VL-AUC) of 
RSV challenge virus as determined by viral 
culture on nasal samples, starting at initial 
administration of IMP up to planned discharge 
from quarantine (Day 12, am). 
• 
Peak viral load of RSV as defined by the 
maximum viral load determined by viral culture 
measurements in nasal samples starting from 
initial administration of IMP up to planned 
discharge from quarantine (Day 12, am). 
• 
Time (days) to confirmed negative test by viral 
culture measurements in nasal samples starting 
at initial administration of IMP to first confirmed 
undetectable assessment after peak measure. 
• 
Time (days) to confirmed negative test by viral 
culture measurements in nasal samples starting 
from peak viral culture after initial administration 
of IMP to first confirmed undetectable assessment 
after peak measure. 
• 
To evaluate the effect of RV299 
compared to placebo in healthy adult 
participants inoculated with RSV in 
terms of antiviral effect assessed by: 
o 
Clinical symptom-related 
endpoints. 
Clinical symptom-related endpoints include, but are not 
limited to: 
• 
Area under the curve over time of total clinical 
symptoms (TSS-AUC) as measured from 
10 symptoms within the graded symptom scoring 
system collected 3 times daily starting at initial 
administration of IMP up to planned discharge 
from quarantine (Day 12, am). 


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• 
Area under the curve over time of total clinical 
symptoms change from baseline (TSS-AUC- 
CFB) as measured from 10 symptoms within the 
graded symptom scoring system collected 3 times 
daily starting at initial administration of IMP up to 
planned discharge from quarantine (Day 12, am). 
• 
Peak symptoms diary card score: peak total 
clinical symptoms (TSS) as measured from 
10 symptoms within the graded symptom scoring 
system collected 3 times daily starting from initial 
administration of IMP up to planned discharge 
from quarantine (Day 12, am). 
• 
Peak daily symptom score: individual maximum 
daily sum of symptom score from initial 
administration of IMP up to planned discharge 
from quarantine (Day 12, am). 
• 
Time (days) to symptom resolution as measured 
from 10 symptoms within the graded daily 
symptom scoring system starting at initial 
administration of IMP to time of returning to 
baseline score. 
• 
Time (days) to symptom resolution as measured 
from 10 symptoms within the graded daily 
symptom scoring system starting at peak 
symptoms after initial administration of IMP to 
time of returning to baseline score. 
• 
Time (days) to peak as measured from 
10 symptoms within the graded daily symptom 
scoring system starting from initial administration 
of IMP to the time of peak daily symptom score. 
• 
To evaluate the effect of RV299 on 
nasal 
discharge 
in 
healthy 
adult 
participants inoculated with RSV when 
compared to placebo. 
• 
Total weight of mucus produced starting at initial 
administration of IMP up to planned discharge 
from quarantine (Day 12, am). 
• 
Total number of tissues used by participants 
starting at initial administration of IMP up to 
planned discharge from quarantine (Day 12, am). 
Safety 
• 
To evaluate the safety of multiple orally 
administered doses of RV299 when 
compared to placebo. 
• 
Safety data including, but not limited to, 
occurrence of adverse events (AEs) from initial 
administration of IMP up to the Day 28 follow-up. 
• 
Occurrence of serious AEs (SAEs) from initial 
administration of IMP up to the Day 28 follow-up. 


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• 
To monitor the safety of the challenge 
virus. 
• 
Occurrence of AEs related to the viral challenge 
from viral challenge (Day 0) up to the Day 28 
follow-up. 
• 
Occurrence of SAEs related to the viral challenge 
from viral challenge (Day 0) up to the Day 28 
follow-up. 
• 
Use of concomitant medications from viral 
challenge (Day 0) up to the Day 28 follow-up. 
Pharmacokinetics 
• 
To characterise the PK profile of RV299 
after a single oral dose and after 
multiple oral doses in plasma from 
healthy participants inoculated with 
RSV. 
Secondary endpoints related to PK include, but are not 
limited to: 
• 
Time to maximum plasma concentration (tmax), 
terminal half-life (t1/2), maximum observed plasma 
concentration (Cmax), area under the plasma 
concentration-time curve from time zero to the 
end of the dosing interval (AUCτ), area under the 
plasma concentration-time curve over the last 
24 hours dosing interval (AUC0-24h) and area 
under the plasma concentration-time curve from 
time zero to infinity (AUC0-∞). 
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*Note that tertiary objectives and endpoints are optional and might be assessed only if needed; 
therefore, not all testing might be performed and reported. 
Hypothesis 
The main study hypothesis is that treatment with RV299 will show an antiviral effect 
demonstrated by a significant reduction in RSV viral load AUC (measured by qRT- 
PCR) compared to placebo 
IMP 
RV299CCI 
 
dosed twice daily (~12 hours 
interval) for 5 consecutive days (a total of 10 doses) 
Placebo to Match RV299CCI 
 
dosed twice daily (~12 hours interval) for 5 consecutive days (a total of 
10 doses) 
Challenge agent 
RSV-A Memphis 37b 
Challenge agent 
route 
Intranasally 
Challenge agent 
titre 
Approximately 4 log10 plaque-forming units (PFU). 
Study population 
Healthy adult male and female participants aged between 18 to 55 years, with a 
total body weight ≥50 kg and body mass index (BMI) ≥18 kg/m2 and ≤35kg/m2, who 
have been screened to be sero-suitable for infection with the RSV-A Memphis 37b 
virus challenge virus. 
Summary of 
study design 
This is a single-centre, randomised, double-blind, placebo-controlled, proof-of- 
concept study in healthy adult male and female participants from 18 to 55 years of 
age, inclusive. The primary goal of this Phase 1b study is to assess the antiviral 
activity of RV299 against RSV in the viral challenge model. In addition, safety, 
tolerability, and PK of RV299 will be assessed. 
A total of 80 participants is planned to be enrolled in this study: 40 participants on 
RV299 and 40 participants on placebo. 
The study is divided into the following study phases: 
- 
Screening phase: from Day -90 to Day-3 pre-human viral challenge (HVC). 
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 15 days (from Day -2 to Day 12). Procedures will include: 
• 
Pre- HVC: 
o 
Admission to quarantine unit on Day -2/-1. 
o 
Baseline assessments will be conducted as per Schedule of Events 
(SoE) up to Day 0, pre-challenge. 


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• 
HVC: 
o 
RSV-A Memphis 37b virus inoculation on Day 0. 
• 
Post-HVC: 
o 
Randomisation to receive RV299 or matched placebo. 
o 
Administration of IMP (RV299/placebo). Each participant will receive 
IMP twice daily (~12 hours interval) for 5 consecutive days: 
 
IMP dosing to start on confirmation of RSV infection, i.e., after a 
positive result by qualitative integrative cycler polymerase chain 
reaction (qicPCR). The qicPCR of nasal wash will be performed 
twice daily on Days 2-5 (Day 5 morning only), or until a positive 
result is received, whichever is sooner. The earliest start of IMP 
dosing will be in the evening of Day 2 post-HVC (IMP will be initiated 
12 hours ± 1-hour post nasal wash confirmation of infection) 
OR 
 
IMP would start in the evening of Day 5, if no positive result obtained 
by qicPCR 
o 
Day 1 onwards and each day – study assessments will be conducted 
as per SoE. 
o 
Participants will be discharged from the quarantine unit on Day 12 (or 
may remain longer at the discretion of the principal investigator 
[PI]/investigator). 
- 
Outpatient phase: 
• 
Final visit: Day 28 (±3 days). 
Randomisation 
1:1 to RV299 or matched placebo 
Participant 
replacement 
policy 
If a participant discontinues from study intervention OR withdraws from the study for 
reasons not related to AEs, a replacement participant may be enrolled if deemed 
appropriate by the PI/investigator and sponsor. The replacement participant will 
generally receive the same intervention as the participant being replaced. The 
replacement participant will be assigned a unique treatment/randomisation number. 
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 first 
participants planned first 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. 
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CCI 
 
 
Statistics 
Primary and secondary efficacy endpoints will be analysed descriptively. 
Continuous variables will be presented as mean with standard error of the mean 
(SEM) and median, and for log-transformed data the geometric mean with 95% 2- 
sided confidence interval (CI) will also be presented. 
For the primary and some secondary endpoints, formal statistical tests will be 
computed. The Chi-squared test or the Fisher Exact test will be used to compare 
proportions, and the t-test will be used to compare means across groups for 
continuous variables, when the underlying assumptions are fulfilled. For ordinal data 
and continuous data when the underlying assumptions for the t-test are not met, the 
Wilcoxon-Mann-Whitney test will be used to compare the distributions across 
treatment groups. 
S-Cubed will perform the statistical analysis for the study. Full details of the planned 
statistical analysis will be presented in the statistical analysis plan (SAP). Any 
deviations from the SAP will be documented in the clinical study report (CSR). 
Study Analysis Sets: 
The following analysis sets are defined for this study: 
• 
The intent-to-treat (ITT) analysis population, defined as all randomised 
participants who received challenge virus and at least 1 dose of IMP. 
• 
The intent-to-treat infected (ITT-I) analysis population, defined as all 
randomised participants who received challenge virus and at least 1 dose 
of IMP, and meet the criterion for laboratory-confirmed RSV infection. 
• 
The intent-to-treat infected analysis population A (ITT-A) is defined as all 
randomised participants who received challenge virus and at least 1 dose 
of IMP and meet the criterion for laboratory-confirmed RSV infection using 
only assessments prior to taking IMP. 
• 
The intent-to-treat infected analysis population B (ITT-B) is defined as all 
randomised participants who received challenge virus and at least 1 dose 
of IMP and meet the criterion for laboratory-confirmed RSV infection using 
only assessments after taking IMP. 


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• 
The per protocol (PP) analysis population is defined as all ITT-I analysis 
population participants who have no major protocol deviations, and who 
completed the quarantine period up to the final day of quarantine (Day 12) 
and received all 10 doses of IMP. 
• 
The safety analysis population is defined as all randomised participants who 
received challenge virus and at least 1 dose of IMP. 
• 
The PK analysis population is defined as all ITT analysis population 
participants with at least one post-dose PK result. 
The primary efficacy analysis population will be the ITT-I analysis population, and 
the ITT-A, ITT-B, and the PP analysis populations will be used for sensitivity 
analyses. The safety evaluation will be performed on the safety analysis population. 


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1.1. 
Study Schematic: On-study Participant Progression 
 
SCREENING PHASE 
INPATIENT PHASE: QUARANTINE/ISOLATION, HUMAN VIRAL CHALLENGE, AND DOSING 
OUTPATIENT 
PHASE 
Day -90 to Day -3 
Screening* 
Day -2/-1 
Admission to 
quarantine unit 
Day 0 
Inoculation with challenge 
agent & assessments as 
per Schedule of Events 
Days 1 to 11 
Dosing and 
assessments as per 
Schedule of Events 
Day 12 
Discharge from 
quarantine unit** 
Follow-up visit: 
Day 28 (±3 days) 
NOTES: 
*Screening assessments (including repeats, as required), may be performed up to Day -2/-1, defined as the first study day (quarantine admission) at the 
discretion of the PI/investigator and in accordance with the design of the study. 
**Release from quarantine is foreseen at Day 12 (12 days post inoculation) provided that, where appropriate, no virus is detected by qualitative virus antigen 
test or polymerase chain reaction (PCR) (negative virus antigen test or PCR below Ct cut-off) and the participant has no clinically significant symptoms. If the 
participant continues to have clinically significant symptoms and/or detectable virus on Day 12, additional extended quarantine stay may be required at the 
discretion of the PI/investigator. 


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1.2. 
Schedule(s) of Events (SoE) 
 
Study Phase  
Screening 
Phase* 
Inpatient Phase 
(Quarantine Isolation and Human Viral Challenge [HVC]) 
Clinic Visit 
Follow-up 
Early Withdrawal 
Study Day  
Procedure  
D -90 to D -3 
D -2 
D -1 
D 0 
D 1 
D 2 
D 3 
D 4 
D 5 
D 6 
D 7 
D 8 
D 9 
D 10 
D 11 
D12 
(Discharge) 
D 28 
(±3 days) 
Pre-HVC 
HVC 
Post-HVC 
Written informed consent (a) 
X 
Eligibility criteria (+) 
X 
X 
X 
Medical & medication history 
X 
X 
Demographics 
X 
Height & body weight, body mass 
index (BMI) (b) 
X 
X 
(X) 
(X) 
(X) 
Complete physical examination 
X 
X 
X 
X 
X 
Directed physical examination (incl. 
nasal) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
Vital signs (heart rate [HR], respiratory 
rate [RR], systolic blood pressure [BP], 
diastolic BP, oxygen saturation [SpO2]) 
and tympanic membrane temperature 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECG 
X 
X 
X 
X 
X 
X 
Spirometry 
X 
Patient Health Questionnaire (PHQ-9) 
(X) 
(X) 
Generalised Anxiety Disorder 
Questionnaire (GAD-7) 
(X) 
(X) 
Alcohol breath test 
X 
X 
X 
Urinalysis 
X 
X 
X 
X 
X 
Urine drugs of abuse and cotinine 
screen 
X 
X 
X 
Urine pregnancy test 
X 
X 
X 
X 
Symptom diary card (c) 
(X) 
3X 
3X 
3X 
3X 
3X 
3X 
3X 
3X 
3X 
3X 
3X 
3X 
3X 
X 


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Study Phase  
Screening 
Phase* 
Inpatient Phase 
(Quarantine Isolation and Human Viral Challenge [HVC]) 
Clinic Visit 
Follow-up 
 
 
Study Day  
Procedure  
 
 
24-hour paper tissue collection & nasal 
discharge weight (d) 
Product Administration 
Randomisation 
RSV299/placebo dosing (k) 
Challenge virus inoculation 
Collection Of Blood Samples 
Serum follicle-stimulating hormone 
(FSH) (post-menopausal women) 
X 
Serum β-human chorionic 
gonadotrophin (β-hCG) pregnancy test 
(all females) 
 
X 
X 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
X 
 
 
 
(X) 
(X) 
 
X 
 
 
 
(X) 
(2X) 
 
X 
 
 
 
(X) 
(2X) 
 
X 
 
 
 
(X) 
(2X) 
 
X 
 
 
 
 
(2X) 
 
X 
 
 
 
 
(2X) 
 
X 
 
 
 
 
(2X) 
 
X 
 
 
 
 
(2X) 
 
X 
X 
X 
 
 
 
 
(X) 
 
(X) 
 
 
Blood Pharmacokinetics (e) 
(X) 
(X) 
(X) 
X 
X 
X 
X 
X 
X 
X 
X 
Haematology (f) 
X 
X
X 
X 
X 
X 
Biochemistry (f) 
X 
X 
X 
X 
X 
Coagulation 
X 
Cardiac enzymes 
X 
X 
X 
Thyroid function test 
X 
Serum markers of humoral immunity 
(g) 
X 
X 
X 
CCI 
 
C
D -90 to D -3 
D -2 
D -1 
Pre-HVC 
HVC 
D 0 
Post-HVC 
D 1 
D 2 
D 3 
D 4 
D 5 
D 6 
D 7 
D 8 
D 9 
D 10 
D 11 
D12 
(Discharge) 
D 28 
(±3 days) 
Early Withdrawal 


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Study Phase  
Screening 
Phase* 
Inpatient Phase 
(Quarantine Isolation and Human Viral Challenge [HVC]) 
Clinic Visit 
Follow-up 
Early Withdrawal 
Study Day  
Procedure  
D -90 to D -3 
D -2 
D -1 
D 0 
D 1 
D 2 
D 3 
D 4 
D 5 
D 6 
D 7 
D 8 
D 9 
D 10 
D 11 
D12 
(Discharge) 
D 28 
(±3 days) 
Pre-HVC 
HVC 
Post-HVC 
Collection Of Respiratory Samples 
Nasopharyngeal swab - respiratory 
pathogen screen incl. SARS-CoV-2 (h) 
X 
Nasopharyngeal swab- RSV discharge 
test 
(X) 
(X) 
Nasal wash – virology, viral genomics, 
CCI 
 
X 
2X 
2X 
2X 
2X 
2X 
2X 
2X 
2X 
2X 
2X 
X 
qicPCR (i) 
2X 
2X 
2X 
X 
Safety Assessments 
Adverse event (AE) recording (j) 
 
X 
Concomitant medications (j) 
 
X 
 
KEY NOTES FOR TIME AND EVENTS SCHEDULE 
 
(X) 
The assessment may be optional, or at the PI's discretion. The PI may perform additional safety assessments as required. 
X 
Once daily, at approximately the same time each day, where applicable. 
2X 
Twice daily (~12 hours between assessments [± 1 hour]). 
3X 
Three times daily (at the same times each day [± 1 hour]). 
* 
Potential participants will be screened using the hVIVO generic screening process, and individuals who pass this screen will be admitted to the quarantine unit 1 to 
2 days before challenge with study virus and provide study-specific informed consent. They will then be screened for eligibility for this study before viral challenge on 
Day 0. Results of tests or examinations performed under hVIVO generic screening process may be used to determine eligibility without the need to repeat the 
assessment if it is within 28 days prior to viral challenge/dosing with IMP. 


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+ 
Only the applicable inclusion/exclusion criteria will be reviewed at each time point. 
a 
Study-specific consent may occur on the day of admission, providing all required eligibility information has been collected through the Health Research Authority - 
approved hVIVO generic screening process. 
b 
Height will be taken at screening only. 
c 
After the baseline has been set, assessments will be performed at the same time each day (±1 hour from baseline) during quarantine. 
• 
Symptom diary card baseline: Day -1 (measurements on this day will be taken approximately 8 hours apart, ±1 hour). 
• 
Nasal wash baseline: Day 2 (sampling will be performed approximately 12 hours apart, ±1 hour). 
d 
Distribution of paper tissues and bags will start on Day -1, with the first collection on Day 0. Thereafter, collection of paper tissues will occur at the same time each 
day (±1 hour) with tissues distributed 24 hours ahead. 
e 
Blood Pharmacokinetics: plasma samples for RV299 assay will be collected as follows: 
• 
First dose (Dose 1): 0.5 hours pre-dose, and at the following hours post-first dose: 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8,10, 12, 24, 36, 48, 60, 72, 84 and 96 hours 
(note samples taken up to and including 10 hours post-dose should be taken at the indicated time point ±5 minutes. Samples taken thereafter at 12, 24, 36, 
48, 60, 72, 84, and 96 hours post-first dose should be taken within the 30 minutes before the next IMP intake). 
• 
Last dose (Dose 10): 0.5 hours pre-dose, and at the following hours post-last dose: 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8,10, 12, 24, 36, 48, 60, 72, 84, and 96 hours 
(note samples taken up to and including 10 hours post-dose should be taken at the indicated time point ±5 minutes; samples taken thereafter should be 
taken at the indicated time point ±30 minutes). 
For participants who started dosing on Day 4, am, onwards, the 60-hour, 72-hour, 84-hour, or 96-hour timepoints after Dose 10 could occur after the participant has 
met the discharge criteria on Day 12. Thus, for a subset of participants, these timepoints could be after discharge. The guidance for the 60-hour, 72-hour, 84-hour, 
and 96-hour PK sample collection is as follows: 
• 
For participants who started dosing on Day 4, am, onwards, and who meet the discharge criteria on Day 12, the 60-hour, 72-hour, 84-hour, and 96-hour 
timepoint samples may be omitted, as applicable, if it occurs after discharge. 
• 
For participants who started dosing on Day 4, am, onwards, and who do not meet the discharge criteria on Day 12 the 60-hour, 72-hour, 84-hour, and 96- 
hour PK timepoint samples should be collected up to the point where participant meets the discharge criteria. 
f 
Blood will be drawn under non-fasted conditions. Repeat bloods may be drawn under fasted conditions if a lipid profile (triglyceride) or glucose is required (at the PI’s 
discretion). 
All participants will be dosed under fasted conditions. For all doses, a pre-dose and post-dose fasting period of 0.5 hour to 1 hour applies. No fluid intake (including 
water) is allowed for 1 hour pre-dose to 1-hour post-dose). 
g 
Virus serology (RSV neutralisation antibody assay) will be performed to determine eligibility and seroconversion. 
h 
Upper respiratory tract swab (e.g., nasopharyngeal swab, mid-turbinate swab, oropharyngeal swab) for respiratory virus screen to assess for the presence of 
respiratory pathogens; if found positive for any pathogen in the panel, the participant will not be eligible for the current quarantine. 
i 
Post inoculation nasal wash virology samples will be collected at the same time each day during quarantine (± 1 hour from baseline on Day 2) and used for qRT- 
PCR and viral culture assay (as appropriate). Samples may be used for related viral genomicsCCI 
Samples collected between the morning of Day 2 and the morning of Day 5 will also be used for qicPCR until a positive result is received (to support triggered dosing). 
j 
Adverse events and concomitant medications are reviewed throughout the study including pre- and post-dosing with IMP and pre- and post-RSV virus inoculation. 


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k 
IMP doses as oral solution/suspension will be taken with 140 mL of water (50 mL water rinse of IMP bottle following administration, and 90 mL post-dose). 
All participants will be dosed orally, in the seated position, under fasted conditions, under the direct supervision of the investigator (or delegate), and in accordance 
with the randomisation schedule. Each participant will receive IMP twice daily (~12 hours interval) for 5 consecutive days, in total 10 doses, IMP dosing to start on 
confirmation of RSV infection. The earliest start of IMP dosing will be in the evening of Day 2 post-HVC or IMP dosing will start in the evening of Day 5, if no 
confirmation of RSV infection. 
Note: 
Parenthesis indicates the assessment may be optional, or at the PI’s discretion. 
The PI/investigator may perform additional safety assessments as required. 
Where any nasal sampling time points occur together, the order of sampling will typically be (1) nasopharyngeal swab followed by (2) nasal wash. 


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CCI 
 
GENOMIC, TRANSCRIPTOMIC AND PROTEOMIC SAMPLES 
Deoxyribonucleic 
acid 
(DNA)/ 
ribonucleic 
acid 
(RNA)/proteomic 
sample collection: 
Yes 
 
No 
 
Viral RNA sequencing may be performed on laboratory-confirmed positive nasal wash samples. 
DNA pharmacogenomicsCCI 
 may be explored in appropriate samples. 
Consent considerations: 
Genetic consent. 
Nasal samples may be tested for suspected community-acquired infections. 
Blood and nasal samples may be used and/or retained forCCI 
purposes related to the study objectives 
and respiratory virus infections. 


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2. 
Introduction 
2.1. 
Respiratory Syncytial Virus 
 
Respiratory syncytial virus (RSV) is a significant pathogen of the very young, the immunocompromised, 
and the elderly (Simões et al, 2015), in whom infections are associated with significant morbidity and 
mortality (Bagga et al, 2013; Fleming et al, 2015; Hall et al, 2009; Scheltema et al, 2017). It is highly 
infectious and is transmitted through respiratory secretions via close contact with infected individuals, 
through droplets, or through contaminated surfaces (Collins and Karron, 2013). RSV outbreaks and 
epidemics are highly predictable year by year, peaking between January and April in the Northern 
Hemisphere and during the Southern Hemisphere winter season. This predictability and the presence of 
well-established surveillance systems in many countries is useful in alerting healthcare providers and public 
health systems to the presence of RSV and the need for screening patients with suspected RSV infection 
who are at risk of disease. Accurate diagnosis and confirmation of RSV infection is now feasible due to the 
availability of effective point of care diagnostic assays. 
In infants and small children, RSV is the major cause of lower respiratory tract infections (LRTI), manifesting 
as bronchiolitis or pneumonia. It has also been associated with an increased risk of recurrent wheezing and 
asthma. Comorbidity factors which significantly increase the risk of severe LRTI in infants include 
prematurity, cyanotic or complicated congenital heart disease and chronic lung disease due to prematurity. 
The mortality rate in the very young at-risk infants is 2 – 3 % in most developed countries. However, 
approximately 96% of children admitted to hospital with RSV infection are full-term and otherwise healthy. 
In the United States of America (USA) between 100,000 and 126,000 infants under one year of age have 
been hospitalised in each of the last 5 years. 
In those over 60 years old, in the USA there are estimated to be more than 2 million consultations with 
physicians each year due to RSV infection. The virus is also a significant problem in adults with chronic 
obstructive pulmonary disease (COPD) where it is a major cause of exacerbations. RSV notably causes 
annual outbreaks of infection and disease in elderly residents of nursing homes during outbreaks. 
Hospitalisation due to RSV infection is a major and significant burden on health care providers and hospitals 
during an RSV outbreak. Although the relationship between viral load and disease severity has not been 
fully established, there is growing evidence that hospitalised children with RSV disease have higher nasal 
viral titres than age-matched controls with less severe disease suggesting a potential opportunity to 
intervene with an effective antiviral agent. 
Opportunities for intervention, either therapeutically or prophylactically, exist in all these populations. 
Studies have demonstrated that children can see up to 3 physicians prior to hospital admission presenting 
multiple opportunities for diagnosis and intervention. Increasing awareness of RSV infection and its 
consequences in the elderly and in adults with co-morbidities that put them at risk of complicated RSV 
disease, along with the development of rapid diagnostics, will provide opportunities to treat or prevent RSV 
infection and disease in these vulnerable populations. Due to the high risk of RSV in haematopoietic stem 
cell transplantation patients, this population is routinely monitored during RSV epidemics and early 
treatment to prevent significant morbidity and mortality is required. 


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Currently there are limited treatment options for RSV infection. There are no RSV vaccines and only 
2 approved therapeutic agents. The first, Ribavirin, is a nucleoside analogue, but clinical use is restricted 
due to its limited antiviral potency, delivery route, toxicity, and teratogenic potential (Kim et al, 2017). The 
other is the prophylactic monoclonal antibody Synagis® (palivizumab), which interacts with the 
F-glycoprotein of the RSV virus. Palivizumab has been shown to provide protection in infants but needs to 
be given before infection and throughout the winter season. It is approved for use in infants with a history 
of prematurity, haemodynamically significant cardiac disease, or chronic lung disease of prematurity. Cost 
of treatment also limits its use. There is therefore an ongoing unmet medical need for an effective therapy 
for RSV infection and a number of new treatments targeting various mechanisms of action are in 
development, including inhibitors targeting RSV fusion, polymerase, and N protein as well as prophylactic 
agents and vaccines. 
In summary, due to the current lack of availability of suitable therapeutic and prophylactic agents and 
vaccines against RSV and the significant unmet clinical need there is urgent need for a well-tolerated and 
effective anti-RSV agent. Populations that will particularly benefit from a small molecule therapeutic or 
prophylactic agent include infants and small children as well as adults, particularly the elderly, those with 
co-morbid disease such as COPD, and the immunocompromised. 
2.2. 
RV299 
 
RSV, a member of the Pneumovirus family, is an enveloped virus with a negative single strand ribonucleic 
acid (RNA) genome that encodes for 11 proteins, including 3 surface glycoproteins (F, G, and SH). After 
fusion, the RSV RNA enters the cell and directs the synthesis of virus proteins, including the virus 
polymerase (L) and N protein involved in replicating the virus RNA. The N protein is an essential component 
of the RSV replication machinery and coats the newly synthesised viral RNA antigenome allowing new RSV 
genome to be synthesised. There are 2 major RSV subtypes, A and B, that cause similar disease and 
although they may co-circulate, one type usually predominates in alternative years. 
RV299 is an inhibitor of the RSV N protein, which is an essential component of the RSV replication 
machinery. Inhibitors of the N protein can prevent the replication of the virus in the host cell and thus prevent 
new virus particles from being formed and transmitted. 
2.2.1. 
Summary of Pre-clinical and Clinical Experience 
 
RV299 is a novel replication inhibitor of RSV. It is a potent inhibitor of RSV infection in in vitro assays and 
is effective against a panel of RSV laboratory and clinical isolates of RSV A and B strains. RV299 is specific 
for RSV with no cross-activity against other viruses tested, and the antiviral effect is not due to cytotoxicity. 
Following prolonged in vitro culture, RSV resistant to RV299 was selected; genotypic analysis and cross 
resistance studies suggest that the compound targets RSV nucleoprotein (N), an essential component of 
viral RNA-dependent RNA polymerase, which is responsible for viral replication and transcription. 
Single dose absorption, distribution and metabolism studies demonstrated RV299 has good oral 
absorption, low clearance, and low-moderate volume of distribution, resulting in moderate exposure and 
high oral bioavailability. Plasma protein binding of RV299 was moderate-high in rats, dogs, and humans. 
In vitro experiments in human cytosol showed that RV299 was metabolised by aldehyde oxidase, and in 
human microsomes, an oxidative metabolite was observed that was not present in vivo in rats or dogs. 


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RV299 does not exhibit competitive cytochrome P450 (CYP) enzyme inhibition against any of the major 
CYP isoforms with the exception of CYP2C8 (50% inhibitory concentration [IC50] = 5.70 μM) but at the 
proposed doses, is not anticipated to cause a clinical drug-drug interaction (DDI). However, as the in vitro 
assay was limited due to solubility, it cannot be discounted that there may be a possibility of CYP3A4 
inhibition in the intestine. RV299 is also an inhibitor of organic anion transporter protein B, organic cation 
transporter 2, and bile salt export pump (IC50 ≤16.3 μM) but at the proposed doses it is not anticipated that 
this will cause a clinical DDI. RV299 did not show measurable P-glycoprotein (P-gp) or breast cancer 
resistance protein inhibition in the in vitro assay (IC50 >30 μM). Even though the concentration of RV299 
investigated in this assay was limited due to low solubility, when an IC50 of 30 μM (worst case scenario) is 
used in predictions, this suggests that a DDI in the intestine is unlikely. RV299 caused a >2-fold increase 
in CYP3A4 and CYP2B6 messenger RNA (mRNA) and a >20% increase in catalytic activity compared to 
the respective positive controls. It is anticipated that RV299 may have the potential for enzyme induction in 
humans 
Good Laboratory Practice (GLP)-complaint toxicity studies of up to 14 days duration have been conducted 
with RV299 in rats (25, 80, 250 mg/kg/day) and dogs (15, 50, 150 mg/kg/day), by once daily oral 
administration. The highest dose tested in rats, 250 mg/kg/day, was considered the no-observed-adverse- 
effect-level (NOAEL). In dogs, adverse clinical observations were noted at 150 mg/kg/day and animals 
assigned to a 2-week recovery period were terminated prematurely within 5 days of cessation of dosing. 
The 
principal 
target 
organs 
for 
toxicity 
were 
lymphohematopoietic 
tissues. 
Marked 
myelosuppression/immunodepression, including thrombocytopenia, decreases in reticulocyte and white 
cell counts and pronounced decreases in cellularity in bone marrow and lymphoid tissues, were noted at 
50 mg/kg/day and 150 mg/kg/day. Adverse effects (inflammation and atrophy) were also noted in the gall 
bladder. These findings were noted where mean maximum observed plasma concentration (Cmax) and area 
under the plasma concentration-time curve over the last 24 hours dosing interval (AUC0-24h) values were 4- 
fold greater than the mean values following a clinical dose of 65 mg twice a day (bis in die; BID). 
Overall, data from in vitro and in vivo for genotoxicity studies demonstrated RV299 was not genotoxic. 
RV299 had no effects on the respiratory, or central nervous systems in rats at oral doses up to 250 mg/kg, 
nor on the cardiovascular system of telemetered dogs at an oral dose of 50 mg/kg. 
RV299 has been evaluated in a single clinical study (REVD001) in a total of 32 healthy adult subjects and 
a cumulative total of 136 doses spanning single doses of 25 to 125 mg and multiple doses of 35 to 65 mg 
BID for 9 doses. The study also included 10 subjects on matched placebo. The study is ongoing and so the 
data from this study is still blinded and the safety profile of RV299 has therefore been assessed in aggregate 
form with placebo. 
The data to date suggest that RV299 has a favourable safety profile across the range of doses covered. 
There have been no clinically significant findings to date on any safety parameters including laboratory 
results, telemetry, electrocardiograms (ECGs), or vital signs. There have been no serious adverse events 
(SAEs), nor any moderate or severe non-SAEs. All adverse events (AEs) have been mild, self-limiting, and 
resolved completely. There have been no emerging trends in any safety findings either in isolation within 
individual cohorts or in comparison with previous cohorts. The data review committee has reviewed the 
data for each completed cohort to support progression to the next cohort, and in all instances has approved 
dose progression. 


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RV299 demonstrated predictable pharmacokinetics (PK) across the dose range studied. Half-life, 
clearance, and apparent volume of distribution values were consistent across the doses. RV299 PK after 
both single and multiple twice daily dosing demonstrated reasonable dose proportionality across the 
respective dose ranges studied. The multiple-dose data suggests that RV299 plasma PK are linear upon 
multiple dosing. 
Geometric mean AUC0-24h and Cmax on Day 5 following the 65 mg BID dose regimen provide a 4-fold margin 
to the respective NOAELs that have been set by the 14-day dog GLP study at a dose of 15 mg/kg/day. 
Even when using the maximum observed values in the 65 mg BID dose regimen, there was still a 2-fold 
safety margin to the respective NOAELs for AUC0-24h and Cmax. 
The administration of RV299 with food marginally decreased the rate of absorption and Cmax but had no 
observable effect on the overall exposure indicated by AUC0-∞. On this basis RV299 can be administered 
without regard to food. 
2.3. 
The Respiratory Syncytial Virus Human Challenge Model 
 
The RSV human challenge model was developed to not only aid understanding of RSV disease, but to also 
assess the efficacy of RSV antivirals, immunomodulators and vaccines. The RSV-A Memphis 37b 
challenge strain has been used for over 15 years by both hVIVO and others and has helped assess the 
efficacy of numerous RSV therapies (as reviewed by Lambkin-Williams et al, 2018; DeVincenzo et al, 
2020a; DeVincenzo et al, 2020b; Stevens et al, 2018) and vaccines (Sadof et al, 2021; Pfizer 2021; 
Bavarian Nordic 2021). Specifically, hVIVO have safely and successfully used the RSV challenge strain in 
over 1400 healthy participants (18 to 60 years of age) including the inoculation of 24 participants between 
60 and 75 years of age. Additionally, another clone of the same strain of live RSV (Memphis 37c) has been 
used as an inoculation agent and was shown to be safe in over 77 healthy young adults across 3 studies. 
Healthy RSV challenge study participants have approximately 65% to 85% chance of becoming infected 
with RSV following the administration of the virus (DeVincenzo et al, 2010). Typical RSV illness is 
characterised by an abrupt onset of rhinitis, nasal stuffiness, malaise, myalgia (muscle aches), and sore 
throat. In healthy adults, the illness usually resolves without any treatment, with relief of symptoms occurring 
naturally within 7 to 10 days. Respiratory syncytial virus, like many viruses, can cause more substantial 
health issues such as myocarditis (inflammation or damage to the heart muscle). Adults and children 
present with RSV-related myocarditis rarely, with symptomless occurrences likely going undiagnosed in the 
community. 
2.4. 
Study Rationale 
 
Collectively, the clear unmet medical need for an effective therapy for RSV infection and the RV299 pre- 
clinical pharmacology and toxicology profile provide strong rationale for its clinical development. The 
rationale for taking RV299 into further development is the expectation that this compound could be effective 
for the treatment of RSV. Prior to initial testing in the primary target populations (typically the 
immunocompromised, young children and elderly people), the safety, tolerability, antiviral activity, and the 
PK characteristics of the drug in healthy adults will be investigated. 
The purpose of this study is to confirm the antiviral activity of RV299 in a population inoculated with RSV- 
A Memphis 37b challenge strain. 


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The RSV-A Memphis 37b challenge strain has been used for over 15 years by both hVIVO and others and 
has helped assess the efficacy of numerous RSV therapies. Specifically, hVIVO have safely and 
successfully used the RSV challenge strain in over 1400 healthy participants (18 to 60 years of age) 
including the inoculation of 24 participants between 60 and 75 years of age. 
2.5. 
Benefit/Risk Assessment 
2.5.1. 
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. 
 
There is currently limited clinical experience with RV299. More detailed information about the known and 
expected benefits and risks and reasonably expected AEs of RV299 may be found in the Investigator’s 
Brochure. 


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Table 2-1: 
Risk Assessment 
 
Potential Risk of 
Clinical Significance 
Description of Risk 
Mitigation Strategy 
Study Intervention 
Oral dosing with RV299 
1) RV299 has not previously been tested in human 
subjects infected with RSV and may not confer 
any antiviral protection against RSV in humans 
despite encouraging pre-clinical evidence. 
2) Pre-clinical 
studies 
have 
identified 
myelosuppressive effects (including reduced 
reticulocytes, platelets and white cell counts and 
fractions) 
in 
dogs 
following 
14 
days’ 
administration at doses well in excess of the 
intended human dose (50mg/kg/day). No such 
effects were seen at 15mg/kg/day and this dose 
was used to set the NOAEL for human 
administration of RV299. 
3) RV299 has shown variable PK with some 
subjects 
experiencing 
higher 
exposures 
(doubling) for a given dose than other subjects, 
possibly due to differences in clearance. 
1) Subjects will be monitored for severe RSV-related disease 
throughout the study and managed accordingly with 
supportive measures and may be withdrawn from the study 
at the investigator’s discretion at any time. 
2) The 65mg dose has been administrated to healthy human 
volunteers twice daily for 5 days and there has been no 
evidence of myelosuppressive effects during dosing or 
during the 3-week follow-up period after the last dose. The 
same study confirmed that the 65mg dose produces PK 
exposures in humans that are 2- to 4-fold below the 
NOAEL, providing an adequate safety margin. Subjects in 
the viral challenge study will have safety bloods assessed 
throughout the dosing interval and during follow-up to 
continue to monitor for any myelosuppressive effects. 
3) The dose has been selected to ensure that the NOAEL 
safety margin is not exceeded even in subjects who may 
experience doubling in RV299 exposure for a given dose. 
Oral 
dosing 
with 
placebo 
Given that the placebo is a pharmacologically inert 
material, there should be no risk. 
Not applicable. 
Pregnancy 
and 
birth 
control 
No 
reproductive 
system 
studies 
have 
been 
conducted with RV299 to date. 
Drugs or other substances known to be substrates for 
CYP3A4 or inhibitors of aldehyde oxidase (AO), P- 
gp) or breast cancer resistance protein (BCRP) may 
interact with RV299, which has shown in vitro 
evidence of being a CYP3A4 inhibitor and an AO, 
PgP, and BCRP substrate. Caution should be applied 
in 
co-administering 
such 
therapies, 
including 
monitoring for toxicity or subtherapeutic effects. 
1) Specific contraceptive requirements will be in place for 
participants. 
2) Contraceptive guidance will be used in inclusion criteria. 
3) Female participants will need evidence of negative 
pregnancy tests prior to dosing. 


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Potential Risk of 
Clinical Significance 
Description of Risk 
Mitigation Strategy 
In particular, female participants who are on 
hormonal contraception or hormonal replacement 
therapy that contains oestradiol or ethinyl-oestradiol 
(both of which are substrates of CYP3A4) should 
require their male partners to use additional barrier 
contraceptive methods such as condoms with 
spermicide during RV299 administration and for at 
least one menstrual cycle after a course of RV299. 
Study procedures 
Blood Sampling 
(venepuncture or via a 
peripheral venous 
catheter) 
Pain or bruising at the site where blood is drawn. 
Blood samples will be obtained by a trained professional. 
Syncope (fainting) can occur following or even before 
any blood draw as a psychogenic response to the 
needle insertion. 
Blood samples will be obtained by a trained professional and 
procedures will be put in place to avoid injury from fainting. 
There is a possibility that in the process of collecting 
blood a nerve may be injured. 
Procedure to be performed by qualified personnel. 
Blood tests performed to address the health of the 
participants at screening and during the study may 
indicate that a participant has an infection that he/she 
was not previously aware of (such as human 
immunodeficiency virus [HIV] or hepatitis) or an 
unexpected illness. 
The hVIVO doctor will provide the participant’s general 
practitioner (GP), or doctor with a referral letter if the participant 
agrees. 
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 
RSV infection from inoculation 
RSV infection & severe 
complications 
65% to 85% chance of becoming infected with RSV- 
A Memphis 37b. Typical RSV illness: abrupt onset of 
rhinitis, nasal stuffiness, fever, malaise, myalgia 
(muscle aches), and sore throat. 
The safety profile of the RSV-A Memphis 37b is well 
characterised in healthy adults as this has been used for over 
15 years by hVIVO. At hVIVO more than 1400 healthy adults 
aged 18 to 60 years have been challenged with the RSV 
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Potential Risk of 
Clinical Significance 
Description of Risk 
Mitigation Strategy 
Severe RSV infections are known to occur in both 
infants and adults. In adult populations, multiple 
factors but not older age, are independently 
associated with severe RSV complications including 
persons of any age with chronic co-morbidities and 
significant immune compromise. 
RSV, like many viruses, can cause more substantial 
health issues such as myocarditis (inflammation or 
damage to the heart muscle). Adults and children 
present with RSV-related myocarditis rarely, with 
symptomless occurrences likely going undiagnosed 
in the community. Within our RSV viral challenge 
studies, of over 1400 participants who have received 
the challenge virus to date, the occurrence of 
myocarditis is uncommon. None of these participants 
reported any symptoms due to myocarditis and, 
where follow-up was completed, the diagnostic tests 
related to the follow-up returned to normal without 
treatment. 
RSV infection in healthy adults usually resolves without 
treatment within 7 to 10 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 12 days post human viral challenge (HVC). 
Qualified medical and nursing staff in the quarantine unit will 
monitor for and manage any symptoms. 
Participants will be closely followed up while being in 
quarantine. Electrocardiograms will be performed, and cardiac 
enzymes will be tested at least 7 days and 11 days post-viral 
challenge. 
Transient increase in alanine aminotransferase 
(ALT) or aspartate aminotransferase (AST) without 
clinical presentation, with a good prognosis upon 
improvement of infection. 
ALT and AST will be monitored. 
Transmission of RSV to 
participants’ close 
contacts 
RSV 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 
1400 inoculations, As appropriate, the PI/delegate may request 
additional testing of nasal swab samples using a qualitative 
virus antigen test or PCR 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 


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Potential Risk of 
Clinical Significance 
Description of Risk 
Mitigation Strategy 
Section 2.5.1.1, Vulnerable Persons, for 2 weeks after they 
leave the quarantine unit. 
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 the study intervention. 


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2.5.1.1. 
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 
Chronic pulmonary disease (e.g., severe asthma, COPD). 
o 
Chronic cardiovascular disease (e.g., cardiomyopathy, congestive heart failure, cardiac 
surgery, ischaemic heart disease, known anatomic defects). 
o 
Contacts that required medical follow-up or hospitalisation during the past 5 years because 
of chronic metabolic disease (e.g., insulin dependent diabetes mellitus, renal dysfunction, 
haemoglobinopathies). 
o 
Immunosuppression or cancer. 
o 
Neurological and neurodevelopmental conditions (e.g., cerebral palsy, epilepsy, stroke, 
seizures). 
 
2.5.1.2. 
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: 
It has not been established that severity of COVID-19 infection could increase if contracted after inoculation 
with RSV-A Memphis 37b. 
Participants will be tested for respiratory pathogens, including COVID-19, upon their arrival at the 
quarantine unit. They will be advised on protective measures and will need to follow infection control 
regimens. 
Risk of Increased Severity of COVID-19 Infection After Study Intervention Administration: 
There is no evidence that severity of COVID-19 infection would increase if contracted after RV299 
administration. 
All participants will be instructed to follow UK Government COVID-19 guidelines and will be provided with 
personal protective equipment while resident in the quarantine unit. 
 
COVID-19-related emerging data will be monitored on an ongoing basis. 


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2.5.2. 
Benefit Assessment 
 
Healthy participants will not receive direct benefit from treatment during their participation in this clinical 
study. 
Participants may develop some immunity to RSV-A Memphis 37b 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. 
 
2.5.3. 
Overall Benefit: Risk Conclusion 
 
Considering the measures taken to minimise risk to participants in this study, the potential risks identified 
in association with RSV virus infection and RV299 treatment are justified by the anticipated benefits linked 
to the evaluation of the antiviral activity of RV299 in the viral challenge model which will contribute to the 
development of a new therapy for the treatment of RSV infection. 


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3. 
Objectives and Endpoints 
 
Objectives 
Endpoints 
Primary: 
Efficacy 
• 
To assess the antiviral activity of RV299 
compared to placebo in healthy adult 
participants 
infected 
with 
RSV-A 
Memphis 37b. 
• 
The area under the curve (AUC) for RSV viral load 
measured in nasal washes by quantitative real time 
reverse transcription polymerase chain reaction 
(qRT-PCR) in participants inoculated with RSV-A 
Memphis 37b, starting at initial administration of 
investigational medicinal product (IMP) up to 
planned discharge from quarantine (Day 12, am). 
Secondary: 
Efficacy 
• 
To evaluate the effect of RV299 
compared to placebo in healthy adult 
participants inoculated with RSV in terms 
of antiviral effect assessed by: 
o 
Viral-load related endpoints. 
Additional viral load endpoints relating to antiviral effect 
include, but are not limited to: 
• 
Peak viral load of RSV as defined by the maximum 
viral load determined by qRT-PCR measurements 
in nasal samples starting from initial administration 
of IMP up to planned discharge from quarantine 
(Day 12, am). 
• 
Time (days) to confirmed negative test by qRT- 
PCR measurements in nasal samples starting at 
initial administration of IMP to first confirmed 
undetectable assessment after peak measure. 
• 
Time (days) to confirmed negative test by qRT- 
PCR measurements in nasal samples starting from 
peak qRT-PCR after initial administration of IMP to 
first confirmed undetectable assessment after peak 
measure. 
• 
Time (days) to peak qRT-PCR in nasal samples, 
starting from initial administration of IMP. 
• 
Area under the viral load-time curve (VL-AUC) of 
RSV challenge virus as determined by viral culture 
on nasal samples, starting at initial administration 


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Objectives 
Endpoints 
of IMP up to planned discharge from quarantine 
(Day 12, am). 
• 
Peak viral load of RSV as defined by the maximum 
viral 
load 
determined 
by 
viral 
culture 
measurements in nasal samples starting from initial 
administration of IMP up to planned discharge from 
quarantine (Day 12, am). 
• 
Time (days) to confirmed negative test by viral 
culture measurements in nasal samples starting at 
initial administration of IMP to first confirmed 
undetectable assessment after peak measure. 
• 
Time (days) to confirmed negative test by viral 
culture measurements in nasal samples starting 
from peak viral culture after initial administration of 
IMP to first confirmed undetectable assessment 
after peak measure. 
• 
To evaluate the effect of RV299 
compared to placebo in healthy adult 
participants inoculated with RSV in terms 
of antiviral effect assessed by: 
o 
Clinical symptom-related endpoints. 
Clinical symptom-related endpoints include, but are not 
limited to: 
• 
Area under the curve over time of total clinical 
symptoms  (TSS-AUC)  as  measured  from 
10 symptoms within the graded symptom scoring 
system collected 3 times daily starting at initial 
administration of IMP up to planned discharge from 
quarantine (Day 12, am). 
• 
Area under the curve over time of total clinical 
symptoms change from baseline (TSS-AUC-CFB) 
as measured from 10 symptoms within the graded 
symptom scoring system collected 3 times daily 
starting at initial administration of IMP up to planned 
discharge from quarantine (Day 12, am). 
• 
Peak symptoms diary card score: peak total clinical 
symptoms (TSS) as measured from 10 symptoms 
within the graded symptom scoring system 
collected 3 times daily starting from initial 
administration of IMP up to planned discharge from 
quarantine (Day 12, am). 
• 
Peak daily symptom score: individual maximum 
daily  sum  of  symptom  score  from  initial 


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Objectives 
Endpoints 
administration of IMP up to planned discharge from 
quarantine (Day 12, am). 
• 
Time (days) to symptom resolution as measured 
from 10 symptoms within the graded daily symptom 
scoring system starting at initial administration of 
IMP to time of returning to baseline score. 
• 
Time (days) to symptom resolution as measured 
from 10 symptoms within the graded daily symptom 
scoring system starting at peak symptoms after 
initial administration of IMP to time of returning to 
baseline score. 
• 
Time  (days)  to  peak  as  measured  from 
10 symptoms within the graded daily symptom 
scoring system starting from initial administration of 
IMP to the time of peak daily symptom score. 
• 
To evaluate the effect of RV299 on nasal 
discharge in healthy adult participants 
inoculated with RSV when compared to 
placebo. 
• 
Total weight of mucus produced starting at initial 
administration of IMP up to planned discharge from 
quarantine (Day 12, am). 
• 
Total number of tissues used by participants 
starting at initial administration of IMP up to planned 
discharge from quarantine (Day 12, am). 
Safety 
• 
To evaluate the safety of multiple orally 
administered doses of RV299 when 
compared to placebo. 
• 
Safety data including, but not limited to, occurrence 
of AEs from initial administration of IMP up to the 
Day 28 follow-up. 
• 
Occurrence of SAEs from initial administration of 
IMP up to the Day 28 follow-up. 
• 
To monitor the safety of the challenge 
virus. 
• 
Occurrence of AEs related to the viral challenge 
from viral challenge (Day 0) up to the Day 28 
follow-up. 
• 
Occurrence of SAEs related to the viral challenge 
from viral challenge (Day 0) up to the Day 28 follow- 
up. 
• 
Use of concomitant medications from viral 
challenge (Day 0) up to the Day 28 follow-up. 


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Objectives 
Endpoints 
Pharmacokinetics 
• 
To characterise the PK profile of RV299 
after a single oral dose and after multiple 
oral doses in plasma from healthy 
participants inoculated with RSV. 
Secondary endpoints related to PK include, but are not 
limited to: 
• 
Time to maximum plasma concentration (tmax), 
terminal half-life (t1/2), Cmax, area under the plasma 
concentration-time curve from time zero to the end 
of the dosing interval (AUCτ), AUC0-24h, and area 
under the plasma concentration-time curve from 
time zero to infinity (AUC0-∞). 
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*Note that tertiary 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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4. 
Study Design 
4.1. 
Overall Design 
 
This is a single-centre, randomised, double-blind, placebo-controlled, proof-of-concept study in healthy 
adult male and female participants from 18 to 55 years of age, inclusive, utilising: 
• 
IMP (active): RV299 
 
dosed twice daily (~12 hours interval) for 5 consecutive days (a total of 
10 doses) 
• 
IMP (placebo): Placebo to Match RV299CCI 
dosed twice daily (~12 hours interval) for 5 consecutive days (a total of 10 doses) 
• 
Challenge agent: RSV-A Memphis 37b, intranasally administered 
The primary goal of this Phase 1b study is to assess the antiviral activity of RV299 against RSV in the viral 
challenge model. In addition, the safety, tolerability, and PK of RV299 will be assessed. 
A total of 80 participants is planned to be enrolled in this study: 40 participants on RV299 and 40 participants 
on placebo. 
The expected duration of study participation for a participant is 1 month (screening not included), with the 
following sequence and duration of study phases: 
- 
Screening phase: from Day -90 to Day-3 pre-HVC. 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 15 days (from 
Day -2 to Day 12). Procedures will include: 
• 
Pre-HVC: 
o 
Admission to quarantine unit on Day -2/-1. 
o 
Baseline assessments will be conducted as per Schedule of Events (SoE) up to Day 0, pre- 
challenge. 
• 
HVC: 
o 
RSV-A Memphis 37b virus inoculation on Day 0. 
• 
Post-HVC: 
o 
Randomisation to receive RV299 or matched placebo. 
o 
Administration of IMP (RV299/placebo). Each participant will receive IMP twice daily (~12 hours 
interval) for 5 consecutive days: 
 
IMP dosing to start on confirmation of RSV infection, i.e., after a positive result by qualitative 
integrative cycler polymerase chain reaction (qicPCR). The qicPCR of nasal wash will be 
performed twice daily on Days 2-5 (Day 5 morning only), or until a positive result is 
received, whichever is sooner. The earliest start of IMP dosing will be in the evening of 
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Day 2 post-HVC (IMP will be initiated 12 hours ± 1-hour post nasal wash confirmation of 
infection) 
OR 
 
IMP would start in the evening of Day 5, if no positive result obtained by qicPCR 
o 
Day 1 onwards and each day – study assessments will be conducted as per SoE. 
o 
Participants will be discharged from the quarantine unit on Day 12 (or may remain longer at the 
discretion of the principal investigator [PI]/investigator). 
- 
Outpatient phase: 
• 
Final visit: Day 28 (±3 days). 
The Study Schematic, showing participant progression through the study, is presented in Section 1.1, Study 
Schematic. 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 RSV 
challenge studies. Numerous studies have been performed using experimental RSV infection in human 
participants. To date, in hVIVO’s studies, over 1400 participants have been successfully and safely 
inoculated with RSV-A Memphis 37b. These studies demonstrated that adults could be infected by nasal 
inoculation and that experimental infection was safe. This RSV strain has been shown to cause symptoms 
and virus shedding that closely match natural infection. 
Administration of IMP and challenge with RSV-A Memphis 37b will take place in hVIVO’s specialised clinical 
facilities, either in a quarantine unit or an outpatient clinic. 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 RV299. 
Blinding will prevent the occurrence of conscious and unconscious bias in the conduct and interpretation of 
the trial. 
Randomisation will be used to prevent bias in the assignment of participants to treatment arms (active 
treatment, placebo), 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 
 
The dose of RV299 for this study will be 65 mg twice daily for 5 days. The rationale for this dose selection 
is based on 3 key elements: 
1. PK modelling that predicts that the human exposures achieved with the 65 mg dose given twice 
daily for 5 days will exceed 4 times the in vitro 90% effective concentration (EC90) for RSV for the 


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full duration of therapy following the first dose and for at least 24 hours after the last dose, based 
on the PK data generated from the multiple-ascending dose study in humans. 
2. The 65 mg dose given twice daily for 5 days provides a 2- to 4-fold margin of safety for Cmax and 
AUC0-24h below the NOAEL set by the 14-day dog GLP study in which myelosuppressive effects 
were observed at 50 mg/kg/day but not at 15 mg/kg/day. 
3. The first study in humans included a cohort of healthy volunteers who were randomised to receive 
65 mg twice daily for 9 doses (n=6) or matched placebo (n=2), and the dosing regimen was shown 
to be well tolerated with a favourable safety profile. There were no SAEs or withdrawals. There 
were only 5 AEs reported (back pain, gastritis, incidental coryzal illness, bowel movement 
irregularity and headache) and all were assessed as mild and resolved completely; none were 
assessed as possibly or likely related to RV299. Safety blood analysis showed no clinically 
concerning changes, and in particular there were no changes in any haematology markers during 
therapy or during the 3-week follow-up period to suggest any evidence of myelosuppressive effect. 
An inoculum titre of approximately 4 log10 plaque-forming units (PFU) of the RSV-A Memphis 37b 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. 
Rationale for Trial Endpoints 
 
The measures for evaluation of the safety and tolerability profile of oral RV299 administration are standard 
for most clinical studies and follow the recommendations in the International Council for Harmonisation 
(ICH) guidelines. 
The measures for evaluation of the antiviral activity of RV299 against RSV have been employed in previous 
studies conducted by hVIVO and are appropriate to characterise the efficacy of RV299, considering the 
RV299 mode of action. 
The assessments for determining RV299 plasma concentrations are appropriate to characterise the PK 
profile of RV299. 
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4.5. 
Population to be Studied 
 
Healthy participants 
 
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 visit shown in the SoE or the last unscheduled visit, as applicable. If a safety 
visit is required after the last scheduled 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 
 
Participants are eligible to be included in the study only if all the following criteria apply: 
 
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, 
and no clinically significant test abnormalities that that will interfere with participant safety, as 
defined by medical history, physical examination, (including vital signs), ECG, and routine 
laboratory tests as determined by the investigator. 
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. Post-menopausal females defined as amenorrhea for ≥12 months with no 
alternative medical cause. A high follicle-stimulating hormone (FSH) level, within 
appropriate post-menopausal range, may be used to confirm post-menopausal 
state in the absence of combined hormonal contraception or hormone 
replacement therapy. If there is <12 months of amenorrhea 2 FSH samples are 
required at least 4 to 6 weeks apart. 
b. Documented status as being surgically sterile (e.g., tubal ligation, hysterectomy, 
bilateral salpingectomy, and bilateral oophorectomy). 


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No. 
hVIVO APPROVED STANDARD INCLUSION CRITERIA 
(Viral Challenge Volunteer Studies) 
Final v11.0, 08FEB2022 
7. 
The following criteria apply to female and male participants: 
a) Female participants of childbearing potential must use one form of highly effective 
contraception. Hormonal methods must be in place from at least 14 days prior to the 
first study visit. The contraception use must continue until 90 days after the last dose 
of IMP. Highly effective contraception is as described below: 
a. Established use of hormonal methods of contraception described below (for a 
minimum of 14 days prior to the first study visit). When hormonal methods of 
contraception are used, male partners are required to use a condom with a 
spermicide: 
i. 
combined 
(oestrogen- 
and 
progestogen 
containing) 
hormonal 
contraception associated with inhibition of ovulation: 
1. oral 
2. intravaginal 
3. transdermal 
ii. 
progestogen-only hormonal contraception associated with inhibition of 
ovulation: 
1. oral 
2. injectable 
3. implantable 
b. Intrauterine device. 
c. Intrauterine hormone-releasing system. 
d. Bilateral tubal ligation. 
e. Male sterilisation (with the appropriate post vasectomy documentation of the 
absence of sperm in the ejaculate) where the vasectomised male is the sole 
partner for that woman. 
f. 
True abstinence – sexual abstinence is considered a highly effective method only 
if defined as refraining from heterosexual intercourse during the entire period of 
risk associated with the study treatments. The reliability of sexual abstinence 
needs to be evaluated in relation to the duration of the clinical trial and the 
preferred and usual lifestyle of the participant. 
b) Male participants must agree to the contraceptive requirements below at entry to 
quarantine and continuing until 90 days after the last dose of IMP. 


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No. 
hVIVO APPROVED STANDARD INCLUSION CRITERIA 
(Viral Challenge Volunteer Studies) 
Final v11.0, 08FEB2022 
a. Use a condom with a spermicide to prevent pregnancy in a female partner or to 
prevent exposure of any partner (male or female) to the IMP. 
b. Male sterilisation with the appropriate post vasectomy documentation of the 
absence of sperm in the ejaculate (please note that the use of condom with 
spermicide will still be required to prevent partner exposure). This applies only to 
males participating in the study. 
c. In addition, for female partners of childbearing potential, that partner must use 
another form of contraception such as one of the highly effective methods 
mentioned above for female participants. 
d. True abstinence – sexual abstinence is considered a highly effective method only 
if defined as refraining from heterosexual intercourse during the entire period of 
risk associated with the study treatments. The reliability of sexual abstinence 
needs to be evaluated in relation to the duration of the clinical study and the 
preferred and usual lifestyle of the participant. 
c) In addition to the contraceptive requirements above, male participants must have 
agreed not to donate sperm following discharge from quarantine until 90 days after 
the last dose of IMP. 
8. 
Sero-suitable for the challenge virus 
• 
The serology result obtained from the RSV-A Memphis 37b virus antibody assay 
suggests that the participant is sensitive to RSV-A Memphis 37b virus infection (i.e., 
they are likely to be infected following inoculation with the challenge virus). 


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5.2. 
Exclusion Criteria 
 
Participants are excluded from the study if any the following criteria apply: 
 
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 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. The following 
conditions apply: 
a) Participants with a history of resolved depression and/or anxiety one or more years 
ago can be included if the Patient Health Questionnaire (PHQ-9) and the 
Generalised Anxiety Disorder Questionnaire (GAD-7) is less than or equal to 4 on 
admission. Participants with a history of stress-related illness, which is not ongoing 
or requiring current therapy, with good evidence of preceding stressors may be 
included at the PI's discretion. As required, participants will be assessed prior to 
enrolment with a PHQ-9 and GAD-7 questionnaire. 
b) Rhinitis (including hay fever) which is clinically active or history of moderate to 
severe rhinitis, or history of seasonal allergic rhinitis likely to be active at the time 
of inclusion into the study and/or requiring regular nasal corticosteroids on an at 
least weekly basis, within 30 days of admission to quarantine will be excluded. 
Participants with a history of currently inactive rhinitis (within the last 30 days) or 
mild rhinitis may be included at the PI’s discretion. 
c) Atopic dermatitis/eczema which is clinically severe and/or requiring moderate to 
large amounts of daily dermal corticosteroids will be excluded. Participants with 
mild to moderate atopic dermatitis/eczema, taking small amounts of regular dermal 
corticosteroids may be included at the PI’s discretion. 
d) Any concurrent serious illness, including history of malignancy, that may interfere 
with a participant completing the study. Basal cell carcinoma within 5 years of initial 
diagnosis or with evidence of recurrence is also an exclusion. 


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NO 
hVIVO APPROVED STANDARD EXCLUSION CRITERIA 
(Viral Challenge Volunteer Studies) 
Final v11.0, 08FEB2022 
e) Participants reporting concurrent physician-diagnosed migraine at screening or a 
history of migraine likely be active at the time of inclusion into the study, is an 
exclusion. Cluster headache/migraine or prophylactic treatment for migraine is an 
exclusion. 
f) 
Participants with physician-diagnosed mild irritable bowel syndrome not requiring 
regular treatment can be included at the discretion of the PI. 
g) Participants with a history of asthma where their last symptoms/treatment were in 
adolescence and over 6 years ago may be included at the discretion of the PI. Any 
participants with symptoms or treatment in adulthood would be excluded. 
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). 
4. 
Females who: 
a) Are breastfeeding, or 
b) Have been pregnant within 6 months prior to the study, or 
c) Have a positive pregnancy test at any point during screening or prior to viral 
challenge. 
5. 
Lifetime history of anaphylaxis and/or a lifetime history of severe allergic reaction. 
Significant intolerance to any food or drug in the last 12 months, as assessed by the PI. 
6. 
Venous access deemed inadequate for the phlebotomy and cannulation demands of the 
study. 
7. 
a) Any significant abnormality altering the anatomy of the nose in a substantial way or 
nasopharynx that may interfere with the aims of the study and, in particular, any of 
the nasal assessments or viral challenge (historical nasal polyps can be included, 
but large nasal polyps causing current and significant symptoms and/or requiring 
regular treatments in the last month will be excluded). 
b) Any clinically significant history of epistaxis (large nosebleeds) within the last 
3 months of the first study visit and/or history of being hospitalised due to epistaxis 
on any previous occasion. 
c) Any nasal or sinus surgery within 3 months of the first study visit. 


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NO 
hVIVO APPROVED STANDARD EXCLUSION CRITERIA 
(Viral Challenge Volunteer Studies) 
Final v11.0, 08FEB2022 
Prior or Concomitant Medications and Assessments 
8. 
a) Evidence of vaccinations within the 4 weeks prior to the planned date of viral 
challenge. 
b) Intention to receive any vaccination(s) before the last day of follow-up (with the 
exception of vaccinations recommended for Covid-19 as defined by Medicines 
and Healthcare products Regulatory Agency (MHRA)/government vaccination 
guidelines). 
c) No travel restrictions apply after the Day 28 (±3 days) follow-up visit 
9. 
Receipt of blood or blood products, or loss (including blood donations) of 550 mL or more 
of blood during the 3 months prior to the planned date of viral challenge or planned during 
the 3 months after the final visit. 
10. 
a) Receipt of any investigational drug within 3 months prior to the planned date of viral 
challenge. 
b) Receipt of 3 or more investigational drugs within the previous 12 months prior to 
the planned date of viral challenge. 
c) Prior inoculation with a virus from the same virus-family as the challenge virus. 
d) Prior participation in another HVC 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 study physician/PI, the medication 
will not interfere with the study procedures or compromise participant safety. Specifically, 
the following are excluded: 
a) Herbal supplements within 7 days prior to the planned date of Viral Challenge. 
b) Chronically used medications, vitamins, or dietary supplements, including any 
medications (including St John’s wort) known to be potent inducers or inhibitors of 
CYP enzymes, within 21 days prior to the planned date of Viral Challenge. 
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 viral challenge has 
exceeded the maximum permissible 24-hour dose (e.g., ≥4 grams paracetamol 
over the preceding week). 


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NO 
hVIVO APPROVED STANDARD EXCLUSION CRITERIA 
(Viral Challenge Volunteer Studies) 
Final v11.0, 08FEB2022 
d)  Systemic antiviral administration within 4 weeks of viral challenge. 
12. 
a) Confirmed positive test for drugs of abuse and cotinine on first study visit. 
One repeat test is allowed at PI discretion. 
b) 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 forced expiratory volume in 1 second (FEV1) <80%. 
14. 
Positive HIV, hepatitis B virus, or hepatitis C virus test. 
15. 
Presence of fever, defined as participant presenting with a temperature reading of ≥37.9°C 
on Day -2, Day -1, and/or pre-challenge on Day 0. 
Other 
16. 
Those employed or immediate relatives of those employed at hVIVO or the sponsor. 
17. 
Any other medical, psychiatric, social, or occupational condition and/or responsibility that, 
in the opinion of the investigator, would interfere with or serve as a contraindication to 
protocol adherence or the assessment of safety, will deem the participant unsuitable for the 
study. Any other reason that in the opinion of the investigator raises a concern that the 
subject will not be able to cope with quarantine requirements. 
 
5.3. 
Lifestyle Considerations 
5.3.1. 
Meals and Dietary Restrictions 
 
All participants will be dosed under fasted conditions. 
For all doses, a pre- and post-dose fasting period of 0.5 hour to 1 hour applies. No fluid intake (including 
water) is allowed for 1 hour pre-dose to 1 hour post-dose. 
Refrain from consumption of red wine, Seville oranges, grapefruit, or grapefruit juice, pomelos, exotic citrus 
fruits, grapefruit hybrids, or fruit juices from 7 days before the start of study intervention until after the final 
dose. 


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Participants must not consume any food containing poppy seeds or any codeine-containing formulation 
starting 72 hours before any study visit and before admission to the quarantine unit (in order to avoid 
false-positive urine drug screen). 
5.3.2. 
Caffeine, Alcohol, and Tobacco 
 
Participants must abstain from ingesting caffeine- or xanthine-containing products (e.g., coffee, tea, cola 
drinks, and chocolate) for 48 hours prior to and during quarantine and for 48 hours prior to all visits requiring 
spirometry. 
Participants must not consume alcohol for 72 hours prior to and during quarantine and for 72 hours prior to 
any clinic visits. 
Participants must not smoke or use tobacco or nicotine containing products for 72 hours prior to and during 
quarantine. Participants that are current smokers may be enrolled in the study if, in the opinion of the 
PI/investigator, cessation of smoking during quarantine will not lead to withdrawal symptoms which could 
interfere with the accurate recording on the symptom diary card. 
5.3.3. 
Activity 
 
Participants must refrain from strenuous exercise for 48 hours prior to and during quarantine and for at 
least 48 hours prior to each clinic visit (unless it is within the usual activity of the participant) and participants 
are advised to avoid any new strenuous activities for 1 week prior to clinic visits such as weightlifting or 
running to avoid potential spurious elevation of clinical laboratory safety parameters. 
5.4. 
Screen Failures 
 
Screen failures are defined as participants who sign the study-specific informed consent form (ICF) but are 
not subsequently enrolled into the study on that occasion. Screen failures may be invited back for repeat 
assessments and screening and if eligible, for study enrolment. 
For individuals who do not meet the criteria for participation in this study (screen failure), the PI/investigator 
will decide whether the participant should be permanently excluded from the study or invited back for repeat 
assessments (i.e., repeat clinical laboratory test) if the initial screening assessments are still within the 
allowed screening windows or rescreening for a later quarantine, as appropriate. 


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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 
IMP (Active) 
IMP (Placebo) 
RSV-A Memphis 37b 
Type 
Drug 
Placebo 
Virus 
Dose Formulation 
RV299 CCI 
 
Placebo 
to 
RV299CCI 
match 
Capped vial, Liquid 
Unit Dose Strength(s) 
65 mg as RV299 (i.e., 
~130 mg as RV299 CCI  
Placebo 
to 
RV299  CCI 
Match 
The challenge agent 
titre is determined in an 
infectivity  assay.  The 
 
dose is approximately 
4 log10 PFU 
Dosage Level(s) 
65 mg as RV299 (i.e., 
CCI 
 
dosed 
twice 
daily 
A 
single 
dose 
of 
challenge agent will be 
~130 mg as RV299 CCI 
(~12 hours interval) for 
delivered 
5 consecutive 
days 
(a total of 10 doses) 
dosed 
twice daily (~12 hours 
interval) 
for 
5 consecutive days (a 
total of 10 doses) 
Route of 
Administration 
Oral 
Oral 
Intranasal 
Use 
Experimental 
Other/placebo 
Infectious 
challenge 
agent 
Sourcing 
Provided 
Limited 
by 
ReViral 
Commercially available 
Provided centrally by 
hVIVO 


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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 
RSV challenge agent 
will be provided in vials. 
The 
details 
of 
the 
challenge 
agent 
provision 
will 
be 
provided 
in 
the 
analytical plan 
Current/Former 
Name(s) or Alias(es) 
Not applicable 
Not applicable 
Not applicable 
 
 
6.2. 
Preparation/Handling/Storage/Accountability/Administration 
6.2.1. 
Investigational Medicinal Product 
 
hVIVO will receive supplies of Qualified Person-certified IMP (measured doses RV299CCI 
 
after it has been authorised for shipment by the sponsor from the Manufacturing 
and Import Authorisation (IMP) licensed Good Manufacturing Practice (GMP) facility. All IMP supplies to 
hVIVO will be used only for this protocol and for no other purpose. 
IMP will be supplied throughout the study. Once received at hVIVO, hVIVO study staff will perform stock 
level accountability and the IMP will be stored securely, according to the storage conditions described 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 temperature of the storage location of the IMP is monitored. 
Accurate records will be 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. 
Prior to dosing RV299 CCI 
 
RV299CCI 
 or placebo 
doses will be taken with 140 mL of water (50 mL water rinse of RV299/placebo bottle following 
administration, and 90 mL post-dose). All participants will be dosed orally, in the seated position, under 
fasted conditions, and under the direct supervision of the investigator (or delegate), and in accordance with 
the randomisation schedule. 


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6.2.2. 
Challenge Agent 
 
The challenge agent used in this study is RSV-A Memphis 37b. 
The challenge agent stock was manufactured under current GMP (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 rangeCCI 
Inoculum vials containing the challenge agent will be used for intranasal inoculation of each participant. 
The inoculum will be prepared and/or provided according to the hVIVO analytical plan (AP) and 
administered in accordance with hVIVO standard operating procedures (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 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. 
Following challenge agent inoculation, participants will be closely observed specifically for potential allergic 
reactions and any AEs for the following 24 hours. Post inoculation, participants will lie flat for 10 min then 
sit up with nose pegs on for 20 min. Participants will continue to be monitored throughout the clinical phase 
of the study. 
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 IMP are provided in the pharmacy 
manual. 
6.3. 
Randomisation and Blinding 
 
hVIVO assigns a unique 6-digit number to each participant in the hVIVO database. This number will be 
used to identify a participant up to the point of randomisation, on source documents, on all study 
correspondence and in the study database. A separate randomisation number will be allocated to the 


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participants at randomisation and will be used for allocation to a study arm. The randomisation number 
encodes the participant’s assignment to 1 of 2 study arms (RV299/placebo) in a 1:1 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/designee preparing the IMP, 
so that IMP 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, labelled with his/her unique randomisation number, 
throughout the study. With the exception of the unblinded pharmacist, unblinded IMP management 
personnel at the clinical site, 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. 
The PI/investigator will be provided with a tamper-evident sealed envelope containing details of the 
treatment for each participant. All opened and unopened envelopes will be collected or destroyed after the 
end of the study, as agreed with the sponsor. 
Individual emergency code break envelopes will be provided to the PI/investigator should it be necessary 
to break the blind for a participant. The PI/investigator will ensure there is an appropriate procedure in place 
to allow access to the code break envelopes in case of an emergency arising during the quarantine period, 
as per hVIVO’s SOPs. An emergency means that the relevant medical decision on the further care of a 
participant is dependent on the actual identity of the study treatment that the participant has received. 
The emergency code break envelopes will contain details of the treatment for each participant. 
When the code break envelope is opened, the PI/investigator must note the date, time, reason for 
unblinding and the details of the PI/investigator and or designated site staff that broke the blind and record 
this information according to hVIVO SOPs. The PI/investigator must also immediately notify the sponsor’s 
medical monitor that the code has been broken. If possible, the sponsor should be consulted before the 
code is broken, but this will only occur if the safety of the participant will not be compromised. 


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Even if the code is broken, blood samples for safety, efficacy, PK, and other assessments will continue to 
be drawn for the remainder of the planned study period following the last dose if doing so will not 
compromise participant welfare. 
Dosing with IMP must be discontinued after unblinding, but the participant will be followed up until resolution 
of any AEs. 
6.4. 
Study Intervention Compliance 
When participants are dosed at the site, they will receive study intervention and challenge agent directly 
from the PI/investigator or designee, under medical supervision. The date and time of each dose 
administered at the study site will be recorded in the source documents and recorded in the electronic case 
report form (eCRF). The dose of study intervention and study participant identification will be confirmed at 
the time of dosing by a member of the PI/investigator site staff other than the person administering the 
study intervention. 
Any noncompliance or problems with the administration of the study intervention will be recorded in the 
participant’s source notes and reported to the sponsor, if appropriate. 
 
6.5. 
Concomitant Therapy 
 
Any medications taken and changes in medications will be recorded in the source data from the time of the 
participant signing the study-specific ICF up to final study contact Day 28 (±3 days). Any medication 
(including over-the-counter or prescription medicines, vitamins, and/or herbal supplements) that the 
participant is receiving at the time of enrolment or receives during the quarantine/outpatient stage will be 
stored, prescribed, and administered in line with their label-specific requirements, and recorded according 
to the parameters required by the clinical database. 
Participants will be reminded to refrain from using any over-the-counter medication without the approval of 
the PI/investigator and must notify the study staff as soon as possible if they are prescribed any medication. 
All medications must be stopped prior to the planned date of viral challenge unless in the opinion of the 
PI/investigator and/or sponsor’s medical expert (SME), the medication will not interfere with the study 
procedures or compromise participant safety. 
Medications prohibited throughout the study are shown in Table 6-2. 
 
Table 6-2:   Prohibited Medication (Healthy Participants) 
Prohibited medication 
Washout 
Systemic (oral and parenteral) antiviral drugs. 
4 weeks prior to first study visit. 
Use or anticipated use during conduct of the study 
of concomitant medications (prescription and non- 
prescription), including vitamins or herbal and 
dietary supplements, unless in the opinion of the 
PI/investigator the medication will not interfere with 
the study procedures or compromise participant 
safety. 
7 days prior to the planned date of viral challenge: 
• 
Herbal supplements 
• 
Any medication or product (prescription or 
over-the-counter) for symptoms of nasal 
congestion 
• 
Short and long-acting antihistamines 


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Prohibited medication 
Washout 
Within 21 days prior to the planned date of viral 
challenge: 
• 
Chronically used medications, vitamins, or 
dietary 
supplements, 
including 
any 
medication known to be moderate/potent 
inducers or inhibitors of cytochrome P450 
enzyme 
Any IMP used in another study. 
Within 3 months or 5 half-lives of the IMP used in 
the other study, whichever is greater, prior to the 
planned date of viral challenge. 
 
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. 
The use of paracetamol and/or other allowed medications is permissible up to 7 days before the planned 
date of viral challenge. During the study, the PI/investigator may permit a limited amount of paracetamol 
(no more than 4 g per day, i.e., maximum daily dose) or topical medication, as clinically required for the 
treatment of headache or any other pain. Other medication to treat AEs may be prescribed if required. 
Medications which are permitted throughout the study are shown in Table 6-3. 
 
Table 6-3:   Permitted Medication 
Permitted medication 
Time period 
Paracetamol 
Maximum 4 g daily throughout the study duration 
at the discretion of the PI/investigator. 
Oral contraceptives 
Allowed at any time during the study. 
Prescription and non-prescription medications, including vitamins or herbal and dietary supplements, not 
listed in prohibited medications are subject to approval by the PI/investigator. 
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. 


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6.7. 
Treatment of Overdose 
 
For this study, any dose of study 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 PK analysis approximately 4 hours after study drug administration. 
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 
 
A participant may withdraw their consent to participate in the study at any time, for any reason, without 
prejudice to his/her future medical care. Participants may decline to give a reason for their withdrawal. 
Additionally, the PI/investigator may withdraw a participant if, in their clinical judgement, it is in the best 
interest of the participant or if the participant cannot comply with the protocol. Wherever possible, the tests 
and evaluations listed for the early withdrawal visit should be carried out, and if clinically indicated, the 
participant should be invited back for a final follow-up visit. 
The sponsor should be notified of all study withdrawals in a timely manner, and in cases where the 
withdrawal is due to a medical reason the participant would be referred to his/her GP. 
Participants will be counselled that early withdrawal from the HVC phase of the study is strongly 
discouraged, as it may pose a risk both to the participant and his/her contacts. In the event of a participant 
insisting on early withdrawal during the quarantine isolation period, the participant will be encouraged to 
stay and would be advised of the potential risks of carrying RSV infection into the community, and to 
vulnerable groups in particular as described in Section 2.5.1.1, Vulnerable Persons. 
If the participant withdraws consent for disclosure of future information, the sponsor may retain and continue 
to use any data collected before such a withdrawal of consent. 
If a participant withdraws from the study, he/she may request destruction of any samples taken and not 
tested, and the PI/investigator must document this in the site study records. 
7.2. 
Participant Discontinuation 
Enrolled participants will be discontinued from study drug receipt for any of the reasons listed below. These 
participants must not receive any additional intervention but should continue to be followed for safety. 
Additional unscheduled visits may be performed for safety reasons. 
• 
Noncompliance with the study requirements and restrictions. 
• 
Clinically significant abnormal laboratory findings, which in the opinion of the PI/investigator and/or 
sponsor precludes further participation in the study. 
• 
Development of intercurrent illness, which in the opinion of the PI/investigator would compromise 
the health of the participant or the study objectives. 
• 
The PI/investigator’s decision that withdrawal from further participation would be in the participant’s 
best interest. 
• 
Termination of the study at the discretion of the PI/investigator or sponsor for safety, behavioural, 
or administrative reasons. 
• 
The wish of the participant. 
• 
Any intervention-related SAEs. 
• 
Anaphylactic reaction following dosing. 


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• 
The participant becomes pregnant (if pregnancy is specified as an exclusion criterion). 
 
Enrolled 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 
 
If a participant is found to be ineligible due to transient circumstances (such as acute disease and/or fever) 
at the quarantine admission, inoculation with challenge agent will be postponed until the transient 
circumstances have been resolved and the participant may be re-invited to a later quarantine group within 
the allowed time window. For participant rescreening refer to Section 5.4, Screen Failures. 
 
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 as a whole 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. 
If a participant discontinues from study intervention OR withdraws from the study for reasons not related to 
AEs, a replacement participant may be enrolled if deemed appropriate by the investigator and sponsor. The 
replacement participant will generally receive the same intervention as the participant being replaced. The 
replacement participant will be assigned a unique treatment/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. 
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. 


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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. 
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, stabilisation, it is judged by the PI/investigator to be no longer clinically significant, the participant 
is lost to follow-up, or an alternative explanation has been provided. 
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. 


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7.6. 
Adaptive Features 
 
This study is designed to be able to utilise adaptive 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 adaptive features will be documented in a non-substantial 
amendment. Generic adaptive features may be implemented at any time at the discretion of the 
PI/investigator. 
Table 7-2:    Adaptive Features 
Adaptive Design 
Category 
Feature 
Limit 
Generic 
Cohort(s) 
1. Participants 
who 
have 
been 
withdrawn (for any reason) may be 
replaced 
(sponsor 
and/or 
PI 
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 
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. Replacement participants will be 
given replacement randomisation 
numbers 
(see 
Section 
7.4, 
Participant Replacement Strategy). 
3. All 
protocol-defined 
rules 
and 
safety criteria must be met before 
any study part, cohort, or 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 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 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 


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Adaptive Design 
Category 
Feature 
Limit 
suitability for residential stay will be 
assessed on a case-by-case basis. 
As such, a maximum length of stay 
cannot be prospectively defined. 
Study-specific 
Participants 
Not applicable 
- 
Dosing 
Not applicable 
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8. 
Study Assessments and Procedures 
Unless otherwise stated, study assessments will be performed according to hVIVO SOPs. 
Study procedures and their timing are summarised in the SoE (Section 1.2, Schedule of Events). Protocol 
waivers or exemptions are not allowed. Adherence to the study design requirements, including those 
specified in the SoE, is essential and required for study conduct. Immediate safety concerns should be 
discussed with the sponsor upon occurrence or awareness to determine if the participant should continue 
or discontinue study intervention. 
All screening evaluations must be completed and reviewed to confirm that potential participants meet all 
eligibility criteria. The PI/investigator will maintain a screening log to record details of all participants 
screened and to document eligibility or record the reasons for screening failure, as applicable. 
For all study assessments, the pre-dose value obtained nearest to dosing will be used as the baseline 
measure for assessments, unless stated otherwise. 
Procedures conducted as part of the hVIVO generic screening process and obtained before signing of the 
study-specific ICF may be utilised for screening or baseline purposes provided the procedures met the 
protocol-specified criteria and were performed within the time frame defined in the SoE. 
The maximum volume of blood collected from each participant over the duration of the study (i.e., from 
screening through final follow-up visit) will not exceed 550 mL. Repeat or unscheduled samples may be 
taken for safety reasons or for technical issues with the samples. If additional samples are required in 
excess of this amount, e.g., to monitor laboratory abnormalities, these will be taken at the discretion of the 
PI/investigator. 
Where applicable, unless otherwise stated, normal ranges will be identified in the PI/investigator trial master 
file. 
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 
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8.1.4. 
Challenge Agent Serology Samples 
 
A participant must be sero-suitable 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 and/or generic screening analytical plan. 
Serum levels of pre-existing RSV-A Memphis 37b-specific antibodies will be determined using RSV 
challenge virus neutralisation assay, as described in the AP. 
8.1.5. 
Patient Health Questionnaire and Generalised Anxiety Disorder 
Questionnaire 
 
PHQ-9 and GAD-7 questionnaires will be used at the discretion of the PI/investigator to assess participants’ 
eligibility in terms of ability to tolerate isolation in the quarantine unit. 
 
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8.2.3. 
Viral Shedding for Dosing 
 
Viral shedding will be confirmed by qicPCR assay of nasal wash samples. 
 
8.2.4. 
Viral Sequencing 
 
Laboratory-confirmed positive nasal wash samples may be analysed for resistance mutations. 
Resistance monitoring will be conducted by sequencing or other appropriate methodology of the challenge 
agent to monitor for treatment-emergent resistance mutations. The nasal wash sample will be sent to a 
sponsor-designated laboratory (or hVIVO where applicable) for analysis in accordance with the AP. 
 
8.3. 
Efficacy Assessments 
8.3.1. 
Viral Shedding Assessment 
 
Viral titre will be determined by qRT-PCR and a viral culture assay (as appropriate) 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 
 
Symptom Diary Card 
Participants will report and assess the severity of any challenge agent-related signs and symptoms 3 times 
per day during quarantine, at the same time each day (±1 hour), using the hVIVO symptom diary card. This 
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The following symptoms in the 13-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 and wheeze have 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 
• 
Chest tightness 
• 
Shortness of breath 
• 
Wheeze 
Additional to the categorical symptom diary card, a visual analogue scale diary card using a 100 mm scale, 
with the same symptoms, will be completed by the participants. 
Previous studies with RSV-A Memphis 37b have used a 10-item symptom questionnaire. The 10 symptoms 
out of the 13 listed above will be used for the primary analysis, and excludes the following 3 symptoms that 
may be additionally explored separately: 
• 
Chilliness/feverishness 
• 
Chest tightness 
• 
Wheeze 
 
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 on Day -1, with the first collection on Day 0. Thereafter, collection of 
paper tissues will occur at the same time each day (±1 hour) with tissues distributed 24 hours ahead. 
24-hour paper tissue collections will be analysed to determine the following over the quarantine period: 


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• 
24-hour nasal discharge weight 
• 
The number of paper tissues used for nose blowing or sneezing over each 24-hour period 
 
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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 
(via stethoscope). 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. 
Assessment and grading of any upper respiratory tract (URT) (nasal discharge, otitis, pharyngitis, sinus 
tenderness) and lower respiratory tract (LRT) symptoms (abnormal breath sounds externally [e.g., stridor, 
wheezing] and on chest auscultation [rhonchi, crepitations, or other]) will be performed, as applicable. 
Physician-reported assessments of challenge agent-related illness will be graded in accordance with its 
intensity and documented in the source data. 
Following challenge agent inoculation, additional symptoms that are not available in the list of symptoms of 
the symptom diary card and are deemed to be clinically significant (in the opinion of the PI/investigator) will 
be captured as AEs (for more details see Section 10.3.6.2, Assessment). 
Following challenge agent inoculation all unexpected (in the opinion of the PI/investigator) symptom- 
directed physical examination findings will be captured as AEs, along with all other occurrences that meet 
the criteria for an AE. 
8.4.3. 
Vital Signs and Tympanic Temperature 
 
Vital signs assessments will be recorded as follows: 
• 
Heart rate (HR) will be recorded in beats per minute. 
• 
Respiratory rate (RR): respirations will be counted and recorded as breaths per minute. 


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• 
Blood pressure (BP): systolic BP and diastolic BP will be measured in millimetres of mercury 
(mmHg); measurements will be made supine. Where possible, the same arm will be used for all 
measurements. 
• 
Peripheral arterial oxygen saturation (SpO2%) will be assessed using pulse oximetry. 
• 
Tympanic temperature will be measured. 
If a participant has an unexpected abnormal or out-of-normal-range result, the assessment may be 
repeated after at least 2 minutes to exclude a technical fault and confirm the original result. The assessment 
may then be repeated at the discretion of the PI/investigator and in accordance with hVIVO SOPs. 
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 Common Terminology Criteria for Adverse Events (CTCAE) grading 
table November 2017. 
Deterioration in a vital sign (compared to baseline) should only be reported as an AE if the deterioration 
fulfils the criteria for an AE. If deterioration in a vital sign is associated with clinical signs and symptoms, 
the sign or symptom will be reported as an AE and the associated vital sign will be considered as additional 
information. 
Temperature may be monitored more frequently during quarantine, if appropriate. 
Following challenge agent inoculation, pyrexia (temperature ≥37.9oC) will be expected and presumed to 
represent infection consequent to viral challenge and will not be additionally captured as an AE unless it 
meets the definition of an AE and is deemed to be clinically significant (in the opinion of the PI/investigator) 
to be classed as an AE. 
Following challenge agent inoculation, all unexpected (in the opinion of the PI/investigator) pyrexia will be 
captured as an AE, along with all other occurrences that meet the criteria for an AE. 
8.4.4. 
Electrocardiogram 
 
Study-specific normal ranges are provided in Appendix 4, Normal Ranges. 
Twelve-lead ECGs will be obtained to evaluate the electrical activity of the heart. Electrocardiograms will 
be read on-site by an appropriately qualified physician or a member or the investigator site staff. Wherever 
possible the same qualified physician or a member or the investigator site staff will review subsequent 
ECGs from the same participant for the assessment of any change from baseline. 
Any changes from baseline during the study will be assessed for their clinical significance. Clinically 
significant changes will be reported as AEs. The PI/investigator or delegate will assess nonclinical 
significant changes to determine whether they should be recorded. 


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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. 
If the dipstick yields potentially clinically significant abnormal results, a urine sample may be sent for 
microscopy, culture, and sensitivity examination, at the discretion of the PI/investigator. Microscopy, culture, 
and sensitivity examination will include but is not limited to red blood cells, white blood cells, epithelial cells, 
crystals, casts, and bacteria. 
Urine safety analysis values will be evaluated by the PI/investigator for clinical relevance. Those values that 
meet the criteria for an AE and are deemed to be clinically significant, will be reported as AEs. 
 
8.4.5.2. 
Drugs of Misuse and Cotinine 
 
Urinalysis will be performed for drugs of abuse and cotinine using commercially available kits that provide 
an instant result, which will be documented in the source data. 
Drugs of abuse screen will include (but is not limited to) amphetamines, barbiturates, cocaine, opiates, 
cannabinoids, and benzodiazepines. 
8.4.5.3. 
Alcohol Breath Testing 
 
Alcohol breath testing will be conducted to determine compliance with the study alcohol restrictions. 
Additional tests may be conducted for assessing eligibility at the discretion of the PI/investigator. Results 
will be recorded in the source documents. 
8.4.5.4. 
Safety Blood Analysis and Assessments 
 
Appendix 2, Clinical Laboratory Tests, describes the safety blood tests that will be performed including, but 
not limited to, haematology, biochemistry, serology (HIV, hepatitis), thyroid function test, and cardiac 
enzymes. Additional safety assessments (e.g., coagulation) will be conducted at the discretion of the 
PI/investigator, as required. 
8.4.6. 
Pregnancy Tests and Follicle-stimulating Hormone 
 
Female participants of childbearing potential are to have a urine pregnancy test at screening. Participants 
will only be enrolled if the pregnancy test is negative. 
Note: Pregnancy test must be performed even if the participant is menstruating at the time of the study visit. 
All female participants will have a serum sample tested for β-human chorionic gonadotrophin (β-hCG) on 
admission to quarantine. 
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8.4.7. 
Lung Function 
 
Spirometry 
Spirometry will be performed according to hVIVO SOPs. Height at screening will be used as the baseline 
measurement for all spirometry assessments. 
Spirometry should meet the American Thoracic Society/European Respiratory Society guidelines criteria 
(Graham et al, 2019). For FEV1 and forced vital capacity (FVC), the highest value from a minimum of 
3 technically satisfactory attempts will be considered. For FEV1 and FVC the highest and the second- 
highest value should not exceed more than 150 mL or 5% (whichever is greater). If the difference is larger, 
up to 8 technically acceptable measurements will be made with repeatability assessed after each additional 
attempt. If after 8 technically acceptable attempts the difference remains greater than 150 mL or 5% 
(whichever is greater) the highest values will be reported, and an operator comment will be made to the 
source data. Values for FEV1 and FVC will be assessed and reported as the highest values regardless of 
curve. 
Predicted values will be calculated according to the formula of the Report of the Global Lung Function 
Initiative, ERS Task Force Lung Function Reference Values (Quanjer et al, 2012). 
Spirometry may be performed at any time in the event of respiratory signs or symptoms (repeated coughing, 
bradypnea, tachypnoea, rales, and rhonchi) or respiratory difficulties. 
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 
at the time points specified in the SoE. 
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 
 
After the initial AE/SAE report, the PI/investigator is required to proactively follow each participant at 
subsequent visits/contacts. All AEs/SAEs will be followed 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. Further information on follow-up procedures is provided in Appendix 3, Adverse Events: 
Definitions and Procedures for Recording, Evaluating, Follow-up, and Reporting. 
8.5.4. 
Regulatory Reporting Requirements for Serious Adverse Events 
 
Any SAE will be reported immediately by the PI/investigator to the sponsor (in practice reporting within 
24 hours of the PI/investigator’s knowledge of the event). This is essential so that the sponsor can meet its 
regulatory and REC reporting obligations for the study. Immediate reports may be verbal (a written record 
of this verbal notification will be retained) or in writing. Immediate reports must be followed up promptly by 
detailed, written reports. 
The sponsor has a legal responsibility to notify both the local regulatory authority and other regulatory 
agencies about the safety of a study intervention under clinical investigation. The sponsor will comply with 
country-specific regulatory requirements relating to safety reporting to the regulatory authority, REC, and 
investigators. 
Investigator safety reports must be prepared for SUSARs according to local regulatory requirements and 
sponsor policy and forwarded to investigators, as necessary. 
A PI/investigator who receives an investigator safety report describing an SAE or other specific safety 
information (e.g., summary or listing of SAEs) from the sponsor will review and then file it along with the 
Investigator’s Brochure and will notify the REC, if appropriate according to local requirements. 
Further information on regulatory reporting requirements is provided in Appendix 3, Adverse Events: 
Definitions and Procedures for Recording, Evaluating, Follow-up, and Reporting. 
8.5.5. 
Pregnancy 
 
Details of all pregnancies in female participants and, if indicated, female partners of male participants will 
be collected from signing of the study-specific ICF onwards until the last study assessment as outlined in 
the SoE. If a pregnancy is reported, the PI/investigator should inform the sponsor within 24 hours of learning 
of the pregnancy and should follow the procedures outlined in Appendix 3, Adverse Events: Definitions and 
Procedures for Recording, Evaluating, Follow-up, and Reporting. 


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Abnormal pregnancy outcomes (e.g., spontaneous abortion, foetal distress, foetal death, stillbirth, 
congenital anomaly/birth defect, ectopic pregnancy) are considered SAEs. 
8.6. 
Pharmacokinetics 
 
Blood samples will be collected for measurement of plasma concentrations of RV299 as specified in the 
SoE. RV299 concentrations in nasal washes may be explored. 
Further to emerging data on RV299, additional blood samples (within the blood volume limit) 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 PK of RV299. Samples collected for analyses of RV299 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 
 
Blood samples for the evaluation of PK parameters of RV299 will be collected according to the SoE, and 
processed and sent to the sponsor’s PK vendor according to the AP. 
8.6.2. 
Pharmacokinetic Parameters 
 
Pharmacokinetic parameters of interest may include: 
AUCτ, AUC0-24h, AUC0-∞, Cmax, tmax, t½ 
Pharmacokinetic parameters will be calculated using non-compartmental methods. Parameters will be 
summarised descriptively. 
 
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9. 
Statistical Considerations 
9.1. 
Statistical Hypotheses 
 
The primary statistical hypothesis is that treatment with RV299 will show an antiviral effect demonstrated 
by a significant reduction in RSV viral load AUC (measured by qRT-PCR) compared to placebo. 
 
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9.3. 
Populations for Analyses 
 
The following populations are defined in Table 9-1. 
 
Table 9-1: 
Study Populations 
Population 
Description 
Intent-to-treat (ITT) analysis 
population 
All randomised participants who received challenge virus and at least 
1 dose of IMP 
Intent-to-treat infected (ITT-I) 
analysis population 
All randomised participants who received challenge virus and at least 
1 dose of IMP, and meet the criterion for laboratory-confirmed RSV 
infection 
Intent-to-treat infected 
analysis population A (ITT-A) 
All randomised participants who received challenge virus and at least 
1 dose of IMP and meet the criterion for laboratory-confirmed RSV 
infection using only assessments prior to taking IMP 
Intent-to-treat infected 
analysis population B (ITT-B) 
All randomised participants who received challenge virus and at least 
1 dose of IMP and meet the criterion for laboratory-confirmed RSV 
infection using only assessments after taking IMP 
Per protocol (PP) analysis 
population 
All ITT-I analysis population participants who have no major protocol 
deviations, and who completed the quarantine period up to the final day 
of quarantine (Day 12) and received all 10 doses of IMP 


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Population 
Description 
Safety analysis population 
All randomised participants who received challenge virus and at least 
1 dose of IMP 
PK analysis population 
All ITT analysis population participants with at least one post-dose PK 
result 
 
Membership of participants in each analysis set will be determined at a planned blinded data review meeting, 
prior to any analysis and database lock. 
The primary efficacy analysis population will be on the ITT-I analysis population, and the ITT-A, ITT-B, and 
PP analysis populations will be used for sensitivity analysis, as defined in the statistical analysis plan (SAP). 
The safety evaluation will be performed on the safety analysis population. 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. 
 
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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. Full details of the planned statistical analysis will be presented in 
the SAP that will include a more technical and detailed description of the statistical analyses described in 
the current protocol section. 
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 
(CSR). 
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9.4.2. 
General Considerations 
 
9.4.2.1. 
Descriptive Statistics 
 
Primary, secondary,CCI 
 endpoints will be analysed descriptively. 
Continuous variables will be summarised using number of available data, number of missing data, mean 
(and/or geometric mean, where applicable), SD, median, lower quartile, upper quartile, minimum, and 
maximum values. When relevant, confidence intervals (CIs) will be computed for the mean and/or the 
median. 


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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% 2-sided 
significance level, except if otherwise specified. No adjustment for multiple testing will be performed (see 
Section 9.1, Statistical Hypothesis). 
For continuous variables (either raw data or log-transformed data) the difference in means, the standard 
error and the 95% 2-sided CI 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 its 95% 
2-sided CI 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 
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 RV299, 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 blinded 
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 and across all participants. Medical history information will be listed. Other 
baseline characteristics will be defined in the SAP. 


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9.4.3.4. 
Compliance to Study Intervention 
 
Compliance with IMP will be computed for each study intervention arm as proportion of participants actually 
receiving IMP as prescribed. For each participant, the proportion of planned dose actually received will be 
computed. 
9.4.4. 
Primary Efficacy Analysis 
 
The primary efficacy analysis will be conducted on the ITT-I analysis population. 
The main estimator of the primary endpoint, the median AUC of qRT-PCR viral load as determined on nasal 
samples (virology) starting at initial administration of investigational medicinal product (IMP) up to discharge 
from quarantine (Day 12), will be analysed on the ITT-I analysis population. 
Descriptive statistics and the 95% CI will be presented by treatment arm. The differences between RV299 
and the placebo arm will be analysed using the t-test or Wilcoxon rank sum test if the assumptions for the 
t-test are not met. 
Further details 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 treatment 
arm. Inferential tests will be performed according to Table 9-2. Further details will be provided in the SAP. 
Table 9-2:   Analysis of Secondary Efficacy Endpoints 
 
Endpoint 
Analysis 
Peak viral load by qRT-PCR 
Descriptive statistics for continuous variables (see 
Section 9.4.2, General Considerations). 
Inferential analysis: t-test or Wilcoxon rank sum 
test. 
Time to confirmed negative test by qRT-PCR 
starting at initial administration of IMP 
Descriptive statistics for continuous variables (see 
Section 9.4.2, General Considerations). 
Kaplan Meier curves will be prepared. 
No inferential analysis. 
Time to confirmed negative test by qRT-PCR 
starting from peak qRT-PCR after initial 
administration of IMP 
Time (days) to peak qRT-PCR in nasal samples, 
starting from initial administration of IMP 
VL-AUC of RSV challenge virus as determined 
by viral culture on nasal samples 
Descriptive statistics for continuous variables (see 
Section 9.4.2, General Considerations). 


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Endpoint 
Analysis 
Peak viral load of RSV as defined by the 
maximum viral load determined by viral culture 
measurements in nasal samples starting from 
initial administration of IMP up to planned 
discharge from quarantine (Day 12, am). 
Inferential analysis: t-test or Wilcoxon rank sum 
test. 
Time (days) to confirmed negative test by viral 
culture measurements in nasal samples starting 
at initial administration of IMP 
Descriptive statistics for continuous variables (see 
Section 9.4.2, General Considerations). 
No inferential analysis. 
Time (days) to confirmed negative test by 
quantifiable viral culture measurements in nasal 
samples starting from peak viral culture after initial 
administration of IMP 
Time (days) to peak viral culture in nasal samples, 
starting from initial administration of IMP 
TSS-AUC starting at initial administration of IMP 
Descriptive statistics for continuous variables (see 
Section 9.4.2, General Considerations). 
Inferential analysis: t-test or Wilcoxon rank sum 
test. 
TSS-AUC-CFB starting at initial administration of 
IMP 
Peak TSS starting from initial administration of 
IMP 
Peak daily symptom score 
Descriptive statistics for continuous variables (see 
Section 9.4.2, General Considerations). 
No inferential analysis. 
Time to symptom resolution starting at initial 
administration of IMP 
Descriptive statistics for continuous variables (see 
Section 9.4.2, General Considerations). 
No inferential analysis. 
Time to symptom resolution starting at peak 
symptoms after initial administration of IMP 
Time to peak TSS 
Total weight of mucus produced 
Descriptive statistics for continuous variables (see 
Section 9.4.2, General Considerations). 
No inferential analysis 
Total number of tissues used by participants 


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AUC: area under the curve; qRT-PCR: quantitative reverse transcriptase-polymerase chain reaction; TSS: Total 
symptom score 
 
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9.4.7. 
Safety Analyse(s) 
 
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 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. 
A by-participant AE data listing including onset and resolution dates, verbatim term, preferred term, 
treatment, severity, relationship to treatment, action taken, and outcome will be provided. 
Other safety endpoints that will be presented by study intervention arm include laboratory evaluations 
(biochemistry, haematology, cardiac enzymes, and urinalysis), vital signs assessments, physical 
examinations, 12-lead ECG, and spirometry. Additionally, physical examinations will be listed. 
9.4.8. 
Pharmacokinetic Analysis 
 
Descriptive statistics will be calculated for the plasma concentrations of RV299 at each applicable time 
point and for the derived plasma PK parameters. Statistics include sample size (n), mean, SD, coefficient 
of variation, geometric mean, median, minimum, and maximum. 
For each participant, plasma concentration-time data of RV299 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. 
 
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. 
In addition to regulatory submission, the protocol, protocol amendments, ICF, Investigator’s Brochure, and 
other relevant documents (e.g., advertisements) must be submitted to a REC by the PI/investigator and 
reviewed and approved by the REC before the study is initiated. 
Substantial amendments to the protocol will require regulatory authority and REC approval before 
implementation of changes made to the study design, except for changes necessary to eliminate an 
immediate hazard to study participants. 
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 
 
Investigators and sub-investigators will provide the sponsor with sufficient, accurate financial information 
as requested to allow the sponsor to submit complete and accurate financial certification or disclosure 
statements to the appropriate regulatory authorities. Investigators are responsible for providing information 
on financial interests during the study and for 1 year after completion of the study. 
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 quarantine admission visit, 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 trial master file. 
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. 
 
. 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. 


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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 ICF. 
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. However, participant safety will be continuously 
monitored by the investigator and sponsor which includes ongoing safety oversight (to include safety signal 
detection at any time during the study). 
10.1.7. 
Dissemination of Clinical Study Data 
 
The key design elements of this protocol will be posted on publicly accessible registry. A ‘public registry’ is 
defined as any register on the World Health Organisation list of primary registries or the International 
Committee of Medical Journal Editors list of registries, e.g., ClinicalTrials.gov or International Standardised 
Randomised Controlled Trial Number registry. 
It is the sponsor’s (or sponsor delegate) responsibility to send the Clinical Trial Summary Report to the REC 
and MHRA (if required) within 1 year of the end of the study, and where applicable, to publish the summary 
results within 1 year of the end of the study in the public register(s) where the clinical trial was registered. 
The PI/investigator shall provide assurance to participants that their confidentiality will be maintained. 
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 have a legal obligation to protect at all times the confidentiality of participant personal data from the 
point of capture, through processing, dissemination in line with consent from the participant and to its final 
disposition. 
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. Monitoring details describing strategy 
(e.g., risk-based initiatives in operations and quality such as Risk Management and Mitigation Strategies 
and Analytical Risk-based Monitoring), methods, responsibilities, and requirements, including handling of 
noncompliance issues and monitoring techniques (remote or on-site monitoring) are provided in the 
Monitoring Plan. 
Study monitors will perform ongoing source data verification to confirm that data entered into the eCRF by 
authorised investigator site staff are accurate, complete, and verifiable from source documents; that the 


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safety and rights of participants are being protected and that the study is being conducted in accordance 
with the currently approved protocol and any other study agreements, ICH GCP, and all applicable 
regulatory requirements. 
Records and documents, including signed ICFs, pertaining to the conduct of this study must be retained by 
the PI/investigator during the retention period as agreed with the sponsor and as required by local 
regulations or institutional policies. 
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. 
Data entered in the eCRF that are transcribed from source documents must be consistent with the source 
documents or the discrepancies must be explained. The PI/investigator may need to request previous 
medical records or transfer of records, depending on the study. Also, current medical records must be 
available. 
Definition of what constitutes source data for the study can be found in the Source Data Agreement. 
 
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 suspended 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. 
If the study is suspended or terminated for safety reason(s), the sponsor will promptly inform the 
PI/investigator, and will also inform the regulatory authorities of the suspension or termination of the study 
and the reason(s) for the action. 
The PI/investigator is responsible for promptly informing the REC and providing the reason(s) for the 
suspension or termination of the study. 
If the study is prematurely terminated, all study data must be returned to the sponsor. In addition, the site 
must conduct final disposition of all unused IMPs in accordance with the sponsor’s procedures for the study. 
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. 


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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. 
Verbal or written discussion of results prior to study completion and full reporting should only be undertaken 
with written consent from the sponsor. 


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10.2. Appendix 2: Clinical Laboratory Tests 
 
The tests detailed in Table 10-1 will be performed by the local laboratory. 
Study-specific requirements for inclusion or exclusion of participants are detailed in Section 5, Study 
Population. 
Additional tests may be performed at any time during the study as determined necessary by the 
PI/investigator or required by local regulations. 
Table 10-1: 
Protocol-Required Safety Laboratory Assessments 
Laboratory Assessments 
Parameters 
Haematology 
Platelet count 
White blood cell count (absolute) 
White blood cell count differential: 
• 
Neutrophils 
• 
Lymphocyte 
• 
Monocytes 
• 
Eosinophils 
• 
Basophils 
Red blood cell count 
Reticulocyte count (% and absolute) 
Haemoglobin 
Haematocrit 
Mean corpuscular volume 
Mean corpuscular haemoglobin 
Mean corpuscular haemoglobin concentration 
Coagulation 
Prothrombin time 
Activated partial thromboplastin time 
Biochemistry 
Sodium 
Potassium 
Glucose 
Albumin 
Chloride 
Bicarbonate 
Calcium 
Uric acid 
Total protein 
Creatinine 
Total, direct, and indirect bilirubin 
Inorganic phosphate 
Blood urea nitrogen 


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Laboratory Assessments 
Parameters 
C-reactive protein 
Gamma glutamyl transferase 
Alkaline phosphatase 
Alanine transaminase 
Lactate dehydrogenase 
Aspartate transaminase 
Urea 
Thyroid function 
Thyroid stimulating hormone at screening only 
Thyroxine at screening only 
Cardiac enzymes 
Creatine kinase 
Troponin (T) 
Routine urinalysis 
Colour 
Specific gravity 
Appearance 
pH 
Presence of blood, glucose, leukocytes, ketones, nitrites, proteins, 
urobilinogen, and bilirubin by dipstick 
If the dipstick yields potentially clinically significant abnormal results: 
microscopy, culture, and sensitivity examination 
Other 
screening/eligibility 
tests 
FSH* 
β-hCG* 
Urine pregnancy test* 
Urine drugs of abuse and cotinine 
Alcohol breath test 
Total cholesterol** 
Antibodies against HIV-1 and HIV-2 
Hepatitis A immunoglobulin M** 
Hepatitis B surface antigen 
Hepatitis C antibodies 
Glycated haemoglobin** 
Immunoglobulin A antibodies** 
* FSH only for post-menopausal female participants, β-hCG for all female participants, and urine pregnancy test 
only for female participants of childbearing potential. 
**Optional at the discretion of the PI/investigator. 
Investigators must document their review of each laboratory safety report. 
Laboratory results that could unblind the study will not be reported to investigative sites or other blinded 
study staff until the study has been unblinded. 


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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 
 
AE Definition 
An AE is defined as any untoward medical occurrence in clinical study participants administered a 
pharmaceutical (investigational or non-investigation) product. An AE does not necessarily have a causal 
relationship with the study intervention. An AE can therefore be any unfavourable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a 
medicinal (investigational or non-investigational) product (definition as per ICH). 
This will also cover any AEs occurring after study intervention(s) including administration with the 
challenge agent in viral challenge studies. 
Unsolicited AEs 
Unsolicited AEs are defined as any AEs observed by the participant or PI/investigator which are not pre- 
listed on the symptom diary card. Unsolicited AEs will be collected upon signature of study-specific ICF 
until the end of the study. Any unsolicited AEs observed by the PI/investigator and/or reported by the 
participant must be recorded in the eCRF regardless of causality in relationship with IMP. 
 
 
Events Meeting the AE Definition 
• 
Exacerbation of a pre-existing illness. 
• 
Increase in frequency or severity of a pre-existing episodic condition. 
• 
A condition detected or diagnosed after study intervention administration even though it may 
have been present prior to the start of the study. 
• 
A complication that occurs during a hospitalisation. 
• 
A clinically significant change in laboratory parameter. 
 
 
Events NOT Meeting the AE Definition 
• 
Medical or surgical procedures (e.g., surgery, endoscopy, tooth extraction, transfusion); the 
condition that leads to the procedure is an AE. 
• 
Pre-existing disease or condition present or detected prior to start of study intervention 
administration that does not worsen (including screening findings such as abnormal laboratory 
results). 


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• 
Hospitalisation for elective surgery, social and/or convenience admissions provided they are 
arranged before the start of study intervention administration and the reason does not worsen. 
• 
Over-administration of either the study intervention or concomitant medication without any signs 
or symptoms. 
• 
An uncomplicated pregnancy or an induced elective abortion to terminate a pregnancy without 
medical reason. 
• 
Typical/normal/solicited viral infection symptoms on symptom diary cards. 
• 
Procedure-related events may be noted during the study while conducting nasal sampling 
(collection of nasal wash samples, nasopharyngeal swabs, or other nasal samples), specifically: 
o 
Nasal discomfort/irritation 
o 
Nasal abrasions 
o 
Nasal epistaxis 
o 
Sneezing 
o 
Watery eyes 
When mild in nature and as expected in the opinion of the PI/investigator or delegated physician, 
these events will not be reported as AEs. 
• 
Asymptomatic bruising following venepuncture, or removal of an intravenous cannula. 
• 
Dry lips and skin if solely due to the air-conditioning in the quarantine unit, with or without the 
use of emollients to maintain skin integrity. 
 
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. 
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. 


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10.3.4. 
Serious Adverse Event 
 
SAE Definition 
An SAE is defined as any untoward medical occurrence that, at any dose: 
a. 
Results in death 
b. 
Is life threatening 
The term ‘life threatening’ in the definition of ‘serious’ refers to an event in which the participant was at 
risk of death at the time of the event. It does not refer to an event, which hypothetically might have 
caused death, if it were more severe. 
c. 
Requires inpatient hospitalisation or prolongation of existing hospitalisation 
• 
In general, hospitalisation signifies that the participant has been detained (usually involving at 
least an overnight stay) at the hospital or emergency ward for observation and/or treatment 
that would not have been appropriate in the physician’s office or outpatient setting. 
Complications that occur during hospitalisation are AEs. If a complication prolongs 
hospitalisation or fulfils any other serious criteria, the event is serious. When in doubt as to 
whether “hospitalisation” occurred or was necessary, the AE should be considered serious. 
• 
Hospitalisation for elective treatment of a pre-existing condition that did not worsen from 
baseline is not considered an AE. 
d. 
Results in persistent disability/incapacity 
• 
The term disability means a substantial disruption of a person’s ability to conduct normal life 
functions. 
• 
This definition is not intended to include experiences of relatively minor medical significance 
such as uncomplicated headache, nausea, vomiting, diarrhoea, influenza, and accidental 
trauma (e.g., sprained ankle) which may interfere with or prevent everyday life functions but do 
not constitute a substantial disruption. 
e. 
Is a congenital anomaly/birth defect 
f. 
Is an important medical event 
• 
Important medical events’ – some medical events may jeopardise the participant or may 
require an intervention to prevent one of the above characteristics/consequences. Such events 
should also be considered as ‘serious’ in accordance with the above definition. 
• 
Medical judgement should be exercised in deciding whether an adverse event/reaction is 
serious. Important adverse events/reactions that are not immediately life threatening or do not 
result in death or hospitalisation but may jeopardise the participant or may require intervention 
to prevent one of the other outcomes listed in the definition above occurring, should also be 
considered serious. Details of the SAE must be provided. 


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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. 
Medical events will be assessed for expectedness against the reference safety information section of the 
Investigator’s Brochure or equivalent, and any available Investigator’s Brochure addendum. Any changes 
to the reference safety information will be deemed as a change to the risk/benefit profile and will require a 
substantial amendment to be submitted to the MHRA. This amendment must be approved before the 
changes are implemented in the study. 
*The term ‘severity’ is used here to describe the intensity of a specific event. This is not the same as ‘serious’ 
which is based on participant/event outcome or action criteria. 
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. Adverse events will be fully recorded in the 
source documents as they are reported whether spontaneously reported by a participant or in response to 
questioning about wellbeing at each face-to-face study visit and during telephone calls. Enquiries about 
AEs should cover the period between the previous and current visit. 
The following are examples of open-ended, non-leading questions that may be used to obtain this 
information: 
• 
How are you feeling? 
• 
Have you had any medical problems since your last visit/assessment? 
• 
Have you taken any new medicines, other than those given to you in this study, since your last 
visit/assessment? 
Following the reporting of AEs and concomitant medication, the PI/investigator should assess the 
participant’s eligibility to continue in the study. 
The PI/investigator will record all relevant information regarding an AE/SAE in the source documents and 
evaluate AEs/SAEs using the following guidelines: 
• 
Description of event (if the event consists of a cluster of signs and symptoms, a diagnosis should 
be recorded) 
• 
Seriousness 
• 
Grade (or severity) 
• 
Onset date and time 
• 
Frequency 


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• 
Date and time of resolution (or ‘continuing’ if unresolved) 
• 
Action taken 
• 
Concomitant medication 
• 
Clinical outcome 
• 
Relationship or causality (IMP/challenge agent/study procedures/concomitant medication/other). 
Any clinically significant abnormal laboratory result, vital sign or other measure will be followed 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, or an alternative explanation has been 
provided. 
If an AE is not resolved at the end of the study, the AE should be followed until it has resolved or (in the 
case of pregnancy) the pregnancy has been terminated (including spontaneous abortion), resulted in a 
birth, or a decision has been made by the sponsor that no further follow-up is required. 
Even if the AE/SAE is assessed by the PI/investigator as not reasonably attributable to the challenge agent, 
its occurrence must be fully documented in the source notes. 
10.3.6.2. Assessment 
 
Description 
If the event consists of a cluster of signs and symptoms, a diagnosis should be recorded (e.g., 
gastroenteritis) rather than each sign and symptom. 
Onset and end 
The dates and times of the onset and end of the event should be recorded. 
 
Assessment 
Challenge Agent-related Symptoms 
The PI/investigator will assess, and review challenge agent-related symptoms recorded in participants’ 
hVIVO symptom diary cards. Symptoms greater than Grade 0 will be expected and presumed to 
represent infection consequent to challenge agent inoculation and will not be additionally captured as 
AEs unless they meet the definition of an AE and are deemed to be clinically significant (in the opinion 
of the PI/investigator). 
Following challenge agent inoculation all unexpected (in the opinion of the PI/investigator) symptoms 
post inoculation will be captured as AEs, along with all other occurrences that meet the criteria for an 
AE. 
Physical Examination 
Any clinically significant change in complete physical examination findings during the study will be 
documented as an AE. 


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Symptom-directed Physical Examination 
Following challenge agent inoculation, URT symptoms (nasal discharge, otitis, pharyngitis, sinus 
tenderness) and LRT symptoms (abnormal breath sounds externally [e.g., stridor, wheezing] and on 
chest auscultation [rhonchi, crepitations or other]) will be expected and presumed to represent infection 
consequent to challenge agent and will not be additionally captured as AEs unless they meet the 
definition of an AE and are deemed to be clinically significant (in the opinion of the PI/investigator). 
Vital Signs 
Deterioration in a vital sign (compared to baseline) should only be reported as an AE if the deterioration 
fulfils the criteria for an AE. If deterioration in a vital sign is associated with clinical signs and symptoms, 
the sign or symptom will be reported as an AE and the associated vital sign will be considered as 
additional information. 
Temperature 
Following challenge agent inoculation, pyrexia (temperature ≥37.9oC) will be expected and presumed to 
represent infection consequent to challenge agent and will not be additionally captured as an AE unless 
it meets the definition of an AE and is deemed to be clinically significant (in the opinion of the 
PI/investigator) to be classed as an AE. 
Following challenge agent inoculation all unexpected (in the opinion of the PI/investigator) pyrexia will 
be captured as an AE, along with all other occurrences that meet the criteria for an AE. 
Spirometry 
A 15% drop in a spirometry value (compared to baseline) confirmed by a repeat on the same day, will 
be a Grade 1 (mild) AE. The PI/investigator will use his/her clinical judgement to assign severity grades 
above Grade 1, based on evaluation of clinical signs and symptoms. If the repeated value has returned 
to normal an AE will not be raised. 
Laboratory Values 
Deterioration in a laboratory value (compared to baseline) should only be reported as an AE if the 
deterioration meets the criteria for an AE and is deemed to be clinically significant (in the opinion of the 
PI/investigator). If deterioration in a laboratory result is associated with clinical signs and symptoms, the 
sign or symptom will be reported as an AE and the associated laboratory result will be considered as 
additional information. 
The PI/investigator and/or SME will judge whether abnormal laboratory values are clinically significant or 
not clinically significant, and record this in the source document. This entry should be signed and dated 
by the relevant PI/investigator. Laboratory abnormalities detected at screening will be considered as part 
of the medical history and will not be reported as AEs. 
Challenge agent associated laboratory abnormalities (e.g., elevated alanine transferase, aspartate 
aminotransferase, or gamma glutamyl transferase; decreased neutrophils) may be recorded as AEs (at 
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C-reactive Protein 
Any value above 5 mg/L but less than 60 mg/L will be a Grade 1 (mild) AE (unless deemed non clinically 
significant by the PI/investigator). The PI/investigator will use his/her clinical judgement to assign severity 
grades above Grade 1, based on evaluation of clinical signs and symptoms. 
 
10.3.6.3. Assessment of Intensity 
 
The term ’severe’ is often used to describe the intensity (severity) of a specific event. This is not the same 
as ‘serious’ which is based on participant/event outcome or action criteria. 
The PI/investigator will use the CTCAE grading scale as a reference when collecting, reporting, and 
clarifying database queries of AEs, SAEs, and adverse reactions. 
The severity of an AE that does not appear in the CTCAE grading scale should be determined according 
to the definitions in Table 10-2. 
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 
 
The frequency of the AE should be categorised as one of the following: 
• 
Single 
• 
Intermittent 
• 
Continuous 
 
10.3.6.5. Assessment of Causality 
 
• 
The PI/investigator is obligated to assess the relationship between study intervention and each 
occurrence of each AE/SAE. 


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• 
A ‘reasonable possibility’ of a relationship conveys that there are facts, evidence, and/or arguments 
to suggest a causal relationship, rather than a relationship cannot be ruled out. 
• 
The PI/investigator will use clinical judgement to determine the relationship. 
• 
Alternative causes, such as underlying disease(s), concomitant therapy, and other risk factors, as 
well as the temporal relationship of the event to study intervention administration will be considered 
and investigated. 
• 
The PI/investigator will also consult the Investigator’s Brochure in his/her assessment. 
• 
For each AE/SAE, the PI/investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality. 
• 
There may be situations in which an SAE has occurred, and the PI/investigator has minimal 
information to include in the initial report to the sponsor’s pharmacovigilance (PV) provider. 
However, it is very important that the PI/investigator always assesses causality for every event 
before the initial transmission of the SAE data to sponsor’s PV provider. 
• 
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 
The AE is related to an aetiology other than the IMP (the alternative 
aetiology must be documented in the participant’s medical record). 
Unlikely to be related 
The AE is unlikely to be related to the IMP and likely to be related to factors 
other than IMP. 
Possibly related 
There is an association between the AE and the administration of the IMP, 
and there is a plausible mechanism for the AE to be related to the IMP, but 
there may also be alternative aetiology, such as characteristics of the 
participant’s clinical status or underlying disease. 
Probably related 
A reasonable temporal sequence of the AE and the IMP administration 
exists and based upon the known pharmacological action of the drug, 
known or previously reported adverse reactions to the drug or class of 
drugs, or judgement based on the PI/investigator’s clinical experience, the 
association of the AE with the IMP seems likely. 
Definitely related 
A definite causal relationship exists between the AE and the administration 
of the IMP, and other conditions do not appear to explain the AE. 
Unless an AE is ‘definitely related’ to the IMP, a causal relationship to one of the following should be 
considered, and full details provided on the AE reporting form as appropriate. 
• 
Challenge agent 


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• 
Study procedures 
• 
Concomitant medication 
• 
Other 
 
10.3.6.6. Action Taken 
 
The PI/investigator should ensure that adequate medical care is provided to participants for any AEs/SAEs, 
including clinically significant laboratory values related to the study intervention. In addition, the 
PI/investigator will describe whether any treatment was given for the AE. 
The PI/investigator will classify the action taken regarding the AE/SAE. The action taken should be 
classified according to the following categories and full details provided as appropriate: 
• 
None 
• 
Nondrug therapy given 
• 
Concomitant medication taken 
• 
IMP dose not changed 
• 
IMP dose adjusted 
• 
IMP administration temporarily interrupted 
• 
IMP administration permanently discontinued 
• 
Participant withdrawn 
• 
Participant hospitalised 
• 
Other. 
 
10.3.6.7. Outcome 
 
An AE/SAE should be followed until the PI/investigator has determined and recorded the outcome or an 
alternative explanation. The outcome should be classified according to the categories shown in Table 10-4. 
Table 10-4:   Classification of Adverse Events Outcome 
Classification 
Definition 
Resolved 
Resolution of the AE with no residual signs or symptoms 
Resolved with sequelae 
Resolution of the AE with residual signs or symptoms 
Ongoing 
Either incomplete improvement or no improvement of the AE, such 
that it remains ongoing 
Fatal 
Outcome of the AE was death. ‘Fatal’ should be used when death 
was at least possibly related to the AE 
Unknown (e.g., lost to follow-up) 
Outcome of the AE is not known (e.g., the participant is lost to follow- 
up) 


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10.3.6.8. Follow-up 
 
All AEs/SAEs must be followed up by the PI/investigator for follow-up until they are: 
• 
Resolved (return to normal or baseline values), or 
• 
Stabilised, or 
• 
Judged by the PI/investigator to be no longer clinically significant, or 
• 
The participant is lost to follow-up, or 
• 
An alternative explanation has been provided. 
Where appropriate, the participant may be referred to the participant’s GP or other healthcare professional. 
Additional measurements and/or evaluations may be necessary to investigate the nature and/or causality 
of an AE/SAE. This may include additional laboratory tests, diagnostic procedures, histopathological 
examinations, or consultation with other healthcare professionals. If the participant dies, any post-mortem 
findings (including histopathology) will be provided to the sponsor if possible. 
10.3.7. 
Reporting of Serious Adverse Events 
 
Serious AEs must be documented and reported as per hVIVO SOPs. 
Prompt notification of SAEs by the PI/investigator to the sponsor is essential so that the sponsor can meet 
its regulatory and REC reporting obligations for the study. If the PI/investigator does not have all of the 
details regarding the SAE, he/she will not wait until this information becomes available before making the 
initial report to sponsor. Contact details are detailed in Table 10-5. 
Notification should be made: 
• 
By email to Syneos Health as soon as possible and within 24 hours of the PI/investigator being 
made aware of the event. 
• 
In a detailed written report within 24 hours of the PI/investigator becoming aware of the event, using 
the Syneos Health Serious Adverse Event Report. 
All reports should be directed to sponsor’s PV provider, Syneos Health. The PI/investigator at the site is 
responsible for ensuring that a member of the sponsor study team is made aware of any SAE reports that 
have been transmitted. 


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Table 10-5:   Contact Details for Reporting All Serious Adverse Events 
Contact 
Details 
Name of sponsor’s medical expert: 
PPD 
 
SME SAE telephone number: 
PPD 
 
Pharmacovigilance reporting email: 
PPD 
 
SAE email address: 
PPD 
 
In addition, any AE resulting in permanent study discontinuation for a participant, even if not serious and 
regardless of expectedness or causality, must be reported by telephone, email, or fax to the sponsor within 
7 calendar days of the PI/investigator or any other investigator site staff’s knowledge of the event. 
The SAE form, AE record, and relevant concomitant medication record should be emailed to the sponsor’s 
PV provider, Syneos Health, within 24 hours of the PI/investigator or any investigator site staff’s knowledge 
of an SAE. An updated SAE report form should be forwarded to the sponsor within 24 hours of receipt of 
the new/updated information as relevant. 
Information relating to the participant’s subsequent medical progress must be submitted to the sponsor’s 
PV provider, Syneos Health, as available, until the SAE has subsided or, in the case of permanent 
impairment, until it stabilises, and the overall clinical outcome has been ascertained. 
The PI/investigator will also provide additional information, including a copy of the following documents 
(where applicable): 
• 
Copies of test results, as available 
• 
Hospital discharge summary (as soon as it is available to the PI) 
• 
Autopsy report (as soon as it is available to the PI). 
The PI/investigator must report SAEs/SUSARs to the relevant REC in accordance with applicable 
regulatory requirements and within the relevant timelines. 
The REC will be sent annual safety updates in order to facilitate their continuing review of the study. 
 
10.3.8. 
Reporting of Suspected Unexpected Serious Adverse Reaction 
 
The sponsor is responsible for assessing SUSARs, unblinding potential SUSARs, and reporting SUSARs 
to the MHRA and REC. 
The sponsor shall ensure that all relevant information about a SUSAR that occurs during a clinical study in 
the UK and is fatal or life threatening, is reported as soon as possible to the MHRA and the REC. This 
needs to be done within 7 calendar days after the sponsor became aware of the event. Any additional 
relevant information should be sent within 8 days of the first report being sent. 
The sponsor shall ensure that a SUSAR which is not fatal, or life threatening is reported as soon as possible 
and in any event within 15 calendar days after the sponsor became aware of the event. 


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The procedure of SAE/SUSAR reporting will be described in a Safety Management Plan that will be finalised 
before the start of the study to define the different tasks of the investigator,CCI 
(the sponsor) and 
Syneos Health (acting on behalf ofCCI 
). 
 
10.3.9. 
Adverse Reactions to Non-investigational Medicinal Products 
 
Any AEs/SAEs which are related to/caused by a concomitant medication or challenge agent, should not be 
classed as adverse reactions, serious adverse reactions, or SUSARs (adverse reactions, serious adverse 
reactions, SUSARs relate only to IMP by definition). However, an SAE caused by a non-IMP would need 
to be reported to the MHRA/REC and participants must be followed up until the event is considered 
resolved, judged by the PI/investigator to be no longer clinically significant, the participant is lost to follow- 
up, an alternative reason has been provided, or until the PI in conjunction with the sponsor deem the event 
stable and a decision for no further follow-up has been taken (see Section 10.3.6.7, Outcome, and 
Section 10.3.6.8, Follow-up). 
10.3.10. Post-study Adverse Events and Serious Adverse Events 
 
All SAEs that occur during the study from ICF signature until last participant last scheduled visit must be 
reported by the PI/investigator to Syneos Health as soon as possible, in accordance with hVIVO SOPs, and 
at the latest within 24 hours of becoming aware of the event. 
All AEs/SAEs that have not resolved by the end of the study, or that have not resolved upon discontinuation 
of the participant’s participation in the study, must be followed up until the event is considered resolved, 
judged by the PI/investigator to be no longer clinically significant, the participant is lost to follow-up, an 
alternative reason has been provided, or until the PI in conjunction with the sponsor deem the event stable 
and a decision for no further follow-up has been taken (see Section 10.3.6.8, Follow-up). 
10.3.11. Pregnancy 
 
If a female participant or female partner of a male participant becomes pregnant during of the study, this 
must be reported by the PI/investigator to the SME and study monitor by telephone as soon as possible, in 
accordance with hVIVO SOPs, and at the latest within 24 hours of becoming aware of the event. 
Following the telephone notification, the PI/investigator must fully and accurately complete the appropriate 
pregnancy reporting form, which must be emailed to the SME and the study monitor at the latest within 
24 hours of becoming aware of the pregnancy. 
Participants will be advised to contact their GP or a specialist, as appropriate. 
Consent for follow-up of the pregnancy and pregnancy outcome will be sought from the pregnant study 
participant or the pregnant partner of the male study participant as applicable. Consent for follow-up will be 
documented on an hVIVO Pregnancy Follow-up ICF. 
Provided that the appropriate consent is in place, information related to the pregnancy will be collected as 
per hVIVO SOPs and the sponsor’s requirements. The completed reporting form(s) will be sent to the 
sponsor for review and assessment, and subsequent reporting as required. 


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• 
A complete evaluation will be documented in the source data to permit transfer to the clinical 
database. 
• 
The emergency code break envelopes will be requested (Section 6.3, Randomisation and Blinding) 
to break the blind for the appropriate study participant to ensure that further care can be based on 
the actual identity of the study intervention that the participant received. 
• 
hVIVO will maintain contact with the participant for a protracted period, but certainly until after the 
birth, in order to assess for outcomes that may be reportable as related AEs, and for reporting to 
the sponsor as appropriate. 
• 
hVIVO, in consultation with the participant, will keep the participant’s GP informed. 
• 
All cases of foetal drug exposure via the parent as a study participant will be reported to the sponsor 
and the REC. 
• 
Abnormal pregnancy outcomes (e.g., spontaneous abortion, foetal distress, foetal death, stillbirth, 
congenital anomaly/birth defect, ectopic pregnancy) are considered SAEs. 


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10.4. Appendix 4: Normal Ranges 
 
Vital signs normal ranges 
 
Vital Signs 
Lower Limit 
Higher Limit 
Units 
Tympanic temperature 
(above 37.8 classed as 
pyrexia) 
35.5 
37.8 
oC 
Oxygen saturation 
Normal is ≥95 
% 
Respiratory rate 
10 
20 
breaths per minute 
Heart rate 
40 
100 
beats per minute 
Systolic BP 
90 
140 
mmHg 
Diastolic BP 
50 
90 
mmHg 
ECG 
 
ECG Parameters 
Lower Limit 
Higher Limit 
Units 
HR 
40 
100 
bpm 
QRS 
60 
120 
ms 
PR interval 
120 
220 
ms 
QT 
320 
450 
ms 
QTc (Fridericia/Bazett) 
320 
<450 (females) 
ms 
<430 (males) 
Spirometry 
 
Spirometry Parameters 
Lower Limit 
Higher Limit 
Units 
FEV1 
Normal if ≥80% of the predicted value 
litres 
FEV1/FVC 
Normal if ≥70% (≥0.7) of the predicted value 
litres 
No single value should be used in isolation, all spirometry reference ranges require physician interpretation 
of the participant’s overall status to determine their relevance. 


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10.6. Appendix 6: Abbreviations 
 
Abbreviation 
Term 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
AP 
Analytical plan 
AST 
Aspartate aminotransferase 
AUC 
Area under the curve 
AUC0-24h 
Area under the plasma concentration-time curve over the last 24 hours dosing 
interval 
AUC0-∞ 
Area under the plasma concentration-time curve from time zero to infinity 
AUCτ 
Area under the plasma concentration-time curve from time zero to the end of the 
dosing interval 
BCRP 
Breast cancer resistance protein 
BID 
bis in die, twice a day 
β-hCG 
β-human chorionic gonadotrophin 
BMI 
Body mass index 
BP 
Blood pressure 
cGMP 
current Good Manufacturing Practice 
CI 
Confidence interval 
COPD 
Chronic obstructive pulmonary disease 
CSR 
Clinical study report 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
Cytochrome P450 
DDI 
Drug-drug interaction 
DNA 
Deoxyribonucleic acid 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
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 
GMP 
Good Manufacturing Practice 
GP 
General practitioner 
HIV 
Human immunodeficiency virus 
HR 
Heart rate 
HVC 
Human viral challenge 
IC50 
50% inhibitory concentration 
ICF 
Inform consent form 
ICH 
International Council for Harmonisation 
IMP 
Investigational medicinal product 
ITT 
Intent-to-treat 
ITT-I 
Intent-to-treat infected 
ITT-A 
Intent-to-treat infected analysis population A 
ITT-B 
Intent-to-treat infected analysis population B 
LRT 
Lower respiratory tract 
LRTI 
Lower respiratory tract infections 
MHRA 
Medicines and Healthcare products Regulatory Agency 
mRNA 
messenger RNA 


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Abbreviation 
Term 
NOAEL 
No-observed-adverse-effect-level 
PCR 
Polymerase chain reaction 
PFU 
Plaque-forming unit 
P-gp 
P-glycoprotein 
PHQ 
Patient Health Questionnaire 
PI 
Principal investigator 
PK 
Pharmacokinetic(s) 
PP 
Per protocol 
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on 
REC 
Research Ethics Committee 
RNA 
Ribonucleic acid 
RR 
Respiratory rate 
RSV 
Respiratory syncytial virus 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SARS 
Severe acute respiratory syndrome 
SD 
Standard deviation 
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SEM 
Standard error of the mean 
SME 
Sponsor’s medical expert 
SoE 
Schedule of events 
SOP 
Standard operating procedure 
SUSAR 
Suspected unexpected adverse reaction 
t1/2 
Terminal half-life 
tmax 
Time to maximum plasma concentration 
TSS 
Total symptoms score 
TSS-AUC 
Area under the curve over time of total clinical symptoms 
TSS-AUC-CFB 
Area under the curve over time of total clinical symptoms change from baseline 
UK 
United Kingdom 
URT 
Upper respiratory tract 
USA 
United States of America 
VL-AUC 
Area under the viral load-time curve 


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Version: final v3.0, 31Oct2022 
10.7. Appendix 7: Definitions 
10.7.1. 
General 
 
TERM 
hVIVO Services Limited Definition 
Completion (of a participant’s 
participation in the study) 
A participant will be considered to have completed the study after 
his/her attendance at the last planned study visit, or the last 
unscheduled visit as applicable. 
Baseline 
For safety assessments the nearest assessments completed prior to 
inoculation will be used as the baseline measure, unless stated 
otherwise. 
Enrolment (of a participant into 
the study) 
A participant will be considered to be ‘enrolled’ into the study once 
he/she has been inoculated. 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. 
First study visit (of a participant) 
The visit in which the study-specific consent is signed. 
Infectious titre 
The titre of inoculum producing viral infection in a participant. The 
term ‘titre’ applies to the quantity or concentration of inoculum 
(depending on the units documented). 
Quarantine group 
A group of participants who are admitted to and are resident in the 
quarantine unit for a particular quarantine period (i.e., participants 
whose Day 0 and scheduled discharge date are the same). 
Quarantine period 
The period when clinical study participants are isolated in the 
quarantine unit during an HVC study. 
Randomisation number 
The number allocated to a participant at randomisation, generated as 
stated in the protocol (NB. Not applicable will be recorded for “screen 
fail” participants or participants who are not randomised). 
Subject number 
The unique number assigned to a subject in the hVIVO subject 
database, which is used to identify the subject prior to randomisation. 
This number will be used throughout the recruitment and generic 
screening process to identify the subject. 
Challenge 
The inoculation of a participant with challenge agent inoculum. By 
definition, the day of challenge is Day 0. 


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10.7.2. 
Study Definition of Infection and Illness 
 
TERM 
CRITERIA 
The following definitions should only be applied to data collected from Day 1 onwards 
Lower respiratory tract (LRT) 
Illness 
Any one of the following signs and/or symptoms on 2 consecutive 
scheduled assessments, at least one of which must feature Grade 2 
severity, or if any of the following attain Grade 3 severity once: 
• 
Self-reported symptoms: cough, shortness of breath, chest 
tightness and wheeze 
• 
Physician findings: Abnormal breath sounds externally (e.g., 
stridor, wheezing) and on chest auscultation (rhonchi, 
crepitations or other). 
Upper respiratory tract (URT) 
Illness 
Any one of the following signs and/or symptoms on 2 consecutive 
scheduled assessments, at least one of which must feature Grade 2 
severity, or if any of the following attain Grade 3 severity once: 
• 
Self-reported symptoms: rhinorrhoea (runny nose), nasal 
congestion (stuffy nose), sore throat, sneezing. 
• 
Physician findings: nasal discharge, otitis, pharyngitis, sinus 
tenderness. 
Systemic illness 
Fulfils the criteria for febrile illness, or fulfils the definition of URT 
illness and/or LRT illness, 
and 
any one of the following symptoms on 2 consecutive scheduled 
assessments, at least one of which must feature Grade 2 severity, or 
if any of the following attain Grade 3 severity once: 
• 
malaise 
• 
headache 
• 
muscles and/or joint ache 
• 
chilliness 
• 
feverishness. 
Febrile illness 
Any occurrence of temperature CCI 
Viral shedding (for dosing) 
1 positive detection by qicPCR 


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TERM 
CRITERIA 
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10.8. Appendix 8: Protocol Amendment History 
Protocol Amendment Summary of Changes Table 
PROTOCOL HISTORY 
Document 
Date 
Amendment Type 
Initial Clinical Trial Protocol 
(v1.0) 
06May2022 
Not applicable. First Version. 
Amendment 01 (v2.0) 
28Jul2022 
Substantial Amendment 
Amendment 02 (v3.0) 
31Oct2022 
Substantial Amendment 
 
 
Amendment 02 (31-Oct-2022) 
Overall Rationale for the Amendment: 
 
 
Section # and Name 
Description of Change 
Brief Rationale 
Principal Investigator 
Signatory (p.3) & 
Study Staff Contact 
Information(p.4) 
Principal Investigator (PI) name and contact 
details updated to reflect the change in PI from P  
P 
Substantial 
Amendment to the 
Protocol to document 
change in PI. 
 
Amendment 01 (28-Jul-2022) 
Overall Rationale for the Amendment: 
 
Section # and Name 
Description of Change 
Brief Rationale 
Principal Investigator 
Signatory (p.3) & 
Study Staff Contact 
Information(p.4) 
Principal Investigator (PI) name and contact 
details updated to reflect the change in PI from P  
P 
Substantial 
Amendment to the 
Protocol to document 
change in PI. 
Section 1.2 Schedule 
of Events (SoE) 
(p.23) 
Removal of Directed Physical Exam (DPE) from 
the Schedule of assessments for the Early 
Withdrawal visit as a Complete Physical Exam will 
be performed and therefore DPE is not required. 


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Section 1.2 Key 
notes for time and 
events schedule 
(p.26) 
Clarification added to key note ‘e’ to confirm the 
60-hour, 72-hour, 84-hour, and 96-hour timepoint 
PK samples may be omitted, as applicable, if it 
occurs after discharge, for participants who 
commence dosing on Day 4 and Day 5. 
Minor administrative 
changes for 
clarification. 


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11. 
References 
Bagga B, Woods CW, Veldman, TH et al. Antiviral Ther 2013 18: 785-791. 
Bavarian Nordic. MVA-BN RSV Human Challenge Trial Results. (Accessed September 16, 2021, at 
https://www.bavarian-nordic.com/media/309881/210901-mva-bn-hct-results-en.pdf.). 
Collins PL and Karron RA. Fields Virology. Editors-in-chief. Howley PM and Knipe DM. Wolters Kluwer, 
Netherlands, 2013. 
Common Terminology Criteria for Adverse Events (CTCAE). Version 5.0. November 2017. 
DeVincenzo JP, Wilkinson T, Vaishnaw A, Cehelsky J, Meyers R, Nochur S et al. Viral load drives disease 
in humans experimentally infected with respiratory syncytial virus. Am J Respir Crit Care Med. 
2010;182:1305-1314. 
DeVincenzo J, Tait D, Efthimiou J, Mori J, Kim YI, Thomas E et al. A Randomized, Placebo-Controlled, 
Respiratory Syncytial Virus Human Challenge Study of the Antiviral Efficacy, Safety, and Pharmacokinetics 
of RV521, an Inhibitor of the RSV-F Protein. Antimicrob Agents Chemother. 2020a;64(2):e01884-19. 
DeVincenzo J, Cass L, Murray A, Woodward K, Meals E, Coates M et al. Safety and Anti-viral Effects of 
Nebulized PC786 in a Respiratory Syncytial Virus Challenge Study. J Infect Dis. 2020b Nov 20;jiaa716. 
doi: 10.1093/infdis/jiaa716. Epub ahead of print. PMID: 33216113. 
Fleming DM, Taylor RJ, Lustig RL et al. BMC Infect Dis 2015 15: 443. 
Graham BL, Steenbruggen I, Miller MR, Barjaktarevic IZ, Cooper BG, Hall GL et al. Standardization of 
spirometry 2019 update. An official American Thoracic Society and European Society technical statement. 
American Journal and Critical Care Medicine. 2019;200(8):70-88. 
Hall CB, Weinberg GA, Iwane MK, Blumkin AK, Edwards KM, Staat MA et al. The burden of respiratory 
syncytial virus infection in young children. N Engl J Med. 2009;360:588-598. 
Kim YI, Pareek R, Murphy R et al. Influenza Other Respir Viruses 2017; 11(6):525-30. 
Lambkin-Williams R, Noulin N, Mann A, Catchpole A, and Gilbert AS. The human viral challenge model: 
accelerating the evaluation of respiratory antivirals, vaccines, and novel diagnostics. Respir Res. 
2018;19:123. 
Pfizer. RSVpreF Vaccination and RSV challenge in healthy adults preliminary trial results. (Accessed 
December 13, 2021 at https://s21.q4cdn.com/317678438/files/doc_financials/2021/q2/Q2-2021-Earnings- 
Charts-FINAL.pdf. 
Quanjer PH, Stanojevic S, Cole TJ, Baur X, Hall GL, Culver BH et al. Multi-ethnic reference values for 
spirometry for the 3–95 year age range: the global lung function 2012 equations. Report of the Global Lung 
Function Initiative (GLI), ERS Task Force to establish improved lung function reference values. Eur Respir 
J. 2012;40(6):1324–1343. 
Sadoff J, De Paepe E, DeVincenzo J, Gymnopoulou E, Menten J, Murray B et al. Prevention of respiratory 
syncytial virus infection in healthy adults by a single immunization of Ad26.RSV.preF in a human challenge 
study. J Infect Dis 2021. doi: 10.1093/infdis/jiab003. Online ahead of print. 
Scheltema NM, Gentile A, Lucion F et al. Lancet Glob Health 2017(10):e984-91. 


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Simões EAF, DeVincenzo JP, Michael Boeckh M. Challenges and Opportunities in Developing Respiratory 
Syncytial Virus Therapeutics. J Infect Dis 2015 211(S1): S1–20 
Stevens M, Rusch S, DeVincenzo J, Kim YI, Harrison L, Meals EA et al. Antiviral Activity of Oral JNJ- 
53718678 in Healthy Adult Volunteers Challenged With Respiratory Syncytial Virus: A Placebo-Controlled 
Study. J Infect Dis. 2018;218(5):748-756. 

SAP_001.pdf: 
ReViral Limited/REVD002 [hVIVO Services Ltd/VIR-CST-001] - CONFIDENTIAL 
Statistical Analysis Plan Page 1 of 113 
Version 01-00, 20DEC2022 
 
 
 
 
 
 
 
 
 
STATISTICAL ANALYSIS PLAN 
VERSION FINAL 01.00, 20DECEMBER2022 
 
A Randomised, Phase 1b, Double-Blind, Placebo-Controlled Study to Evaluate 
the Safety, Pharmacokinetics, and Antiviral Activity Of RV299 Against 
Respiratory Syncytial Virus in the Viral Challenge Model 
Protocol No: REVD002 
hVIVO Study No: VIR-CST-001 
 
 
 
 
 
CCI 
 
 
For: hVIVO Services Ltd 


ReViral Limited/REVD002 [hVIVO Services Ltd/VIR-CST-001] - CONFIDENTIAL 
Statistical Analysis Plan Page 2 of 113 
Version 01-00, 20DEC2022 
 
 
 
CONTENTS 
1. 
STATISTICAL ANALYSIS PLAN APPROVAL FORM ................................................................................. 5 
2. 
STATISTICAL ANALYSIS PLAN AUTHOR................................................................................................ 6 
3. 
LIST OF ABBREVIATIONS ..................................................................................................................... 7 
4. 
INTRODUCTION .................................................................................................................................. 9 
5. 
STUDY OBJECTIVES ........................................................................................................................... 10 
5.1. Primary Objective ..................................................................................................................... 10 
5.2. Secondary Objectives ............................................................................................................... 10 
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6. 
STUDY DESIGN .................................................................................................................................. 11 
6.1. Summary of Study Design ......................................................................................................... 11 
6.2. Randomisation / Treatment Allocation and Blinding ............................................................... 13 
6.3. Time and Events Schedule ........................................................................................................ 13 
6.4. Interim Analysis / Data Monitoring .......................................................................................... 19 
7. 
STUDY ENDPOINTS ........................................................................................................................... 20 
7.1. Primary Endpoint ...................................................................................................................... 20 
7.2. Secondary Endpoints ................................................................................................................ 20 
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9. 
STUDY POPULATIONS ....................................................................................................................... 24 
9.1. Intent-to-Treat (ITT) Population ............................................................................................... 24 
9.2. Intent-to-Treat Infected (ITT-I) Population ............................................................................... 24 
9.3. Intent-to-Treat Infected Analysis Population A (ITT-A) Population .......................................... 24 
9.4. Intent-to-Treat Infected Analysis Population B (ITT-B) Population .......................................... 25 
9.5. Per Protocol (PP) Population .................................................................................................... 25 
9.6. Safety Population ..................................................................................................................... 25 
9.7. PK Population ........................................................................................................................... 25 
10. PLANNED STATISTICAL METHODS .................................................................................................... 26 
10.1. Statistical Considerations.......................................................................................................... 26 
10.1.1. General Definitions ....................................................................................................... 26 
10.1.2. Data Presentation ........................................................................................................ 26 
10.1.3. Early Withdrawal Visit .................................................................................................. 28 
 


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10.1.4. Statistical Testing and Estimation ................................................................................ 28 
10.1.5. Handling of Dropouts or Missing Data ......................................................................... 28 
10.1.6. Interim Analysis and Data Monitoring ......................................................................... 29 
10.1.7. Multiple Comparison/Multiplicity ................................................................................. 29 
10.1.8. Model Checking and Sensitivity Analyses ..................................................................... 29 
10.1.9. Data Conversion (CDISC) .............................................................................................. 29 
10.1.10. Software ................................................................................................................... 29 
10.2. Participant Disposition .............................................................................................................. 29 
10.3. Protocol Deviations .................................................................................................................. 29 
10.4. Demographic and Other Baseline Characteristics .................................................................... 30 
10.4.1. Demographics .............................................................................................................. 30 
10.4.2. Substance Use History and Recreational Drugs of Misuse ........................................... 30 
10.4.3. Reproductive Status and Contraceptive Use ................................................................ 30 
10.4.4. Medical History ............................................................................................................ 30 
10.5. Prior and Concomitant Medications ......................................................................................... 30 
10.6. IMP Exposure and Compliance ................................................................................................. 31 
10.7. Statistical Analysis .................................................................................................................... 31 
10.7.1. Primary Endpoint .......................................................................................................... 31 
10.7.2. Secondary Endpoints .................................................................................................... 33 
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10.8. Pharmacokinetic Analysis ......................................................................................................... 41 
10.9. Safety Analysis .......................................................................................................................... 41 
10.9.1. Adverse Events ............................................................................................................. 41 
10.9.2. Laboratory Variables .................................................................................................... 42 
10.9.3. Vital Signs ..................................................................................................................... 43 
10.9.4. Spirometry .................................................................................................................... 43 
10.9.5. Physical Examination .................................................................................................... 43 
10.9.6. 12-Lead Electrocardiograms ......................................................................................... 43 
11. CHANGES TO THE PROTOCOL SPECIFIED ANALYSIS DETAILED IN THE STATISTICAL ANALYSIS PLAN 
44 
12. REFERENCES ...................................................................................................................................... 45 
13. TABLES, FIGURES AND LISTINGS ....................................................................................................... 46 
13.1. Specific Presentation Details .................................................................................................... 46 
13.2. List of Tables ............................................................................................................................. 47 
13.3. List of Figures ............................................................................................................................ 50 


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13.4. List of Listings............................................................................................................................ 52 
14. TABLE AND LISTING SHELLS .............................................................................................................. 54 
15. APPENDICES .................................................................................................................................... 112 
15.1. Study VIR-CST-001 assay cut-offs and reporting..................................................................... 112 


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Statistical Analysis Plan Page 5 of 113 
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1. STATISTICAL ANALYSIS PLAN APPROVAL FORM 
 
 
 
Signature 
Date 
(ddmmmyyyy) 
Time 
(hh:mm) 
Local Time 
Zone 
Author(s): 
PPD 
 
Senior Statistician, 
PPD 
 
Approval(s): 
PPD 
  
PPD 
 
 
ReViral, a Pfizer Company 
PPD 
 
PPD 
 
hVIVO Ltd 
 
 
 


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2. STATISTICAL ANALYSIS PLAN AUTHOR 
 
 
PPD 
 BSc (Hons) 
Senior Statistician 
PPD 
 
 
 


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3. LIST OF ABBREVIATIONS 
 
 
Abbreviation 
Definition 
AE 
Adverse event 
ALP 
Alkaline phosphatase 
ALQ 
Above the limit of quantification 
ALT 
Alanine transaminase 
APTT 
Activated partial thromboplastin time 
AST 
Aspartate transaminase 
AUC 
Area under the curve 
BDR 
Blind Data Review 
BDRM 
Blind Data Review Meeting 
β-HCG 
Beta human chorionic gonadotropin 
BLQ 
Below the level of quantification 
BMI 
Body mass index 
BPM 
Beats per minute 
CI 
Confidence interval 
CK 
Creatinine Kinase 
Covid-19 
Coronavirus disease 2019 
CRF 
Case Report Form 
CRP 
C-reactive protein 
CSR 
Clinical Study Report 
DBP 
Diastolic blood pressure 
DP 
Decimal places 
ECG 
Electrocardiogram 
ET 
Early termination 
FEV1 
Forced expiratory volume in 1 second 
FSH 
Follicle-stimulating hormone 
FU 
Follow-up 
FVC 
Forced vital capacity 
GGT 
Gamma glutamyl transferase 
GM 
Geometric Mean 
GSD 
Geometric Standard Deviation 
HbA1C 
Glycated haemoglobin 
HIV 
Human immunodeficiency virus 
HR 
Heart Rate 
HVC 
Human Viral Challenge 
hVIVO 
hVIVO Services Limited 
ICF 
Informed consent form 
IMP 
Investigational medicinal product 
INR 
International normalised ratio 
IQR 
Inter-quartile range 
ITT 
Intention-to-Treat 
ITT-I 
Intention-to-Treat Infected 
ITT-A 
Intention-to-Treat Infected Analysis Population A 
ITT-B 
Intention-to-Treat Infected Analysis Population B 
LDH 
Lactate dehydrogenase 
LRT 
Lower respiratory tract 


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Abbreviation 
Definition 
MCH 
Mean corpuscular haemoglobin 
MCHC 
Mean corpuscular haemoglobin concentration 
MCV 
Mean corpuscular volume 
MedDRA 
Medical dictionary for regulatory activities 
NCI 
New-onset chronic illness 
PCR 
Polymerase chain reaction 
PD 
Protocol deviation 
PE 
Physical examination 
PEF 
Peak expiratory flow 
PFU 
Plaque forming units 
PK 
Pharmacokinetic 
PP 
Per protocol 
PT 
Preferred term 
PT 
Prothrombin time 
PTT 
Partial thromboplastin time 
RR 
Respiratory rate 
Q1 
Lower quartile 
Q3 
Upper quartile 
qicPCR 
Qualitative integrative cycler polymerase chain reaction 
qRT-PCR 
Quantitative reverse transcription polymerase chain reaction 
RBC 
Red blood cells 
RNA 
Ribonucleic acid 
RSV 
Respiratory Syncytial Virus 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SARS-CoV-2 
Sever acute respiratory syndrome coronavirus 2 
SBP 
Systolic blood pressure 
SD 
Standard deviation 
SE 
Standard error 
SOC 
System organ class 
SoE 
Schedule of Events 
SpO2 
Peripheral arterial oxygen saturation 
TEAE 
Treatment emergent adverse event 
TFL 
Tables, Figures and Listings 
TSS 
Total clinical symptoms 
ULN 
Upper limit of normal 
ULOQ 
Upper limit of quantification 
URT 
Upper respiratory tract 
VL 
Viral load 
WBC 
White blood cells 
WHO 
World Health Organisation 


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Statistical Analysis Plan Page 9 of 113 
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4. INTRODUCTION 
This statistical analysis plan (SAP) explains in detail the statistical analyses that will performed for the 
ReViral Limited study REVD002 [hVIVO study no: VIR-CST-001]. The analysis is outlined within the study 
protocol V3.0 (dated 31 October 2022) and this SAP contains a more technical and detailed description 
of those analyses. In particular, the SAP provides information on the definitions of the participant 
populations, analysis methods, and details the list of Tables, Figures and Listings (TFL) that will be 
produced by S-cubed Biometrics for use and inclusion within the Clinical Study Report (CSR). The SAP 
has been written and finalised before any unblinding of the study and prior to the database being locked. 
 
Any deviations from the protocol specified analyses, and deviations from analyses stated within this SAP 
will be described within the CSR. 


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Statistical Analysis Plan Page 10 of 113 
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5. STUDY OBJECTIVES 
 
5.1. 
Primary Objective 
 
The primary objective is to assess the antiviral activity of RV299 compared to placebo in healthy adult 
participants infected with RSV-A Memphis 37b. 
 
5.2. 
Secondary Objectives 
• 
To evaluate the effect of RV299 compared to placebo in healthy adult participants inoculated with 
RSV in terms of antiviral effect assessed by: 
o viral-load related endpoints; 
o clinical symptom-related endpoints (using the 10 predefined symptoms in the graded 
symptom scoring system). 
• 
To evaluate the effect of RV299 on nasal discharge in healthy adult participants inoculated with RSV 
when compared to placebo. 
• 
To evaluate the safety of multiple orally administered doses of RV299 when compared to placebo. 
• 
To monitor the safety of the challenge virus. 
• 
To characterise the PK profile of RV299 after a single oral dose and after multiple oral doses in 
plasma from healthy participants inoculated with RSV. 
 
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6. STUDY DESIGN 
 
6.1. 
Summary of Study Design 
 
This is a single-centre, randomised, double-blind, placebo-controlled, proof-of-concept study in healthy 
adult male and female participants from 18 to 55 years of age, inclusive. The primary goal of this Phase 
1b study is to assess the antiviral activity of RV299 against RSV in the viral challenge model. In addition, 
the safety, tolerability, and PK of RV299 will be assessed. 
 
A total of 80 participants is planned to be enrolled in this study: 40 participants on RV299 and 40 
participants on placebo. 
 
The study is divided into the following study phases: 
• 
Screening phase: from Day -90 to Day-3 pre-human viral challenge (HVC). 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 15 days (from 
Day -2 to Day 12). Procedures will include: 
o Pre-HVC: 
 
Admission to quarantine unit on Day -2/-1. 
 
Baseline assessments will be conducted as per Schedule of Events (SoE) up to Day 
0, pre-challenge. 
o HVC: RSV-A Memphis 37b virus inoculation on Day 0. 
o Post-HVC: 
 
Randomisation to receive RV299 or matched placebo. 
 
Administration of IMP (RV299/placebo). Each participant will receive IMP twice 
daily (~12 hours interval) for 5 consecutive days: 
• 
IMP dosing to start on confirmation of RSV infection, i.e., after a positive 
result by qualitative integrative cycler polymerase chain reaction (qicPCR). 
The qicPCR of nasal wash will be performed twice daily on Days 2-5 (Day 5 
morning only), or until a positive result is received, whichever is sooner. The 
earliest start of IMP dosing will be in the evening of Day 2 post-HVC (IMP 
will be initiated 12 hours ± 1-hour post nasal wash confirmation of 
infection) 
OR 
• 
IMP would start in the evening of Day 5, if no positive result obtained by 
qicPCR 
 
Day 1 onwards and each day study assessments will be conducted as per SoE. 
 
Participants will be discharged from the quarantine unit on Day 12 (or may remain 
longer at the discretion of the principal investigator [PI]/investigator). 
• 
Outpatient phase: 
o Final visit: Day 28 (±3 days). 
The overall study design is depicted in 


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Table 1. 


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Table 1: Study Schematic: On-study Participant Progression 
SCREENING 
PHASE 
INPATIENT PHASE: QUARANTINE/ISOLATION, HUMAN VIRAL 
CHALLENGE, AND DOSING 
OUTPATIENT 
PHASE 
Day 0 
Days 1 to 11 
Dosing and 
assessments 
as per 
Schedule of 
Events 
Day 12 
Discharge 
from 
quarantine 
unit** 
Follow-up 
visit: 
Day 28 
(±3 days) 
Day -90 to 
Day -3 
Screening* 
Day -2/-1 
Admission 
to 
quarantine 
Inoculation 
with challenge 
agent & 
assessments 
unit 
as per 
Schedule of 
Events 
 
NOTES: 
*Screening assessments (including repeats, as required), may be performed up to Day -2/-1, defined as 
the first study day (quarantine admission) at the discretion of the PI/investigator and in accordance with 
the design of the study. 
**Release from quarantine is foreseen at Day 12 (12 days post inoculation) provided that, where 
appropriate, no virus is detected by qualitative virus antigen test or polymerase chain reaction (PCR) 
(negative virus antigen test or PCR below Ct cut-off) and the participant has no clinically significant 
symptoms. If the participant continues to have clinically significant symptoms and/or detectable virus on 
Day 12, additional extended quarantine stay may be required at the discretion of the PI/investigator. 


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6.2. 
Randomisation / Treatment Allocation and Blinding 
 
hVIVO assigns a unique 6-digit number to each participant in the hVIVO database. This number will be 
used to identify a participant up to the point of randomisation, on source documents, on all study 
correspondence, and in the study database. A separate randomisation number will be allocated to the 
participants at randomisation and will be used for allocation to a study arm. The randomisation 
number encodes the participant’s assignment to 1 of 2 study arms (RV299/placebo) in a 1:1 ratio. 
 
Randomisation numbers will be assigned sequentially in ascending order, and once assigned, that 
randomisation number will 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/designee preparing the 
IMP, so that IMP can be prepared for each participant as appropriate. An independent statistician 
prepares the randomisation schedule, and the GMP pharmacy provider’s pharmacy/designee will 
prepare the participant level IMP doses in line with the randomisation schedule. 
 
Each participant will be dispensed blinded IMP, labelled with his/her unique randomisation number, 
throughout the study. With the exception of the unblinded pharmacist, unblinded IMP management 
personnel at the clinical site, 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 for analysis. 
 
6.3. 
Time and Events Schedule 
 
Details of the timing of study assessments and procedures can be found in Table 2. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Table 2: Schedule(s) of Events (SoE) 
Study Phase  
Screening 
Phase* 
Inpatient Phase 
(Quarantine Isolation and Human Viral Challenge [HVC]) 
Clinic Visit 
Follow-up 
Early Withdrawal 
Study Day  
Procedure  
D -90 to D -3 
D -2 
D -1 
D 0 
D 1 
D 2 
D 3 
D 4 
D 5 
D 6 
D 7 
D 8 
D 9 
D 10 
D 11 
D12 
(Discharge) 
D 28 
(±3 days) 
Pre-HVC 
HVC 
Post-HVC 
Written informed consent (a) 
X 
Eligibility criteria (+) 
X 
X 
X 
Medical & medication history 
X 
X 
Demographics 
X 
Height & body weight, body mass 
index (BMI) (b) 
X 
X 
(X) 
(X) 
(X) 
Complete physical examination 
X 
X 
X 
X 
X 
Directed physical examination (incl. 
nasal) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
Vital signs (heart rate [HR], respiratory 
rate [RR], systolic blood pressure [BP], 
diastolic BP, oxygen saturation [SpO2]) 
and tympanic membrane temperature 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECG 
X 
X 
X 
X 
X 
X 
Spirometry 
X 
Patient Health Questionnaire (PHQ-9) 
(X) 
(X) 
Generalised Anxiety Disorder 
Questionnaire (GAD-7) 
(X) 
(X) 
Alcohol breath test 
X 
X 
X 
Urinalysis 
X 
X 
X 
X 
X 
Urine drugs of abuse and cotinine 
screen 
X 
X 
X 
Urine pregnancy test 
X 
X 
X 
X 
Symptom diary card (c) 
(X) 
3X 
3X 
3X 
3X 
3X 
3X 
3X 
3X 
3X 
3X 
3X 
3X 
3X 
X 
24-hour paper tissue collection & nasal 
discharge weight (d) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
(X) 


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Study Phase  
Screening 
Phase* 
Inpatient Phase 
(Quarantine Isolation and Human Viral Challenge [HVC]) 
Clinic Visit 
Follow-up 
Early Withdrawal 
Study Day  
Procedure  
D -90 to D -3 
D -2 
D -1 
D 0 
D 1 
D 2 
D 3 
D 4 
D 5 
D 6 
D 7 
D 8 
D 9 
D 10 
D 11 
D12 
(Discharge) 
D 28 
(±3 days) 
Pre-HVC 
HVC 
Post-HVC 
Product Administration 
Randomisation 
(X) 
(X) 
(X) 
(X) 
RSV299/placebo dosing (k) 
(X) 
(2X) 
(2X) 
(2X) 
(2X) 
(2X) 
(2X) 
(2X) 
(X) 
Challenge virus inoculation 
X 
Collection Of Blood Samples 
Serum follicle-stimulating hormone 
(FSH) (post-menopausal women) 
X 
Serum β-human chorionic 
gonadotrophin (β-hCG) pregnancy test 
(all females) 
X 
Hepatitis B, & C, human 
immunodeficiency virus (HIV) serology 
X 
Blood Pharmacokinetics (e) 
(X) 
(X) 
(X) 
X 
X 
X 
X 
X 
X 
X 
X 
Haematology (f) 
X 
X 
X 
X 
X 
X 
Biochemistry (f) 
X 
X 
X 
X 
X 
X 
Coagulation 
X 
Cardiac enzymes 
X 
X 
X 
X 
Thyroid function test 
X 
CCI 
 
 
 
 
 
X 


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Study Phase  
Screening 
Phase* 
Inpatient Phase 
(Quarantine Isolation and Human Viral Challenge [HVC]) 
Clinic Visit 
Follow-up 
Early Withdrawal 
Study Day  
Procedure  
D -90 to D -3 
D -2 
D -1 
D 0 
D 1 
D 2 
D 3 
D 4 
D 5 
D 6 
D 7 
D 8 
D 9 
D 10 
D 11 
D12 
(Discharge) 
D 28 
(±3 days) 
Pre-HVC 
HVC 
Post-HVC 
Collection Of Respiratory Samples 
Nasopharyngeal swab - respiratory 
pathogen screen incl. SARS-CoV-2 (h) 
X 
Nasopharyngeal swab- RSV discharge 
test 
(X) 
(X) 
CCI 
 
 
 
 
 
 
 
 
 
 
 
 
qicPCR (i) 
2X 
2X 
2X 
X 
Safety Assessments 
Adverse event (AE) recording (j) 
 
X 
Concomitant medications (j) 
 
X 
 
 
KEY NOTES FOR TIME AND EVENTS SCHEDULE: 
 
(X) 
The assessment may be optional, or at the PI's discretion. The PI may perform additional safety assessments as required. 
X 
Once daily, at approximately the same time each day, where applicable. 
2X 
Twice daily (~12 hours between assessments [± 1 hour]). 
3X 
Three times daily (at the same times each day [± 1 hour]). 
* 
Potential participants will be screened using the hVIVO generic screening process, and individuals who pass this screen will be admitted to the quarantine unit 1 to 2 days before 
challenge with study virus and provide study-specific informed consent. They will then be screened for eligibility for this study before viral challenge on Day 0. Results of tests or 
examinations performed under hVIVO generic screening process may be used to determine eligibility without the need to repeat the assessment if it is within 28 days prior to viral 
challenge/dosing with IMP. 
+ 
Only the applicable inclusion/exclusion criteria will be reviewed at each time point. 
a 
Study-specific consent may occur on the day of admission, providing all required eligibility information has been collected through the Health Research Authority -approved hVIVO 
generic screening process. 


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b 
Height will be taken at screening only. 
c 
After the baseline has been set, assessments will be performed at the same time each day (±1 hour from baseline) during quarantine. 
• 
Symptom diary card baseline: Day -1 (measurements on this day will be taken approximately 8 hours apart, ±1 hour). 
• 
Nasal wash baseline: Day 2 (sampling will be performed approximately 12 hours apart, ±1 hour). 
d 
Distribution of paper tissues and bags will start on Day -1, with the first collection on Day 0. Thereafter, collection of paper tissues will occur at the same time each day (±1 hour) 
with tissues distributed 24 hours ahead. 
e 
Blood Pharmacokinetics: plasma samples for RV299 assay will be collected as follows: 
• 
First dose (Dose 1): 0.5 hours pre-dose, and at the following hours post-first dose: 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8,10, 12, 24, 36, 48, 60, 72, 84 and 96 hours (note samples 
taken up to and including 10 hours post-dose should be taken at the indicated time point ±5 minutes. Samples taken thereafter at 12, 24, 36, 48, 60, 72, 84, and 96 hours 
post-first dose should be taken within the 30 minutes before the next IMP intake). 
• 
Last dose (Dose 10): 0.5 hours pre-dose, and at the following hours post-last dose: 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8,10, 12, 24, 36, 48, 60, 72, 84, and 96 hours (note samples 
taken up to and including 10 hours post-dose should be taken at the indicated time point ±5 minutes; samples taken thereafter should be taken at the indicated time 
point ±30 minutes). 
For participants who started dosing on Day 4, am, onwards, the 60-hour, 72-hour, 84-hour, or 96-hour timepoints after Dose 10 could occur after the participant has met the 
discharge criteria on Day 12. Thus, for a subset of participants, these timepoints could be after discharge. The guidance for the 60-hour, 72-hour, 84-hour, and 96-hour PK sample 
collection is as follows: 
• 
For participants who started dosing on Day 4, am, onwards, and who meet the discharge criteria on Day 12, the 60-hour, 72-hour, 84-hour, and 96-hour timepoint 
samples may be omitted, as applicable, if it occurs after discharge. 
• 
For participants who started dosing on Day 4, am, onwards, and who do not meet the discharge criteria on Day 12 the 60-hour, 72-hour, 84-hour, and 96-hour PK 
timepoint samples should be collected up to the point where participant meets the discharge criteria. 
f 
Blood will be drawn under non-fasted conditions. Repeat bloods may be drawn under fasted conditions if a lipid profile (triglyceride) or glucose is required (at the PI’s discretion). 
All participants will be dosed under fasted conditions. For all doses, a pre-dose and post-dose fasting period of 0.5 hour to 1 hour applies. No fluid intake (including water) is allowed 
for 1 hour pre-dose to 1-hour post-dose). 
g 
Virus serology (RSV neutralisation antibody assay) will be performed to determine eligibility and seroconversion. 
h 
Upper respiratory tract swab (e.g., nasopharyngeal swab, mid-turbinate swab, oropharyngeal swab) for respiratory virus screen to assess for the presence of respiratory pathogens; 
if found positive for any pathogen in the panel, the participant will not be eligible for the current quarantine. 
i 
Post inoculation nasal wash virology samples will be collected at the same time each day during quarantine (± 1 hour from baseline on Day 2) and used for qRT-PCR and viral culture 
assay (as appropriate). Samples may be used for related viral genomics CCI 
. 
Samples collected between the morning of Day 2 and the morning of Day 5 will also be used for qicPCR until a positive result is received (to support triggered dosing). 
j 
Adverse events and concomitant medications are reviewed throughout the study including pre- and post-dosing with IMP and pre- and post-RSV virus inoculation. 


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k 
IMP doses as oral solution/suspension will be taken with 140 mL of water (50 mL water rinse of IMP bottle following administration, and 90 mL post-dose). 
All participants will be dosed orally, in the seated position, under fasted conditions, under the direct supervision of the investigator (or delegate), and in accordance with the 
randomisation schedule. Each participant will receive IMP twice daily (~12 hours interval) for 5 consecutive days, in total 10 doses, IMP dosing to start on confirmation of RSV 
infection. The earliest start of IMP dosing will be in the evening of Day 2 post-HVC or IMP dosing will start in the evening of Day 5, if no confirmation of RSV infection. 
Note: 
Parenthesis indicates the assessment may be optional, or at the PI’s discretion. 
The PI/investigator may perform additional safety assessments as required. 
Where any nasal sampling time points occur together, the order of sampling will typically be (1) nasopharyngeal swab followed by (2) nasal wash. 


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6.4. 
Interim Analysis / Data Monitoring 
 
No interim analysis (i.e., an analysis of early trial data, before enrolment is completed, to detect trends 
that might warrant modification of the protocol, change in data being collected or trial termination) is 
planned for the study. 


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7. STUDY ENDPOINTS 
 
7.1. 
Primary Endpoint 
 
The primary endpoint is: 
 
The area under the curve (AUC) for RSV viral load measured in nasal washes by quantitative real time 
reverse transcription polymerase chain reaction (qRT-PCR) in participants inoculated with RSV-A 
Memphis 37b, starting at initial administration of investigational medicinal product (IMP) up to 
planned discharge from quarantine (Day 12, am). 
 
7.2. 
Secondary Endpoints 
 
The secondary endpoints are: 
• 
Additional viral load endpoints relating to antiviral effect include but are not limited to: 
o Peak viral load of RSV as defined by the maximum viral load determined by qRT-PCR 
measurements in nasal samples starting from initial administration of IMP up to planned 
discharge from quarantine (Day 12, am). 
o Time (days) to confirmed negative test by qRT-PCR measurements in nasal samples 
starting at initial administration of IMP to first confirmed undetectable assessment after 
peak measure. 
o Time (days) to confirmed negative test by qRT-PCR measurements in nasal samples 
starting from peak qRT-PCR after initial administration of IMP to first confirmed 
undetectable assessment after peak measure. 
o Time (days) to peak qRT-PCR in nasal samples, starting from initial administration of IMP. 
o Area under the viral load-time curve (VL-AUC) of RSV challenge virus as determined by viral 
culture on nasal samples, starting at initial administration of IMP up to planned discharge 
from quarantine (Day 12, am). 
o Peak viral load of RSV as defined by the maximum viral load determined by viral culture 
measurements in nasal samples starting from initial administration of IMP up to planned 
discharge from quarantine (Day 12, am). 
o Time (days) to confirmed negative test by viral culture measurements in nasal samples 
starting at initial administration of IMP to first confirmed undetectable assessment after 
peak measure. 
o Time (days) to confirmed negative test by viral culture measurements in nasal samples 
starting from peak viral culture after initial administration of IMP to first confirmed 
undetectable assessment after peak measure. 
o Time (days) to peak viral culture in nasal samples, starting from initial administration of 
IMP. 
• 
Clinical symptom-related endpoints include, but are not limited to: 
o Area under the curve over time of total clinical symptoms (TSS-AUC) as measured from 10 
symptoms within the graded symptom scoring system collected 3 times daily starting at 
initial administration of IMP up to planned discharge from quarantine (Day 12, am). 
o Area under the curve over time of total clinical symptoms change from baseline (TSS- 
AUCCFB) as measured from 10 symptoms within the graded symptom scoring system 


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collected 3 times daily starting at initial administration of IMP up to planned discharge 
from quarantine (Day 12, am). 
o Peak symptoms diary card score: peak total clinical symptoms (TSS) as measured from 10 
symptoms within the graded symptom scoring system collected 3 times daily starting from 
initial administration of IMP up to planned discharge from quarantine (Day 12, am). 
o Peak daily symptom score: individual maximum daily sum of symptom score from initial 
administration of IMP up to planned discharge from quarantine (Day 12, am). 
o Time (days) to symptom resolution as measured from 10 symptoms within the graded 
daily symptom scoring system starting at initial administration of IMP to time of returning 
to baseline score. 
o Time (days) to symptom resolution as measured from 10 symptoms within the graded 
daily symptom scoring system starting at peak symptoms after initial administration of 
IMP to time of returning to baseline score. 
o Time (days) to peak as measured from 10 symptoms within the graded daily symptom 
scoring system starting from initial administration of IMP to the time of peak daily 
symptom score. 
o Total weight of mucus produced starting at initial administration of IMP up to planned 
discharge from quarantine (Day 12, am). 
o Total number of tissues used by participants starting at initial administration of IMP up to 
planned discharge from quarantine (Day 12, am). 
• 
Safety data including, but not limited to: 
o Occurrence of adverse events (AEs) from initial administration of IMP up to the Day 28 
follow-up. 
o Occurrence of serious AEs (SAEs) from initial administration of IMP up to the Day 28 follow- 
up. 
o Occurrence of AEs related to the viral challenge from viral challenge (Day 0) up to the Day 
28 follow-up. 
o Occurrence of SAEs related to the viral challenge from viral challenge (Day 0) up to the Day 
28 follow-up. 
o Use of concomitant medications from viral challenge (Day 0) up to the Day 28 follow-up. 
• 
Secondary endpoints related to PK include, but are not limited to: 
o Time to maximum plasma concentration (tmax), terminal half-life (t1/2), maximum observed 
plasma concentration (Cmax), area under the plasma concentration-time curve from time 
zero to the end of the dosing interval (AUCτ), area under the plasma concentration-time 
curve over the last 24 hours dosing interval (AUC0-24h) and area under the plasma 
concentration-time curve from time zero to infinity (AUC0-∞). 
 
CCI 
 
 
 


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CCI 
 
 
 
 


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CCI 
 
 
 
 
 
 


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9. STUDY POPULATIONS 
Populations defined below will be reviewed against the study database at a blinded data review 
meeting (BDRM). The database at this time will be nearly final (i.e., the meeting may result in further 
data queries/changes post meeting), so inclusion/exclusion of participants from populations defined 
at this meeting will be further checked (post meeting) against a final locked database and will then be 
finalised prior to unblinding. 
 
9.1. 
Intent-to-Treat (ITT) Population 
 
The intent-to-treat (ITT) population will consist of all randomised participants who received challenge 
virus and at least 1 dose of IMP. Participants will be analysed in the treatment group they were 
randomised to. 
 
9.2. 
Intent-to-Treat Infected (ITT-I) Population 
 
The intent-to-treat infected (ITT-I) population will consist of all randomised participants who received 
challenge virus and at least 1 dose of IMP, and meet the criterion for RSV infection. Participants will be 
analysed in the treatment group they were randomised to. 
 
As per Section 10.7.2 in the protocol, a laboratory-confirmed RSV infection requires one or both of the 
following definitions to be met: 
• 
At least 2 positive detections by viral load qRT-PCR assay specific for the challenge virus, 
reported on 2 consecutive days; 
• 
One positive detection by viral load qRT-PCR assay, specific for the challenge virus, in which an 
aliquot of the same sample has also tested positive in a viral culture assay appropriate for 
detecting the challenge virus. 
 
For qRT-PCR and the viral culture assay a positive detection is any positive numeric or “detected” value. 
 
9.3. 
Intent-to-Treat Infected Analysis Population A (ITT-A) Population 
 
The intent-to-treat infected analysis population A (ITT-A) population will consist of all randomised 
participants who received challenge virus and at least 1 dose of IMP, and meet the criterion for 
laboratory-confirmed RSV infection as defined for the ITT-I, using only assessments prior to taking IMP. 
Participants will be analysed in the treatment group they were randomised to. 
 
The assessments prior to taking IMP includes all qRT-PCR assessments performed before dosing, 
including the assessment immediately before dosing. In addition, if the infection was seen (via a 
positive qRT-PCR value) before dosing but the confirmatory value (as per the first part of the viral 
shedding definition in Section 10.7.2 of the protocol) was taken after dosing, then the participant will 
be declared as infected before IMP administration, and hence will form part of the ITT-A Population. 
 
Note: The assessments prior to dosing with IMP will include all qRT-PCR and viral culture assessments 
performed on samples collected before dosing, including the sample collected immediately prior to 
dosing. 


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9.4. 
Intent-to-Treat Infected Analysis Population B (ITT-B) Population 
 
The intent-to-treat infected analysis population B (ITT-B) population will consist of all randomised 
participants not already in the ITT-A Population, who received challenge virus and at least 1 dose of 
IMP, and meet the criterion for laboratory-confirmed RSV infection as defined for the ITT-I, using only 
assessments after taking IMP. Participants will be analysed in the treatment group they were 
randomised to. 
 
Note: The assessments after dosing with IMP will include all qRT-PCR and viral culture assessments on 
samples that are collected after dosing and will not include the sample collected immediately prior to 
dosing. 
 
9.5. 
Per Protocol (PP) Population 
 
The per-protocol (PP) population will consist of all ITT-I population participants who have no major 
protocol deviations, and who completed the quarantine period up to the final day of quarantine 
(Day 12) and received all 10 doses of IMP. Participants will be analysed in the treatment group they 
were randomised to. 
 
9.6. 
Safety Population 
 
The safety population will consist of all randomised participants who received challenge virus and at 
least 1 dose of IMP. Participants will be analysed according to the treatment they received. 
 
9.7. 
PK Population 
 
The PK population will consist of all ITT population participants with at least one post-dose PK result. 
Participants will be analysed according to the treatment they received. 


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10. 
PLANNED STATISTICAL METHODS 
 
10.1. Statistical Considerations 
 
10.1.1. 
General Definitions 
 
In all applicable summary/analysis presentations of safety endpoints, Baseline is defined as the last 
non-missing assessment value for a participant, for that particular parameter, that is prior to 
inoculation of challenge virus, unless over-ruled after review of data at the BDRM or otherwise stated 
in the appropriate endpoint sections below, whatever the reason for that assessment (e.g. if it is a 
repeat assessment, then it should be used as the baseline). For efficacy endpoints, the baseline 
definition is as per the appropriate endpoint sections below. For the derivation of most efficacy 
endpoints, the first assessment to be used should be the assessment that was taken at the time of first 
administration of IMP. For example, if a participant was first dosed on the morning of Day 3 then the 
first qRT-PCR value to be used in the AUC of qRT-PCR viral load (from time of first administration) 
derivation should be the Day 3 morning assessment. For endpoints using symptom diary card data, the 
definition of baseline will be defined in greater detail within the appropriate sections of the SAP. 
 
A participant will be classed as infected, and therefore randomised to be dosed, when they have a 
positive result for RSV-A Memphis 37b by qualitative integrative cycler polymerase chain reaction 
(qicPCR) from nasal wash sample. IMP administration will be initiated 12 hours after a positive result. 
However, if a participant remains uninfected, IMP administration will begin on the evening of Day 5. 
 
For participants that extend their time in quarantine beyond Day 12, the additional assessments 
beyond Day 12 will be listed only, and will not be used for the derivation of any efficacy endpoints. For 
the avoidance of doubt, the assessment performed on the morning of Day 12 will be the final 
assessment used for all analyses and summaries for all participants. If additional assessments are taken 
on Day 12, then they will be listed only. However, the use of data beyond the morning of Day 12 will 
be discussed at the BDRM. 
 
A participant will be considered to have completed the study after their attendance at the last planned 
study visit (Day 28 (+ 3 days)), or the last unscheduled visit (if any occur), as applicable. 
 
Data recorded for replaced participants will be listed. However, these participants will only be included 
in tables where they meets the inclusion criteria for the relevant population. 
 
Within summary presentations/analyses it is envisaged that only scheduled protocol visit values will 
be used for post-baseline time points and unscheduled visits will not be summarised in tables. All 
unscheduled visits will be listed. However, at the BDRM the occurrence of such non-scheduled data 
will be reviewed for each participant to decide if (and how) any such data point(s) should be included 
within summary presentations/analyses. Any such decisions will be documented in the BDRM minutes. 
 
For assessments made on Day 0 (either pre or post challenge), the date and time of inoculation will be 
compared to the date and time of assessment to ensure they are assigned to either pre or post 
challenge accurately. 
 
10.1.2. 
Data Presentation 
 
The specific format and content of each data presentation is shown in Section Error! Reference source 
not found.. 


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Summary tables will be presented by treatment group. For demographic, baseline, and safety data 
these will also be summarised for all participants. 
 
Within all Tables and Figures, the treatment groups will be labelled and ordered as follows: 
• 
RV299 
• 
Placebo 
• 
Overall (including RV299 and placebo participants, for demographic, baseline and safety data) 
The scheduled protocol visits will be labelled in report presentations as follows: 
• 
“Admission (Day-2/Day-1)” 
• 
“Day 0 (pre-HVC)” 
• 
“Day 0 (HVC)” 
• 
“Day 0 (post-HVC)” 
• 
“Day x” (where x=1 to 12) 
• 
“Follow-up (Day 28)” 
• 
“Early Withdrawal” 
As the study day of IMP administration day will differ between participants, “x Days from IMP 
Administration” (where x=0 to 11) will be presented for efficacy outputs relating to clinical symptoms 
and PK. These assessments should be presented in relation to the IMP administration, rather than the 
inoculation day. 
 
For data with multiple assessments on one study day, each assessment will be numbered sequentially 
(e.g. Assessment 1, Assessment 2 etc.) and will be relative to the first administration of IMP. Further 
details will be provided in the relevant sections of the SAP. 
 
Within some tables, only “Baseline” may be shown (as applicable) instead of the scheduled visits Day 0 
(pre-HVC) and Day-2/Day-1 (with baseline being chosen as defined in Section 10.1.1 and in the relevant 
endpoint sections). 
 
Where duplicate information is collected on both the database and on the vendor data transfer(s) (e.g., 
sampling date and time) this information will be reconciled by data management and then the 
information from the vendor data transfer(s) will be included in Participant Listings. 
 
All variables will be listed to the same number of decimal places as reported. Continuous endpoints 
will be summarised by: n, n missing, mean, standard deviation (SD), %CV, median, lower quartile (Q1), 
upper quartile (Q3), minimum (Min) and maximum (Max). Where appropriate, 95% confidence 
intervals (CIs) for the mean and/or median may be presented. For selected summaries the geometric 
mean (GM) and geometric standard deviation (GSD) will also be presented to aid interpretation. The 
SD will only be presented in summaries where the corresponding n is greater than or equal to 3. 
The number of decimal places (DP) each summary statistic is rounded to for display in the summary 
tables, relative to the number of DP the parameter is recorded to, is shown in Table 3. 
 
Table 3: Number of decimal places to use to display each summary statistic. 
 Statistics 
Number of DP for display 
 
Min, Max 
Same as recorded 
Mean, GM, Median, Q1, Q3 
1 more DP than recorded 


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 SD, GSD, %CV, 95% CI 
2 more DP than recorded 
 
 
For endpoints that require a geometric mean to be produced, and those endpoints can have raw values 
of 0 (zero), the GM calculation will add an appropriate constant value to all raw values prior to logging 
and will subtract that constant value from the final calculated anti-logged mean. The constant value 
used will be documented in the footnote of the tables. The value is typically 1 however it may be 
another small value which is in line with the scale of the data should a value of 1 be unsuitable. The 
GM and GSD are calculated as follows: 
 
GM = anti-log ( mean ( log10 ( endpoint values + constant ) ) ) - constant 
GSD = anti-log ( SD ( log10 ( endpoint values ) ) ) 
The %CV will be calculated as %CV = 100 * ( SD / mean ) using untransformed values. 
 
Categorical variables will be summarised using proportions (counts and percentages). The specific 
approach to calculating percentages (relevant denominator) is detailed within each (relevant) Table 
template (Section Error! Reference source not found.). 
 
All collected data will be included within participant listings. 
 
10.1.3. 
Early Withdrawal Visit 
 
If a participant withdraws prior to Day 28 they will complete an early withdrawal visit. The data 
collected at this visit will be summarised as the nearest scheduled visit, unless the nearest visit already 
has data, in which case it will be summarised as the next scheduled visit. The data collected at the early 
withdrawal visit will be listed as the early withdrawal visit. 
 
For example, if a participant withdraws at the Day 8 visit the data collected at the early withdrawal 
visit will be included in the summaries of Day 8. If, however, the participant withdrew between Day 8 
and Day 9, after attending as normal on Day 8, the data collected at their early withdrawal visit will be 
included in the Day 9 summaries. 
 
10.1.4. 
Statistical Testing and Estimation 
 
Statistical analyses for the primary and secondary endpoints will be performed using appropriate two- 
sided hypothesis tests at the 5% significance level. 
 
For continuous data, an analysis of covariance (ANCOVA) will be used to compare means between the 
RV299 and placebo groups. The ANCOVA will have treatment group as a fixed effect and baseline viral 
load as a covariate, unless stated otherwise in the relevant endpoint section. Should data not satisfy 
the assumptions, an appropriate alternative test, e.g., Wilcoxon Rank-Sum test will be used. 
 
P-values will be rounded to 4 decimal places. All p-values that round to 0.0000 will be presented as 
<0.0001 and p-values that round to 1.000 will be presented as >0.9999. 
 
10.1.5. 
Handling of Dropouts or Missing Data 
 
No imputation methods will be used to manage the occurrence of missing data. Only observed data at 
each scheduled visit will be reported. 


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For adverse events and concomitant medications the approach to handle missing data has been 
described in Sections 10.9.1 and 10.5 respectively. For any other data which has partial dates, these 
dates will be completed using a suitably conservative approach. 
 
Any other mechanisms to adjust for missing data will be outlined within the relevant endpoints section. 
 
10.1.6. 
Interim Analysis and Data Monitoring 
 
No interim analyses are planned to be performed. 
 
10.1.7. 
Multiple Comparison/Multiplicity 
 
As this is an early phase study, no adjustments will be made to address multiplicity. 
 
10.1.8. 
Model Checking and Sensitivity Analyses 
 
Statistical hypothesis testing will be presented using parametric tests where an ANCOVA will be the 
preferred statistical method. However, if the parametric test assumptions fail, non-parametric 
alternatives will be presented. 
 
The normality of the error term from fitted models will be checked by performing the Shapiro-Wilk’s 
test of normality of the residuals and producing normality probability plots of the residuals. 
 
For cases where the normality assumption fails to hold, the treatment effect will be assessed by the 
non-parametric Wilcoxon rank-sum test. 
 
10.1.9. 
Data Conversion (CDISC) 
 
For the reporting of this study there is no requirement for CDISC SDTM and/or ADaM standards to be 
applied. 
 
10.1.10. Software 
 
Data will be reported using SAS version 9.4 (SAS Institute Inc, Cary, North Carolina, USA). 
 
10.2. Participant Disposition 
 
The number of participants enrolled (signed ICF), the numbered receiving challenge agent inoculation, 
the number randomised, the number receiving at least one dose of IMP and receiving all doses of IMP, 
the number discontinuing IMP early, the number withdrawing from the study, those completing the 
study (Day 28 visit), and the numbers in each population will be summarised for all participants and by 
treatment group. The reasons for early discontinuation of IMP and reasons for withdrawal from the 
study will also be summarised by treatment group. 
 
A listing will be provided including details of informed consent, randomisation and quarantine 
admission. 
 
10.3. Protocol Deviations 
 
Participants data will be reviewed for major protocol deviations by a qualified clinical reviewer prior 
to database lock and unblinding, at the BDRM. Participants with any major protocol deviations will be 
documented within the BDRM minutes, and such participants will be excluded from the PP population. 


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All protocol deviations will be listed. 
 
10.4. Demographic and Other Baseline Characteristics 
 
The safety population will be used in summaries of demographic and baseline data. No statistical 
testing will be used to compare treatment groups for different baseline characteristics. 
 
10.4.1. 
Demographics 
 
Demographic variables collected at Screening; sex, age, ethnicity, race, height (cm), weight (kg) and 
body mass index (BMI) will be summarised by treatment group and across all participants. 
 
Age at screening and BMI are recorded in the database and do not need require derivation. 
 
10.4.2. 
Substance Use History and Recreational Drugs of Misuse 
 
Substance use history and any recreational drug misuse will be collected at screening and listed for all 
participants. 
 
10.4.3. 
Reproductive Status and Contraceptive Use 
 
The reproductive status and use of contraception will be collected at screening and listed for all 
participants. 
 
10.4.4. 
Medical History 
 
Medical history data will be coded using MedDRA, Version 25.0 (March 2022) and all data will be listed. 
 
10.5. Prior and Concomitant Medications 
 
Prior and concomitant medication terms will be coded using the World Health Organisation (WHO) 
Drug Dictionary Enhanced (WHO Drug Global, Version March 1 2022). A medication will be assigned as 
being prior to inoculation based on the start and stop dates of the medication and the date of challenge 
agent inoculation. If the medication stop date is before the inoculation date, the medication will be 
assigned as being prior to inoculation. A medication will be assigned as being prior to IMP or 
concomitant with IMP, based on the start and stop dates of the medication and the IMP. If the 
medication stop date is before the IMP start date and after the date of inoculation, the medication will 
be assigned as being prior to IMP. In all other situations, the medication will be assigned as being 
concomitant with IMP. If a participant has separate periods of taking specific medications, then that 
medication is only counted once within the specific period of observation (i.e., prior, or concomitant) 
where it is taken. 
 
Note: Start and Stop times will not be used for determining if a medication is concomitant or not. 
 
Concomitant medications up to the Day 28 visit will be summarised, using the Safety Population, by 
treatment group (and across all participants), Drug Class (L3) and preferred base name (01001). If Level 
3 is missing for a medication then Level 2 will be used instead. 
 
Prior medications will not be summarised but these will be listed. 


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10.6. IMP Exposure and Compliance 
 
The study consists of 10 doses of IMP administered twice daily for 5 consecutive days. The expected 
number of doses will be calculated using the start/stop dates and times for each participant. 
Compliance with IMP will be derived as: 
 
(number of doses received/number of doses expected) * 100. 
 
Compliance will be summarised by treatment group and for all participants as a continuous variable 
and will also be summarised categorically in the following classifications: <80%, 80-120% and >120%. 
 
10.7. Statistical Analysis 
 
All efficacy analyses will be based on the ITT-I population as the primary analysis. Where the 
populations differ to ITT-I population by 1 participant within a treatment group, the primary and 
selected secondary analyses will be repeated for the ITT-A, ITT-B, ITT and PP populations. This will be 
reviewed and documented at the BDRM. 
 
10.7.1. 
Primary Endpoint 
 
10.7.1.1 
Main Analysis 
 
The primary endpoint is the AUC of RSV-A Memphis 37b viral load measured in nasal washes by 
qRT-PCR, from the last measurement collected prior to the first administration of IMP until the last 
measurement collected up to the morning of Day 12 (Quarantine discharge). The viral load data will 
be supplied as log10 copies/mL and will be used for this main analysis and to calculate the AUC using 
the trapezoidal rule [1]. 
 
The AUC will be summarised for RV299 and placebo using descriptive statistics and an ANCOVA with 
treatment group as a main effect and the baseline value as a covariate. The baseline value will be the 
qRT-PCR viral load value from the last measurement collected prior to the first administration of IMP. 
The treatment comparison will be presented, including the LS mean treatment difference with the 
corresponding two-sided 95% confidence interval and p-value. The equivalent Wilcoxon rank-sum 
tests will be provided in place of the ANCOVA where the assumptions of the parametric test are not 
met. 
 
As nasal washes are scheduled to be taken twice daily for Days 2 to 11 (and once on Day 12), in order 
to calculate the AUC, the actual time that the assessment was collected will be used within the AUC 
calculation. The AUC calculation will be based on the available non-missing assessment values between 
the start and end of the defined AUC time period. However, for an AUC to be derived, a participant 
should have at least one non-missing data recording at the start of the AUC period (e.g. date of first 
administration of IMP) and also at the end of the AUC time period (e.g. Day 12). In addition, the 
participant should have at least 1 non-missing data recording on each day between the start and end 
of the defined AUC time period (i.e. at least 1 out of the 2 possible assessments on each Day)). Any 
missing data will be reviewed at the BDRM, for its potential impact on this endpoint, and any decisions 
to exclude participants as a result of these criteria will be documented in the BDRM minutes. For the 
reporting of AUC, where appropriate, qRT-PCR values that are ‘Not Detected’ or ‘Detected’ will be re- 
assigned using the substitution values shown in the table in Appendix 15.1. 
 
As well as a descriptive statistics summary of AUC values, the mean qRT-PCR values (+/- 1 Standard 
Error (SE)) will be displayed graphically by day (relative to first dose of IMP) and assessment, and 
treatment group. In order to calculate the time point that each assessment will be presented against, 


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a relative day and relative assessment will be assigned. The last qRT-PCR measurement collected prior 
to the first dose of IMP will be assigned to be the value at time point 1, while measurements collected 
on subsequent assessments and days will be assigned to subsequent time points in sequential order 
(i.e. time point 2, 3 and so on). Time point 1 will be presented against Day 0 assessment 1, while 
subsequent time points will be presented against Day 0 assessment 2, Day 1 assessment 1, and so on. 
 
[Line graph: y-axis = mean of qRT-PCR (log10 copies/mL), x-axis = day relative to dosing, one line for 
each treatment on same plot]. 
 
A boxplot will also be presented by day (relative to first dose of IMP) and assessment, plotting the 
median and mean qRT-PCT values for each treatment group, with the corresponding summary 
statistics. 
 
[Box plot: y-axis = mean of qRT-PCR (log10 copies/mL), x-axis = day relative to dosing, one box-and- 
whisker for each day, with each treatment panelled with RV299 at the top and placebo below]. 
 
Note: For multiple assessments taken within each day, so as to be able to plot mean values across 
participants (within a treatment group) by day, the actual collection time point (which may differ 
across participants) will not be used. Rather all first and second assessments will have mean values 
separately calculated and plotted as two means within each day. These two means will be shown 
equally spaced along the x-axis within the graph. 
 
10.7.1.2 
Sensitivity Analyses 
1. The first sensitivity analysis of the AUC of RSV viral load measured in nasal washes by qRT-PCR 
will be presented for a fixed time period, from the last measurement collected prior to the first 
administration of IMP to the scheduled assessment occurring 6.5 days afterwards (e.g. if a 
participant does not have a positive qicPCR then they will be dosed on Day 5 (evening) and 
they will be followed up to the morning of Day 12 with 14 assessments in total) – which 
represents the AUC over the longest possible time period over which all subjects are sampled. 
2. A second sensitivity analysis of the AUC of RSV viral load measured in nasal washes by qRT- 
PCR will be presented for a fixed time period, which will include data from the morning 
assessment on Day 2 (i.e. the first qRT-PCR assessment measured) through to the morning of 
Day 12. 
3. A third sensitivity analysis of the AUC of RSV viral load measured in nasal washes by qRT-PCR, 
from the last measurement collected prior to the first administration of IMP until the last 
measurement collected up to the morning of Day 12 (Quarantine discharge), will be presented 
where the AUC will be calculated using unlogged viral load data (i.e. the supplied value will be 
anti-logged to get a value as copies/mL). 
 
The AUC analyses will be summarised by treatment group. The same statistical testing methods as 
applied to the main analysis of the primary endpoint will be applied to each sensitivity analysis. For the 
third sensitivity analysis, the data will be log-transformed (base 10) prior to statistical analysis. 


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10.7.2. 
Secondary Endpoints 
 
10.7.2.3 
Viral Load Endpoints 
 
Peak Viral Load of RSV as Defined by the Maximum Viral Load Determined by qRT-PCR 
Measurements in Nasal Samples Starting from Initial Administration of IMP up to Planned Discharge 
from Quarantine 
 
Using the scheduled protocol assessments from the last measurement collected prior to the first dose 
of IMP to morning of Day 12 (Quarantine discharge), the highest qRT-PCR viral load value observed in 
nasal samples for each participant will be summarised and analysed in a similar fashion to the primary 
efficacy endpoint described in Section 10.7.1. 
 
Participants who stay undetectable (i.e. a ’Not Detected’ value) during quarantine will be replaced with 
the ‘Not Detected’ value shown in the table in Appendix 15.1. 
 
Time to Confirmed Negative Test by qRT-PCR Measurements in Nasal Samples Starting from Initial 
Administration of IMP to First Confirmed Undetectable Assessment after Peak Measure 
 
The time from the first administration of IMP to the first confirmed negative qRT-PCR test after the 
peak qRT-PCR measurement will be calculated in days as: 
 
Date and time of first confirmed negative test after peak qRT-PCR measurement – Date of and time 
of first IMP administration. 
 
A negative test is defined as two consecutive ‘Not Detected’ results in the qRT-PCR test, with the 
date and time of the first negative test being utilised in the calculations. The peak qRT-PCR is defined 
as the highest viral load value obtained by a participant after their first administration of IMP. 
Participants who did not have a confirmed undetectable assessment after first administration of IMP 
are censored at their last detectable assessment after their peak qRT-PCR measurement. Participants 
who stay undetectable during quarantine will be excluded from this analysis. Participants who return 
a positive result after two consecutive ‘not detected’ results will remain within the analysis. 
 
The time to confirmed negative test will be summarised descriptively by treatment group. Kaplan 
Meier [2] curves will be produced for each treatment group, overlayed on one plot. A supporting table 
will include the median, 25th and 75th percentiles for each group and will be accompanied by a log rank 
test to compare between RV299 and placebo with the corresponding p-value presented. 
 
[Kaplan-Meier plot: y-axis = cumulative proportion of participants without a negative test, x-axis = day 
relative to initial administration of IMP, one line for each treatment overlayed on the same plot]. 
 
Time to Confirmed Negative Test by qRT-PCR Measurements in Nasal Samples Starting from Peak 
qRT-PCR after Initial Administration of IMP to First Confirmed Undetectable Assessment after Peak 
Measure 
 
The time from the peak qRT-PCR measurement after administration of IMP to the first confirmed 
negative qRT-PCR test will be calculated in days as: 
 
Date and time of first confirmed negative test – Date and time of first IMP administration. 
 
A negative test is defined as two consecutive ‘Not Detected’ results in the qRT-PCR test, with the 
date and time of the first negative test being utilised in the calculations. The peak qRT-PCR is defined 
as the highest viral load value obtained by a participant after their first administration of IMP. 


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Participants who did not have a confirmed undetectable assessment after their peak qRT-PCR after 
first administration of IMP are censored at their last detectable assessment. Participants who stay 
undetectable during quarantine will be excluded from this analysis. 
 
The time to confirmed negative test will be summarised descriptively by treatment group. Kaplan 
Meier curves will be produced for each treatment group, overlayed on one plot. A supporting table 
will include the median, 25th and 75th percentiles for each group and will be accompanied by a log rank 
test to compare between RV299 and placebo with the corresponding p-value presented. 
 
[Kaplan-Meier plot: y-axis = cumulative proportion of participants without a negative test, x-axis = day 
relative to initial administration of IMP, one line for each treatment overlayed on the same plot]. 
 
Time to Peak qRT-PCR in Nasal Samples Starting from Initial Administration of IMP 
 
The time to the peak qRT-PCR measurement starting from the initial administration of IMP will be 
calculated in days as: 
 
Date and time of peak qRT-PCR measurement – Date and time of first IMP administration. 
 
The peak qRT-PCR measurement is defined as the highest viral load value obtained by a participant 
after their first administration of IMP. Participants who stay undetectable during quarantine will be 
excluded from this analysis. 
 
The time to peak qRT-PCR measurement will be summarised descriptively by treatment group. Kaplan 
Meier curves will be produced for each treatment group, overlayed on one plot. A supporting table 
will include the median, 25th and 75th percentiles for each group and will be accompanied by a log rank 
test to compare between RV299 and placebo with the corresponding p-value presented. 
 
[Kaplan-Meier plot: y-axis = cumulative proportion of participants not yet reaching peak qRT-PCR, x- 
axis = day relative to initial administration of IMP, one line for each treatment overlayed on the same 
plot]. 
 
Area under the Viral Load-Time Curve (VL-AUC) of RSV Challenge Virus as Determined by Viral Culture 
in Nasal Samples, Starting from Initial Administration of IMP up to Planned Discharge from 
Quarantine 
 
The area under the viral-load curve (VL-AUC) for RSV-A Memphis 37b measured in nasal washes by 
viral culture, from the last measurement collected prior to the first dose of IMP until the morning of 
Day 12 (Quarantine discharge) will be summarised and analysed as described in Section 10.7.1. 
 
Viral culture analysis is only carried out on samples where the qRT-PCR results is at least detectable. 
Any missing viral culture results will be imputed with ‘Not Detected’ if the corresponding qRT-PCR 
result is not detected. 
 
Peak Viral Load of RSV as Defined by the Maximum Viral Load determined by Viral Culture 
Measurements in Nasal Samples Starting from Initial Administration of IMP up to Planned Discharge 
From Quarantine 
 
Using the scheduled protocol assessments from the last measurement collected prior to the first dose 
of IMP to the morning of Day 12 (Quarantine discharge), the highest viral culture measurement 
observed in nasal samples for each participant will be summarised and analysed in a similar fashion to 
the primary efficacy endpoint described in Section 10.7.1. 


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Participants who stay undetectable (i.e. a ’Not Detected’ value) during quarantine will be replaced with 
the ‘Not Detected’ value shown in the table in Appendix 15.1. 
 
Time to Confirmed Negative Test by Viral Culture Measurements in Nasal Samples Starting from 
Initial Administration of IMP to First Confirmed Undetectable Assessment after Peak Measure 
 
The time from the first administration of IMP to the first confirmed negative viral culture measurement 
after the peak viral culture measurement will be calculated in days as: 
 
Date and time of first confirmed negative test after peak viral culture measurement – Date and time 
of first IMP administration. 
 
A negative test is defined as a ‘Not Detected’ result in the viral culture test, with the date and time of 
the first negative test being utilised in the calculations. The peak viral culture measurement is 
defined as the highest viral load value obtained by a participant after their first administration of 
IMP. Participants who did not have a confirmed undetectable assessment after first administration of 
IMP are censored at their last detectable assessment after their peak viral culture measurement. 
Participants who stay undetectable during quarantine will be excluded from this analysis. 
 
The time to the confirmed negative test will be summarised descriptively by treatment group. Kaplan 
Meier curves will be produced for each treatment group, overlayed on one plot. A supporting table 
will include the median, 25th and 75th percentiles for each group and will be accompanied by a log rank 
test to compare between RV299 and placebo with the corresponding p-value presented. 
 
[Kaplan-Meier plot: y-axis = cumulative proportion of participants without a negative test, x-axis = day 
relative to initial administration of IMP, one line for each treatment overlayed on the same plot]. 
 
Time to Confirmed Negative Test by Viral Culture Measurements in Nasal Samples Starting from Peak 
Viral Culture after Initial Administration of IMP to First Confirmed Undetectable Assessment after 
Peak Measure 
 
The time from the peak viral culture measurement after administration of IMP to the first confirmed 
negative viral culture measurement will be calculated in days as: 
 
Date of and time first confirmed negative test – Date and time of first IMP administration. 
 
A negative test is defined as two consecutive ‘Not Detected’ results in the viral culture test, with the 
date and time of the first negative test being utilised in the calculations. The peak viral culture 
measurement is defined as the highest viral load value obtained by a participant after their first 
administration of IMP. Participants who did not have a confirmed undetectable assessment after 
their peak viral culture measurement after first administration of IMP are censored at their last 
detectable assessment. Participants who stay undetectable during quarantine will be excluded from 
this analysis. 
 
The time to confirmed negative test will be summarised descriptively by treatment group. Kaplan 
Meier curves will be produced for each treatment group, overlayed on one plot. A supporting table 
will include the median, 25th and 75th percentiles for each group and will be accompanied by a log rank 
test to compare between RV299 and placebo with the corresponding p-value presented. 
 
[Kaplan-Meier plot: y-axis = cumulative proportion of participants without a negative test, x-axis = day 
relative to initial administration of IMP, one line for each treatment overlayed on the same plot]. 


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Time to Peak qRT-PCR in Nasal Samples Starting from Initial Administration of IMP 
 
The time to the peak qRT-PCR measurement starting from the initial administration of IMP will be 
calculated in days as: 
 
Date and time of peak qRT-PCR measurement – Date and time of first IMP administration. 
 
The peak qRT-PCR measurement is defined as the highest viral load value obtained by a participant 
after their first administration of IMP. Participants who stay undetectable during quarantine will be 
excluded from this analysis. 
 
The time to peak qRT-PCR measurement will be summarised using a descriptive summary. Kaplan 
Meier curves will be produced for each treatment group, overlayed on one plot. A supporting summary 
table will include the median, 25th and 75th percentiles for each group and will be accompanied by a 
log rank test to compare between RV299 and placebo with the corresponding p-value presented. 
 
[Kaplan-Meier plot: y-axis = cumulative proportion of participants not yet reaching peak qRT-PCR, x- 
axis = day relative to initial administration of IMP, one line for each treatment overlayed on the same 
plot]. 
 
10.7.2.4 
Clinical Symptom-Related Endpoints 
 
Area under the Curve over Time of Total Clinical Symptoms (TSS-AUC) as Measured from 
10 Symptoms within the Graded Symptom Scoring System Collected 3 Times Daily Starting at Initial 
Administration of IMP up to Planned Discharge from Quarantine 
 
Total symptom scores (from 10 items of the 13-item symptom diary card) will be used to calculate the 
AUC, from the assessment nearest to the time of the first administration of IMP (can be prior to or 
after dosing, depending on whether dosed in the morning or evening), i.e. baseline, until Day 12 
(Quarantine discharge), for each participant using the trapezoidal rule [1]. 
 
Symptoms are assessed 3 times daily for Day 1 to Day 11 (and once for Day 12) and recorded on the 
symptom diary cards at each assessment. The following types of symptoms are recorded (on a grading 
scale, 0 to 3 (or 0 to 4 for the Shortness of Breath symptom)): 
• 
Upper Respiratory Tract (URT): runny nose, stuffy nose, sore throat, sneezing, earache. 
• 
Lower Respiratory Tract (LRT): cough, shortness of breath. 
• 
Systemic: headache, malaise, muscle/joint ache/stiffness. 
• 
Not used for analyses: chilliness/feverishness, chest tightness, wheeze. 
A total symptom score will be derived for each participant, separately for each assessment (symptom 
diary card) on each day (Day 0 to Day 12) as follows: 
• 
For each assessment, sum the 10 observed symptom grade values for each symptom diary 
card to obtain a total symptom score for each symptom diary card. If the participant does not 
have all 10 observed values on a specific symptom diary card being considered, then total 
symptom score will not be calculated for that symptom diary card. It is expected that 
participants will not have missing data. 
• 
The AUC calculation will be based on the available non-missing calculated total symptom 
scores between the start and end of the defined AUC time. However, for an AUC to be derived, 
the participant should have at least 1 non-missing calculated total symptom scores at the start 
of the AUC period (e.g. date of first dose of IMP) and also at the end of the AUC time period 


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(e.g. Day 12). In addition, the participant should have at least 2 non-missing data recording on 
each day between the day after the start, and the day before the end, of the defined AUC time 
period (i.e. at least 2 out of the 3 possible assessments on each Day)). Any missing total 
symptom score data will be reviewed at the BDRM, for its potential impact on this endpoint, 
and any decisions to exclude participants as a result of these criteria will be documented in 
the BDRM minutes. 
• 
As symptoms are scheduled to be taken 3 times daily for Days 0 to 11 (and once on Day 12), 
in order to calculate the AUC, the actual time that the assessment was collected will be used 
within the AUC calculation starting from the assessment at the time of the first administration 
of IMP. 
 
The AUC of the total symptom score will be summarised by treatment group and modelled in the same 
way as the main analysis of the primary endpoint described in Section 10.7.1, including sensitivity 
analyses 1 and 2, as described therein. 
 
The total symptom scores and the change from baseline scores will be summarised by timepoint (i.e. 
day relative to first administration of IMP and assessment) and treatment group. The symptom scores 
and the visual analogue score (VAS) in millimetres from the 13-item symptom diary card will be listed. 
 
As well as a descriptive statistics summary of total symptom score values, the mean total symptom 
score values (+/- 1 Standard Error (SE)) will be displayed graphically by day (relative to first dose of 
IMP) and assessment, and treatment group. In order to calculate the time point that each assessment 
will be presented against, a relative day and relative assessment will be assigned. The last total 
symptom score measurement collected at the time of the first dose of IMP will be assigned to be the 
value at time point 1, while measurements collected on subsequent assessments and days will be 
assigned to subsequent time points in sequential order (i.e. time point 2, 3 and so on). Time point 1 
will be presented against Day 0 assessment 1, while subsequent time points will be presented against 
Day 0 assessment 2, Day 0 assessment 3, Day 1 assessment 1, and so on. Negative timepoints relative 
to dosing will also be included and will be presented as Day -1 assessment 1. 
 
[Line graph: y-axis = mean of total symptoms score, x-axis = day relative to dosing (the axis will be 
negative to include days prior to IMP administration), one line for each treatment group on same plot]. 
 
A boxplot will also be presented by day (relative to first dose of IMP) and assessment, plotting the 
median and mean qRT-PCT values for each treatment group, with the corresponding summary 
statistics. 
 
[Box plot: y-axis = mean of qRT-PCR (log10 copies/mL), x-axis = day relative to dosing, one box-and- 
whisker for each day, with each treatment panelled with RV299 at the top and placebo below]. 
 
Note: For multiple assessments taken within each day, so as to be able to plot mean values across 
participants (within a treatment group) by day, the actual collection time point (which may differ 
across participants) will not be used. Rather all first, second and third assessments will have mean 
values separately calculated and plotted as three means within each day. These three means will be 
shown equally spaced along the x-axis within the graph. 
 
Area under the Curve over Time of Total Clinical Symptoms Change from Baseline (TSS-AUC-CFB) as 
Measured from 10 Symptoms within the Graded Symptom Scoring System Collected 3 Times Daily 
Starting at Initial Administration of IMP up to Planned Discharge from Quarantine 
 
The change from baseline will be calculated for each assessment following administration of IMP and 
an AUC calculated using these scores will be analysed in the same manner as described above 


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(including sensitivity analyses 1 and 2), where the baseline assessment is the assessment nearest to 
the time of the first administration of IMP (can be prior to or after dosing, depending on whether dosed 
in the morning or evening). 
 
Peak Symptoms Diary Card Score: Peak Total Clinical Symptoms (TSS) as Measured from 
10 Symptoms within the Graded Symptom Scoring System Collected 3 Times Daily Starting from 
Initial Administration of IMP up to Planned Discharge from Quarantine 
 
Using the scheduled protocol assessments from the assessment at the time of the first dose of IMP to 
Day 12 (Quarantine discharge), the highest total symptom score (defined as the sum of all 10 individual 
composite symptoms) will be summarised by treatment group and modelled in the same way as the 
main analysis of the primary endpoint. 
 
Participants who do not record any symptoms will be assigned a peak of 0. 
 
Peak Daily Symptom Score: Individual Maximum Daily Sum of Symptom Score from Initial 
Administration of IMP up to Planned Discharge from Quarantine 
 
The highest total symptom score recorded on each day, across the three assessments, for each 
participant will be summarised descriptively by treatment group and assessment day. 
 
Time to Symptom Resolution as Measured from 10 Symptoms within the Graded Daily Symptom 
Scoring System Starting at Initial Administration of IMP to 24-hours Symptom Free 
 
Symptom resolution is defined as a participant scoring 0 for the total symptom score for a 24 hour 
period (e.g a minimum of three consecutive symptom diary cards, each with a score of 0) after their 
peak symptom score. 
 
The time from the assessment at the time of the first administration of IMP until symptom resolution 
will be calculated in days as: 
 
Date and time of symptom resolution – Date and time of assessment at IMP administration. 
 
The time to symptom resolution will be summarised by treatment group using descriptive 
summaries. 
 
If the peak symptom score occurs on more than one day then the first occurrence will be selected. 
Participants who do not record 24 hours symptom free after their highest total symptom score 
during the quarantine period will be censored at their last assessment and participants who record 
no symptoms during quarantine will be excluded from this analysis. 
 
Time to Symptom Resolution as Measured from 10 Symptoms within the Graded Daily Symptom 
Scoring System Starting at Peak Symptoms after Initial Administration of IMP to 24-hours Symptom 
Free 
 
The time from the highest total symptom score following administration of IMP until symptom 
resolution will be calculated in days as: 
 
Date and time of symptom resolution – Date and time of highest total symptom score. 
 
The time to symptom resolution after the peak symptom score will be summarised by treatment 
group using descriptive summaries. 


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If the peak symptom score occurs on more than one day then the first occurrence will be selected. 
Participants who do not record 24 hours symptom free after their highest total symptom score 
during the quarantine period will be censored at their last assessment and participants who record 
no symptoms during quarantine will excluded from this analysis. 
 
Time to Peak as Measured from 10 Symptoms within the Graded Daily Symptom Scoring System 
Starting from Initial Administration of IMP to the Time of Peak Daily Symptom Score 
 
The time from the assessment at the time of the first dose of IMP (can be prior to or after dosing, 
depending on whether dosed in the morning or evening) until the highest total symptom score will 
be calculated in days as: 
 
Date and time of highest total symptom score – Date of and time of assessment at IMP 
administration. 
 
The time to peak daily symptom score will be summarised by treatment group using descriptive 
summaries. 
 
If the peak symptom score occurs on more than one day then the first occurrence will be selected. 
Participants who record no symptoms during quarantine will be censored at their last assessment. 
 
10.7.2.5 
Nasal Discharge Endpoints 
 
Total Weight of Mucus Produced Starting at Initial Administration of IMP up to Planned Discharge 
from Quarantine 
 
Total weight of nasal mucus (grams) will be calculated as the sum of mucus weights taken from the 
assessment at the time of the first administration of IMP (can be prior to or after dosing, depending 
on whether dosed in the morning or evening) to morning of Day 12 (Quarantine discharge). Total 
mucus weight will be summarised by treatment group and will include the change from baseline, 
where baseline is the last assessment recorded prior to receiving a positive result for RSV by qicPCR. 
For participants who did not receive a positive result, the final assessment prior to the first 
administration of IMP will be defined as the baseline score. 
 
Total Number of Tissues Used by Participants Starting At Initial Administration of IMP up to Planned 
Discharge from Quarantine 
 
Total number of tissues will be counted from the assessment at the time of the first dose of IMP (can 
be prior to or after dosing, depending on whether dosed in the morning or evening) to morning of Day 
12 (Quarantine discharge). This count will be summarised by treatment group and will include the 
change from baseline, where baseline is the last assessment recorded prior to receiving a positive 
result for RSV by qicPCR. For participants who did not receive a positive result, the final assessment 
prior to the first administration of IMP will be defined as the baseline score. 
 
CCI 
 
 
 


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CCI 
 
 
 
 
 
CCI 
 
 
 
 
 
 
 
 
 
 
 


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10.8. Pharmacokinetic Analysis 
 
Summary of the pharmacokinetic (PK) data and endpoints will not be performed by S-cubed and will 
therefore not be a part of this SAP. Details of the PK Analysis will be found in the CPAP provided by 
VENN. Discussion of the PK parameter correlation can be found in Section 10.7.3.1.. 
 
10.9. Safety Analysis 
 
All analyses of safety endpoints will be descriptive only. The safety population will be used for all safety 
presentations. 
 
10.9.1. 
Adverse Events 
 
All adverse events (AE) will be coded using MedDRA, Version 25.0. 
 
An adverse event is defined as treatment emergent if the onset date is on or after the date of first 
dosing with IMP. Should any onset date for an adverse event be missing or only a partial date recorded 
(such that it cannot be determined if the event onset was prior to start of IMP or not) then it will be 
assumed that the event is treatment emergent, unless the adverse event stop date indicates 
otherwise. 
 
Similarly, an AE is defined as challenge emergent if the onset date is on or after the date of inoculation. 
Should any onset date for an adverse event be missing or only a partial date recorded (such that it 
cannot be determined if the event onset was prior to inoculation or not) then it will be assumed that 
the event is challenge emergent, unless the adverse event stop date indicates otherwise. 
 
An AE can be both challenge emergent and treatment emergent. Any AE with an onset date earlier 
than the inoculation date will be classified as a pre-treatment AE. 
 
If a participant experiences more than one adverse event with the same preferred term, that preferred 
term will be counted only once. It will be assigned the greatest observed severity and the strongest 
relationship to IMP among those events for the tables in which those characteristics are summarised. 
 
Pre-treatment AEs will be identified in a patient listing. 
 
A summary of treatment-emergent AEs will be presented by treatment group showing the number of 
events, number of participants with events (also split by severity; mild, moderate, severe), number of 
participants with SAEs, number of participants with related events, number of participants with events 
CCI 


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leading to early withdrawal from the study and the number of participants with events leading to early 
discontinuation of IMP. 
 
Further summaries will present the treatment-emergent AEs by: 
• 
Treatment group, SOC and PT. 
• 
Treatment group, SOC, PT and severity. 
• 
Treatment group, SOC, PT and relationship to IMP. 
 
Further summaries will present the challenge-emergent AEs by: 
• 
Treatment group, SOC, PT and relationship to challenge agent. 
Tables presented by relationship will only include the subset of adverse events that are judged as being 
‘Related’ to IMP or challenge agent, i.e. correspond to adverse events where relationship is recorded 
on the adverse event page as being ‘Unlikely’, ‘Possibly’, ‘Probably’, ‘Definitely’, or a relationship is not 
given. 
 
In all AE summary tables results will be displayed ordered in terms of decreasing frequency of SOC 
occurrence (based on total across all participants), and within each SOC also ordered in terms of 
decreasing frequency of preferred term occurrence (also based on total across all participants). In all 
AE summary tables a total column including data across all participants will also be presented. 
 
10.9.2. 
Laboratory Variables 
 
For all laboratory variables, baseline is defined as the assessment collected prior to the first 
administration of IMP. 
 
The following parameters will be included within summary presentations (and presented in the units 
as shown): 
 
• 
Haematology: platelet count (10^9/L), white blood cell (WBC) count (absolute) (10^9/L), 
neutrophils (% and absolute (10^9/L)), lymphocytes (% and absolute (10^9/L)), monocytes (% 
and absolute (10^9/L)), eosinophils (% and absolute (10^9/L)), basophils (% and absolute 
(10^9/L)), red blood cell (RBC) count (10^12/L), reticulocyte count (% and absolute (10^9/L), 
haemoglobin (g/L), haematocrit (%), mean corpuscular volume (MCV) (fL), mean corpuscular 
haemoglobin (MCH) (PG), mean corpuscular haemoglobin concentration (MCHC) (g/L). 
• 
Coagulation: prothrombin time (PT) (secs), activated partial thromboplastin time (APTT) (secs). 
• 
Biochemistry: sodium (mmol/L), potassium (mmol/L), glucose (mmol/L), albumin (g/L), 
chloride (mmol/L), bicarbonate (mmol/L), calcium (mmol/L), uric acid (umol/L), total protein 
(g/L), creatinine (umol/L), total bilirubin (umol/L), indirect bilirubin (umol/L), direct bilirubin 
(umol/L), inorganic phosphate (mmol/L), blood urea nitrogen (mg/dL), C-reactive protein (CRP) 
(mg/L), gamma glutamyl transferase (GGT) (IU/L), alkaline phosphatase (ALP) (IU/L), alanine 
transaminase (ALT) (IU/L), lactate dehydrogenase (LDH) (IU/L), aspartate transaminase (AST) 
(IU/L), urea (mmol/L). 
• 
Thyroid Function Tests (screening only): Free thyroxine (pmol/L), Thyroid Stimulating Hormone 
(mIU/L). 
• 
Cardiac Enzymes: creatine kinase (IU/L), troponin T (ng/L). 
• 
Urinalysis: colour, specific gravity, appearance, pH, dipstick presence of: blood, glucose, 
leukocytes, ketones, nitrite, protein, urobilinogen, bilirubin. 


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• 
Human Immunodeficiency Virus and Hepatitis A, B and C: HIV-1 and HIV-2 antibodies, hepatitis 
A antibodies (HepA IgM), hepatitis B surface antigen (HBsAg), hepatitis C antibodies (HCAb). 
 
Observed parameter values and changes from baseline will be summarised appropriately for the above 
haematology, chemistry, coagulation and cardiac enzyme parameters. Any other laboratory 
parameters collected as part of the study will only be included in participant listings. Laboratory data 
collected in different units to that shown will be converted to the above specified units (if possible) for 
presentation in tables and listings. 
 
Laboratory values outside the reference range will be identified in the participant listings as above or 
below the reference range. Laboratory values that are below the limit of quantification (BLQ) will be 
set to zero in computations for summary presentations but will be noted as BLQ in participant listings. 
Laboratory values that are missing will remain missing and will be noted as such in listings. 
 
10.9.3. 
Vital Signs 
 
Vital signs parameters to be summarised are: 
• 
Heart Rate (beats per minute), systolic blood pressure (mmHg), diastolic blood pressure 
(mmHg), respiratory rate (breaths per minute), peripheral arterial oxygen saturation (%) and 
tympanic temperature (OC). 
 
Vital signs parameters will be summarised as observed parameter values and changes from baseline, 
by treatment group for all scheduled protocol visits, where baseline is defined as the assessment 
performed prior to the first administration of IMP. 
 
10.9.4. 
Spirometry 
 
Summary statistics for absolute values and change from baseline by time point will be tabulated, by 
group, for spirometry parameters (FEV1(absolute), FEV1(% predicted), Forced vital capacity (FVC) 
(absolute), FVC (% predicted), FEV1/FVC ratio (absolute), FEV1/FVC ratio (% predicted)) and will also be 
included within participant listings. 
 
The spirometry baseline is the assessment performed at screening. 
 
10.9.5. 
Physical Examination 
 
Physical examination findings (both for the complete examination and also any directed examination 
assessments) will be included within participant listings. 
 
10.9.6. 
12-Lead Electrocardiograms 
 
Summary statistics for absolute values and change from baseline by time point will be tabulated, by 
treatment group for the following ECG parameters: (Heart Rate (bpm), PR interval (sec), QRS duration 
(sec), QT interval (sec), QTc interval (sec), QTcB interval (sec), QTcF interval (sec) and RR interval (sec)). 
For all ECG parameters, the baseline assessment is defined as the assessment performed prior to IMP 
dosing. All data will be included within participant listings. 


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11. 
CHANGES TO THE PROTOCOL SPECIFIED ANALYSIS DETAILED IN THE 
STATISTICAL ANALYSIS PLAN 
1. Clarity has been added to the definitions for the ITT-A and ITT-B populations to ensure they are 
mutually exclusive and are accounting for subjects who have a positive detection either side of 
IMP administration. 
 
2. The protocol incorrectly used median AUC as the main estimator of the primary endpoint. This 
has been corrected within the SAP to use the mean AUC. 
 
3. Inferential analysis was not required for any time to event secondary endpoints within the 
protocol. However, this have been deemed as necessary to support the study outcome and log 
rank tests have been added to the appropriate endpoints. 
 
4. The endpoint ‘Time (days) to peak viral culture in nasal samples, starting from initial 
administration of IMP’ had been missed in the list of endpoints within the protocol, though 
referred to in later sections. This endpoint has been added to the SAP. 
5. Symptom resolution was included within the wording of the secondary clinical-symptom related 
endpoints and referred to as ‘returning to baseline score’. This was deemed not to fit the 
requirements of the endpoint and has instead been amended to be 24-hours symptom free. 
 
6. The endpoint ‘Time to symptom resolution … starting at initial administration of IMP to time of 
returning to baseline score’ has been expanded to include the caveat that the symptom-free 
period must occur after the peak symptom score. 


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12. 
REFERENCES 
[1] Matthews JNS, Altman DG, Campbell MJ, Royston P. Analysis of serial measurements in medical 
research. Br Med J (1990); 300: 230-5. 
 
[2] Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. Journal of American 
Statistical Association. 1958; 53:457-481. 


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13. 
TABLES, FIGURES AND LISTINGS 
 
13.1. Specific Presentation Details 
 
Tables, listings, and figures will be provided in a WORD document [and programmed off CDISC 
compliant SDTM SAS data sets.]. All summary tables and figures will have source data footnotes that 
refer to the relevant listings. Dates will appear as ddmmmyyyy; times as hh:mm. All listings will be 
ordered by treatment group, participant number, and scheduled visit. For the presentation of 
summary data, values will be aligned based on the unit column, and not left/right justified. For 
example: 
 
 
Parameter 
 
 
 
 
 
 
 
 
 
All tables, listings and figures will have the SAS program name, output filename and date of production 
in the footnote. 
 
All tables, listings and figures will include the following study header and footer: 
 
 
CONFIDENTIAL 
 hVIVO Services Ltd 
Page x of y 
REVD002 [VIR-CST-001] 
 
Table x.x 
Title 
Participant population 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Source Data: Listing 16.2.x {Source data footnote only appears for tables, where x references relevant listing 
number} 
 
Program: xxxxxxxxx 
Output: xxxxxxx 
Date: xxxxxxxxx 
n 
xx 
xx 
Mean (SD) 
xx.x (xx.xx) 
xx.x (xx.xx) 
GM (GSD) 
xx.x (xx.xx) 
xx.x (xx.xx) 
%CV 
xx.x 
xx.x 
SE 
xx.xx 
xx.xx 
Median 
xx.x 
xx.x 
Q1, Q3 
xx.x, xx.x 
xx.x, xx.x 
Min, Max 
xx, xx 
xx, xx 


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13.2. List of Tables 
 
For the primary endpoint and selected secondary CCI 
 tables will be 
repeated for the ITT-A, ITT-B, ITT and PP Populations where the difference between the ITT-I is greater 
than 1 participant within a treatment group. Where tables are to be repeated on any additional 
populations, an X has been marked in the relevant column. If a table is repeated, the original table 
number as produced for the ITT-I population will have .1 added and this final digit will be increased by 
1 for repeats on the ITT-A. Similarly, for repeats on ITT-B the number will increase by 2, for repeats on 
ITT the number will increase by 3 and for repeats on the PP the number will increase by 4. For example, 
table 14.2.1.1 will be produced for the ITT-I population and will be repeated as 14.2.1.2, 14.2.1.3, 
14.2.1.4 and 14.2.1.5 for the ITT-A, ITT-B, ITT and PP populations respectively. If no repeats of a table 
are required then the original table will not require the final .1. 
 
Repeated for 
Table 
Number 
Table Title 
ITT- 
A 
ITT- 
B 
ITT 
PP 
14.1.1 
Participant Disposition – All Participants 
14.1.2 
Demography – Safety Population 
14.1.3 
IMP Exposure and Compliance – Safety Population 
14.1.4 
Concomitant Medications – Safety Population 
14.2.1.1 
AUC of RSV Challenge Virus Viral Load by qRT-PCR from 
Initial Administration of IMP to Quarantine Discharge – ITT- 
I Population 
X 
X 
X 
X 
14.2.1.2 
AUC of RSV Challenge Virus Viral Load by qRT-PCR from 
Initial Administration of IMP for 6.5 Days – ITT-I Population 
X 
14.2.1.3 
AUC of RSV Challenge Virus Viral Load by qRT-PCR from Day 
2 to Day 12 – ITT-I Population 
X 
14.2.1.4 
AUC of RSV Challenge Virus Viral Load by qRT-PCR from 
Initial Administration of IMP to Quarantine Discharge 
(Untransformed Data) – ITT-I Population 
X 
14.2.2.1 
Peak Viral Load of RSV Challenge Virus by qRT-PCR from 
Initial Administration of IMP to Quarantine Discharge – ITT- 
I Population 
X 
14.2.2.2 
Time to First Confirmed Undetectable Assessment of RSV 
Challenge Virus by qRT-PCR from Initial Administration of 
IMP – ITT-I Population 
X 
14.2.2.3 
Time to First Confirmed Undetectable Assessment of RSV 
Challenge Virus after Peak Measure by qRT-PCR following 
Initial Administration of IMP – ITT-I Population 
X 
14.2.2.4 
Time to Peak RSV Challenge Virus by qRT-PCR following 
Initial Administration of IMP – ITT-I Population 
X 
14.2.2.5.1 
AUC of RSV Challenge Virus Viral Load by Viral Culture from 
Initial Administration of IMP to Quarantine Discharge – ITT- 
I Population 
X 
X 
X 
X 
14.2.2.5.2 
AUC of RSV Challenge Virus Viral Load by Viral Culture from 
Initial Administration of IMP for 6.5 Days – ITT-I Population 
X 
14.2.2.5.3 
AUC of RSV Challenge Virus Viral Load by Viral Culture from 
X 
Day 2 to Day 12 – ITT-I Population 
 
 


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Repeated for 
Table 
ITT- 
ITT- 
ITT 
PP 
Number 
Table Title 
A 
B 
14.2.2.5.4 
AUC of RSV Challenge Virus Viral Load by Viral Culture from 
X 
Initial Administration of IMP to Quarantine Discharge 
(Untransformed Data) – ITT-I Population 
14.2.2.6 
Peak Viral Load of RSV Challenge Virus by Viral Culture from 
X 
Initial Administration of IMP to Quarantine Discharge – ITT- 
I Population 
14.2.2.7 
Time to First Confirmed Undetectable Assessment of RSV 
X 
Challenge Virus after Peak Measure by Viral Culture starting 
from Initial Administration of IMP - ITT-I Population 
14.2.2.8 
Time to First Confirmed Undetectable Assessment of RSV 
X 
Challenge Virus by Viral Culture starting from Peak Measure 
- ITT-I Population 
14.2.2.9 
Time to Peak RSV Challenge Virus by Viral Culture following 
X 
Initial Administration of IMP – ITT-I Population 
14.2.3.1.1 
AUC of Total Symptom Score from 10-Item Diary Card from 
X 
X 
X 
X 
First Administration of IMP to Quarantine Discharge - ITT-I 
Population 
14.2.3.1.2 
AUC of Total Symptom Score from 10-Item Diary Card from 
X 
First Administration of IMP for 6.5 Days - ITT-I Population 
14.2.3.1.3 
AUC of Total Symptom Score from 10-Item Diary Card from 
X 
Day 2 to Day 12 - ITT-I Population 
14.2.3.2.1 
AUC of Total Symptom Score Change from Baseline from 10- 
X 
X 
X 
X 
Item Diary Card from First Administration of IMP to 
Quarantine Discharge - ITT-I Population 
14.2.3.2.2 
AUC of Total Symptom Score Change from Baseline from 10- 
X 
Item Diary Card from First Administration of IMP for 6.5 days 
- ITT-I Population 
14.2.3.2.3 
AUC of Total Symptom Score Change from Baseline from 10- 
X 
Item Diary Card from Day 2 to Day 12 - ITT-I Population 
14.2.3.3 
Total  Symptom  Score  from  10-Item  Diary  Card  by 
X 
X 
X 
X 
Assessment - ITT-I Population 
14.2.3.4 
Peak Total Symptom Score from 10-Item Diary Card from 
X 
First Administration of IMP to Quarantine Discharge - ITT-I 
Population 
14.2.3.5 
Peak Total Symptom Score from 10-Item Diary Card by Day 
- ITT-I Population 
14.2.3.6 
Peak Daily Symptom Score from 10-Item Diary Card - ITT-I 
Population 
14.2.3.7 
Time to Symptom Resolution by 10-Item Diary Card from 
X 
Initial Administration of IMP to 24-Hours Symptom Free - 
ITT-I Population 
14.2.3.8 
Time to Symptom Resolution by 10-Item Diary Card from 
X 
Peak Total Symptom Score to 24-Hours Symptom Free - ITT- 
I Population 


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Repeated for 
Table 
Number 
Table Title 
14.2.3.9 
Time to Peak Symptom Score by 10-Item Diary Card from 
Initial Administration of IMP - ITT-I Population 
14.2.4.1 
Total Weight of Mucus Produced from Initial Administration 
of IMP to Quarantine Discharge by Assessment - ITT-I 
Population 
14.2.4.2 
Total Number of Tissues Used from Initial Administration of 
IMP to Quarantine Discharge by Assessment - ITT-I 
Population 
ITT- 
A 
X 
X 
ITT- 
B 
ITT 
PP 
CCI 
 
 
 
 
 
 
X 
 
 
14.3.1.1 
Overall Summary of Treatment Emergent Adverse Events – 
Safety Population 
14.3.1.2 
Treatment Emergent Adverse Events by System Organ Class 
and Preferred Term – Safety Population 
14.3.1.3 
Treatment Emergent Adverse Events by System Organ Class, 
Preferred Term and Severity – Safety Population 
14.3.1.4 
Treatment Emergent Adverse Events Related to RV299 by 
System Organ Class and Preferred Term– Safety Population 
14.3.1.5 
Adverse Events Related to Challenge Agent by System Organ 
Class and Preferred Term – Safety Population 
14.3.2 
Haematology Parameters: Summary – Safety Population 
14.3.3 
Biochemistry Parameters: Summary – Safety Population 
14.3.4 
Coagulation Parameters: Summary – Safety Population 
14.3.5 
Cardiac Enzymes Parameters: Summary – Safety Population 
14.3.6 
Urinalysis Parameters: Summary – Safety Population 
14.3.7 
Vital Signs Parameters: Summary – Safety Population 
14.3.8 
Spirometry Parameters: Summary – Safety Population 
14.3.9 
12-Lead Electrocardiogram Parameters: Summary – Safety 
 
Population 
 


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13.3. List of Figures 
 
For the primary endpoint and selected secondaryCCI 
 figures will be 
repeated for the ITT-A, ITT-B, ITT and PP Populations where the difference between the ITT-I is greater 
than 1 participant within a treatment group. Where figures are to be repeated on any additional 
populations, an X has been marked in the relevant column. If a figure is repeated, the original figure 
number as produced for the ITT-I population will have .1 added and this final digit will be increased by 
1 for repeats on the ITT-A. Similarly, for repeats on ITT-B the number will increase by 2, for repeats on 
ITT the number will increase by 3 and for repeats on the PP the number will increase by 4. For example, 
figure 14.2.1.1 will be produced for the ITT-I population and will be repeated as 14.2.1.2, 14.2.1.3, 
14.2.1.4 and 14.2.1.5 for the ITT-A, ITT-B, ITT and PP populations respectively. If no repeats of a table 
are required then the original table will not require the final .1. 
 
Repeated for 
Figure 
ITT- 
ITT- 
ITT 
PP 
Number 
Figure Title 
A 
B 
14.2.1.1 
Mean RSV Challenge Virus Viral Load by qRT-PCR by Days 
X 
X 
X 
X 
from IMP Administration – ITT-I Population 
14.2.1.2 
Boxplot of RSV Challenge Virus Viral Load by qRT-PCR by 
X 
X 
X 
X 
Days from IMP Administration – ITT-I Population 
14.2.2.1 
Peak RSV Challenge Virus Viral Load by qRT-PCR by Days 
X 
from IMP Administration – ITT-I Population 
14.2.2.2 
Kaplan-Meier Plot of Time to First Confirmed Undetectable 
X 
Assessment of RSV Challenge Virus by qRT-PCR from Initial 
Administration of IMP – ITT-I Analysis Set 
14.2.2.3 
Kaplan-Meier Plot of Time to First Confirmed Undetectable 
X 
Assessment of RSV Challenge Virus after Peak Measure by 
qRT-PCR following Initial Administration of IMP – ITT-I 
Population 
14.2.2.4 
Kaplan-Meier Plot of Time to Peak RSV Challenge Virus by 
X 
qRT-PCR following Initial Administration of IMP – ITT-I 
Population 
14.2.2.5.1 
Mean RSV Challenge Virus Viral Load by Viral Culture by 
X 
X 
X 
X 
Days from IMP Administration – ITT-I Population 
14.2.2.5.2 
Boxplot of RSV Challenge Virus Viral Load by Viral Culture by 
X 
X 
X 
X 
Days from IMP Administration – ITT-I Population 
14.2.2.6 
Peak RSV Challenge Virus Viral Load by Viral Culture by Days 
X 
from IMP Administration – ITT-I Population 
14.2.2.7 
Kaplan-Meier  Plot  of First  Confirmed Undetectable 
X 
Assessment of RSV Challenge Virus after Peak Measure by 
Viral Culture starting from Initial Administration of IMP – 
ITT-I Population 
14.2.2.8 
Kaplan-Meier  Plot  of First  Confirmed Undetectable 
X 
Assessment of RSV Challenge Virus by Viral Culture starting 
from Peak Measure – ITT-I Population 
14.2.3.1.1 
Mean Daily Total Symptom Score from 10-item Diary Card 
X 
X 
X 
X 
by Days from IMP Administration – ITT-I Population 
14.2.3.2.1 
Peak Daily Total Symptom Score from 10-item Diary Card by 
X 
Days from IMP Administration – ITT-I Population 
CCI 
 


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CCI 
 
 
Repeated for 
Figure 
Number 
Figure Title 
ITT- 
A 
ITT- 
B 
ITT 
PP 
 
 
 
 


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13.4. List of Listings 
 
 
Listing Number 
Listing Title 
 
16.2.1.1 
Participant Disposition 
16.2.1.2 
Failed Inclusion and Exclusion Criteria 
16.2.2 
Protocol Deviations 
16.2.3 
Participant Populations 
16.2.4.1 
Demographics 
16.2.4.2 
Reproductive Status and Contraceptive Use 
16.2.4.3 
Smoking History 
16.2.4.4 
Alcohol Use 
16.2.4.5 
Recreational Drugs of Abuse 
16.2.4.6 
Medical History 
16.2.4.7 
Prior and Concomitant Medications 
16.2.5.1 
Challenge Virus Inoculation Administration 
16.2.5.2 
Viral Shedding Results 
16.2.5.3 
IMP Administration 
16.2.6.1.1 
Viral Load by Nasal Samples qRT-PCR Results 
16.2.6.1.2 
Viral Load by Nasal Samples qRT-PCR Derivations 
16.2.6.2.1 
Viral Load by Nasal Samples Viral Culture Results 
16.2.6.2.2 
Viral Load by Nasal Samples Viral Culture Derivations 
16.2.6.3.1 
Symptom Scores from Symptom Diary Card 
16.2.6.3.2 
Visual Analogue Scale from Symptom Diary Card 
16.2.6.3.3 
Total Symptom Score: AUC Derivations 
16.2.6.3.4 
Total Symptom Score: Other Derivations 
16.2.6.4 
Mucus Weight and Tissue Bag Distribution 
16.2.6.5 
Nasopharyngeal Swab: Respiratory Virus Screen/Rapid Viral Antigen Test 
16.2.6.6 
Plasma PK Parameters 
16.2.7 
Adverse Events 
16.2.8.1 
Blood Sample Collection 
16.2.8.2 
Haematology 
16.2.8.3 
Coagulation 
16.2.8.4 
Biochemistry 
16.2.8.5 
Thyroid Function Tests 
16.2.8.6 
Cardiac Enzymes 
16.2.8.7 
Human Immunodeficiency Virus and Hepatitis A, B and C 
16.2.8.8.1 
Other Laboratory Tests: TDL 
16.2.8.9.1 
Other Laboratory Tests: Urine Pregnancy 
16.2.8.9.2 
Other Laboratory Tests: Drugs of Abuse Screen 
16.2.8.9.3 
Other Laboratory Tests: Urine Cotinine 
16.2.8.9.4 
Other Laboratory Tests: Alcohol Breath Test 
16.2.9.1 
Urinalysis 
16.2.9.2 
Urinalysis (TDL): Microscopy 
 


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Listing Number 
Listing Title 
 
16.2.10 
Vital Signs 
16.2.11 
Spirometry 
16.2.12.1 
Physical Examination 
16.2.12.2 
Rhinoscopic Examination 
16.2.13 
ECG 
16.2.14 
Visit Dates 
 


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14. 
TABLE AND LISTING SHELLS 


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Table 14.1.56 
Statistical Analysis Plan 
Page 56 of 113 
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Participant Disposition 
All Participants 
 
 
 
RV299 
(N=xx) 
Treatment Group  
Placebo 
(N=xx) 
 
Overall 
(N=xx) 
n 
(%) 
n 
(%) 
n 
(%) 
 
 
Enrolled 
Received challenge agent 
XX 
XX 
Randomised 
XX 
XX 
XX 
Received at least 1 dose of IMP 
XX 
(XX.X) 
XX 
(XX.X) 
XX 
(XX.X) 
Received all doses of IMP 
XX 
(XX.X) 
XX 
(XX.X) 
XX 
(XX.X) 
ITT Population [1] 
XX 
(XX.X) 
XX 
(XX.X) 
XX 
(XX.X) 
ITT-I Population [2] 
XX 
(XX.X) 
XX 
(XX.X) 
XX 
(XX.X) 
ITT-A Population [3] 
XX 
(XX.X) 
XX 
(XX.X) 
XX 
(XX.X) 
ITT-B Population [4] 
XX 
(XX.X) 
XX 
(XX.X) 
XX 
(XX.X) 
Per Protocol Population [5] 
XX 
(XX.X) 
XX 
(XX.X) 
XX 
(XX.X) 
Safety Population [6] 
XX 
(XX.X) 
XX 
(XX.X) 
XX 
(XX.X 
PK Population [7] 
XX 
(XX.X) 
XX 
(XX.X) 
XX 
(XX.X) 
Discontinued IMP 
XX 
(XX.X) 
XX 
(XX.X) 
XX 
(XX.X) 
Completed study 
XX 
(XX.X) 
XX 
(XX.X) 
XX 
(XX.X) 
Withdrew from study 
XX 
(XX.X) 
XX 
(XX.X) 
XX 
(XX.X) 
Reason for Discontinuation of IMP: 
Death 
XX 
(XX.X) 
XX 
(XX.X) 
XX 
(XX.X) 
Adverse Event 
XX 
(XX.X) 
XX 
(XX.X) 
XX 
(XX.X) 
Withdrawal by Subject 
XX 
(XX.X) 
XX 
(XX.X) 
XX 
(XX.X) 
Investigator’s Decision 
XX 
(XX.X) 
XX 
(XX.X) 
XX 
(XX.X) 
Reason for Study Withdrawal: 
Death 
XX 
(XX.X) 
XX 
(XX.X) 
XX 
(XX.X) 
Adverse Event 
XX 
(XX.X) 
XX 
(XX.X) 
XX 
(XX.X) 
Withdrawal by Subject 
XX 
(XX.X) 
XX 
(XX.X) 
XX 
(XX.X) 
Investigator’s Decision 
XX 
(XX.X) 
XX 
(XX.X) 
XX 
(XX.X) 
Non-compliance with Study Requirements 
XX 
(XX.X) 
XX 
(XX.X) 
XX 
(XX.X) 
Pregnancy 
XX 
(XX.X) 
XX 
(XX.X) 
XX 
(XX.X) 
Study Terminated by Sponsor 
XX 
(XX.X) 
XX 
(XX.X) 
XX 
(XX.X) 
Lost to Follow-up 
XX 
(XX.X) 
XX 
(XX.X) 
XX 
(XX.X) 
Never dosed 
XX 
(XX.X) 
XX 
(XX.X) 
XX 
(XX.X) 
Other 
XX 
(XX.X) 
XX 
(XX.X) 
XX 
(XX.X) 
 
 
[1] Intent to Treat (ITT) Population = All randomised participants receiving challenge virus and at least one dose of IMP. 
[2] Intent to Treat Infected (ITT-I) Population = All randomised participants receiving challenge virus and at least 1 dose of IMP, and meeting the criterion for laboratory confirmed 
RSV infection. 
[3] Intent to Treat Infected Pre-dose (ITT-A) Population = All randomised participants receiving challenge virus and at least 1 dose of IMP, and meeting the criterion for laboratory 
confirmed RSV infection, using only assessments prior to taking IMP. 
[4] Intent to Treat Infected Post-dose (ITT-B) Population = All randomised participants receiving challenge virus and at least 1 dose of IMP, and meeting the criterion for laboratory 
confirmed RSV infection, using only assessments after IMP. 
[5] Per Protocol (PP) Population = All ITT-I population participants who have no major protocol deviations, and who complete the quarantine period up to the final day of quarantine 
(Study Day 12) and receive all 10 doses of IMP. 
[6] Safety Population = All randomised participants receiving challenge virus and at least one dose of IMP. 
[7] The PK Population = All ITT participants with at least one post-dose PK result. 
[8] Completed Study = Participating in the study up to and including Day 28 (Follow-up). 
Note: Percentages are based on all randomised participants. 


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Table 14.1.2 
Demography 
Safety Population 
 
 
Treatment Group 
RV299 
(N=xx) 
Placebo 
(N=xx) 
Overall 
(N=xx) 
Ethnicity 
Hispanic or Latino 
n (%) 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
Not Hispanic or Latino 
n (%) 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
Not Reported 
n (%) 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
Unknown 
n (%) 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
Race 
American Indian or Alaska Native 
n (%) 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
Asian 
n (%) 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
Black or African American 
n (%) 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
Native Hawaiian or Other Pacific Islander 
n (%) 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
White 
n (%) 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
Other 
n (%) 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
Height at Screening (m) 
n 
Mean (SD) 
Median 
Q1, Q3 
Min, Max 
XX 
XX.X (XX.XX) 
XX.X 
XX.X, X.XX 
XX, XX 
XX 
XX.X (XX.XX) 
XX.X 
XX.X, X.XX 
XX, XX 
XX 
XX.X (XX.XX) 
XX.X 
XX.X, X.XX 
XX, XX 
Weight at Screening (kg) 
n 
Mean (SD) 
Median 
Q1, Q3 
Min, Max 
XX 
XX.X (XX.XX) 
XX.X 
XX.X, X.XX 
XX, XX 
XX 
XX.X (XX.XX) 
XX.X 
XX.X, X.XX 
XX, XX 
XX 
XX.X (XX.XX) 
XX.X 
XX.X, X.XX 
XX, XX 
BMI at Screening (kg/m^2) 
n 
Mean (SD) 
Median 
Q1, Q3 
Min, Max 
XX 
XX.X (XX.XX) 
XX.X 
XX.X, X.XX 
XX, XX 
XX 
XX.X (XX.XX) 
XX.X 
XX.X, X.XX 
XX, XX 
XX 
XX.X (XX.XX) 
XX.X 
XX.X, X.XX 
XX, XX 
 
 
BMI = Body Mass Index 
Note: Percentages are based on the safety population. 
 
Programming note: If any categorical parameters have missing values for certain participants, then include a missing value category. 


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Table 14.1.3 
IMP Exposure and Compliance 
Safety Population 
 
 
Treatment Group 
RV299 
(N=xx) 
Placebo 
(N=xx) 
Overall 
(N=xx) 
Number of doses of IMP received 
n 
Mean (SD) 
Median 
Q1, Q3 
Min, Max 
XX 
XX.X (XX.XX) 
XX.X 
XX.X, X.XX 
XX, XX 
XX 
XX.X (XX.XX) 
XX.X 
XX.X, X.XX 
XX, XX 
XX 
XX.X (XX.XX) 
XX.X 
XX.X, X.XX 
XX, XX 
Compliance 
<80% 
n (%) 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
80% – 120% 
n (%) 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
>120% 
n (%) 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
 
Note: Compliance = (number of doses received / number of doses expected) * 100. 


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Table 14.1.4 
Concomitant Medications 
Safety Population 
 
 
 
 
Drug Class (L2)/ 
WHO Drug Name [1] 
 
 
RV299 
(N=xx) 
Treatment Group  
 
Placebo 
(N=xx) 
 
 
Overall 
(N=xx) 
n 
% 
n 
% 
n 
% 
 
 
Number of Subjects with any Medication 
XX 
(XX.X) 
XX 
(XX.X) 
XX 
(XX.X) 
Drug Class 1 
XX 
(XX.X) 
XX 
(XX.X) 
XX 
(XX.X) 
WHO Drug Name 1 
XX 
(XX.X) 
XX 
(XX.X) 
XX 
(XX.X) 
WHO Drug Name 2 
XX 
(XX.X) 
XX 
(XX.X) 
XX 
(XX.X) 
Drug Class 2 
XX 
(XX.X) 
XX 
(XX.X) 
XX 
(XX.X) 
WHO Drug Name 1 
XX 
(XX.X) 
XX 
(XX.X) 
XX 
(XX.X) 
WHO Drug Name 2 
XX 
(XX.X) 
XX 
(XX.X) 
XX 
(XX.X) 
 
 
[1] All medications will be coded using the WHO Drug Global Version March 1 2022. 
Note: Concomitant medications correspond to medications where medication stop date is not before the date of IMP treatment. 
Note: Table shows distinct number of participants with each WHO Drug Name/Drug Class. 
Note: Percentages are based on the safety population. 


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Table 14.2.1.1 
AUC of RSV Challenge Virus Viral Load by qRT-PCR from Initial Administration of IMP to Quarantine Discharge 
ITT-I Population 
 
 
AUC(hours*Log10 copies/mL) 
RV299 
 
Treatment Group 
 
 
Placebo 
 
(N=xx) 
(N=xx) 
 
 
n 
XX 
XX 
Mean (SD) 
XX.X (XX.XX) 
XX.X (XX.XX) 
%CV 
XX.XX 
XX.XX 
Median 
XX.X 
XX.X 
Q1, Q3 
XX.X, X.XX 
XX.X, X.XX 
Min, Max 
XX, XX 
XX, XX 
Difference in LS means [1] 
95% Confidence interval for difference 
P-value [1] 
XX.XX 
XX.XXX, XX.XXX 
X.XXX 
 
 
[1] Comparison of RV299 and placebo using an ANCOVA with treatment group as a fixed effect and baseline viral load as the covariate. 
 
This table may be repeated on the ITT-A, ITT-B, ITT and PP Populations as .2, .3, .4 and .5 respectively. 
 
 
 
 
 
 
This layout will be utilised for the following tables: 
 
Table 14.2.1.2 
AUC of RSV Challenge Virus Viral Load by qRT-PCR from Initial Administration of IMP for 6.5 Days – ITT-I Population 
Table 14.2.1.3 
AUC of RSV Challenge Virus Viral Load by qRT-PCR from Day 2 to Day 12 – ITT-I Population 
Table 14.2.1.4 
AUC of RSV Challenge Virus Viral Load by qRT-PCR from Initial Administration of IMP to Quarantine Discharge (Untransformed Data) – ITT-I Population 
Table 14.2.2.1 
Peak Viral Load of RSV Challenge Virus by qRT-PCR from Initial Administration of IMP to Quarantine Discharge - ITT-I Population 
Table 14.2.2.5.1 AUC of RSV Challenge Virus Viral Load by Viral Culture from Initial Administration of IMP to Quarantine Discharge - ITT-I Population 
Table 14.2.2.5.2 AUC of RSV Challenge Virus Viral Load by Viral Culture from Initial Administration of IMP for 6.5 Days – ITT-I Population 
Table 14.2.2.5.3 AUC of RSV Challenge Virus Viral Load by Viral Culture from Day 2 to Day 12 – ITT-I Population 
Table 14.2.2.5.4 AUC of RSV Challenge Virus Viral Load by Viral Culture from Initial Administration of IMP to Quarantine Discharge (Untransformed Data) – ITT-I Population 
Table 14.2.2.6 
Peak Viral Load of RSV Challenge Virus by Viral Culture from Initial Administration of IMP to Quarantine Discharge - ITT-I Population 
 
Where appropriate, these tables may be repeated on the ITT-A, ITT-B, ITT and PP Populations as .2, .3, .4 and .5 respectively. 
 
Programming Note: It is possible that the parametric methods will fail to meet the required assumptions for the main or repeated tables. Therefore, we will provide a Wilcoxon 
test (see Section 10.1.4). The alternative presentation for this is shown below and will require the following footnote to be updated: [1] Comparison of RV299 and placebo using a 
Wilcoxon rank sum test. 
 
 
Median difference in LS means [1] 
XX.XX 
P-value [1] 
X.XXX 


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Table 14.2.2.2.1 
Statistical Analysis Plan 
Page 61 of 113 
Version 01-00, 20DEC2022 
 
 
Time to First Confirmed Undetectable Assessment of RSV Challenge Virus by qRT-PCR from Initial Administration of IMP 
ITT-I Population 
 
 
Treatment Group 
 
RV299 
(N=xx) 
 
Placebo 
(N=xxx) 
 
Kaplan-Meier 
Kaplan-Meier 
 Time (days) 
n 
N# 
Estimate 
n 
N# 
Estimate 
 
 
X 
xx 
xx 
0.xxx 
xx 
xx 
0.xxx 
X 
xx 
xx 
0.xxx 
xx 
xx 
0.xxx 
X 
xx 
xx 
0.xxx 
xx 
xx 
0.xxx 
X 
xx 
xx 
0.xxx 
xx 
xx 
0.xxx 
X 
xx 
xx 
0.xxx 
xx 
xx 
0.xxx 
X 
xx 
xx 
0.xxx 
xx 
xx 
0.xxx 
X 
xx 
xx 
0.xxx 
xx 
xx 
0.xxx 
X 
xx 
Xx 
0.xxx 
xx 
xx 
0.xxx 
X 
xx 
Xx 
0.xxx 
xx 
xx 
0.xxx 
X 
xx 
Xx 
0.xxx 
xx 
xx 
0.xxx 
X 
xx 
Xx 
0.xxx 
xx 
xx 
0.xxx 
X 
xx 
Xx 
0.xxx 
xx 
xx 
0.xxx 
25th percentile [1] 
50th percentile [1] 
75th percentile [1] 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
p-value [2] 
x.xxxx 
 
 
 
n = number of participants with a confirmed undetectable assessment by the end of the period. N# = number of participants at risk. 
[1] Percentiles are obtained from the Kaplan-Meier estimates. 
[2] P-value obtained from a log-ank test compared RV299 and placebo. 
Note: Time to First Confirmed Undetectable Assessment from Initial Administration of IMP = (Date of first confirmed negative test after peak qRT-PCR measurement – Date of first 
administration of IMP) + 1. 
 
This table may be repeated on the ITT-A, ITT-B, ITT and PP Populations as .2, .3, .4 and .5 respectively. 
 
 
 
 
This layout will be utilised for the following tables: 
 
Table 14.2.2.3.1 Time to First Confirmed Undetectable Assessment of RSV Challenge Virus after Peak Measure by qRT-PCR from qRT-PCR following Initial Administration of IMP - ITT- 
I Population 
Table 14.2.2.4.1 Time to Peak RSV Challenge Virus qRT-PCR following Initial Administration of IMP - ITT-I Population 
Table 14.2.2.7.1 Time to First Confirmed Undetectable Assessment of RSV Challenge Virus after Peak Measure by Viral Culture starting from Initial Administration of IMP - ITT-I 
Population 
Table 14.2.2.8.1 Time to First Confirmed Undetectable Assessment of RSV Challenge Virus by Viral Culture starting from Peak Measure - ITT-I Population 
Where appropriate, these tables may be repeated on the ITT-A, ITT-B, ITT and PP Populations as .2, .3, .4 and .5 respectively. 


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Table 14.2.3.1.1 
. Statistical Analysis Plan 
Page 62 of 113 
Version 01-00, 20DEC2022 
 
 
AUC of Total Symptom Score from 10-Item Diary Card from First Administration of IMP to Quarantine Discharge 
ITT-I Population 
 
 
 
AUC(hours*score) 
RV299 
Treatment Group  
Placebo 
 
(N=xx) 
(N=xx) 
 
 
n 
XX 
XX 
Mean (SD) 
XX.X (XX.XX) 
XX.X (XX.XX) 
GM (GSD) 
XX.X (XX.XX) 
XX.X (XX.XX) 
%CV 
XX.XX 
XX.XX 
Median 
XX.X 
XX.X 
Q1, Q3 
XX.X, X.XX 
XX.X, X.XX 
Min, Max 
XX, XX 
XX, XX 
Difference in LS means [1] 
95% Confidence interval for difference 
P-value [1] 
XX.XX 
XX.XXX, XX.XXX 
X.XXX 
 
 
[1] Comparison of RV299 and placebo using an ANCOVA with treatment group as a fixed effect and baseline viral load as the covariate. 
Note: Total symptom scores at the time of the first administration of IMP can be prior to or after dosing, depending on whether dosed in the morning or evening. 
Note: GM is derived by antilog( mean( exp( TSS-AUC + 1 ) ) ) – 1. 
 
 
This table may be repeated on the ITT-A, ITT-B, ITT and PP Populations as .2, .3, .4 and .5 respectively. 
 
 
 
This layout will be utilised for the following tables: 
 
Table 14.2.3.1.2 AUC of Total Symptom Score from 10-Item Diary Card from First Administration of IMP for 6.5 Days - ITT-I Population 
Table 14.2.3.1.3 AUC of Total Symptom Score from 10-Item Diary Card from Day 2 to Day 12 - ITT-I Population 
Table 14.2.3.2.1 AUC of Total Symptom Score Change from Baseline from 10-Item Diary Card from First Administration of IMP to Quarantine Discharge - ITT-I Population 
Table 14.2.3.2.2 AUC of Total Symptom Score Change from Baseline from 10-Item Diary Card from First Administration of IMP for 6.5 Days - ITT-I Population 
Table 14.2.3.2.3 AUC of Total Symptom Score Change from Baseline from 10-Item Diary Card from Day 2 to Day 12 - ITT-I Population 
Table 14.2.3.4.1 Peak Total Symptom Score from 10-Item Diary Card from First Administration of IMP to Quarantine Discharge - ITT-I Population 
 
Where appropriate, these tables will be repeated on the ITT-A, ITT-B, ITT and PP Populations as .2, .3, .4 and .5 respectively. 
 
Programming Note: It is highly likely that the parametric methods will fail to meet the required assumptions. Therefore, we will provide a Wilcoxon test (see Section 10.1.4). The 
alternative presentation for this is shown below and will require the following footnote update: [1] Comparison of RV299 and placebo using a Wilcoxon rank sum test. 
 
 
Median difference in LS means [1] 
XX.XX 
P-value [1] 
X.XXX 
 


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Table 14.2.3.3.1 
Statistical Analysis Plan 
Page 63 of 113 
Version 01-00, 20DEC2022 
 
 
Total Symptom Score from 10-Item Diary Card by Assessment 
ITT-I Population 
 
 
RV299 
(N=xx) 
 
Treatment Group 
 
 
Placebo 
(N=xx) 
Days from IMP Administration 
Assessment 
Observed 
Change from Baseline 
Observed 
Change from 
Baseline 
0 Days 
n 
XX 
XX 
Assessment 1 
Mean (SD) 
GM (GSD) 
%CV 
Median 
Q1, Q3 
Min, Max 
XX.X (XX.XX) 
XX.X (XX.XX) 
XX.XX 
XX.X 
XX.X, X.XX 
XX, XX 
XX.X (XX.XX) 
XX.X (XX.XX) 
XX.XX 
XX.X 
XX.X, X.XX 
XX, XX 
0 Days 
n 
XX 
XX 
XX 
XX 
Assessment 2 
Mean (SD) 
GM (GSD) 
%CV 
Median 
Q1, Q3 
Min, Max 
XX.X (XX.XX) 
XX.X (XX.XX) 
XX.XX 
XX.X 
XX.X, X.XX 
XX, XX 
XX.X (XX.XX) 
XX.X (XX.XX) 
XX.XX 
XX.X 
XX.X, X.XX 
XX, XX 
XX.X (XX.XX) 
XX.X (XX.XX) 
XX.XX 
XX.X 
XX.X, X.XX 
XX, XX 
XX.X (XX.XX) 
XX.X (XX.XX) 
XX.XX 
XX.X 
XX.X, X.XX 
XX, XX 
 
[Repeat for all assessments during Quarantine Period] 
 
Note: Assessments are relative to first administration of IMP. 
Note: Total symptom scores at the time of the first administration of IMP can be prior to or after dosing, depending on whether dosed in the morning or evening. 
This table may be repeated on the ITT-A, ITT-B, ITT and PP Populations as .2, .3, .4 and .5 respectively. 
 
 
This layout will be utilised for the following tables: 
 
Table 14.2.3.5.1 Peak Total Symptom Score from 10-Item Diary Card by Day - ITT-I Population 
 
The table may be repeated on the ITT-A, ITT-B, ITT and PP Populations as .2, .3, .4 and .5 as appropriate. 


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Table 14.2.3.6.1 
Peak Daily Symptom Score from 10-Item Diary Card 
ITT-I Population 
 
Treatment Group 
RV299 
(N=xx) 
Placebo 
(N=xx) 
Days from IMP Administration 
Observed 
Change from Baseline 
Observed 
Change from Baseline 
0 Days 
n 
Mean (SD) 
GM (GSD) 
%CV 
Median 
Q1, Q3 
Min, Max 
XX 
XX.X (XX.XX) 
XX.X (XX.XX) 
XX.XX 
XX.X 
XX.X, X.XX 
XX, XX 
XX 
XX.X (XX.XX) 
XX.X (XX.XX) 
XX.XX 
XX.X 
XX.X, X.XX 
XX, XX 
1 Day 
n 
Mean (SD) 
Median 
GM (GSD) 
%CV 
Q1, Q3 
Min, Max 
XX 
XX.X (XX.XX) 
XX.X 
XX.X (XX.XX) 
XX.XX 
XX.X, X.XX 
XX, XX 
XX 
XX.X (XX.XX) 
XX.X 
XX.X (XX.XX) 
XX.XX 
XX.X, X.XX 
XX, XX 
XX 
XX.X (XX.XX) 
XX.X 
XX.X (XX.XX) 
XX.XX 
XX.X, X.XX 
XX, XX 
XX 
XX.X (XX.XX) 
XX.X 
XX.X (XX.XX) 
XX.XX 
XX.X, X.XX 
XX, XX 
 
[Repeat for all days during Quarantine Period] 
 
Note: Days are relative to first administration of IMP. 
Note: Total symptom scores on the day of the first administration of IMP can be prior to or after dosing, depending on whether dosed in the morning or evening. 


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Statistical Analysis Plan 
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Version 01-00, 20DEC2022 
 
 
 
 
Table 14.2.3.7.1 
Time to Symptom Resolution by 10-Item Diary Card from Initial Administration of IMP to 24-Hours Symptom Free 
ITT-I Population 
 
 
 
RV299 
Treatment Group  
Placebo 
 Time (days) 
(N=xx) 
(N=xx) 
 
 
n 
XX 
XX 
Mean (SD) 
XX.X (XX.XX) 
XX.X (XX.XX) 
GM (GSD) 
XX.X (XX.XX) 
XX.X (XX.XX) 
%CV 
XX.XX 
XX.XX 
Median 
XX.X 
XX.X 
Q1, Q3 
XX.X, X.XX 
XX.X, X.XX 
Min, Max 
XX, XX 
XX, XX 
 
 
Note: Time to Symptom Resolution from Initial Administration of IMP = (Date and time of symptom resolution – Date of and time of assessment at time of IMP administration) + 1. 
 
 
 
 
This layout will be utilised for the following tables: 
 
Table 14.2.3.8.1 Time to Symptom Resolution by 10-Item Diary Card from Peak Total Symptom Score to 24-Hours Symptom Free - ITT-I Population 
Table 14.2.3.9.1 Time to Peak Symptom Score by 10-Item Diary Card from Initial Administration of IMP - ITT-I Population 
 
The layout will be repeated for the following tables, without the GM (GSD) row: 
Table 14.2.4.1.1 Total Weight of Mucus Produced from Initial Administration of IMP to Quarantine Discharge - ITT-I Population 
Table 14.2.4.2.1 Total Number of Tissues Used from Initial Administration of IMP to Quarantine Discharge by Assessment - ITT-I Population 


hVIVO Services Ltd/VIR-CST-001 
CONFIDENTIAL 
Statistical Analysis Plan 
Page 66 of 113 
Version 01-00, 20DEC2022 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


hVIVO Services Ltd/VIR-CST-001 
CONFIDENTIAL 
Table 14.3.1.67 
Statistical Analysis Plan 
Page 67 of 113 
Version 01-00, 20DEC2022 
 
 
Overall Summary of Treatment Emergent Adverse Events 
Safety Population 
 
Treatment Group 
RV299 
(N=xx) 
Placebo 
(N=xxx) 
Overall 
(N=xx) 
n 
(%) 
n 
(%) 
n 
(%) 
Number of Events 
XX 
XX 
XX 
Number of Participants with any Adverse Event 
XX 
(XX.X) 
XX 
(XX.X) 
XX 
(XX.X) 
Mild 
XX 
(XX.X) 
XX 
(XX.X) 
XX 
(XX.X) 
Moderate 
XX 
(XX.X) 
XX 
(XX.X) 
XX 
(XX.X) 
Severe 
XX 
(XX.X) 
XX 
(XX.X) 
XX 
(XX.X) 
Number of Participants with any Serious Adverse Event 
XX 
(XX.X) 
XX 
(XX.X) 
XX 
(XX.X) 
Number of Participants with any Related Adverse Event 
XX 
(XX.X) 
XX 
(XX.X) 
XX 
(XX.X) 
Number of Participants with any Adverse Event Leading 
to Withdrawal from the Study 
XX 
(XX.X) 
XX 
(XX.X) 
XX 
(XX.X) 
Number of Participants with any Adverse Event Leading 
to Discontinuation of IMP 
XX 
(XX.X) 
XX 
(XX.X) 
XX 
(XX.X) 
 
 
Note: Treatment emergent events are those events with an onset on or after the start of IMP dosing. 
Note: If a participant experiences more than one event, then the event with the worst severity or strongest relationship is included in the relevant level of summarisation. 
Note: Related = ‘Unlikely’, ‘Possibly’, ‘Probably’, ‘Definitely’ or ‘Not assessed’. 
Note: Adverse Event Leading to Discontinuation from the Study = Participant withdrew from the study due to an adverse event. 
Note: Adverse Event Leading to Discontinuation of Dosing = Action taken of ‘Trial/Study drug permanently discontinued’. 
Note: Percentages are based on the safety population. 


hVIVO Services Ltd/VIR-CST-001 
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Table 14.3.1.68 
Statistical Analysis Plan 
Page 68 of 113 
Version 01-00, 20DEC2022 
 
 
Treatment Emergent Adverse Events by System Organ Class and Preferred Term 
Safety Population 
 
 
 
System Organ Class/ 
 
 
RV299 
(N=xx) 
 
Treatment Group 
 
 
Placebo 
(N=xxx) 
 
Preferred Term [1] 
n 
(%) 
n 
(%) 
 
 
Number of Events 
Number of Subjects with any adverse event 
System Organ Class 1 
XX 
XX 
XX 
(XX.X) 
(XX.X) 
XX 
XX 
XX 
(XX.X) 
(XX.X) 
Preferred Term 1 
XX 
(XX.X) 
XX 
(XX.X) 
Preferred Term 2 
XX 
(XX.X) 
XX 
(XX.X) 
System Organ Class 2 
XX 
(XX.X) 
XX 
(XX.X) 
Preferred Term 1 
XX 
(XX.X) 
XX 
(XX.X) 
Preferred Term 2 
XX 
(XX.X) 
XX 
(XX.X) 
 
 
[1] MedDRA Version 25.0. 
Note: Treatment emergent events are those events with an onset on or after the first administration of IMP. 
Note: Table shows distinct number of participants with events for each system organ class/preferred term. 
Note: Percentages are based on the safety population. 


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Statistical Analysis Plan 
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Version 01-00, 20DEC2022 
 
 
 
Table 14.3.1.3 
Treatment Emergent Adverse Events by System Organ Class, Preferred Term and Severity 
Safety Population 
 
 
 
System Organ Class/ 
 
 
RV299 
(N=xx) 
 
Treatment Group 
 
 
Placebo 
(N=xxx) 
 
Preferred Term [1] 
n 
(%) 
n 
(%) 
 
 
System Organ Class 1 
Mild 
XX 
XX 
(XX.X) 
(XX.X) 
XX 
XX 
(XX.X) 
(XX.X) 
Moderate 
XX 
(XX.X) 
XX 
(XX.X) 
Severe 
XX 
(XX.X) 
XX 
(XX.X) 
Preferred Term 1 
XX 
(XX.X) 
XX 
(XX.X) 
Mild 
XX 
(XX.X) 
XX 
(XX.X) 
Moderate 
XX 
(XX.X) 
XX 
(XX.X) 
Severe 
XX 
(XX.X) 
XX 
(XX.X) 
Preferred Term 2 
XX 
(XX.X) 
XX 
(XX.X) 
Mild 
XX 
(XX.X) 
XX 
(XX.X) 
Moderate 
XX 
(XX.X) 
XX 
(XX.X) 
Severe 
XX 
(XX.X) 
XX 
(XX.X) 
System Organ Class 2 
XX 
(XX.X) 
XX 
(XX.X) 
Mild 
XX 
(XX.X) 
XX 
(XX.X) 
Moderate 
XX 
(XX.X) 
XX 
(XX.X) 
Severe 
XX 
(XX.X) 
XX 
(XX.X) 
Preferred Term 1 
XX 
(XX.X) 
XX 
(XX.X) 
Mild 
XX 
(XX.X) 
XX 
(XX.X) 
Moderate 
XX 
(XX.X) 
XX 
(XX.X) 
Severe 
XX 
(XX.X) 
XX 
(XX.X) 
 
 
[1] MedDRA Version 25.0. 
Note: Treatment emergent events are those events with an onset on or after the first administration of IMP. 
Note: This table shows distinct number of participants with events for each system organ class/preferred term/severity. If a participant experienced a specific event more than once 
then the event with the worst severity is summarised. 
Note: Percentages are based on the safety population. 


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Statistical Analysis Plan 
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Version 01-00, 20DEC2022 
 
 
 
Table 14.3.1.4 
Treatment Emergent Adverse Events Related to RV299 by System Organ Class and Preferred Term 
Safety Population 
 
System Organ Class/ 
Preferred Term [1]/ 
 
RV299 
(N=xx) 
Treatment Group  
Placebo 
(N=xxx) 
 
Relationship 
n 
(%) 
n 
(%) 
 
 
System Organ Class 1 
Not Assessed 
XX 
XX 
(XX.X) 
(XX.X) 
XX 
XX 
(XX.X) 
(XX.X) 
Unlikely Related 
XX 
(XX.X) 
XX 
(XX.X) 
Possibly Related 
XX 
(XX.X) 
XX 
(XX.X) 
Probably Related 
XX 
(XX.X) 
XX 
(XX.X) 
Definitely Related 
XX 
(XX.X) 
XX 
(XX.X) 
Preferred Term 1 
XX 
(XX.X) 
XX 
(XX.X) 
Not Assessed 
XX 
(XX.X) 
XX 
(XX.X) 
Unlikely Related 
XX 
(XX.X) 
XX 
(XX.X) 
Possibly Related 
XX 
(XX.X) 
XX 
(XX.X) 
Probably Related 
XX 
(XX.X) 
XX 
(XX.X) 
Definitely Related 
XX 
(XX.X) 
XX 
(XX.X) 
Preferred Term 2 
XX 
(XX.X) 
XX 
(XX.X) 
Not Assessed 
XX 
(XX.X) 
XX 
(XX.X) 
Unlikely Related 
XX 
(XX.X) 
XX 
(XX.X) 
Possibly Related 
XX 
(XX.X) 
XX 
(XX.X) 
Probably Related 
XX 
(XX.X) 
XX 
(XX.X) 
Definitely Related 
XX 
(XX.X) 
XX 
(XX.X) 
System Organ Class 2 
XX 
(XX.X) 
XX 
(XX.X) 
Not Assessed 
XX 
(XX.X) 
XX 
(XX.X) 
Unlikely Related 
XX 
(XX.X) 
XX 
(XX.X) 
Possibly Related 
XX 
(XX.X) 
XX 
(XX.X) 
Probably Related 
XX 
(XX.X) 
XX 
(XX.X) 
Definitely Related 
XX 
(XX.X) 
XX 
(XX.X) 
Preferred Term 1 
XX 
(XX.X) 
XX 
(XX.X) 
Not Assessed 
XX 
(XX.X) 
XX 
(XX.X) 
Unlikely Related 
XX 
(XX.X) 
XX 
(XX.X) 
Possibly Related 
XX 
(XX.X) 
XX 
(XX.X) 
Probably Related 
XX 
(XX.X) 
XX 
(XX.X) 
Definitely Related 
XX 
(XX.X) 
XX 
(XX.X) 
 
 
[1] MedDRA Version 25.0. 
Note: Treatment emergent events are those events with an onset on or after the first administration of IMP. 
Note: This table shows distinct number of participants with events for each system organ class/preferred term/relationship. If a participant experiences a specific event more than 
once then the event with the greatest relationship is summarised. 
Note: Only the subset of AEs that are judged to be related to IMP have been considered (i.e. relationship = Possibly Related/Probably Related/Definitely Related/Not Assessed) in 
the table. 
Note: Percentages are based on the safety population. 
This layout will be utilised for the following table: 
Table 14.3.1.5 
Adverse Events Related to Challenge Agent by System Organ Class and Preferred Term – Safety Population 
With the following footnote: 
Note: Only the subset of AEs that are judged to be related to challenge agent have been considered (i.e. relationship = Possibly Related/Probably Related/Definitely 
Related/Not Assessed) in the table. 


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Statistical Analysis Plan 
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Table 14.3.2 
Haematology Parameters: Summary 
Safety Population 
 
 
RV299 
(N=xx) 
 
Treatment Group 
 
 
Placebo 
(N=xx) 
Parameter (units) 
Observed 
Change from Baseline 
Observed 
Change from Baseline 
Baseline 
n 
Mean (SD) 
%CV 
Median 
Q1, Q3 
Min, Max 
XX 
XX.X (XX.XX) 
XX.XX 
XX.X 
XX.X, X.XX 
XX, XX 
XX 
XX.X (XX.XX) 
XX.XX 
XX.X 
XX.X, X.XX 
XX, XX 
Day 7 
n 
Mean (SD) 
%CV 
Median 
Q1, Q3 
Min, Max 
XX 
XX.X (XX.XX) 
XX.XX 
XX.X 
XX.X, X.XX 
XX, XX 
XX 
XX.X (XX.XX) 
XX.XX 
XX.X 
XX.X, X.XX 
XX, XX 
XX 
XX.X (XX.XX) 
XX.XX 
XX.X 
XX.X, X.XX 
XX, XX 
XX 
XX.X (XX.XX) 
XX.XX 
XX.X 
XX.X, X.XX 
XX, XX 
 
[Repeat for all scheduled post-baseline assessments and parameters] 
 
 
This layout will be utilised for the following tables: 
 
Table 14.3.3 
Biochemistry Parameters: Summary – Safety Population 
Table 14.3.4 
Coagulation Parameters: Summary – Safety Population 
Table 14.3.5 
Cardiac Enzyme Parameters: Summary – Safety Population 
Table 14.3.6 
Urinalysis Parameters: Summary – Safety Population 
Table 14.3.7 
Vital Signs Parameters: Summary – Safety Population 
Table 14.3.8 
Spirometry Parameters: Summary – Safety Population 
Table 14.3.9 
12-Lead Electrocardiogram Parameters: Summary – Safety Population 


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Statistical Analysis Plan 
Page 72 of 113 
Version 01-00, 20DEC2022 
 
 
 
 
Listing 16.2.1.1 
Participant Disposition 
 
 
 
 
 
Treatment 
Group 
 
 
 
Participant 
Number / 
Randomisation 
Number 
 
Date/Time of Informed Consent: 
V2 / 
V3 / 
V5.1 / 
V8 / 
Genetic testing V1 / 
Genetic testing V2 
 
Date/Time of: 
Quarantine Admission / 
Randomisation / 
Challenge Agent Administration / 
First IMP Administration / 
Quarantine Discharge 
 
 
 
 
Eligible for randomisation? [1] / 
Completed IMP? / 
Completed Study? [2] 
 
 
 
 
Reason not randomized / 
Reason for discontinuation of IMP / 
Reason for withdrawal 
 
xxxxxxx 
xxxxxx / 
xxxxxx 
 
ddmmmyyyy hh:mm / 
NA / 
ddmmmyyyy hh:mm / 
ddmmmyyyy hh:mm / 
NA / 
ddmmmyyyy hh:mm 
 
ddmmmyyyy hh:mm / 
ddmmmyyyy hh:mm / 
ddmmmyyyy hh:mm / 
ddmmmyyyy hh:mm / 
ddmmmyyyy hh:mm 
 
Yes or No / 
Yes or No / 
Yes or No 
 
xxxxxxxxxxxxxxxxxx / 
xxxxxxxxxxxxxxxxxx / 
xxxxxxxxxxxxxxxxxx 
 
 
 
NA = Not applicable. 
[1] Eligible for randomisation based on criteria at Admission (Day -2/-1). 
[2] Completed Study = Participating in the study up to and including Day 28 (Follow-up). 


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Statistical Analysis Plan 
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Listing 16.2.1.2 
Failed Inclusion and Exclusion Criteria 
 
Treatment Group 
Participant 
Reason for Exclusion 
xxxxxxx 
xxxxxx 
xxxxxxxxxxxxxxxxxxxx 
 
 
 
Programming note: Listing not required if no participants fail the criteria. 


hVIVO Services Ltd/VIR-CST-001 
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Listing 16.2.74 
Statistical Analysis Plan 
Page 74 of 113 
Version 01-00, 20DEC2022 
 
 
Protocol Deviations 
 
Treatment 
Group 
Participant 
Deviations 
Reported 
Date Occurred 
(Study Day) 
Deviation 
Category [a] 
Other, 
Specify 
Deviation 
Description 
Serious 
Breach? 
xxxxxxx 
xxxxxx 
Yes/No 
ddmmmyyyy (xx) 
n 
xxxx 
xxxxxxxxxx 
Yes / No 
 
 
[a] – Deviation categories: Informed Consent procedure [1] / Subject error [2] / Inclusion/exclusion criteria [3] / Investigational product [4] / Visit window [5] / Concomitant 
medication/therapy [6] / Study procedure/assessment window [7] / SAE reporting [8] / Study procedure/assessment performance [9] / Randomisation [10] / Missing assessment/sample 
[11] / Other [12] 


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Listing 16.2.75 
. Statistical Analysis Plan 
Page 75 of 113 
Version 01-00, 20DEC2022 
 
 
Participant Populations 
 
ITT 
ITT-I 
ITT-A 
ITT-B 
PP Population 
Safety 
PK Population 
Treatment Group 
Participant 
Population [1] 
Population [2] 
Population [3] 
Population [4] 
[5] 
Population [6] 
[7] 
 
xxxxxxx 
xxxxxx 
Yes / No 
Yes / No 
Yes / No 
Yes / No 
Yes / No 
Yes / No 
Yes / No 
 
 
[1] Intent to Treat (ITT) Population = All randomised participants receiving challenge virus and at least one dose IMP 
[2] Intent to Treat Infected (ITT-I) Population = All randomised participants receiving challenge virus and at least 1 dose of IMP, and meeting the criterion for laboratory confirmed 
RSV infection. A laboratory-confirmed RSV infection is defined as the presence of viral shedding, measured in nasal wash where one or both of the following definitions must be met: 
At least 2 positive detections by viral load qRT-PCR assay specific for the challenge virus, reported on 2 or more consecutive days; One positive detection by viral load qRT-PCR 
assay, specific for the challenge virus, in which an aliquot of the same sample has also tested positive in a cell-based assay appropriate for detecting the challenge virus. 
[3] Intent to Treat Infected Pre-dose (ITT-A) Population = All randomised participants receiving challenge virus and at least 1 dose of IMP, and meeting the criterion for laboratory 
confirmed RSV infection, using only assessments prior to taking IMP. 
[4] Intent to Treat Infected Post-dose (ITT-B) Population = All randomised participants receiving challenge virus and at least 1 dose of IMP, and meeting the criterion for laboratory 
confirmed RSV infection, using only assessments after IMP. 
[5] Per Protocol (PP) Population = All ITT-I population participants who have no major protocol deviations, and who complete the quarantine period up to the final day of quarantine 
(Study Day 12) and receive all 10 doses of IMP. 
[6] Safety Population = All randomised participants receiving challenge virus and at least one dose of IMP. 
[7] The PK Population = All ITT participants with at least one post-dose PK result. 


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Listing 16.2.4.76 
Statistical Analysis Plan 
Page 76 of 113 
Version 01-00, 20DEC2022 
 
 
Demographics 
Treatment 
Group 
Age at Time of 
Participant 
screening (years) 
Sex 
Race / Ethnicity 
Visit 
Date / Time 
Height 
(cm) 
Weight 
(kg) 
BMI 
(kg/m^2) 
Comments 
xxxxxxx 
xxxxxx 
xx 
Male / 
Female 
xxxxxx / xxxxxx 
Screening 
ddmmmyyyy / hh:mm 
xxx 
xx.xx 
xx 
xxxxxxx 
 
 
NA = Not Applicable. 
Note: Results for height, weight and BMI are shown for all visits at which they were recorded. 
 
Programming note: For height, weight, and BMI if recording is repeated, then all sets of results should be shown. 


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Listing 16.2.4.77 
Statistical Analysis Plan 
Page 77 of 113 
Version 01-00, 20DEC2022 
 
 
Reproductive Status and Contraceptive Use 
 
Breast Feeding/ 
Pregnant Recently 
/ 
(Hetero) 
Treatment 
Planning 
Child-bearing 
Agree to not 
Sexually 
Agree to 
Contraception 
Group 
Participant 
Sex 
Pregnancy 
potential? 
donate sperm 
active? 
contraception 
methods [1] 
xxxxxxx 
xxxxxx 
Male 
NA 
NA 
Yes / No 
Yes / No 
Yes / No 
1 
xxxxxxx 
xxxxxx 
Female 
Yes / No 
Yes / 
No; menopausal / 
No; incapable 
NA 
Yes / No 
Yes / No 
3 
 
[1] 1 Male sterilisation where vasectomised male is the sole partner for that woman. 
2 Oral, injected or implanted hormonal methods of contraception (minimum 2 weeks prior to admission). 
3 An intrauterine device (IUD) or intrauterine hormone-releasing system (IUS) or bilateral tubal ligation. 
4 Male condom with spermicide and female partner using a highly effective method of contraception (e.g. IUD, IUS, bilateral ligation). 
5 Other method. 


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Listing 16.2.4.78 
Statistical Analysis Plan 
Page 78 of 113 
Version 01-00, 20DEC2022 
 
 
Smoking History 
 
Treatment 
Group 
Participant 
Smoking History 
Start Date 
Stop Date 
Date Last 
Smoked 
Category 
Amount 
Years 
Comments 
xxxxxxx 
xxxxxx 
xxxxxxxxxxx 
ddmmyyyy 
ddmmyyyy 
ddmmyyyy 
Number of cigarettes smoked per day 
xx 
xx 
xxxxxxxxxxx 
Number of cigars smoked per day 
xx 
xx 
xxxxxxxxxxx 
Tobacco smoked per week (grams) 
xx 
xx 
xxxxxxxxxxx 
Pack years 
xx 
xx 
xxxxxxxxxxx 
 
 
 
* Date estimated. 
Note: Comments are collected for the combined smoking, alcohol and drugs of abuse module and hence may relate to any of these parameters. 


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Listing 16.2.4.79 
Statistical Analysis Plan 
Page 79 of 113 
Version 01-00, 20DEC2022 
 
 
Alcohol Use 
 
Treatment 
Group 
Participant 
Alcohol Use History 
Weekly alcohol intake (units) 
Willing to refrain from alcohol intake 
Comments 
 
xxxxxxx 
xxxxxx 
Never / 
Current User / 
Previous User 
xx 
Yes / No 
xxxxxxxxxxx 
 
 
 
 
 
 
 
Note: Comments are collected for the combined smoking, alcohol and drugs of abuse module and hence may relate to any of these parameters. 


hVIVO Services Ltd/VIR-CST-001 
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Listing 16.2.4.80 
Statistical Analysis Plan 
Page 80 of 113 
Version 01-00, 20DEC2022 
 
 
Recreational Drugs of Misuse 
 
 
Treatment 
Group 
Participant 
 
Current or recent 
user of 
recreational drugs? 
Start Date 
Stop Date 
 
 
Recreational 
drug(s) used 
Volume 
Route 
Comments 
xxxxxxx 
xxxxxx 
Yes / No 
ddmmmyyyy* 
ddmmmyyyy / hh:mm 
XXXX 
XXXX 
XXXX 
XXXX 
NA = Not Applicable. * = Date estimated. 


hVIVO Services Ltd/VIR-CST-001 
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Listing 16.2.4.81 
Statistical Analysis Plan 
Page 81 of 113 
Version 01-00, 20DEC2022 
 
 
Medical History 
Treatment 
Group 
Participant 
MedDRA SOC / 
Preferred Term [1] / 
Medical Condition 
Start Date 
/ End Date 
Line No. 
Frequency 
Ongoing 
Concomitant medication 
taken for this condition? 
xxxxxxx 
xxxxxx 
Xxxxxxxxx 
Xxxxxxxxx 
Xxxxxxxxxx 
ddmmmyyyy / 
ddmmmyyyy 
xxxx 
Single Episode / 
Intermittent / 
Continuous / 
Other 
Yes / No 
Yes / No 
 
 
 
 
 
 
 
* Date estimated. 
[1] MedDRA Version 25.0. The modified term is the term that was used for MedDRA coding of the event when the event required multiple codes. 


hVIVO Services Ltd/VIR-CST-001 
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Listing 16.2.4.82 
Statistical Analysis Plan 
Page 82 of 113 
Version 01-00, 20DEC2022 
 
 
Prior and Concomitant Medications 
 
Treatment 
Drug Class (L2)/ 
WHO Drug Name/ 
Start Date 
Stop Date 
Indication / 
AE/ 
Dose / 
Dose 
Frequency 
[2] 
Route 
[3] 
PI / P / 
Group 
Participant 
Medication (verbatim)[1] 
/ Time 
/ Time 
Ongoing 
Medical History Line 
units 
C [4] 
xxxxxxx 
xxxxxx 
Xxxxxxxxx 
Xxxxxxxxx 
Xxxxxxxxxx 
ddmmmyyyy / 
hh:mm 
ddmmmyyyy / 
hh:mm 
Yes / No 
Xxxxxxxxx / 
Xxxxxxxxx / 
Xxxxxxxxx 
XX xx 
XXX 
XXX 
PI 
 
 
 
 
 
 
* = Date/time estimated. 
[1] WHO Drug Global Version 2022:1, March 1, 2022. 
[2] QD = Once a day, BD = Twice a day, PRN = As needed, TDS = Three times a day, QDS = Four times a day. 
[3] PO = oral, TOP = topical, PRN = Take as needed. 
[4] PI = Prior to Inoculation, P = Prior to IMP treatment and after inoculation, C = Concomitant with IMP treatment. 
Note: If the medication stop date is before the date of inoculation the medication will be assigned as prior to inoculation. If the medication stop date is before the date of IMP 
treatment but after the date of inoculation, the medication will be assigned as being prior to IMP treatment. In all other cases, the medication is assigned as concomitant with 
IMP treatment. 


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Listing 16.2.5.83 
Statistical Analysis Plan 
Page 83 of 113 
Version 01-00, 20DEC2022 
 
 
Challenge Virus Inoculation Administration 
xxxxxxx 
xxxxxx 
ddmmmyyyy / hh:mm 
Yes / No 
Yes / No 
Yes / No 
Yes / No 
XXXXXXX 
 
 
 
 
 
Change in health in 
Treatment 
Administration 
Administered 
Administered to 
Administered 
30 minutes post 
Group 
Participant 
Date / Time 
intranasally? 
both nostrils? 
successfully? 
administration? 
Comments 


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Listing 16.2.5.84 
Statistical Analysis Plan 
Page 84 of 113 
Version 01-00, 20DEC2022 
 
 
Viral Shedding Results 
Treatment 
Group 
Participant 
Study day and nasal wash time-point 
qicPCR result 
Comments 
xxxxxxx 
xxxxxx 
Day X AM/PM 
Day X AM/PM 
… 
Subject to be dosed Day 5 PM 
Positive/Negative/Invalid/NA 
Positive/Negative/Invalid/NA 
NA 
XXXXXXXX 
XXXXXXXX 
XXXXXXXX 
 
 
 


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Listing 16.2.5.3 
IMP Administration 
Statistical Analysis Plan 
Page 85 of 113 
Version 01-00, 20DEC2022 
 
 
Treatment 
Group 
Participant 
Dose 
Number 
Administered? 
Administration Date / 
Time 
Was dose fully 
administered? 
Comments 
xxxxxxx 
xxxxxx 
XX 
Yes / No 
ddmmmyyyy / hh:mm 
Yes / No 
XXXXXXXX 
 
 
 
 
 


hVIVO Services Ltd/VIR-CST-001 
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Listing 16.2.6.1.1 
Viral Load by Nasal Samples qRT-PCR Results 
Statistical Analysis Plan 
Page 86 of 113 
Version 01-00, 20DEC2022 
 
 
 
Treatment 
Group 
Participant 
Sample Collection 
Date / Time 
(Study Day) 
Assessment 
Virus Titre 
(Log10 Copies/mL) 
Did 
Participant 
Bleed? 
Comments 
xxxxxxx 
xxxxxx 
ddmmyyyy / hh:mm 
(xx) 
1 / 2 
Xxxxx 
Yes / No 
xxxxxxxxxxxx 
 
 
 
 
 
 
Programming Note: The Limit of Detection and Lower limit of Quantification will be shown in the footnote. 


hVIVO Services Ltd/VIR-CST-001 
CONFIDENTIAL 
Listing 16.2.6.1.2 
Viral Load by Nasal Samples qRT-PCR Derivations 
Statistical Analysis Plan 
Page 87 of 113 
Version 01-00, 20DEC2022 
 
 
 
AUC 
Peak Viral Load 
Time from IMP 
Time from Peak 
IMP administration 
IMP administration 
(from IMP 
administration 
measure after IMP 
Time to 
to planned discharge 
for 6.5 days 
Day 2 to Day 12 
IMP administration 
administration to 
to negative 
administration to 
Peak 
Treatment 
(hours*Log10 
(hours*Log10 
(hours*Log10 
to planned discharge 
Day 12) 
test after Peak 
negative test after 
Measure 
Group 
Participant 
Copies/mL) 
Copies/mL) 
Copies/mL) 
(hours*Copies/mL) 
(Log10 Copies/mL) 
measure (days) 
peak measure (days) 
(days) 
xxxxxxx 
xxxxxx 
XX.XX 
XX.XX 
XX.XX 
XX.XX 
XX.XX 
XX 
XX 
XX 
 
 
 
 
 
 
* = Censored value. 
Note: For the calculation of AUCs, values that are ‘Not Detected’, ‘Detected’ or are at or below the limit of quantification have been re-assigned to 0. 


hVIVO Services Ltd/VIR-CST-001 
CONFIDENTIAL 
Listing 16.2.6.2.1 
Viral Load by Nasal Samples Viral Culture Results 
Statistical Analysis Plan 
Page 88 of 113 
Version 01-00, 20DEC2022 
 
 
 
Treatment 
Group 
Sample 
Participant 
Type 
Sample Collection 
Date / Time 
(Study Day) 
Virus Titre 
Assessment 
(Log10 Copies/mL) 
Comments 
xxxxxxx 
xxxxxx 
Xxxxxxxxxx 
ddmmyyyy / 
hh:mm 
(xx) 
1 / 2 
xxxx 
xxxxxxxxxxxxxxxxxxx 
 
 
 
 
 
 
Programming Note: The Limit of Detection and Lower limit of Quantification will be shown in the footnote. 


hVIVO Services Ltd/VIR-CST-001 
CONFIDENTIAL 
Listing 16.2.6.2.2 
Viral Load by Nasal Samples Viral Culture Derivations 
Statistical Analysis Plan 
Page 89 of 113 
Version 01-00, 20DEC2022 
 
 
AUC 
Peak Viral Load 
Time from Peak 
IMP administration 
IMP administration 
IMP 
(from IMP 
Time from IMP 
measure after IMP 
Time to 
to planned discharge 
for 6.5 days 
Day 2 to Day 12 
administration to 
administration to 
administration to 
administration to 
Peak 
Treatment 
(hours*Log10 
(hours*Log10 
(hours*Log10 
planned discharge 
Day 12) 
negative test after 
negative test after 
Measure 
Group 
Participant 
Copies/mL) 
Copies/mL) 
Copies/mL) 
(hours*Copies/mL) 
(Log10 Copies/mL) 
Peak measure (days) 
peak measure (days) 
(days) 
xxxxxxx 
xxxxxx 
XX.XX 
XX.XX 
XX.XX 
XX.XX 
XX.XX 
XX 
XX 
XX 
 
 
 
 
 
 
* = Censored value. 
Note: For the calculation of AUCs, values that are ‘Not Detected’, ‘Detected’ or are at or below the limit of quantification have been re-assigned to 0. 


hVIVO Services Ltd/VIR-CST-001 
CONFIDENTIAL 
Listing 16.2.6.3.1 
Symptom Scores from Symptom Diary Card 
Statistical Analysis Plan 
Page 90 of 113 
Version 01-00, 20DEC2022 
 
 
 
Treatment 
Group 
Participant 
Diary Card Completion 
Date / Time 
(Study Day) 
Days from IMP 
Administration 
Assessment 
LRT 
Grades 
[1] 
URT 
Grades 
S Grades 
[2] 
[3] 
10-item Symptom 
Score [4] 
13-item Symptom 
Score 
Total 
CFB 
Total 
CFB 
xxxxxxx 
xxxxxx 
ddmmyyyy / 
hh:mm 
(xx) 
XX 
1 / 2 / 3 
X/X/X/X 
X/X/X/X/ 
X/X/X/X 
X 
xx 
xx 
xx 
xx 
 
 
 
 
 
 
LRT = Lower respiratory tract. URT = Upper respiratory tract. S = Systemic. CFB = Change from Baseline. 
[1] Cough/Shortness of Breath/Chest Tightness/Wheeze 
[2] Runny Nose/Stuffy Nose/Sneezing/Sore Throat/Earache 
[3] Headache/Malaise/Muscle Joint, Ache/Chilliness, Feverishness 
[4] Includes Cough/Shortness of Breath/Runny Nose/Stuffy Nose/Sneezing/Sore Throat/Earache Headache/Malaise/Muscle Joint, Ache. 
Note: A total symptom score requires at least one symptom to be scored. 


hVIVO Services Ltd/VIR-CST-001 
CONFIDENTIAL 
Listing 16.2.6.3.2 
Visual Analogue Scale from Symptom Diary Card 
Statistical Analysis Plan 
Page 91 of 113 
Version 01-00, 20DEC2022 
 
 
 
Treatment 
Group 
Participant 
Diary Card Completion 
Date / Time 
(Study Day) 
Days from IMP 
Administration 
Assessment 
LRT 
Grades 
(mm)[1] 
URT 
Grades 
S Grades 
(mm)[2] 
(mm) [3] 
xxxxxxx 
xxxxxx 
ddmmyyyy / 
hh:mm 
(xx) 
XX 
1 / 2 / 3 
XX/XX/XX 
/XX 
XX/XX/XX 
XX/XX/XX/ 
/XX/XX 
XX 
 
 
 
 
 
 
LRT = Lower respiratory tract. URT = Upper respiratory tract. S = Systemic. 
[1] Cough/Shortness of Breath/Chest Tightness/Wheeze 
[2] Runny Nose/Stuffy Nose/Sneezing/Sore Throat/Earache 
[3] Headache/Malaise/Muscle Joint, Ache/Chilliness, Feverishness 


hVIVO Services Ltd/VIR-CST-001 
CONFIDENTIAL 
Listing 16.2.6.3.3 
Total Symptom Score: AUC Derivations 
Statistical Analysis Plan 
Page 92 of 113 
Version 01-00, 20DEC2022 
 
 
 
 
Total Symptom Score AUC [1] 
Total Symptom Score Change from Baseline AUC 
Total Symptom Score AUC [2] 
IMP 
IMP 
IMP 
IMP 
IMP 
IMP 
Treatment 
Group 
Participant 
administration to 
planned discharge 
administration 
for 6.5 days 
Day 2 to 
administration to 
administration 
Day 12 
planned discharge 
for 6.5 days 
Day 2 to 
Day 12 
administration to 
administration 
planned discharge 
for 6.5 days 
Day 2 to 
Day 12 
xxxxxxx 
xxxxxx 
XX 
XX 
XX 
XX 
XX 
XX 
XX 
XX 
XX 
 
 
 
 
 
 
[1] Derivations made using 10-items of the 13-item symptom diary card. 
[2] Derivations made using all 13-items of the symptom diary card. 


hVIVO Services Ltd/VIR-CST-001 
CONFIDENTIAL 
Listing 16.2.6.3.4 
Total Symptom Score: Other Derivations 
Statistical Analysis Plan 
Page 93 of 113 
Version 01-00, 20DEC2022 
 
 
 
Sum Total 
Peak Total 
Peak Daily Total 
Time to Symptom 
Symptom Score 
Symptom Score 
Symptom Score 
Time to Symptom 
Resolution from 
Time to Peak 
Days from 
(from IMP 
(from IMP 
(from IMP 
Resolution from 
Peak Symptom 
Total Symptom 
IMP 
administration to 
administration to 
administration to 
IMP 
after IMP 
Score from IMP 
Treatment 
Administra 
planned 
planned 
planned 
administration 
administration 
administration 
Group 
Participant 
tion 
discharge) 
discharge) 
discharge) 
(days) 
(days) 
(days) 
xxxxxxx 
xxxxxx 
XX 
XX 
XX 
XX 
XX 
XX 
XX 
 
 
 
 
 
 
Note: Derivations made for 10-items of the 13-item diary card. 
 
Programming Note: Place the endpoints that are not by study day onto the first row for each participant. 


hVIVO Services Ltd/VIR-CST-001 
CONFIDENTIAL 
Listing 16.2.6.4.1 
Mucus Weight and Tissue Bag Distribution 
Statistical Analysis Plan 
Page 94 of 113 
Version 01-00, 20DEC2022 
 
 
 
Treatment 
Group 
Participant 
Study Day 
Date 
Collected 
 Tissue Bag Distribution 
Time 
Collected/Dispensed 
Tissues 
Taken 
Total Tissues 
Mucus Weight 
Taken 
(g) 
Total Mucus Weight 
(g) 
Comments 
xxxxxxx 
xxxxxx 
xx 
ddmmyyyy 
hh:mm 
xxxx 
xxxx 
xxxx 
xxxx 
 
 
 
 
 
 
Programming note: The Total Mucus Weight and Total Tissues Taken will be listed against the Day 12 observation. 


hVIVO Services Ltd/VIR-CST-001 
CONFIDENTIAL 
Listing 16.2.6.5.1 
Nasopharyngeal Swab: Respiratory Virus Screen/Rapid Viral Antigen Test 
Statistical Analysis Plan 
Page 95 of 113 
Version 01-00, 20DEC2022 
 
 
 
 
Treatment 
 
Sample Collection 
Date / Time 
 Group 
Participant 
(Study Day) 
Result 
Comments  
 
xxxxxxx 
xxxxxx 
ddmmyyyy / 
hh:mm 
(xx) 
Positive / Negative 
xxxxxxxx 
 
 
 
 
 
 


hVIVO Services Ltd/VIR-CST-001 
CONFIDENTIAL 
Listing 16.2.6.6 
Plasma PK Parameters 
Statistical Analysis Plan 
Page 96 of 113 
Version 01-00, 20DEC2022 
 
 
 
Treatment 
Group 
Participant 
Day 
PK Parameter 
Units 
RV299 
Comments 
xxxxxxx 
xxxxxx 
XXX 
XXX 
XXX 
XXX 
xxxxxxxx 
 
 
 
 
 


hVIVO Services Ltd/VIR-CST-001 
CONFIDENTIAL 
Listing 16.2.7 
Adverse Events 
Statistical Analysis Plan 
Page 97 of 113 
Version 01-00, 20DEC2022 
 
 
 
 
Related to [9] 
Treatment 
Start Date Time 
TE [2] / 
IMP / 
Challenge Agent / 
Group / 
MedDRA SOC / 
(study day) / 
CE [3] / 
SAE / 
Outcome [6] / 
Concomitant medication / 
Participant 
Preferred Term [1] / 
Stop Date Time 
Severity / 
Serious 
Action Taken IMP [7] / 
Procedure / 
/AE Number 
Adverse event (verbatim) 
(Study day) 
Frequency [4] 
Criteria [5] 
Action Taken [8] / 
Other 
Comments 
xxxxxxx / 
xxxxxxxxx/ 
ddmmmyyyy hh:mm 
Yes or No / 
Yes or Blank / 
x / 
x / x / x / x / x 
xxxxxxxxxxx 
xxxx / xx 
xxxxxx/ 
xxxxxx 
(xx) / 
ddmmmyyyy hh:mm 
(xx) 
Yes or No / 
Mild, Moderate, 
Severe, Life- 
Threatening / 
xx 
xx 
x / 
x 
xxxxxxxxxxx 
 
 
 
 
 
 
TE = Treatment Emergent. SAE – Serious Adverse Event. 
[1] MedDRA Version 24.0. 
[2] An AE occurring on or after the first administration of IMP. 
[3] An AE occurring on or after the challenge agent inoculation. 
[4] Freq = Frequency. For frequency categories, C = Continuous, I = Intermittent, S = Single Episode. 
[5] Serious Criteria: 1 = Death; 2 = Life-threatening; 3 = Hospitalization; 4 = Persistent or significant disability/incapacity; 5 = Congenital anomaly/birth defect; 6 = Other. 
[6] Outcome: 1 = Resolved; 2 = Resolved with Sequelae; 3 = Ongoing; 4 = Fatal; 5 = Unknown. 
[7] Action Taken IMP: 1 = IMP dosage not changed; 2 = IMP dosage adjusted; 3 = IMP administration temporarily interrupted; 4 = IMP administration discontinued. 
[8] Action Taken: 1 = None; 2 = Non-drug therapy given; 3 = Concomitant medication taken; 4 = Participant withdrawn; 5 = Participant hospitalized; 6 = Other; 7 = Not applicable. 
[9] Related: 1 = Not Related; 2 = Unlikely Related; 3 = Possibly Related; 4 = Probably Related; 5 = Definitely Related. 


hVIVO Services Ltd/VIR-CST-001 
CONFIDENTIAL 
Listing 16.2.8.98 
Statistical Analysis Plan 
Page 98 of 113 
Version 01-00, 20DEC2022 
 
 
Blood Sample Collection 
Treatment 
Sample Collection 
Date / Time 
Clinically 
Significant 
Adverse Event 
associated with 
Group 
Participant 
Visit 
(Study Day) 
Sample Type(s) [1] 
Result? 
Procedure? 
Comments 
xxxxxxx 
xxxxxx 
ddmmyyyy / 
hh:mm 
(xx) 
x x x x x x 
Yes / No 
Yes / No 
xxxxxxxxxxxxxxx 
 
 
 
 
 
 
* see Time and Events Schedule. 
[1] 1 = Biochemistry, 2 = Cardiac enzymes, 3 = Haematology, 4 = Coagulation, 5 = Thyroid function test, 
6 = Hepatitis B, & C, HIV serology, 7 = Serum pregnancy test, 8 = Serum follicle-stimulating hormone, 9 = Serum markers humoral immunity, 10 = Paxgene. 


hVIVO Services Ltd/VIR-CST-001 
CONFIDENTIAL 
Listing 16.2.8.99 
Statistical Analysis Plan 
Page 99 of 113 
Version 01-00, 20DEC2022 
 
 
Haematology 
 
 
Treatment 
Group 
Participant 
Visit 
 
Sample Collection 
Date / Time 
(Study Day) 
Parameter 
Result 
 
 
Change from 
Baseline 
Units 
 
 
Lower 
Limit 
 
 
Upper 
Limit 
Flag 
Comments 
 
 
ddmmyyyy 
hh:mm 
xxxxxxx 
xxxxxx 
xxxx 
(xx) 
Basophils (%) 
x.xx 
x.xx 
% 
x.xx 
x.xx 
L / H 
xxxxxxxxxxxxxxxxxxxx 
Basophils (abs) 
x.xx 
x.xx 
X10^9/L 
x.xx 
x.xx 
Eosinophils (%) 
x.xx 
x.xx 
% 
x.xx 
x.xx 
Eosinophils (abs) 
x.xx 
x.xx 
X10^9/L 
x.xx 
x.xx 
Haematocrit 
x.xx 
x.xx 
% 
xx 
xx 
Haemoglobin 
xxx 
xxx 
g/L 
xxx 
xxx 
Lymphocytes (%) 
x.xx 
x.xx 
% 
x.xx 
x.xx 
Lymphocytes (abs) 
x.xx 
x.xx 
X10^9/L 
x.xx 
x.xx 
MCH 
x.xx 
x.xx 
pg 
xx.x 
xx.x 
MCHC 
xxx 
xxx 
g/L 
xxx 
xxx 
MCV 
x.xx 
x.xx 
fL 
xx.x 
xx.x 
Monocytes (%) 
x.xx 
x.xx 
% 
xx.x 
xx.x 
Monocytes (abs) 
x.xx 
x.xx 
X10^9/L 
xx.x 
xx.x 
Neutrophils (%) 
x.xx 
x.xx 
% 
xx.x 
xx.x 
Neutrophils (abs) 
x.xx 
x.xx 
X10^9/L 
xx.x 
xx.x 
Platelets 
xxx 
xxx 
X10^9/L 
xx.x 
xx.x 
RBC Count 
x.xx 
x.xx 
X10^12/L 
x.xx 
x.xx 
Reticulocytes (%) 
x.xx 
x.xx 
% 
x.xx 
x.xx 
Reticulocytes (abs) 
xx.x 
xx.x 
X10^9/L 
xx.x 
xxx.x 
WBC Count 
x.xx 
x.xx 
X10^9/L 
x.x 
xx.x 
 
 
L = below lower limit, H = above upper limit. 
 
This layout will be utilised for the following listings: 
Listing 16.2.8.3 Coagulation 
Listing 16.2.8.4 Biochemistry 
Listing 16.2.8.5 Cardiac Enzymes 
Listing 16.2.8.6 Thyroid Function Tests 


hVIVO Services Ltd/VIR-CST-001 
CONFIDENTIAL 
Listing 16.2.8.100
Statistical Analysis Plan 
Page 100 of 113 
Version 01-00, 20DEC2022 
 
 
Other Laboratory Tests: TDL 
 
 
Treatment 
 
Sample Collection 
Date / Time 
 Group 
Participant 
Visit 
(Study Day) 
Test 
Result 
 
xxxxxxx 
xxxxxx 
xxxx 
ddmmmyyyy / 
hh:mm 
(xx) 
 
 
HIV 1 and HIV 2 
antibodies 
Positive 
/ 
Negative 
Hepatitis A 
Positive / Negative 
Hepatitis B 
Positive / Negative 
Hepatitis C  
Positive / Negative 
FSH 
xx.x 
Beta HCG 
(IU/L) 
Positive / Negative 
Immunoglobulin 
A antibodies 
xx.x 
HbA1C (%) 
xx.x 
HbA1C 
(mmol/mol) 
xx.x 
 
 
 
L = Low, H = High, ND = Not Done. 
Programming Note: Normal Ranges to be displayed in footnote, if available. 


hVIVO Services Ltd/VIR-CST-001 
CONFIDENTIAL 
Listing 16.2.8.101
Statistical Analysis Plan 
Page 101 of 113 
Version 01-00, 20DEC2022 
 
 
Other Laboratory Tests: Urine Pregnancy 
 
Treatment 
Group 
Participant 
Visit 
Test Date / Time 
(Study Day) 
Participant 
has data 
Result 
Comments 
xxxxxxx 
xxxxxx 
xxxx 
ddmmyyyy / 
hh:mm 
(xx) 
Yes / No / NA - Male 
Positive / Negative 
xxxxxxxxxxxxxxxxxx 
 
 
 
 
 


hVIVO Services Ltd/VIR-CST-001 
CONFIDENTIAL 
Listing 16.2.8.9.2 
Statistical Analysis Plan 
Page 102 of 113 
Version 01-00, 20DEC2022 
 
 
Other Laboratory Tests: Drugs of Abuse Screen 
 
Treatment 
Group 
Participant 
Visit 
Sample Collection 
Date / Time 
(Study Day) 
Test 
Performed 
Time 
Drug 
Result 
Comments 
xxxxxxx 
xxxxxx 
xxxx 
ddmmmyyyy 
hh:mm 
Positive / 
hh:mm 
Cocaine 
Negative / 
(xx) 
Not done 
Positive / 
Cannabinoids 
Negative / 
Not done 
Positive / 
Methadone 
Negative / 
Not done 
Positive / 
Ecstasy 
Negative / 
Not done 
Positive / 
Opiates 
Negative / 
Not done 
Positive / 
Benzodiazepines 
Negative / 
Not done 
Positive / 
Barbituates 
Negative / 
Not done 
Positive / 
Amphetamine 
Negative / 
Not done 
Positive / 
Methamphetamine 
Negative / 
Not done 
Positive / 
Tricyclic 
Negative / 
 
Not done 
 


hVIVO Services Ltd/VIR-CST-001 
CONFIDENTIAL 
Listing 16.2.8.9.
Statistical Analysis Plan 
Page 103 of 113 
Version 01-00, 20DEC2022 
 
 
Other Laboratory Tests: Urine Cotinine 
 
 
Treatment 
 
Test Performed 
Date / Time 
 Group 
Participant 
Visit 
(Study Day) 
Result 
Comments 
 
 
xxxxxxx 
xxxxxx 
xxxx 
ddmmyyyy / 
hh:mm 
(xx) 
Positive / Negative 
xxxxxxxxxxxxxxxxx 
 
 
 
 
 
 


hVIVO Services Ltd/VIR-CST-001 
CONFIDENTIAL 
Listing 16.2.8.9.
Statistical Analysis Plan 
Page 104 of 113 
Version 01-00, 20DEC2022 
 
 
Other Laboratory Tests: Alcohol Breath Test 
 
Treatment 
Test Date / Time 
 Group 
Participant 
Visit 
(Study Day) 
Result 
Comments 
 
 
xxxxxxx 
xxxxxx 
xxxx 
ddmmyyyy / hh:mm 
(xx) 
Positive / Negative 
xxxxxxxxxxxxxxxxx 
 
 
 
 
 
 


hVIVO Services Ltd/VIR-CST-001 
CONFIDENTIAL 
Listing 16.2.9.
Statistical Analysis Plan 
Page 105 of 113 
Version 01-00, 20DEC2022 
 
 
Urinalysis 
 
 
Treatment 
Group 
Participant 
Visit 
 
Sample Collection 
Date / Time 
(Study Day) 
Test Performed Time 
Parameter 
Result [1] 
xxxxxxx 
xxxxxx 
xxxx 
 
ddmmyyyy / 
hh:mm 
(xx) 
hh:mm 
Appearance 
Bilirubin 
Blood – Dip 
Blood – Haemolysed / Non-Haemolysed 
Colour 
Glucose 
Ketones 
Leukocytes 
Nitrite 
Protein 
Specific Gravity 
Urobilinogen 
pH 
 
Interpretation 
Sent for Microscopy 
Comments 
 
 
 
[1] NCS = Not clinically significant, CS = Clinically significant. 
 
Programming note: The physician interpretation and microscopy (Yes/No) will be shown as an additional row at the end of each assessment, with the interpretation/microscopy 
outcome shown in the result column. 
Programming note: for Blood parameter there is a Haemolysed/Non-Haemolysed as well as a result. 


hVIVO Services Ltd/VIR-CST-001 
CONFIDENTIAL 
Listing 16.2.9.
Statistical Analysis Plan 
Page 106 of 113 
Version 01-00, 20DEC2022 
 
 
Urinalysis (TDL): Microscopy 
 
Treatment 
Group 
Participant 
Visit 
Sample Collection 
Date / Time 
(Study Day) 
Urine 
RBC 
Urine 
WBC 
Cellular 
casts 
Granular 
casts 
Hyaline 
casts 
Urine 
culture 
xxxxxxx 
xxxxxx 
xxxx 
ddmmyyyy / 
hh:mm 
(xx) 
xxxxxxx 
xxxxxxx 
xxxxxxx 
xxxxxxx 
xxxxxxx 
xxxxxxxxx 
 
 
 
 
 
 
ND = Not Done, A = Abnormal 


hVIVO Services Ltd/VIR-CST-001 
CONFIDENTIAL 
Listing 16.2.10 
Vital Signs 
Statistical Analysis Plan 
Page 107 of 113 
Version 01-00, 20DEC2022 
 
 
 
Treatment 
Group 
Participant 
Visit 
Date 
Time Started 
Assessment 
Supine 
Collection 
Time 
Parameter 
Result [1] 
Change from 
Baseline 
Units 
Comments 
xxxxxxx 
xxxxxx 
xxxx 
ddmmyyyy 
1 / 2 / 3 
hh:mm 
hh:mm 
Systolic BP 
xxx 
xxx 
mmHg 
Diastolic BP 
xx 
xx 
mmHG 
Heart Rate 
xx 
xx 
bpm 
Rep. Rate 
xx 
xx 
breaths/min 
SpO2 
xx 
xx 
% 
Tympanic 
temperature 
xx.x 
xx.x 
deg C 
Interpretation 
xxxxxxxx 
xxxxxxx 
 
 
 
[1] NCS = Not clinically significant, CS = Clinically significant.* = tympanic temperature >= 37.9 deg C. 
 
 
Programming note: The physician interpretation will be shown as an additional row at the end of each assessment, with the interpretation outcome shown in the result column. Add * 
to any temperature result >=37.9 deg C. 


hVIVO Services Ltd/VIR-CST-001 
CONFIDENTIAL 
Statistical Analysis Plan 
Page 108 of 113 
Version 01-00, 20DEC2022 
 
 
 
 
Listing 16.2.11 
Spirometry 
Treatment 
Date / Time 
Group 
Participant 
Visit 
(Study Day) 
Parameter 
Result [1] 
Units 
xxxxxxx 
xxxxxx 
xxxx 
Ddmmyyyy hh;mm (XX) 
FEV1 (abs) 
x.xx 
L 
FEV1 (% Pred) 
xx 
% 
FEV1/FVC Ratio (abs) 
xx 
FEV1/FVC Ratio (% Pred) 
xx 
% 
FVC (abs) 
x.xx 
L 
FVC (% Pred) 
xx 
% 
FEV1 decreased by > 15% from baseline 
Yes / No 
FEV1 or FVC < 80% of the predicted 
value? 
Yes / No 


hVIVO Services Ltd/VIR-CST-001 
CONFIDENTIAL 
Statistical Analysis Plan 
Page 109 of 113 
Version 01-00, 20DEC2022 
 
 
 
Listing 16.2.12.1 
Physical Examination 
 
Treatment 
Group 
Participant 
Visit 
 
Date / Time 
(Study Day) 
Parameter 
Finding 
Comments 
xxxxxxx 
xxxxxx 
xxxx 
 
 
 
ddmmyyyy hh:mm 
(Study Day) 
General Appearance 
Eyes 
Ears 
Nose 
Throat 
Head and Neck 
Cranial Nerves/Nervous System 
Musculoskeletal 
Skin 
Cardiovascular 
Abdomen/GI System 
Respiratory System 
Chest – Auscultation 
Chest – Vocal Resonance 
Chest – Percussion 
Other Findings 
 
Normal / 
Abnormal Not Clinically Significant / 
Abnormal Clinically Significant / 
Not Done 
 
 
 
 


hVIVO Services Ltd/VIR-CST-001 
CONFIDENTIAL 
. Statistical Analysis Plan 
Page 110 of 113 
Version 01-00, 20DEC2022 
 
 
 
 
Listing 16.2.12.2 
Rhinoscopic Examination 
 
Treatment 
Group 
Participant 
Visit 
 
Date / Time 
(Study Day) 
Assessment 
Level [1] 
Comments 
xxxxxxx 
xxxxxx 
xxxx 
 
ddmmyyyy hh:mm 
(Study Day) 
Nasal Discharge - Left 
Nasal Discharge – Right 
Otitis – Left 
Otitis – Right 
Pharyngitis 
Sinus Tenderness – Left 
Sinus Tenderness – Right 
New Wheezes, Rhonchi – Left 
New Wheezes, Rhonchi – Right 
 
 
 
[1] Nasal Discharge: 0 = None, 1 = Clear, serous; scant but slightly increased, 2 = Clear to white, obvious increased volume, + / - minor blood 
streaks on tissue, 3 = Frankly prudent (yellow or green), or gross blood. 
Otitis: NA = Tympanic membrane not visible, 0 = None, 1 = Dulled tympanic membrane, 2 = Inflamed, injected tympanic membrane, 3 = Retracted or bulging tympanic membrane, 
obvious air, fluid level. 
Pharyngitis: 0 = None, 1 = Mild and / or patchy erythema, 2 = Marked and / or confluent erythema, 3 = Erythema and purulent exudate. 
Sinus Tenderness: 0 = None, 1 = Mild tenderness, 2 = Moderate tenderness, 3 = Severe tenderness or overlying erythema. 
New Wheezes, Rhonchi: 0 = None, 1 = Mild wheezes or rhonchi, 2 = Scattered wheezes or rhonchi, 3 = Widespread wheezes. 


hVIVO Services Ltd/VIR-CST-001 
CONFIDENTIAL 
Listing 16.2.111 
Statistical Analysis Plan 
Page 111 of 113 
Version 01-00, 20DEC2022 
 
 
ECG 
 
Treatment 
Group 
Participant 
Visit 
Date 
 
Time Started 
in Resting Position 
Time Performed 
Parameter 
Result [1] 
Units 
Comments 
xxxxxxx 
xxxxxx 
xxxx 
ddmmyyyy 
hh:mm 
hh:mm 
HR 
xxx 
bpm 
xxxxxx 
PR 
xxx 
ms 
QRS 
xxx 
ms 
QT 
xxx 
ms 
QTc 
xxx 
ms 
QTcB 
xxx 
ms 
QTcF 
xxx 
ms 
RR 
xxx 
ms 
Normal / 
Abnormal NCS / 
 
Interpretation 
Abnormal CS 
 
 
[1] NCS = Not clinically significant, CS = Clinically significant. 
 
Programming note: The physician interpretation will be shown as an additional row at the end of each assessment, with the interpretation outcome shown in the result column. 


hVIVO Services Ltd/VIR-CST-001 
CONFIDENTIAL 
Statistical Analysis Plan 
Page 112 of 113 
Version 01-00, 20DEC2022 
 
 
 
Listing 16.2.14 
Visit Dates 
 
Treatment 
 Group 
Participant 
Visit 
Date 
Source of Unscheduled Visit Comments 
Comments 
 
xxxxxxx 
xxxxxx 
xxxx 
ddmmyyyy 
xxxxxxxxxx 
xxxxxxxxxxxxx 
 
 
 
 
 
 
Programming note: Unscheduled visits and visit information will be taken from specific database modules and the “Reason for additional collection” will be placed in the comments 
column in this listing. 


hVIVO Services Ltd/VIR-CST-001 
CONFIDENTIAL 
Statistical Analysis Plan 
Page 113 of 113 
Version 01-00, 20DEC2022 
 
 
 
15. 
APPENDICES 
15.1. Study VIR-CST-001 assay cut-offs and reporting 
 
Analysis 
Assay 
Associated 
units 
Assay Reporting 
Result 
Reported result 
S-cubed assigned 
value 
RSV titre 
(Viral Load) 
RSV Viral Culture 
assay 
(plaque assay) 
Log10 
PFU/mL 
ALOQ 
ALOQ 
6.34 
Quantifiable Titre 
Value 
Use reported value 
DETECTED 
DETECTED 
1.00 
NOT DETECTED 
NOT DETECTED 
0 
INVALID 
INVALID 
Missing data point 
NOT TESTED 
N/A 
Missing data point 
RSV titre 
(Viral Load) 
qRT-PCR 
(in saline matrix) 
Log10 
Copies/mL 
Quantifiable Titre 
Value 
Use reported value 
DETECTED 
DETECTED 
1.69 
NOT DETECTED 
NOT DETECTED 
0 
INVALID 
INVALID 
Missing data point 
NOT TESTED 
N/A 
Missing data point 
RSV 
antibody 
titre 
RSV 
Neutralisation 
Assay 
(virus focus 
reduction 
neutralisation 
assay) 
None 
Quantifiable Titre 
Value 
Use reported value 
>4209 
>4209 
4209 
<156 
<156 
78 
NDA 
NDA 
10 
INVALID 
INVALID 
Missing data point 
NOT TESTED 
N/A 
Missing data point 
N/A = not applicable; NDA = no detectable antibody.