Clinical trial NCT04225897
Conditions: Respiratory Syncytial Virus (RSV) Lower Resp Tract Infection
Keywords: RV521 Pediatrics Children LRTI Wheezing Rhinitis Cough sisunatovir
Sponsor: Pfizer
Start date: 2019-11-13; Completion date: 2022-12-05
Enrollment: 51 participants; Allocation: RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
The purpose of this clinical trial is to learn about the safety and effects of the study medicine (sisunatovir). Sisunatovir is developed as potential treatment of Respiratory Syncytial Virus (RSV) infections. This study will assess sisunatovir as compared to placebo in infants aged 1 month to 36 months who are hospitalized with RSV lower respiratory tract infection (LRTI). A placebo looks like the study medicine but does not contain any active medicine in it.

This study will be conducted in 3 parts:

In Part A participants aged 6 months to 3 years will be given a single dose of 2.5 mg/kg of sisunatovir in Cohort 1. In Cohort 2, participants age 1 month to 6 months will receive a single dose of 2 mg/kg of sisunatovir only after the completion of Cohort 1. 12-24 participants will be enrolled in Part A In Part B participants age 1 month to 36 months will receive sisunatovir or placebo dosed every 12 hours for 5 days. Doses for part B will be determined after the completion of Part A. 24-40 participants will be enrolled in Part B.

The dose regimen for Part C will be determined after the completion of Part B. Approximately 120 participants age 1 month to 36 months will receive either sisunatovir or placebo.

To participate in this study participants must meet the following criteria:

1. Age 1 month to 36 months
2. Weight ≥ 3.5 kg
3. Diagnosis of LRTI
4. Diagnosis of RSV
5. Hospitalization due to RSV LRTI

Detailed description:
This is a multicentre, 3-part study to evaluate safety, tolerability, PK, PD, and antiviral effect of single and multiple dosing of RV521 in infants hospitalised due to RSV LRTI.

The clinical study consists of 3 parts, the third part (Part C) is optional:

* Part A is an open-label, multicentre, single dose study in infants hospitalised with RSV LRTI (Cohorts 1 \& 2)
* Part B is a randomised, double-blind, placebo-controlled, multicentre multiple dose study in infants hospitalised with RSV LRTI (Cohorts 3, 4 \& 5)
* Part C is a randomised 1:1, double-blind, placebo-controlled, multicentre, multiple-dose study in infants hospitalised with RSV LRTI I The number of subjects enrolled in Parts A and B of the study will depend on the safety and PK data from the group of subjects enrolled in specified age cohorts and the subsequent recommendation of the Data Safety Monitoring Committee (DSMC).

The DSMC may recommend a dose adjustment (either a reduction or an escalation) and/or regimen adjustment (Part B only) for subsequent subjects because of the observation of an unexpected safety/tolerability profile and/or differences between the observed and predicted exposure resulting from a specified dose of RV521.

Arms: arm 1: sisunatovir is formulated as a dry powder blend of RV521 drug substance with mannitol as excipient. The RV521 dry powder blend will be supplied in capsules containing 10, 20, or 50 mg RV521. The Investigational Medicinal Product (IMP) will be dispersed in a defined volume of suspending diluent prior to oral administration on a mg/kg basis. Instructions for opening the capsule(s) and dispersing the contents in a fixed volume of suspending diluent prior to administration will be provided in the Pharmacy Manual.

The proposed dosing regimen for Part A is a single open label dose of RV521. Part B and C is RV521 or placebo administered BID, 12 hours apart, for a period of 5 consecutive days with a total of 10 doses. However, this is subject to the recommendation of the DSMC. arm 2: The placebo capsules administered in Part B and C will contain mannitol and microcrystalline cellulose (vehicle). The placebo dry powder will be dispersed in suspending diluent and given orally BID. Instructions for opening the capsule(s) and dispersing the contents in a fixed volume of suspending diluent prior to administration will be provided in the Pharmacy Manual.
Interventions: intervention 1: RV521 intervention 2: Placebo
Intervention descriptions: intervention 1: RV521 is an RSV F protein inhibitor administered orally intervention 2: vehicle administered orally

Protocol documents:
Prot_000.pdf: 
CLINICAL STUDY PROTOCOL 
A Phase 2 Open-Label Study in Infants with REspiratory Syncytial VIRus 
Lower RespirAtory Tract Infection, Followed by a DoubLe-blind, Placebo- 
controlled Part, to Evaluate the Safety, Tolerability, Pharmacokinetics and 
Antiviral Effect of RV521 (REVIRAL 1) 
 
 
Protocol Number: 
REVC003 
EudraCT Number: 
2018-001010-15 
CCI 
 
 
Investigational Product: 
RV521 (sisunatovir) 
Phase: 
Phase 2 
Sponsor: 
ReViral Ltd 
Stevenage Bioscience Catalyst 
Gunnels Wood Road 
Stevenage 
Hertfordshire SG1 2FX 
England 
Contract Research Organisation: 
Syneos Health 
Corporate Headquarters 
1030 Sync Street 
Morrisville, NC 27560 United States 
Protocol Date: 
30 Jul 2018 
Protocol Version: 
Version 1.0 
Protocol Amendment 1: 
02 Oct 2018 (Version 2.0) 
Protocol Amendment 2: 
13 May 2019 (Version 3.0) 
Protocol Amendment 3: 
15 Jan 2020 (Version 4.0) 
Protocol Amendment 4: 
01 Mar 2021 (Version 5.0) 
Protocol Amendment 5: 
31 Jan 2022 (Version 6.0) 
CONFIDENTIAL 
This protocol may not be reproduced or communicated to a third party without the written 
permission of ReViral Ltd. 
 
 
 
 
REVC003 
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1 
PROTOCOL APPROVAL SIGNATURES 
 
Protocol Title: 
 
 
 
 
Protocol Number: 
A Phase 2 Open-Label Study in Infants with REspiratory Syncytial 
VIRus Lower RespirAtory Tract Infection, Followed by a DoubLe­ 
blind, Placebo-controlled Part, to Evaluate the Safety, Tolerability, 
Pharmacokinetics and Antiviral Effect ofRV521(REVIRAL 1) 
REVC003 
 
This study will be conducted in compliance with the clinical study protocol (and 
amendments), International Council for Harmonisation (ICH) guidelines for current Good 
Clinical Practice (GCP) and applicable regulatory requirements. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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PPD 
PPD 
 
PPD 
PPD 
MD 
PPD 
PPD 
Date 
PPD 
PPD 
PPD 
PPD 


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2 
STUDY PERSONNEL 
 
Sponsor Responsible Medical Expert 
 
Name: 
PPD 
 , MD 
Title: 
PPD 
Address: 
Telephone No.:  PPD 
 
Contract Research Organisation 
 
Name: 
Syneos Health 
Address: 
Corporate Headquarters 
1030 Sync Street 
Morrisville, NC 27560 United States 
Telephone No.: +1 919 876 9300 
 
Central Laboratory 
 
Name: 
Eurofins Central Laboratory Lancaster 
Address: 
2430 New Holland Pike 
Lancaster, PA 17601 
United States 
Telephone No.: +1 717 556 7350 
 
Central Laboratory – Pharmacokinetic Samples 
 
Name: 
Alderley Analytical Lab 
Address: 
Alderley Park 
Macclesfield, Cheshire, SK10 4TG 
United Kingdom 
Telephone No.: +44 (0)1625 238636 


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Central Laboratory – Nasopharyngeal Swab Testing CCI 
 
Testing 
 
CCI 
 
 
 
 
 
 
 
 
Central Laboratory – ECG Analysis 
 
Name: 
ERT 
Address: 
1818 Market St, Suite 1000 
Philadelphia, 
Pennsylvania 19103 
United States 
Telephone No.: +1 215 972 0420 


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3 
SYNOPSIS 
 
Protocol Number: 
REVC003 
Title: 
A Phase 2 Open-Label Study in Infants with REspiratory Syncytial VIRus Lower RespirAtory Tract Infection, 
Followed by a DoubLe-blind, Placebo-controlled Part, to Evaluate the Safety, Tolerability, Pharmacokinetics and 
Antiviral Effect of RV521 (REVIRAL 1). 
 
Investigational Product: 
RV521 
Study Centres: 
Approximately 75 centres in approximately 15 countries from the Northern and Southern Hemispheres 
 
Phase: 
Phase 2 
 
PART A and PART B: Objectives and Endpoints: 
 
Primary Objective 
Primary Endpoints 
To evaluate the safety and tolerability of 
single (Part A) and multiple (Part B) oral 
doses of RV521 in infants hospitalised with 
Respiratory Syncytial Virus (RSV) lower 
respiratory tract infection (LRTI) 
Safety and tolerability parameters to be assessed will include, 
but are not limited to: 
• 
Adverse events (AEs), treatment-emergent AEs (TEAEs), 
serious AEs (SAEs), and withdrawals due to TEAEs 
• 
Physical examinations 
• 
Vital sign parameters (ie, systolic and diastolic blood 
pressure [BP], temperature, respiration rate [RR], heart 
rate [HR], and pulse oximetry), and changes from baseline 
in these parameters at predefined time points 
• 
Laboratory tests (haematology, chemistry, and urinalysis 
test results) and changes from baseline in these 
parameters, at predefined time points 
• 
Electrocardiogram (ECG) measurements and changes 
from baseline in these parameters at predefined time 
points 
Secondary Objectives 
Secondary Endpoints 
To characterise the pharmacokinetics (PK) of 
single (Part A) and multiple (Part B) oral 
doses of RV521 in infants hospitalised with 
RSV LRTI 
Secondary endpoints related to PK will include but are not 
limited to: 
• 
Time to maximum plasma concentration (tmax) 
• 
Maximum observed plasma concentration(Cmax) 
• 
Area under the plasma concentration time curve from time 
zero to 12 hours (AUC0-12) 
• 
Area under the plasma concentration time curve from time 
zero to last measurable plasma concentration (AUC0-t) 
• 
Terminal half-life (t1/2) 
• 
Area under the plasma concentration time curve from time 
zero to infinity (AUC0-∞) 
• 
Predicted plasma clearance 
• 
Apparent volume of distribution of the drug after 
extravascular administration (V/F) 


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• 
Trough concentration at the end of first dosing interval 
(C12) (data permitting) 
In addition for Part B: 
• 
Accumulation ratio, percent fluctuation 
• 
Area under the plasma concentration time curve from time 
zero to the end of last dosing interval (AUC0-tau) 
• 
Average plasma concentration over dosing interval (Cave) 
• 
Minimum observed plasma concentration (Cmin) 
• 
Plasma trough concentration (Ctrough) 
• 
Any other relevant parameters 
Part B: To evaluate the antiviral effects of 
RV521 in infants hospitalised with RSV 
LRTI 
Secondary endpoints related to assessment of antiviral activity 
and efficacy include but are not limited to: 
• 
RSV viral load measured in nasopharyngeal swabs by 
quantitative reverse transcription polymerase chain 
reaction (RT-qPCR) 
• 
RSV viral load measured in nasopharyngeal swabs by 
cell-based infectivity assay (CBIA) 
Part B: Evaluate the effect of RV521 
compared to placebo on the clinical course of 
RSV infection 
• 
Time to resolution of symptoms 
• 
Time to improvement evaluated by reduction in severity 
of symptoms 
• 
Reduction in severity of symptoms by RV521, compared 
to placebo, measured by a composite score over time 
Exploratory Objective 
Exploratory Endpoints 
• 
CCI 
 
 
 
 
 
PART C: Objectives and Endpoints 
Primary Objectives for Part C 
Primary Endpoint 
Evaluate the antiviral effects of RV521, 
compared to placebo, on nasopharyngeal 
shedding of RSV in infants hospitalised with 
RSV LRTI 
• 
Time-weighted average change from Baseline to Day 7 in 
RSV viral load measured in nasopharyngeal swabs by 
RT-qPCR. 
Secondary Objectives for Part C 
Secondary Endpoints 
• 
To evaluate virologic parameters derived 
from the RSV viral load as measured in 
nasopharyngeal swabs 
• 
Virologic parameters derived from the RSV viral load as 
measured in nasal swabs include but are not limited to: 
o 
Change from baseline in viral load (RT-qPCR and 
CBIA) at each time point 
o 
Time to below viral load quantification limit (RT-qPCR 
and CBIA) 
o 
Proportion of subjects with viral load below 
quantification limit (RT-qPCR and CBIA) at each 
timepoint throughout the study 


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• 
CCI 
• 
To evaluate the clinical efficacy of multiple 
oral doses of RV521 in infants hospitalised 
with RSV LRTI 
• 
Evaluate the safety and tolerability of 
RV521 given as a multiple dose regimen 
CCI 
 
• 
Time to resolution in RSV-related symptoms 
• 
Time to improvement of RSV-related symptoms 
• 
Reduction in severity of symptoms by RV521, compared to 
placebo, measured by a composite score over time 
• 
Use of supplemental oxygen, including, but not limited to, 
duration and maximum level of O2 provided 
• 
Time to normalisation of respiratory rate 
• 
Safety of RV521 compared to placebo assessed by 
incidences of AEs, discontinuations due to AEs, SAEs, and 
clinically significant changes in clinical laboratory tests 
CCI 
 
 
 
 
 
 
Study Design: 
The clinical study consists of 3 parts: 
• 
Part A is an open-label, multicentre, single-dose study in infants hospitalised with RSV LRTI 
• 
Part B is a randomised, double-blind, placebo-controlled, multicentre multiple dose study in infants 
hospitalised with RSV LRTI 
• 
Part C is a randomised 1:1:1, double-blind, placebo-controlled, multicentre, multiple-dose study comparing 
two dose levels of RV521 to matching placebo in infants ≥1 months and ≤36 months hospitalised with RSV 
LRTI. 
 
The number of subjects enrolled in Parts A and B of the study will depend on the safety and PK data from the group 
of subjects enrolled in specified cohorts and the subsequent recommendation of the Data Safety Monitoring 
Committee (DSMC). The DSMC will review all available safety and PK data collected from the first 3 subjects and 
subsequent 3 subjects in Cohort 1 and determine the starting dose for subjects in Cohort 2 (either 2 mg/kg or an 
adjusted dose based on Cohort 1 safety and PK data). 
 
The DSMC may recommend a dose adjustment (either a reduction or an escalation) and/or regimen adjustment 
(Part B only) for subsequent subjects because of the observation of an unexpected safety/tolerability profile and/or 
differences between the observed and predicted exposure resulting from a specified dose of RV521. 
 
Part C will evaluate 111 subjects total (37 per treatment arm) aged ≥ 1 month to ≤ 36 months with an aim to have at least 
34 evaluable subjects per treatment group. The primary endpoint will be the time-weighted average change from Baseline 
to Day 7 in RSV viral load measured in nasopharyngeal swabs by RT-qPCR comparing two dose levels of RV521 vs. 
placebo. Secondary endpoints will assess the safety, and efficacy of two dose levels of RV521 vs. placebo. Dose levels in 
Part C will be selected following the analysis of PK data, tolerability and safety from Part B. Two doses (RV521 age 
group specific high dose and RV521 age group specific low dose) will be selected for inclusion in Part C. The high dose 
will be selected for each age group to target approximately 90% of subjects achieving the target trough concentration for 
efficacy (3x EC90), while not exceeding the upper safety limit, based on the paediatric PK model. The low dose will be 
selected such that the target trough level of 3xEC90 is achieved in approximately 75% of the subjects. The high dose 
may be the highest tolerated dose from Part B, or a higher twice daily dose of RV521, depending on the safety, 
tolerability and PK data from Part B. 


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Subjects in Part C will be stratified by age (≥1 to < 6 months of age vs. ≥ 6 months to ≤ 36 months of age) and randomised 
in a 1:1:1 ratio. Both age strata will be enrolled in parallel. To maintain the double-blind, subjects randomised to placebo 
will be allocated to low volume (to match the volume associated with the lowest tested dose of RV521) or the higher 
volume (to match the highest tested dose of RV521). 
 
The DSMC will periodically review the safety and tolerability in Part C in accordance with the DSMC Charter, and may 
make recommendations about study continuance or dose termination. In the event that a higher dose is selected for 
evaluation in Part C than was evaluated in Part B, the safety and PK results of the first 9 subjects in each age stratum (3 
subjects per arm) will be reviewed in an unblinded manner by the DSMC. The primary focus of this DSMC review will be 
on the safety and PK profile of the subjects receiving the new higher dose. In the absence of any safety signals in the first 9 
subjects in each age stratum, the Safety Physician may determine that continued randomisation of additional subjects is 
warranted during the DSMC review period. In the event that there is a safety signal of concern, the Safety Physician will 
make the determination that all randomisation will be halted until the DSMC has completed their review and has 
recommended that further randomisation may continue. An earlier meeting of the DSMC can be convened, as warranted, 
and based on the results of the DSMC review, the DSMC may recommend to the Sponsor that a dose of RV521 be 
terminated. The Sponsor will make the final decision. 
 
Part A (Single dose) 
Part A of the study will be conducted across 2 cohorts and will comprise 2 age groups: 
• 
Cohort 1: subjects ≥ 6 months to ≤ 36 months 
• 
Cohort 2: subjects ≥ 1 month to < 6 months 
The proposed starting doses of RV521 of 2.5 mg/kg for subjects ≥ 6 months to ≤ 36 months of age (Cohort 1) and 
2 mg/kg for subjects ≥ 1 month to < 6 months of age (Cohort 2) are expected to deliver a specified group mean 
exposure (1× EC90 at trough concentration) based on PK modelling and simulation using existing clinical data in 
healthy adult subjects (CCI 
and CCI 
) and nonclinical data. Pharmacokinetic data from groups of 
3 subjects in Cohort 1 and Cohort 2 will be reviewed to identify any differences between the observed and predicted 
exposure resulting from a specified dose of RV521. Safety data will be sent to the DSMC for review prior to any 
dose adjustment. 
 
Enrolment into Part A of the study will commence with the older subjects (Cohort 1). 
 
Any adjustment(s) of dose level that are required within a cohort will occur in a sequential manner. A maximum of 
2 dose adjustments per cohort are planned. Thus, a minimum of 12 subjects (6 per cohort) and a maximum of 
24 subjects (12 per cohort) may be enrolled in Part A. 
 
Part B (Multiple Dose) 
Part B will be conducted across 3 cohorts (Cohorts 3, 4, and 5) comprising the following age groups: 
 
Cohort 3: 
≥ 6 months to ≤ 36 months 
Cohort 4: 
≥ 1 month to < 6 months 
Cohort 5: 
≥ 1 month to < 36 months 
 
After review of the safety and PK data from a specific age group enrolled in Part A, the DSMC will determine the 
dosage and dosing regimen to be used in that age group in Part B, such that the target group mean trough 
concentration is approximately equivalent to 3× EC90, and approve the start of enrolment in that specified age group, 
ie, Cohort 3 can start after Cohort 1 (Part A) has been finalised and Cohort 4 can start after Cohort 2 (Part A) has 
been finalised. It is anticipated that subjects enrolled in Part B of the study will receive RV521 or placebo twice 
daily (BID), 12 hours apart, for a period of 5 consecutive days (total of 10 doses). However, the dosing regimen may 
be adjusted depending on the DSMC recommendations. 
 
Groups of 4 subjects will be randomised to receive RV521 or placebo (3:1) in Cohort 3 and Cohort 4, with 
enrolment occurring in parallel. It is envisioned that data from a group of 4 subjects will be sufficient to confirm the 
dose exposure relationship for RV521 administered according to a multiple dosing regimen and therefore the DSMC 


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will review all available safety and PK data collected from the first group of 4 subjects in each cohort. In order to 
identify the optimum dosage and dosing regimen in each age group, a maximum of 2 dosage/dosing regimen 
adjustments is assumed in either or both of the Cohorts 3 and 4. Subjects ≥ 6 months to ≤ 36 months of age can be 
enrolled in Cohort 5 after the completion of Cohort 3 and subjects ≥ 1 month and < 6 months can be enrolled in 
Cohort 5 after the completion of Cohort 4. Cohort 5 will be opened when either Cohort 3 or 4 is complete. 
Enrolment in Cohort 5 will continue until 24 evaluable subjects have received RV521 or placebo (2:1). The 4 
subjects in the dose group that received the specified dose from each of Cohorts 3 and/or 4 will contribute to this 
overall total. Thus a minimum of 24 subjects and a maximum of 40 subjects (assuming 2 adjustments per age group) 
may be enrolled in Part B. 
 
Part C (Multiple Dose, Parallel Group, Cohort 6) 
Based on the analysis of the safety, PK, and antiviral data following the completion of Part B, Part C will commence to 
confirm the antiviral effects of the two dose levels of RV521 vs. placebo. Part C is a double-blind and placebo- 
controlled study, enrolling 1 cohort (Cohort 6) of up to 111 subjects (≥ 1 month to ≤ 36 months of age). After 
parent/legal guardian informed consent is obtained, and conditional to satisfactory fulfilment of all inclusion criteria 
and none of the exclusion criteria subjects will be randomised in a 1:1:1 ratio to receive RV521 at one of two dose 
levels (RV521 high or low dose) or matching placebo. Subjects will be followed for safety and tolerability, samples 
will be collected for PK levels, and clinical findings will be collected. Nasopharyngeal swabs will be obtained over the 
course of the study period to evaluate viral load, presence of other respiratory pathogens and the CCI 
 
. 
 
Number of Subjects: 
Approximately 175 subjects (24 subjects in Part A, 40 subjects in Part B, and approximately 111 subjects in Part C 
will be evaluated. Eligible subjects ranging in age from ≥ 1 month to ≤ 36 months who are hospitalised because of 
RSV LRTI will be enrolled in the study. It is anticipated that 102 to 126 subjects will receive RV521 (12-24 subjects 
in Part A, 16-28 in Part B, and approximately 74 in Part C), and 45 to 49 subjects will receive placebo (8-12 subjects 
in Part B and approximately 37 in Part C). The actual total number of subjects will be dependent upon the number of 
DSMC-recommended dosage/dosing regimen adjustments in Parts A and B, and whether any doses are dropped from 
Part C following DSMC recommendation. 
Treatment: 
RV521, a potent small molecule inhibitor of RSV fusion protein mediated cell-cell fusion, and of RSV infection, is 
formulated as a dry powder blend of RV521 drug substance with mannitol as excipient. The RV521 dry powder 
blend will be supplied in capsules containing 10, 20, or 50 mg RV521. The placebo capsules will contain mannitol 
and microcrystalline cellulose. The IMP will be dispersed in a defined volume of permitted suspending diluent prior 
to oral administration and dosed on a mg/kg basis. Instructions for opening the capsule(s), and dispersing the 
contents in a fixed volume of suspending diluent prior to administration will be provided in the Pharmacy Manual. 
The proposed starting doses of RV521 for subjects ≥ 6 months to ≤ 36 months and ≥ 1 month to < 6 months of age 
in Part A were calculated from existing clinical and nonclinical data using PK modelling and simulation. A single 
dose of RV521 will be administered in Part A. 
The proposed dosing regimen for Part B is RV521 or placebo administered BID, 12 hours apart, for a period of 5 
consecutive days with a total of 10 doses. However, this is subject to the recommendation of the DSMC. 
In Part C, one of two doses of RV521 or placebo will be administered to subjects according to the dose and regimen 
specified for that age group following completion of Part B/Cohort 5 subjects. 
Investigational medicinal product (IMP) administration should occur within 12 hours of randomisation for all 
subjects across all cohorts, in accordance with their assigned dosage and dosing regimen. The times of completion of 
feeding prior to dosing and commencement of the first feeding after dosing should be recorded in the subject’s 
source notes. 


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Study Duration: 
Part A: Subjects will participate for up to 8 days, and the visit schedule will include: 
Screening Visit (-24 hours to first dose), Dosing Visit 1 (-2 hours pre-dose to 18-24 hours post-dose), Post-dosing 
Visit 2 (48 hours post-dose), and a Telephone Follow-Up (Day 7). 
Part B: Subjects will participate up to 13 days, and the visit schedule will include: 
Screening Visit (-24 hours to first dose), Dosing Visit 1, Dosing Visit 2, Dosing Visit 3, Dosing Visit 4, Dosing 
Visit 5, Follow-Up 40-48 hours Post-Dose 10 (Visit Day 7) and a Telephone Follow-Up (Day 12). 
Part C: Subjects will participate for up to 35 days, and the visit schedule will include: 
Screening (-24 hours to first dose), Dosing Visits 1-5, Follow-Up 40-48 hours Post-Dose 10 (Visit Day 7) and 
additional follow-up on Day 14 and Day 34. Inpatient duration will be determined clinically by the PI or other health 
care provider. Follow-Up days are expected to be on an outpatient basis. 
Study Population: 
Inclusion criteria: 
To be eligible for study entry, subjects must satisfy all of the following criteria at the Screening Visit: 
1. Male or female ≥ 1 month and ≤ 36 months of age. 
2. Weight ≥ 3.5 kg (Parts A, B and C) but ≤ 18 kg (Part C only). 
3. Clinical diagnosis of LRTI defined by 
a. 
Evidence of respiratory infection by one or both of the following with or without fever: 
i. Rhinitis/coryza 
ii. Cough 
AND 
b. Evidence of LRTI by the presence of one or more of the following: 
i. Increased respiratory rate PLUS other evidence of lower respiratory tract disease (eg, laboratory or 
radiographic evidence). 
ii. Increased respiratory effort as evidenced by one or more of the following: 
1. Grunting with expiration 
2. Nasal flaring 
3. Retraction: intercostal or subcostal 
iii. Wheezing: audible or on chest auscultation 
4. A positive RSV diagnostic test (RSV infection confirmed either according to routine site practice [polymerase 
chain reaction or diagnostic quick test], or using a [Sponsor-provided] commercial kit). 
5. Hospitalised because of RSV LRTI (bronchiolitis or bronchopneumonia). 
6. For Part B, symptoms of LRTI must be present for no more than 1 week before the Screening Visit, with the 
first day of symptoms counting as Day 1. 
7. For Part C, symptoms of LRTI must be present for no more than 5 days prior to the Screening Visit, with the 
first day of symptoms counting as Day 1. 
8. Expected to remain in hospital for minimum of 3 days (administration of 6 doses) for Part B only. 
9. The parent(s)/legal guardian(s) of the subject have provided written informed consent for the subject to 
participate. 
10. The parent(s)/legal guardian(s) are able and willing to comply with the study protocol. 
Exclusion criteria: 
Subjects will be excluded from the study if 1 or more of the following criteria are applicable at the Screening Visit: 
1. Premature (gestational age less than 37 weeks) AND <1 year of post-natal age. 
2. Known to have significant comorbidities, including genetic disorders (eg, trisomy 21); cardiopulmonary 
diseases (eg, haemodynamically significant congenital heart disease); significant pulmonary disease (eg, 
bronchopulmonary dysplasia, cystic fibrosis); history of surgery for diaphragmatic hernia; any hereditary or 
acquired metabolic diseases; haematological or other malignancy; or is known to be HIV positive; or has 


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evidence of severe neurologic impairment or developmental delay that would limit the ability to administer 
study drug or evaluate the safety or clinical response to IMP. 
3. 
Current respiratory insufficiency likely to require imminent invasive mechanical ventilation (Part C only). 
4. Malformation of the gastrointestinal tract including unresolved pyloric stenosis, history of necrotising 
enterocolitis, short bowel, or other significant condition that would alter drug absorption or increase the risk of 
diarrhoea. 
5. Any clinically significant electrocardiogram (ECG) abnormalities. 
6. Known to be immunocompromised. 
7. High probability of asthma (per GINA Guidance 2020) with all of the following: 
a. 
Symptoms (cough, wheeze, heavy breathing) for > 10 days during previous upper respiratory infections 
b. History of > 3 episodes per year or severe episodes and /or night worsening 
c. 
Between episodes, child has cough, wheeze, or heavy breathing during play or when laughing 
d. Allergic sensitisation, atopic dermatitis, food allergy, or family history of asthma 
8. Suspected of having a clinically significant bacterial infection as indicated by symptoms or laboratory findings 
consistent with a bacterial infection including but not limited to: elevated white blood cell count, elevated 
C-reactive protein, chest X-ray consistent with bacterial pneumonia, unstable vital signs, hypotension, or 
evidence of shock or poor perfusion. 
9. Has significant oral and/or maxillofacial malformations that would limit the ability to administer IMP. 
10. History of renal failure including renal anomalies likely to be associated with renal insufficiency (eg, clinical 
conditions of renal dysplasia, polycystic renal disease, renal agenesis). 
11. Clinical evidence of hepatic decompensation (eg, hepatic disorder with associated coagulopathy or associated 
encephalopathy) or significantly elevated liver enzymes (aspartate aminotransferase [AST] and/or alanine 
aminotransferase [ALT] >3 × the upper limit of normal). 
12. History of epilepsy or seizures. Subjects with a history of febrile seizures will be permitted to enrol. 
13. Allergy to test medication or constituents. 
14. Known to be concurrently infected with COVID-19 virus (SARS-CoV-2). 
15. Requires any prohibited medication/therapy during the course of the study: 
a. 
Requires inhaled, oral, or IV corticosteroid therapy during the dosing period of the study 
b. Has taken within 21 days before dosing, or requires during the dosing period of the study, any drug that 
could impact on the PK of the investigational product including potent inhibitors or potent and moderate 
inducers of CYP P450s (as listed in Appendix 17.3). 
c. 
Has taken within 21 days before dosing, or requires during the dosing period of the study, any 
prescription medications, over-the-counter (OTC) medications, herbal remedies or dietary supplements 
containing 
or the 
- 
containing products CCI 
 
. 
d. Requires the use of Heliox, leukotriene receptor antagonist (eg, montelukast), exogenous surfactant, or 
mucolytics during the dosing period of the study. 
16. Has received 1 or more doses of palivizumab at any time before Screening or received treatment with antiviral 
therapy for RSV (eg, ribavirin or intravenous [IV] immunoglobulin) within 3 months before the Screening Visit. 
Note: Subjects eligible for palivizumab treatment or other RSV prophylaxis cannot be included in the study. 
17. The subject’s parent(s) or legal guardian(s) is a study team member (ie, has direct involvement in this study or 
other studies under the direction of the Investigator or the study centre) or is a family member of either the 
Investigator or other team members. 
18. Currently participating in any investigational study or at the time of screening, has received an investigational 
product within 3 months or within 5 half-lives of the investigational product, whichever is longer. 
19. Any other reason which in the opinion of the Investigator makes the participant unsuitable for a clinical trial. 
Safety and Statistical Analysis: 
Because of the exploratory nature of Parts A and B of this study, a formal sample size calculation has not been 
performed. Twenty-four evaluable subjects enrolled in Part B and receiving RV521 or placebo (2:1) at the same 


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dose level and according to the same dosing regimen for their specified age range group are expected to be sufficient 
to assess safety, PK and antiviral activity data. 
Estimates for total enrolment into Part C are based on a time-weighted average change in RSV log10 viral load from 
baseline to day 7 in the placebo group of -1.5 log10 vp/ml, with a standard deviation of 1.25. A sample size of 37 per 
group (total 111 subjects randomised 1:1:1; 2 dose levels of RV521 vs placebo) will provide 90% power to detect at 
least 1 log10 decrease in the RV521 groups using a 2-sided significance level of 0.05 and assuming a drop out rate of 
10%. 
Analysis Populations 
All safety data analyses will be based on the Safety Population, defined as all subjects who received a single dose 
(Part A) or any part of any multiple dosing regimen (Parts B and C) of IMP (RV521 or placebo). 
The PK population will be defined as all subjects who received RV521 and have at least 1 post-dose PK 
concentration measured in Parts A, B, or C. 
The mITT Population defined in Part A as all subjects enrolled in the study who have an RT-qPCR viral load 
measurement and/or CBIA, if available, for at least 1 time point including baseline: pre-dose at Dosing Visit 1. In 
Part B the mITT population will include all subjects who received at least one dose of IMP (RV521 or placebo) and 
have a pre-treatment positive RSV nasopharyngeal swab confirmed by the central laboratory and agreed by the 
project team during blind data review. Potential inclusion of subjects who have not completed at least 6 doses of 
IMP will be decided by the project team during the blind data review meeting. Subjects will be analysed as to their 
randomised treatment. The mITT population for Part C will include all subjects who receive at least one dose of the study 
treatments and have a pre-treatment positive RSV confirmed by the central laboratory. 
Evaluation of Safety: For laboratory tests, ECG measures, and vital signs parameters, baseline will be defined as 
the last non-missing result before the first dose of IMP. Results at each visit will be summarised using the statistics: 
n (number of observations), mean, standard deviation (SD), median, minimum and maximum. In addition, change 
from baseline for all safety parameters will also be summarised by post-baseline visits. 
Adverse events will be coded according to the Medical Dictionary for Regulatory Activities (MedDRA) dictionary. 
Summary tables of AEs will be based on TEAEs, defined as events starting, or worsening, after the first dose of 
IMP. Summaries by MedDRA System Organ Class (SOC) and Preferred Term will be provided for all TEAEs, all 
treatment-related TEAEs (with causality assessed as possibly, probably, or definitively related to IMP), all serious 
TEAEs and all TEAEs leading to early discontinuation from the study. Summary tables by maximum severity and 
maximum relationship will be presented. 
Clinical: 
RSV-related signs and symptoms will be summarised by duration (number [%] of subjects analysed, mean, median, 
SD, minimum, maximum). In addition, signs and symptoms will be summarised by highest level of severity by 
treatment group. Also, change from baseline will also be summarised for post-baseline visits. Baseline will be 
defined as the last non-missing result before the first dose of IMP. 
RSV-related signs and symptoms will include, but are not limited to: respiratory rate, heart rate, wheezing 
retractions. 
For Parts B and C: 
Individual RSV symptoms will be summarised by frequency at each time point by treatment assignment. Individual 
RSV-related symptoms will be summarised, for subjects reporting a symptom at study start, for time to resolution 
(mean, median, SD, minimum and maximum times). 
Time to improvement will be calculated for RSV-related signs and symptoms that are classified as moderate or 
severe during the course of the study and will be defined as the time from randomisation until no longer present 
(absent or mild). 
The Overall Time to Improvement will be defined as the time from randomisation to the time that all RSV-related 
signs and symptoms are mild or absent. The overall time to improvement will be summarised for each treatment 
group by mean, median, SD, minimum and maximum and 95% confidence intervals. 
Overall Time to Resolution will be defined as the time of randomisation to the time that all RSV-related signs and 


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symptoms are absent. The overall time to resolution will be summarised for each treatment group by mean, median, 
SD, minimum and maximum and 95% confidence intervals. 
Treatment groups will be compared for differences in overall severity assessed by the composite symptom score on 
each day whilst hospitalised and at follow-up visits. 
Other analyses may include but are not limited to duration of supplemental oxygen, CCI 
 
. 
Pharmacokinetics 
Pharmacokinetic analysis will include listings and summaries of PK concentrations by time point, derived PK 
parameters, and analysis of relationship with dose and body weight. 
Pharmacodynamics analysis will include listing of results of viral load with summary statistics by dose level and 
time point; CCI 
 
. 
Pharmacodynamic parameters, including viral load, DAVG, and any other PD parameters which are derived, will be 
summarised by treatment (dose level). For Parts B and C, comparisons will be made between RV521 and placebo 
using analysis of covariance models. Data will be log transformed as appropriate. CCI 
 
 
 
 
Virology 
For Parts B and C: viral load (determined from nasopharyngeal swabs by RT-qPCR) will be analysed using log 
transformed data. The time-weighted average change in nasopharyngeal RSV viral load will be calculated from 
baseline (Day of Randomisation to Day 7) and compared across treatment groups. 


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4 
TABLE OF CONTENTS 
1 
PROTOCOL APPROVAL SIGNATURES ................................................................... 2 
2 
STUDY PERSONNEL ..................................................................................................... 3 
3 
SYNOPSIS ........................................................................................................................ 5 
4 
TABLE OF CONTENTS ............................................................................................... 14 
4.1 
List of In-Text Tables ...................................................................................................... 18 
4.2 
List of In-Text Figures ..................................................................................................... 18 
5 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ............................... 19 
6 
INTRODUCTION .......................................................................................................... 21 
6.1 
Disease and Indication ..................................................................................................... 21 
6.2 
RV521 Mechanism of Action .......................................................................................... 22 
CCI 
 
 
 
 
CCI 
6.5 
6.6 
 
7 
7.1 
 
 
 
 
7.2 
 
8 
8.1 
8.2 
8.3 
 
 
 
8.4 
 
 
 
 
 
Rationale for the Study .................................................................................................... 26 
Potential Risks and Benefits for Study Participants ......................................................... 26 
STUDY OBJECTIVES .................................................................................................. 27 
PART A and PART B ...................................................................................................... 27 
7.1.1 
Primary Objective ........................................................................................... 27 
7.1.2 
Secondary Objectives ...................................................................................... 27 
7.1.3 
Exploratory Objective ..................................................................................... 28 
PART C: Objectives and Endpoints................................................................................. 28 
INVESTIGATIONAL PLAN ........................................................................................ 29 
Schedule of Assessments ................................................................................................. 29 
Overall Study Design and Plan: Description ................................................................... 46 
Discussion of Study Design ............................................................................................. 49 
8.3.1 
Study Design ................................................................................................... 49 
8.3.2 
Quality Management and Risk Evaluation ..................................................... 54 
Selection of Study Population .......................................................................................... 54 


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8.4.1 
Number of Planned Subjects ........................................................................... 54 
8.4.2 
Inclusion Criteria ............................................................................................ 55 
8.4.3 
Exclusion Criteria ........................................................................................... 56 
8.4.4 
Removal of Subjects from Therapy or Assessments ....................................... 57 
8.4.5 
Interruption of Dosing or Enrolment .............................................................. 58 
8.5 
Investigational Medicinal Products .................................................................................. 59 
8.5.1 
Investigational Medicinal Products Administered .......................................... 59 
8.5.2 
Identity of Investigational Products ................................................................ 61 
8.5.3 
Packaging and Labeling .................................................................................. 62 
8.5.4 
Method of Assigning Subjects to Treatment Groups ...................................... 62 
8.5.5 
Blinding ........................................................................................................... 63 
8.5.6 
Prior and Concomitant Therapy ...................................................................... 63 
8.5.6.1 
Permitted Medication/Therapy ........................................................................ 64 
8.5.6.2 
Prohibited Medication/Therapy ....................................................................... 64 
8.5.6.3 
Rescue Medication .......................................................................................... 64 
8.5.7 
Treatment Compliance .................................................................................... 65 
9 
TIMING OF STUDY PROCEDURES ......................................................................... 66 
9.1 
Pre-treatment .................................................................................................................... 66 
9.1.1 
Screening Visit: Part A, Part B, and Part C (-24 Hours to First Dose) ........... 66 
9.2 
Treatment Period Part A .................................................................................................. 67 
9.2.1 
Dosing (Part A) ............................................................................................... 67 
9.2.2 
Post-Treatment (Part A) .................................................................................. 68 
9.3 
Treatment Period Part B ................................................................................................... 69 
9.3.1 
Dosing Visit 1 (Part B) ................................................................................... 69 
9.3.2 
Dosing Visit 2 (Part B) ................................................................................... 70 
9.3.3 
Dosing Visit 3 (Part B) ................................................................................... 71 
9.3.4 
Dosing Visits 4 and 5 (Part B) ........................................................................ 72 
9.3.5 
Post-Treatment (Part B) .................................................................................. 73 
9.4 
Treatment Part C .............................................................................................................. 73 
9.4.1 
Dosing Visit 1 (Part C) ................................................................................... 74 
9.4.2 
Dosing Visit 2 (Part C) ................................................................................... 76 
9.4.3 
Dosing Visit 3 (Part C) ................................................................................... 77 


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9.4.4 
Dosing Visits 4 and 5 (Part C) ........................................................................ 78 
9.4.5 
Post Treatment (Part C) .................................................................................. 79 
9.5 
Duration of Treatment ...................................................................................................... 80 
10 
PHARMACOKINETICS, EFFICACY AND SAFETY VARIABLES ..................... 82 
10.1 Pharmacokinetics, Efficacy, and Safety Assessments ..................................................... 82 
10.1.1 
Pharmacokinetic Assessments ........................................................................ 82 
10.1.2 
Efficacy Assessments ...................................................................................... 83 
10.1.2.1 
Viral Load Assessments .................................................................................. 83 
10.1.2.2 
Clinical Response Assessments ...................................................................... 83 
10.1.3 
Safety Assessments ......................................................................................... 83 
10.1.3.1 
Adverse Events ............................................................................................... 83 
10.1.3.2 
Serious Adverse Events .................................................................................. 87 
10.1.3.3 
Unexpected Adverse Reactions....................................................................... 88 
10.1.3.4 
Clinical Laboratory Assessments .................................................................... 89 
10.1.3.5 
Clinical Laboratory Evaluation ....................................................................... 89 
10.1.3.6 
Other Laboratory Variables ............................................................................ 90 
10.1.3.7 
Vital Signs ....................................................................................................... 90 
10.1.3.8 
Physical Examination ...................................................................................... 90 
10.1.3.9 
Electrocardiograms .......................................................................................... 90 
10.1.3.10 Other Evaluations ............................................................................................ 91 
10.2 Data Safety Monitoring Committee ................................................................................. 91 
10.3 Appropriateness of Measurements ................................................................................... 91 
11 
STATISTICAL METHODS ......................................................................................... 92 
11.1 Statistical and Analytical Plans ........................................................................................ 92 
11.1.1 
Datasets or Populations Analysed ................................................................... 92 
11.1.2 
Pharmacokinetic Variables ............................................................................. 93 
11.1.3 
Pharmacodynamic Variables ........................................................................... 93 
11.1.4 
CCI 
 ................................................................................. 94 
11.1.5 
Clinical Response Variables ........................................................................... 94 
11.1.6 
Safety Variables .............................................................................................. 95 
11.1.7 
Interim Analyses ............................................................................................. 96 
11.2 Determination of Sample Size ......................................................................................... 96 


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11.3 Protocol Deviations .......................................................................................................... 96 
12 
QUALITY ASSURANCE AND QUALITY CONTROL ........................................... 97 
12.1 Audit and Inspection ........................................................................................................ 97 
12.2 Monitoring........................................................................................................................ 97 
12.3 Data Management and Coding ......................................................................................... 97 
12.4 Quality Management and Risk Evaluation....................................................................... 98 
13 
RECORDS AND SUPPLIES ........................................................................................ 98 
13.1 Drug Accountability ......................................................................................................... 98 
13.2 Financing and Insurance .................................................................................................. 98 
14 
ETHICS .......................................................................................................................... 99 
14.1 Independent Ethics Committee or Institutional Review Board ........................................ 99 
14.2 Regulatory Authorities ..................................................................................................... 99 
14.3 Ethical Conduct of the Study ........................................................................................... 99 
14.4 Informed Consent ............................................................................................................. 99 
14.5 Subject Confidentiality ................................................................................................... 100 
15 
REPORTING AND PUBLICATION, INCLUDING ARCHIVING ....................... 101 
16 
REFERENCES ............................................................................................................. 102 
17 
APPENDICES .............................................................................................................. 104 
17.1 RSV Clinical Scoring System for Infants with RSV Infection ≥ 1 Month of Age 
(Parts A and B) ............................................................................................................... 104 
17.2 ReSVinet Scale for Parental Use ................................................................................... 105 
17.3 List of Drugs Affecting CCI 
 and CCI  ........................................................................ 106 
17.4 RSV-related Signs and Symptoms to be Collected ........................................................ 108 
17.5 Dehydration Evaluation – Part of Physical Examination ............................................... 109 
17.6 ReSVinet Scale for Clinicians ........................................................................................ 110 
17.7 Investigator Signature Page............................................................................................ 111 


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4.1 
List of In-Text Tables 
Table 1. Schedule of Assessments for Part A, Open-Label Part of the Study............................ 30 
Table 2. Schedule of Assessments for Part B, Double-Blind, Placebo-Controlled Part of 
the Study ....................................................................................................................... 32 
Table 3a. Schedule of Assessments for Part C for subjects hospitalised for a minimum of 
3 Dosing Visits ............................................................................................................. 35 
Table 3b. Schedule of Assessments for Part C subjects discharged prior to Dosing Visit 3 ....... 38 
Table 4. Nasopharyngeal Sampling Schedule for the Study ...................................................... 42 
Table 5. PK Sampling Schedule for the Study ........................................................................... 44 
Table 6. Expected Exposure for Infants ≥ 1 to < 6 Months of Age after Administration 
of 2 mg/kg RV521 ........................................................................................................ 51 
Table 7. Expected Exposure for Infants ≥ 6 to ≤ 36 Months of Age after Administration 
of 2.5 mg/kg RV521 ..................................................................................................... 52 
Table 8. Composition of RV521 Capsules ................................................................................. 61 
 
4.2 
List of In-Text Figures 
 
Figure 1. Study Design ................................................................................................................ 50 
Figure 2. Trough Concentrations for Dose 1 and Dose 10 of BID Dosing vs Body 
Weight Adjusted Dose in Infants of Different Age Groups ......................................... 53 


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5 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
 
ADL 
activities of daily living 
AE 
adverse event 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
AUC 
area under the plasma concentration-time curve 
AUC0-12 
area under the plasma concentration-time curve from zero to 12 hours 
AUC0-∞ 
area under the plasma concentration-time curve from zero to infinity 
AUC0-t 
area under the plasma concentration-time curve from zero to the last 
measurable concentration 
AUC0-tau 
area under the plasma concentration-time curve from zero to the end of last 
dosing interval 
bid 
two times per day 
BP 
blood pressure 
C12 
trough concentration at the end of first dosing interval 
Cave 
average plasma concentration over dosing interval 
CBIA 
cell-based infectivity assay 
CL 
plasma clearance 
Cmax 
maximum observed plasma concentration 
Cmin 
minimum observed plasma concentration 
CRF 
case report form 
CTCAE 
Common Terminology Criteria for Adverse Events 
Ctrough 
plasma trough concentration 
DSMC 
Data Safety Monitoring Committee 
EC 
effective concentration 
EC90 
90% of the effective concentration 
ECG 
Electrocardiogram 
eCRF 
electronic case report form 
EDC 
EMA 
electronic data capture 
European Medicines Agency 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
HBP cyclodextrin 
hydroxypropyl-ẞ-cyclodextrin 
HR 
heart rate 
IB 
Investigator’s Brochure 
IC50 
inhibitor concentration that decreases the biotransformation of a substrate 
at a single, specified concentration by 50% 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IEC 
independent ethics committee 
IMP 
investigational medicinal product 
IRB 
institutional review board 
IV 
Intravenous 
LRTI 
lower respiratory tract infection 
MCH 
mean cell haemoglobin 
MedDRA 
Medical Dictionary for Regulatory Activities 
OTC 
over-the-counter 
PCR 
polymerase chain reaction 
PD 
Pharmacodynamics 


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CCI  
PK 
Pharmacokinetics 
PR 
pulse rate 
QTcF 
QT Interval by Fridericia’s Formula 
RR 
respiration rate 
RSI 
reference safety information 
RSV 
respiratory syncytial virus 
RT-qPCR 
reverse transcriptase quantitative polymerase chain reaction 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SpO2 
Pulse Oximeter Oxygen Saturation 
SOC 
system organ class 
SUSAR 
suspected unexpected serious adverse reaction 
t1/2 
terminal half-life 
TEAE 
treatment-emergent adverse event 
tmax 
time to maximum plasma concentration 
V/F 
apparent volume of distribution of the drug after extravascular 
administration 
WHO 
World Health Organisation 


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6 
INTRODUCTION 
 
6.1 
Disease and Indication 
 
Respiratory syncytial virus (RSV), a member of the Pneumoviridae family, is a significant 
pathogen of the very young, the immunocompromised, and the elderly (Simões, 2015). 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). 
Respiratory syncytial virus 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). 
There are 2 major serotypes, A and B, that cause similar disease and although they may co- 
circulate, 1 type usually predominates in alternate years. 
 
By 1 year of age, 60 to 70% of children have been infected with RSV, of whom 2 to 3% will be 
hospitalised. Virtually all children will have been infected by the age of 2 years (Hall, 2009). 
In 2015, RSV was estimated to cause 33.1 million cases of acute respiratory illness in children 
< 5 years of age globally, resulting in 2.7-3.8 million hospital admissions and 48,000 to 
74,500 deaths (Shi, 2017; Scheltema, 2017). The majority of children with RSV infection 
develop upper respiratory tract disease, but 20 to 30% go on to develop bronchiolitis or 
pneumonia. General practitioner visits and hospitalisation due to RSV infection are a major and 
significant burden on health care providers and hospitals during RSV outbreaks (Taylor, 2016). 
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 (DeVincenzo, 2005; El Saleeby, 2011). There is 
evidence to suggest that RSV bronchiolitis may create a long-term risk for the development of 
asthma (Regnier, 2013). 
 
The RSV epidemic is highly predictable year after year. In the northern hemisphere, in general, 
the virus appears in October, the epidemic peaks early in January and ends in April. The virus 
then appears in the Southern hemisphere and causes a similar epidemic during the winter season. 
In the tropics, the virus is present throughout the year (Simões, 2015). Consequently, RSV is a 
worldwide issue. The burden of illness and mortality due to RSV is highest in children in the 
developing world. 
Very limited management options for RSV infection and disease currently exist. There are only 
2 approved therapeutic agents for RSV. The first, ribavirin, a nucleoside analogue has restricted 
clinical use due to limited antiviral potency, inherent toxicity, and teratogenic potential. The 
other approved agent is the prophylactic monoclonal antibody (paluvizimab), which interacts 
with the F glycoprotein of the virus, and has gained widespread use to protect very premature 
babies in developed countries. However, the antibody must be given throughout the winter 
season, and the cost of therapy, about 5000 USD per infant for the winter season, limits wider 
uptake. 
 
RV521 is being developed as a highly potent, selective, orally available agent to treat RSV 
infection and disease. The primary target populations for RV521 are infants and small children, 
the immunocompromised, the elderly, and patients with compromised respiratory (chronic 
obstructive airways disease) or cardiovascular (congestive heart disease) systems. 


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6.2 
RV521 Mechanism of Action 
RV521 is a potent inhibitor of RSV F protein mediated cell-to-cell fusion. The RSV F protein is 
essential for the entry of the virus to the host cell. Cell surface expression of the F protein also 
causes cell-to-cell fusion, leading to the giant syncytia characteristic of RSV infection. 
 
CCI 
 
 
 
 
 


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CCI 
 
CCI 
 
 
CCI 


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CCI 
 
 
 
 
 
 


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CCI 
CCI 


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CCI 
 
 
 
 
 
6.5 
Rationale for the Study 
As described, there remains a large unmet medical need for an effective therapy for RSV 
infection and disease. The RV521 preclinical profile, as well as the safety and tolerability data 
from the first human dosing studies, provide a strong rationale for the clinical development of 
RV521. Study REVC003 is part of the Paediatric Investigational Plan, and is a 3-part, Phase 2 
study in infants hospitalised with RSV lower respiratory tract infection (LRTI) consisting of an 
initial open-label period (Part A, single dose), followed by a randomised, double-blind, placebo- 
controlled Part B (multiple dose), to evaluate the safety, tolerability, pharmacokinetics (PK), and 
antiviral effect of RV521. The safety, tolerability, PK, antiviral and clinical effect of RV521 will 
be further explored in Part C (multiple dose). 
 
6.6 
Potential Risks and Benefits for Study Participants 
Due to its mechanism of action, RV521 is an antiviral agent that targets the RSV F (fusion) 
protein on the surface of the viral envelope and exerts antiviral activity against RSV by 
inhibiting viral entry into host cells and preventing F protein induced cell-cell fusion. In this 
way, F protein inhibition may reduce both viral replication and pathology, reducing the severity 
of the RSV LRTI. In the clinical studies conducted to date, RV521 had a good safety profile. 
Nausea, diarrhoea, abdominal pain, and vomiting occurred in clinical studies of RV521, and are 
considered expected toxicities, clinically. Investigators should use clinical judgement in treating 
subjects with these events. 
 
For more details, please refer to the currently approved version of the IB for RV521. 


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7 
STUDY OBJECTIVES 
 
7.1 
PART A and PART B 
 
7.1.1 Primary Objective 
 
Primary Objective 
Primary Endpoints 
To evaluate the safety and tolerability of 
single (Part A) and multiple (Part B) oral 
doses of RV521 in infants hospitalised with 
RSV LRTI 
Safety and tolerability parameters to be assessed will include, but 
are not limited to: 
• 
AEs, TEAEs, SAEs, and withdrawals due to TEAEs 
• 
Physical examinations 
• 
Vital sign parameters (ie, systolic and diastolic BP, 
temperature, RR, HR, and pulse oximetry), and changes 
from baseline in these parameters at predefined time points 
• 
Laboratory tests (haematology, chemistry, and urinalysis test 
results) and changes from baseline in these parameters, at 
predefined time points 
• 
ECG measurements and changes from baseline in these 
parameters at predefined time points 
 
7.1.2 Secondary Objectives 
 
Secondary Objectives 
Secondary Endpoints 
To characterise the PK of single (Part A) 
and multiple (Part B) oral doses of RV521 
in infants hospitalised with RSV LRTI 
Secondary endpoints related to PK will include but are not limited 
to: 
• 
Time to maximum plasma concentration (tmax) 
• 
Maximum observed plasma concentration(Cmax) 
• 
Area under the plasma concentration time curve from time 
zero to 12 hours (AUC0-12) 
• 
Area under the plasma concentration time curve from time 
zero to last measurable plasma concentration (AUC0-t) 
• 
Terminal half-life (t1/2) 
• 
Area under the plasma concentration time curve from time 
zero to infinity (AUC0-∞) 
• 
Predicted plasma clearance 
• 
Apparent volume of distribution of the drug after 
extravascular administration (V/F) 
• 
Trough concentration at the end of first dosing interval 
(C12) (data permitting) 
In addition for Part B: 
• 
Accumulation ratio, percent fluctuation 
• 
Area under the plasma concentration time curve from time 
zero to the end of last dosing interval (AUC0-tau) 
• 
Average plasma concentration over dosing interval (Cave) 
• 
Minimum observed plasma concentration (Cmin) 
• 
Plasma trough concentration (Ctrough) 
• 
Any other relevant parameters 


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Secondary Objectives 
Secondary Endpoints 
Part B: To evaluate the antiviral effects of 
RV521 in infants hospitalised with RSV 
LRTI 
Secondary endpoints related to assessment of antiviral activity and 
efficacy include but are not limited to: 
• 
RSV viral load measured in nasopharyngeal swabs by 
RT-qPCR 
• 
RSV viral load measured in nasopharyngeal swabs by CBIA 
Part B: Evaluate the effect of RV521 
compared to placebo on the clinical course 
of RSV infection 
• 
Time to resolution of symptoms 
• 
Time to improvement evaluated by reduction in severity of 
symptoms 
• 
Reduction in severity of symptoms by RV521, compared to 
placebo, measured by a composite score over time 
 
7.1.3 
Exploratory Objective 
 
Exploratory Objective 
Exploratory Endpoint 
• 
CCI 
 
 
 
 
 
7.2 
PART C: Objectives and Endpoints 
 
Primary Objectives for Part C 
Primary Endpoint 
• 
Evaluate the antiviral effects of 
RV521, compared to placebo, on 
nasopharyngeal shedding of RSV in 
infants hospitalised with RSV LRTI 
• 
Time-weighted average change from Baseline to Day 7 in RSV 
viral load measured in nasopharyngeal swabs by RT-qPCR. 
Secondary Objectives for Part C 
Secondary Endpoints 
• 
To evaluate virologic parameters derived 
from the RSV viral load as measured in 
nasopharyngeal swabs 
• 
CCI 
 
• Virologic parameters derived from the RSV viral load as measured 
in nasal swabs include but are not limited to: 
o 
Change from baseline in viral load (RT-qPCR and CBIA) at 
each time point 
o 
Time to below viral load quantification limit (RT-qPCR and 
CBIA) 
o 
Proportion of subjects with viral load below quantification 
limit (RT-qPCR and CBIA) at each timepoint throughout the 
study 
• 
CCI 
 


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• 
To evaluate the clinical efficacy of 
multiple oral doses of RV521 in infants 
hospitalised with RSV LRTI 
• 
Evaluate the safety and tolerability of 
RV521 given as a multiple dose 
regimen 
• 
Time to resolution in RSV-related symptoms 
• 
Time to improvement of RSV-related symptoms 
• 
Reduction in severity of symptoms by RV521, compared to 
placebo, measured by a composite score over time 
• 
Use of supplementary oxygen, including, but not limited to, 
duration and maximum level of O2 provided 
• 
Time to normalisation of respiratory rate 
• 
Safety of RV521 compared to placebo assessed by incidences 
of AEs, discontinuations due to AEs, SAEs, and clinically 
significant changes in laboratory tests 
Exploratory Endpoints (Part C) 
CCI 
 
8 
INVESTIGATIONAL PLAN 
 
8.1 
Schedule of Assessments 
 
The schedule of planned study assessments for Part A is shown in Table 1, in Table 2 for Part B, 
and in Table 3a inpatients and Table 3b outpatients for Part C. The nasopharyngeal swab 
sampling schedule is shown in Table 4, and the PK sampling schedule is shown in Table 5. 
Note: For Parts B and C, if the DSMC recommends a regimen adjustment, eg, once-daily dosing 
rather than twice-daily dosing, all study assessments, including nasopharyngeal swab and PK 
sampling schedules will occur as shown in Table 4 and Table 5. In the event of once daily 
dosing, pre and post-dose PK and nasopharyngeal swab time points related to Dose 6 will be 
taken at Dose 3 instead. 


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v. 6.0_31 JAN 2022 
 
Table 1. 
Schedule of Assessments for Part A, Open-Label Part of the Study 
 
Assessment 
Screening 
Treatment Phase 
Post Treatment Phase 
Screening 
Visit 
Dosing Visit 1 
Post-Dosing Visit 2 
Telephone 
Follow- 
Up Visit 
Time Relative to Dose 
-24 h to 
First Dose 
-2 h 
Pre-Dose 
0 h 
Dose 
1-2 h 
Post- 
Dose 
4-5 h 
Post- 
Dose 
6-8 h 
Post- 
Dose 
12 h 
Post- 
Dose 
18-24 h 
Post- 
Dose 
36 h 
Post- 
Dose 
48 h 
Post- 
Dose 
Day 7 
Post- 
Dose 
Written Informed Consenta 
X 
RSV Rapid Diagnostic Test 
X 
Inclusion / Exclusion Criteria 
X 
X 
Demographicsb 
X 
Medical History 
X 
Prior Medication Review 
X 
Physical Examinationc 
X 
X 
X 
X 
Hydration Statusd 
X 
X 
X 
X 
Body Weight / Length / Head 
Circumference 
X 
X 
Vital Signse 
X 
X 
X 
X 
X 
X 
Pulse Oximetry on room airf 
X 
X 
X 
X 
X 
Record Supplemental O2 useg 
X 
X 
X 
X 
X 
12-Lead ECGh 
X 
Xi 
X 
X 
X 
RSV Clinical Scoring Systemj 
X 
X 
X 
X 
Safety Laboratory Tests (Clinical 
Chemistry and Haematology)k 
X 
X 
Urinalysis 
X 
X 
Pharmacokinetics Bloodl 
X 
X 
X 
Xm 
X 
Study Medication Administrationn 
X 
Nasopharyngeal Swabo 
X 
Xp 
X 
Xp 
X 
Concomitant Medication Review 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Events Review 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Footnotes appear on next page. 


REVC003 
Page 31 of 111 
v. 6.0_31 JAN 2022 
 
Abbreviations: ALT = alanine aminotransferase; AST = aspartate aminotransferase; ECG = electrocardiogram; h = hours; IMP = investigational medicinal 
product; PK = pharmacokinetic; RSV = respiratory syncytial virus.Note: All procedures and assessments are presented with the Dosing Visit at which they 
should be conducted. The actual day(s) on which the Dosing Visit falls is dependent upon the time that investigational medicinal product (IMP) is 
administered during Dosing Visit 1. 
a 
Written informed consent includes the consent for participating in Part A of the study and the written informed consent for the optional Sponsor-provided 
commercial RSV test. 
b 
Demographic data to be collected: date of birth, gender, race, and ethnicity. 
c 
Physical examination may also include a symptom-directed examination, general condition, lung auscultation, and respiratory muscles retractions 
(Section 10.1.3.8). 
d 
Refer to Appendix 17.5 for the Dehydration Status Evaluation. 
e 
Vital signs include body temperature, systolic and diastolic blood pressure, respiratory rate, heart rate, and should be conducted before PK and 
nasopharyngeal swab samples for the respective time points are taken. 
f 
Pulse oximetry to be recorded on room air (if deemed safe by PI or health care provider) 
g 
Record supplemental oxygen use 
h 
12-Lead ECG to be performed using the centrally provided ECG machine and before PK and nasopharyngeal swab samples are taken. 
I 
The 12-Lead ECG should only be performed using the centrally provided ECG machine at -2 h Pre-Dose, if the centrally provided ECG machine was not 
used at Screening. 
j 
Refer to Appendix 17.1 for the RSV Clinical Scoring System. 
k 
At Screening, the AST/ALT values should be obtained from the local laboratory. A blood sample will still need to be sent to the Central laboratory. 
l 
The actual day for taking each PK sample is dependent on the time when IMP is administered on Dosing Visit 1 (Day 1) (morning versus afternoon versus 
evening); eg, if the subject received their first dose of IMP at 22:00 on Day 1, the post-dose samples due to be taken at 4-5 h, 6-8 h, 12 h, and 18-24 h would 
be taken on Day 2 from 02:00 to 03:00, 04:00 to 06:00, 10:00, and 16:00 to 22:00, respectively (Table 5). 
m 
The 12 hour PK sampling window is 30 minutes (Table 5). 
n 
The times of the prior feeding and first feeding after dosing should be recorded. 
o 
See Table 4 for nasopharyngeal swab sample schedule. 
p 
Denote optional nasopharyngeal swab samples. 


REVC003 
Page 32 of 111 
v. 6.0_31 JAN 2022 
 
Table 2. 
Schedule of Assessments for Part B, Double-Blind, Placebo-Controlled Part of the Study 
 
Assessment 
Screening 
Treatment Phase 
Post-Treatment Phase 
Screening 
Visit 
Dosing Visit 
1 
Dosing 
Visit 2 
Dosing Visit 
3 
Dosing Visit 
4 
Dosing Visit 
5 
Follow up 
Dose 
1 
Dose 
2 
Dose 
3 
Dose 
4 
Dose 
5 
Dose 
6 
Dose 
7 
Dose 
8 
Dose 
9 
Dose 
10 
Visit Day 7 
TFU 
Time Relative to Dose 
-24 to 
first dose 
-2h 
to 0 
0 h 
+1-2h 
Or 
+4-5h 
Or 
+6-8h 
0 h 
+1-2h 
Or 
+4-5 h 
Or 
+6-8h 
Last 
Dose 
+40-48h 
Post-Dose 10 Day 12 
Written Informed 
Consenta 
X 
RSV Rapid Diagnostic 
Test 
Xr 
Inclusion / Exclusion 
Criteria 
X 
Xs 
Demographicsb 
X 
Medical History 
X 
Prior Medication Review 
X 
Physical Examinationc 
X 
Xs 
X 
Hydration Statusd 
X 
Xs 
X 
X 
X* 
X* 
X 
Body Weight / Length / 
Head Circumference 
X 
X 
Vital Signse 
X 
Xs 
X 
X 
X 
X 
X 
X 
X 
X 
X* 
X* 
X* 
X* 
X 
12-Lead ECGf 
X 
X 
X 
X 
X 
X* 
X* 
X 
RSV Clinical Scoring 
Systemg 
X 
Xs 
X 
X 
X* 
X* 
X 
Record RSV Signs and 
Symptomsh 
X 
Xs 
X 
X 
X 
X 
X 
X* 
X* 
X* 
X* 
X 
Record Supplemental O2 
X 
X 
X 
X 
X 
X 
X* 
X* 
X* 
X* 


REVC003 
Page 33 of 111 
v. 6.0_31 JAN 2022 
 
 
Assessment 
Screening 
Treatment Phase 
Post-Treatment Phase 
Screening 
Visit 
Dosing Visit 
1 
Dosing 
Visit 2 
Dosing Visit 
3 
Dosing Visit 
4 
Dosing Visit 
5 
Follow up 
Dose 
1 
Dose 
2 
Dose 
3 
Dose 
4 
Dose 
5 
Dose 
6 
Dose 
7 
Dose 
8 
Dose 
9 
Dose 
10 
Visit Day 7 
TFU 
Time Relative to Dose 
-24 to 
first dose 
-2h 
to 0 
0 h 
+1-2h 
Or 
+4-5h 
Or 
+6-8h 
0 h 
+1-2h 
Or 
+4-5 h 
Or 
+6-8h 
Last 
Dose 
+40-48h 
Post-Dose 10 Day 12 
Pulse Oximetry on Room 
Air 
X 
X 
X 
X 
X 
X 
X* 
X* 
X* 
X* 
X 
Adapted ReSVinet Scale 
for Parental Usei 
X 
X 
Safety Laboratory Tests 
(Clinical Chemistry and 
Haematology) j 
X 
Xt 
Urinalysis 
X 
Xt 
Randomisation for 
Eligible Subjects 
X 
Pharmacokinetics Blood 
Samplek 
Xl 
Xm 
X 
Xl 
Xm 
X 
Nasopharyngeal Swabn 
X 
X o 
X 
X o 
X 
X 
X*p 
X*o 
X* 
X*o 
X 
Concomitant Medication 
Review 
X 
Xs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Events Review 
X 
Xs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Study Medication 
Administrationq 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Footnotes appear on next page. 


REVC003 
Page 34 of 111 
v. 6.0_31 JAN 2022 
 
Abbreviations: ECG = electrocardiogram; h = hours; PK = pharmacokinetic; RSV = respiratory syncytial virus; TFU = Telephone Follow-up Visit. 
Notes: All procedures and assessments are presented against the Dosing Visit at which they should be conducted. The actual day(s) on which the visit 
falls is dependent upon the time that investigational medicinal product (IMP) is administered during Dosing Visit 1. The Follow-up +40-48 h 
Post-Dose 10 on Visit Day 7 could therefore occur on Study Days 7 or 8, depending on when the subject received his or her first dose of IMP. 
Observations (SpO2, viral signs, inspection of RSV symptoms) should precede any procedures that manipulate the subject (physical examination, 
nasopharyngeal swabs, PK sampling). For the physical examination, listen to the lungs first. In any event, the order should be consistent for all the 
assessment days. 
a Written informed consent includes the consent for participating in Part B of the study and the written informed consent for the optional Sponsor-provided 
commercial RSV test. 
b Demographic data to be collected: date of birth, gender, race, and ethnicity. 
c Physical examination may also include a symptom-directed examination, general condition, lung auscultation, and respiratory muscles retractions 
(Section 10.1.3.8). For days when IMP is administered, physical examination should be conducted before a dose of IMP is administered. 
d Refer to Appendix 17.5 for the Dehydration Status Evaluation. 
e Vital signs include body temperature, systolic and diastolic blood pressure, respiratory rate, heart rate and should be conducted before PK and nasopharyngeal 
swab samples, for the respective time points, are taken. For the days without PK and nasopharyngeal swab samples, vital signs should be taken before a dose 
of IMP is administered. 
f 12-Lead ECG to be performed using the centrally provided ECG machine and before PK and nasopharyngeal swab samples are taken. For days when IMP is 
administered ECG should be performed before a dose of IMP is administered 
g Refer to Appendix 17.1 for the RSV Clinical Scoring System. Note: this assessment is to be done only when subject is hospitalised and at follow-up. 
h Refer to Appendix 17.4 for RSV signs and Symptoms 
i Refer to Appendix 17.2 for the Adapted version of ReSVinet scale for parental use. 
j At Screening, the AST/ALT values should be obtained from the local laboratory. A blood sample will still need to be sent to the Central laboratory. 
k The actual day for taking each PK sample is dependent on the time when IMP is administered on Visit 1 (Day 1) (morning versus afternoon versus evening); 
eg, if the subject received their first dose of IMP at 22:00 on Day 1, the post-dose samples due to be taken at 4-5 h, 6-8 h, 12 h, and 18-24 h would be taken on 
Day 2 from 02:00 to 03:00, 04:00 to 06:00, 10:00, and 16:00 to 22:00, respectively (Table 5). 
l These PK samples will be defined after PK Analysis of Part A. One of those three samples will be requested, the other two will not be required (Table 5). 
m The 12 hour PK sampling window is 30 minutes (Table 5). 
n See Table 4 for nasopharyngeal swab sample schedule. 
o Denote optional nasopharyngeal swab samples. 
p If the subject is discharged from hospital, a nasopharyngeal swab sample should be obtained prior to discharge if the parents/legal guardians are unlikely to 
return for the next visit. Note: this sample is not required if the previous sample was taken less than 12 hours before the subject is discharged (Table 4). 
q The times of the prior feeding and first feeding after dosing should be recorded. IMP should be administered every 12 hours or as dosing regimen 
recommended by the Data Safety Monitoring Committee with a time window of ± 30 minutes. 
r All the screening assessments (except the RSV Rapid Diagnostic Test) should be completed within 24 hours before Dose 1. A positive RSV Rapid Diagnostic 
Test result is required on a sample collected within 48 hours before Dose 1. 
s It is not necessary to repeat the assessment for the -2h to 0h Pre-Dose 1 timepoint, if the assessment was carried out for screening purposes within the 2h Pre- 
Dose 1. However, if the screening assessments were carried out >2 h prior to Dose 1 for screening purposes (i.e. within the first 22 hours of the screening 
window), the assessment must be repeated between -2h to 0h Pre-Dose 1. 
t Allowed time window on the end of treatment safety bloods and urinalysis is +/- 2 days. Should a subject be discharged after Dose 10, the safety blood sample 
should be obtained prior to discharge, particularly if the parents/legal guardians are unlikely to return for the next visit. 
* 
Procedure to be done if subject is in the hospital. 


REVC003 
Page 35 of 111 
v. 6.0_31 JAN 2022 
 
Table 3a.  Schedule of Assessments for Part C for subjects hospitalised for a minimum of 3 Dosing Visits 
 
Assessment 
Screening 
Treatment Phase 
Post-Treatment Phase 
Screening 
Visit 
Dosing 
Visit 1 
Dosing 
Visit 2 
Dosing 
Visit 3 
Dosing 
Visit 4 
Dosing 
Visit 5 
Follow Up 
Dose 
1 
Dose 
2 
Dose 
3 
Dose 
4 
Dose 
5 
Dose 
6 
Dose 
7 
Dose 
8 
Dose 
9 
Dose 
10 
Visit 
Day 7 
Visit Day 
14±1 Day 
Visit Day 
34±1 Day 
Time Relative to 
Dose 
-24 to 
first dose 
-2 h 
to 
0 h 0 h 
+4-5 h 
Post- 
Dosen 
0 h 
+4-5 h 
Post- 
Dosen 
Last 
Dose 
+40-48 h 
Post- 
Dose 10 
Day 14 
Day 34 
Written Informed 
Consenta 
X 
Inclusion / 
Exclusion Criteria 
X 
Xt 
RSV Rapid 
Diagnostic Test 
Xs 
Demographicsb 
X 
Medical History 
X 
Prior Medication 
Review 
X 
Physical 
Examinationc 
X 
Xt 
X 
Hydration Statusd 
X 
Xt 
X 
X 
X* 
X* 
X 
Body Weight / 
Length / Head 
Circumference 
X 
X 
X 
X 
Vital Signse 
X 
Xt 
X 
X 
X 
X 
X 
X 
X 
X* 
X* 
X* 
X* 
X 
X 
X 
12-Lead ECGf 
X 
X 
X 
X 
X 
X* 
X* 
X 
ReSVinet Score for 
Cliniciansg 
X 
Xt 
X 
X 
X* 
X* 
X 
X 
X 
Record RSV Signs 
and Symptomsh 
X 
Xt 
X 
X 
X 
X 
X 
X* 
X* 
X* 
X* 
X 
X 
X 
Record 
Supplemental O2 
X 
X 
X 
X 
X 
X 
X* 
X* 
X* 
X* 


REVC003 
Page 36 of 111 
v. 6.0_31 JAN 2022 
 
 
Assessment 
Screening 
Treatment Phase 
Post-Treatment Phase 
Screening 
Visit 
Dosing 
Visit 1 
Dosing 
Visit 2 
Dosing 
Visit 3 
Dosing 
Visit 4 
Dosing 
Visit 5 
Follow Up 
Dose 
1 
Dose 
2 
Dose 
3 
Dose 
4 
Dose 
5 
Dose 
6 
Dose 
7 
Dose 
8 
Dose 
9 
Dose 
10 
Visit 
Day 7 
Visit Day 
14±1 Day 
Visit Day 
34±1 Day 
Time Relative to 
Dose 
-24 to 
first dose 
-2 h 
to 
0 h 
0 h 
+4-5 h 
Post- 
Dosen 
0 h 
+4-5 h 
Post- 
Dosen 
Last 
Dose 
+40-48 h 
Post- 
Dose 10 
Day 14 
Day 34 
Pulse Oximetry on 
Room Air 
X 
X 
X 
X 
X 
X 
X* 
X* 
X* 
X* 
Adapted ReSVinet 
Scale for Parental 
Usei 
X 
X 
X 
X 
X 
X 
X 
X 
Safety Laboratory 
Tests (Clinical 
Chemistry, and 
Haematology)j 
X 
Xu 
Urinalysis 
X 
Xu 
Randomisation for 
Eligible Subjects 
X 
Pharmacokinetics 
Blood Samplek 
Xl,n 
Xl 
Xl,m 
, 
Xl,m,n 
Xl 
Xl,m 
Nasopharyngeal 
Swabo 
X 
Xp 
X 
Xp 
X 
X 
Xq* 
Xp* 
X* 
Xp* 
X 
X 
X 
Concomitant 
Medication Review 
X 
Xt 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Events 
Review 
X 
Xt 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Study Medication 
Administrationr 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Footnotes appear on next page. 


REVC003 
Page 37 of 111 
v. 6.0_31 JAN 2022 
 
Abbreviations: ECG = electrocardiogram; h = hours; PK = pharmacokinetic; RSV = respiratory syncytial virus. 
Notes: All procedures and assessments are presented against the Dosing Visit at which they should be conducted. The actual day(s) on which the visit 
falls is dependent upon the time that investigational medicinal product (IMP) is administered during Dosing Visit 1. The Follow-up +40–- 48 h 
Post-Dose 10 on Visit Day 7 could therefore occur on Study Day 7 or 8, depending on when the subject received his or her first dose of IMP. 
Observations (SpO2, viral signs, inspection of RSV symptoms) should precede any procedures that manipulate the subject (physical examination, 
nasopharyngeal swabs, PK sampling). For the physical examination, listen to the lungs first. In any event, the order should be consistent for all the 
assessment days. 
a 
Written informed consent includes the consent for participating in Part C of the study and the written informed consent for the optional Sponsor-provided 
commercial RSV test. 
b 
Demographic data to be collected: date of birth, gender, race, and ethnicity. 
c 
Physical examination may also include a symptom-directed examination, general condition, lung auscultation, and respiratory muscles retractions 
(Section 10.1.3.8). For days when IMP is administered, physical examination should be conducted before a dose of IMP is administered. 
d 
Refer to Appendix 17.5 for the Dehydration Status Evaluation. 
e 
Vital signs include body temperature, systolic and diastolic blood pressure, respiratory rate, heart rate and should be conducted before PK and 
nasopharyngeal swab samples, for the respective time points, are taken. For the days without PK and nasopharyngeal swab samples, vital signs should be 
taken before a dose of IMP is administered. 
f 
12-Lead ECG to be performed using the centrally provided ECG machine and before PK and nasopharyngeal swab samples are taken. For days when IMP is 
administered ECG should be performed before a dose of IMP is administered 
g 
Refer to Appendix 17.6 for the ReSVinet score for clinicians. Note: this assessment is to be done only when subject is hospitalised and at follow-up visits. 
h 
Refer to Appendix 17.4 for RSV signs and Symptoms 
i 
Refer to Appendix 17.2 for the Adapted version of ReSVinet scale for parental use. Upon discharge parents/caregivers are to complete at home. 
j 
At Screening, the AST/ALT values should be obtained from the local laboratory. A blood sample will still need to be sent to the Central laboratory. 
k 
The actual day for taking each PK sample is dependent on the time when IMP is administered on Visit 1 (Day 1) (morning versus afternoon versus evening); 
eg, if the subject received their first dose of IMP at 22:00 on Day 1, the post-dose samples due to be taken at 4-5 h, 6-8 h, 12 h and 18-24 h would be taken 
on Day 2 from 02:00 to 03:00, 04:00 to 06:00, 10:00, and 16:00 to 22:00, respectively (Table 5). 
l 
Note: If the PK profile for a dose to be evaluated in Part C was not evaluated in Part B, a total of 6 PK samples will be taken for the first 9 subjects (3 per 
arm) in each age stratum. The DSMC will review the PK data profiles and recommend whether these PK samples are to be taken for subsequently enrolled 
subjects. 
m 
If the PK profile for a dose to be evaluated in Part C was evaluated in Part B, only 3 PK samples will be drawn: Pre-Dose 6, Post Dose 6 sample (+4-5 h), 
and the sample on Visit Day 7. 
n 
The timing of the Post-Dose PK samples and assessments in Part C will be 4-5 h Post-Dose. Please refer to Table 5 for PK sample schedule. 
o 
See Table 4 for nasopharyngeal swab sample schedule. 
p 
Denotes optional nasopharyngeal swab samples. 
q 
If the subject is discharged from hospital, a nasopharyngeal swab sample should be obtained prior to discharge if the parents/legal guardians are unlikely to 
return for the next visit. Note: this sample is not required if the previous sample was taken less than 12 hours before the subject is discharged (Table 4). 
r 
The times of the prior feeding and first feeding after dosing should be recorded. IMP should be administered every 12 hours or as dosing regimen 
recommended by the Data Safety Monitoring Committee with a time window of ± 30 minutes. 
s 
All the screening assessments (except the RSV Rapid Diagnostic Test) should be completed within 24 hours before Dose 1. A positive RSV Rapid 
Diagnostic Test result is required on a sample collected within 48 hours before Dose 1. 
t 
It is not necessary to repeat the assessment for the -2h to 0 h Pre-Dose 1 timepoint, if the assessment was carried out for screening purposes within the 2 h 
Pre-Dose 1. However, if the screening assessments were carried out >2 h prior to Dose 1 for screening purposes (i.e. within the first 22 hours of the 
screening window), the assessment must be repeated between -2h to 0 h Pre-Dose 1. 
u 
Allowed time window on the end of treatment safety bloods and urinalysis is +/- 2 days. Should a subject be discharged after Dose 10, the safety blood 
sample should be obtained prior to discharge.particularly if the parents/legal guardians are unlikely to return for the next visit. 
* 
Procedure to be done if subject is in the hospital. 


REVC003 
Page 38 of 111 
v. 6.0_31 JAN 2022 
 
Table 3b. Schedule of Assessments for Part C subjects discharged prior to Dosing Visit 3 
 
Assessment 
Screening 
Treatment Phase 
Post-Treatment Phase 
Screening 
Visit 
Dosing 
Visit 1 
Dosing 
Visit 2 
Dosing 
Visit 3 
Dosing 
Visit 4 
Dosing 
Visit 5 
Follow Up 
Dose 
1 
Dose 
2 
Dose 
3 
Dose 
4 
Doses 
5 and 6 
Doses 
7 and 8 
Doses 
9 and 10 
Visit Day 
7 
Visit Day 
14±1 Day 
Visit Day 
34±1 Day 
Time Relative to 
Dose 
-24 h 
to 
first dose 
-2 h 
to 
0 h 
0 h 
4-5 h 
Post- 
Dose 
+40-48 h 
Post-Dose 10 
Day 14 
Day 34 
Written Informed 
Consenta 
X 
Inclusion / 
Exclusion Criteria 
X 
Xc 
RSV Rapid 
Diagnostic Test 
Xb 
Demographicsd 
X 
Medical History 
X 
Prior Medication 
Review 
X 
Physical 
Examinatione 
X 
Xc 
X 
Hydration Statusf 
X 
Xc 
Xg 
Xg 
Xg 
Xg 
X 
Body Weight / 
Length / Head 
Circumference 
X 
X 
X 
X 
Vital Signsh 
X 
Xc 
X 
X 
X 
X 
Xi 
Xi 
Xi 
X 
X 
X 
12-Lead ECGj 
X 
X 
X 
(Xk) 
(Xk) 
X 
ReSVinet Score 
for Cliniciansl 
X 
Xc 
X 
Xm 
Xm 
Xm 
X 
X 
X 
Record RSV 
Signs and 
Symptomsn 
X 
Xc 
X 
X 
X 
Xo 
Xo 
Xo 
X 
X 
X 
Record 
Supplemental O2 
X 
X 
X 
X 
X 
X 
X 


REVC003 
Page 39 of 111 
v. 6.0_31 JAN 2022 
 
 
Assessment 
Screening 
Treatment Phase 
Post-Treatment Phase 
Screening 
Visit 
Dosing 
Visit 1 
Dosing 
Visit 2 
Dosing 
Visit 3 
Dosing 
Visit 4 
Dosing 
Visit 5 
Follow Up 
Dose 
1 
Dose 
2 
Dose 
3 
Dose 
4 
Doses 
5 and 6 
Doses 
7 and 8 
Doses 
9 and 10 
Visit Day 
7 
Visit Day 
14±1 Day 
Visit Day 
34±1 Day 
Time Relative to 
Dose 
-24 h 
to 
first dose 
-2 h 
to 
0 h 
0 h 
4-5 h 
Post- 
Dose 
+40-48 h 
Post-Dose 10 
Day 14 
Day 34 
Pulse Oximetry 
on Room Air 
X 
X 
X 
X 
X 
X 
X 
Adapted 
ReSVinet Scale 
for Parental Usep 
X 
X 
X 
X 
X 
X 
X 
X 
Safety Laboratory 
Tests (Clinical 
Chemistry, and 
Haematology)q 
X 
Xr 
Urinalysis 
X 
Xv 
Randomisation for 
Eligible Subjects 
X 
Pharmacokinetics 
Blood Samples 
Xt, 
X 
(Xt,u) 
(Xt,u,v) 
(Xu) 
X 
Nasopharyngeal 
Swab 
X 
Xw 
Xw 
Xw 
X 
X 
X 
X 
X 
X 
Concomitant 
Medication 
Review 
X 
Xc 
X 
X 
X 
Xx 
Xx 
Xx 
Xx 
Xx 
X 
X 
X 
Adverse Events 
Review 
X 
Xc 
X 
X 
X 
Xx 
Xx 
Xx 
Xx 
Xx 
X 
X 
X 
Study Medication 
Administrationy 
X 
X 
X 
X 
X 
X 
X 
Footnotes appear on next page. 


REVC003 
Page 40 of 111 
v. 6.0_31 JAN 2022 
 
Abbreviations: ECG = electrocardiogram; h = hours; PK = pharmacokinetic; RSV = respiratory syncytial virus. 
Notes: This schedule of assessments is for subjects who met the criteria for early discharge prior to Dosing Visit 3. These subjects are being seen as 
outpatients and all the assessments should still be completed. All procedures and assessments are presented against the Dosing Visit at which they 
should be conducted. The actual day(s) on which the visit falls is dependent upon the time that investigational medicinal product (IMP) is administered 
during Dosing Visit 1. The Follow-up +40–- 48 h Post-Dose 10 on Visit Day 7 could therefore occur on Study Day 7 or 8, depending on when the subject 
received his or her first dose of IMP. 
Observations (SpO2, viral signs, inspection of RSV symptoms) should precede any procedures that manipulate the subject (physical examination, 
nasopharyngeal swabs, PK sampling). For the physical examination, listen to the lungs first. In any event, the order should be consistent for all the 
assessment days. 
a 
Written informed consent includes the consent for participating in Part C of the study and the written informed consent for the optional Sponsor-provided 
commercial RSV test. 
b 
All the screening assessments (except the RSV Rapid Diagnostic Test) should be completed within 24 hours before Dose 1. A positive RSV Rapid 
Diagnostic Test result is required on a sample collected within 48 hours before Dose 1. 
c 
It is not necessary to repeat the assessment for the -2h to 0 h Pre-Dose 1 timepoint, if the assessment was carried out for screening purposes within the 2 h 
Pre-Dose 1. However, if the screening assessments were carried out >2 h prior to Dose 1 for screening purposes (i.e. within the first 22 hours of the 
screening window), the assessment must be repeated between -2h to 0 h Pre-Dose 1. 
d 
Demographic data to be collected: date of birth, gender, race, and ethnicity. 
e 
Physical examination may also include a symptom-directed examination, general condition, lung auscultation, and respiratory muscles retractions 
(Section 10.1.3.8). For days when IMP is administered, physical examination should be conducted before a dose of IMP is administered. 
f 
Refer to Appendix 17.5 for the Dehydration Status Evaluation. 
g 
Hydration status post-discharge is to be taken daily at a similar time each day. 
h 
Vital signs include body temperature, systolic and diastolic blood pressure, respiratory rate, heart rate and should be conducted before PK and 
nasopharyngeal swab samples, for the respective time points, are taken. For the days without PK and nasopharyngeal swab samples, vital signs should be 
taken before a dose of IMP is administered. 
i 
Vital signs post-discharge are to be taken daily at a similar time each day and must be taken prior to PK and nasopharyngeal swab sampling 
j 
12-Lead ECG to be performed using the centrally provided ECG machine and before PK and nasopharyngeal swab samples are taken. For days when IMP is 
administered ECG should be performed before a dose of IMP is administered unless a post-dose ECG is scheduled. 
k 
Only one ECG is required at either Dosing Visit 3 or Dosing Visit 4. This ECG should be taken either 4-5 h Post-Dose 6 or 4-5 h Post-Dose 7 to coincide 
with the PK sampling. ECG should be performed prior to the PK sample being collected. 
l 
Refer to Appendix 17.6 for the ReSVinet score for clinicians. 
m 
ReSVinet score post-discharge are to be taken daily at a similar time each day. 
n 
Refer to Appendix 17.4 for RSV Signs and Symptoms 
o 
RSV Signs and Symptoms post-discharge are to be taken daily at a similar time each day. 
p 
Refer to Appendix 17.2 for the Adapted version of ReSVinet scale for parental use. Upon discharge parents/caregivers are to complete at a similar time each 
day at home. 
q 
At Screening, the AST/ALT values should be obtained from the local laboratory. A Screening blood sample will also need to be sent to the Central 
laboratory. 
r 
Allowed time window on the end of treatment safety bloods and urinalysis is +/- 2 days. 


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s  PK samples to be collected Pre-Dose 6 and 4-5 h Post-Dose 6 and 40-48 h Post Dose 10 (Visit Day 7) in all subjects (3 samples). If the Pre- and post-Dose 6 
sampling times are at a time that is unsuitable for the subject to return to the clinic or accept a home visit, then these can be taken Pre-Dose 7 and 4-5 h Post- 
Dose 7 instead. 
An additional 3 samples will be collected in the first 9 subjects in each age stratum, if the dose being evaluated in Part C was not evaluated in Part B (i.e. a 
total of 6 samples will be collected in these 9 subjects). These samples will be taken 4-5 h and 12 h Post-Dose 1 and Pre-Dose 7 (or pre-Dose 8 if the Dose 6 
sampling was conducted relative to Dose 7). The DSMC will review the PK data profiles and recommend whether these PK samples are to be taken for 
subjects enrolled subsequently. Please refer to Table 5 for PK sample schedule. 
The actual day for taking each PK sample is dependent on the time when IMP is administered on Visit 1 (Day 1) (morning versus afternoon versus evening); 
eg, if the subject received their first dose of IMP at 22:00 on Day 1, the post-dose samples due to be taken at 4-5 h, and 12 h would be taken on Day 2 from 
02:00 to 03:00, and 10:00 respectively 
t 
The timing of the Post-Dose PK samples and assessments in Part C will be 4-5 h Post-Dose. 
u 
If the subject is discharged from the hospital and the timing of the Dosing Visit 3 assessments Pre-Dose 6 and Post-Dose 6 fall at a time when it is not 
appropriate for the subject to return to the hospital or accept a home visit, the Pre-Dose 6 and Post-Dose 6 assessments can be moved relative to Dose 7. 
v 
If the PK sampling at Dose 6 is moved relative to Dose 7, then the Pre-Dose 7 PK sample will be moved to Pre-Dose 8. (Note: If the PK sampling is taken 
relative to Dose 6 then the PK sample should be taken Pre-Dose 7.) 
w 
If the subject is discharged from hospital, a nasopharyngeal swab sample should be obtained prior to discharge. Note: this sample is not required if the 
previous sample was taken less than 12 hours before the subject is discharged. See Table 4 for nasopharyngeal swab sample schedule. Samples taken post- 
discharge at Dosing Visits 3, 4 and 5 are to be spaced evenly such that the nasopharyngeal swab samples are taken daily at a similar time each day. For 
instance, the samples should either be taken Pre-Dose 5, Pre-Dose 7 and Pre-Dose 9, OR Pre-Dose 6, Pre-Dose 8 and Pre-Dose 10. 
x 
After discharge the assessment for concomitant medication and Adverse events should be conducted daily during the outpatient visit, whilst the 
parent/caregiver will record in the Patient Booklet their assessment for doses given at home. 
y 
IMP should be administered every 12 hours or as dosing regimen recommended by the Data Safety Monitoring Committee with a time window of ± 30 
minutes. The times of the prior feeding and first feeding after dosing should be recorded. 
( )  Denote samples and assessments that can be taken on either Dosing Visit 


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Table 4. 
Nasopharyngeal Sampling Schedule for the Study 
 
Part 
Dosing 
Visit 1 
Dosing 
Visit 2 
Dosing 
Visit 3 
Dosing 
Visit 4 
Dosing 
Visit 5 
Visit 
Day 7 
Visit 
Day 14 
Visit 
Day 34 
A 
-2 h to 
0 h 
Pre-Dose 
(1 
sample) 
12 h 
Post- Dose 
1 bc 
(optional) 
1 sample 
collected 
24 h Post- 
Dose b 
1 sample 
collected at 
36 h Post- 
Dosebc 
(optional) 
1 sample 
at 48 h 
Post- 
Dose 1b 
NA 
NA 
NA 
NA 
NA 
NA 
NA 
B 
-2 h to 0 h 
Pre-Dose 
(1 
sample) 
12 h 
Post- Dose 
1 (Pre- 
Dose 2)bc 
(optional) 
NA 
NA 
1 sample 
collected 
Pre-Dose 3b. 
Pre-Dose 4c 
sample 
(optional) 
Up to 2 
samples in 
totalb 
1 sample 
collected prior 
to each dose; 
Up to 2 
samples in 
totalab 
1 sample 
collected 
Pre-Dose 7b. 
Pre-Dose 8c 
sample 
(optional) 
Up to 2 
samples in 
total*b 
1 sample 
collected 
Pre-Dose 9b 
Pre-Dose 
10c sample 
(optional). 
Up to 2 
samples in 
total*b 
+40-48 
h Post- 
Dose 
10 
NA 
NA 
C 
-2 h to 0 h 
pre-dose 
(1 
sample) 
12 h Post 
Dose 1 
(pre-dose 
2)bc 
(optional) 
NA 
NA 
1 sample 
collected prior 
to each dose. 
Pre-Dose 4c 
sample 
(optional). 
Up to 2 
samples in 
totalb 
1 sample 
collected prior 
to each dose; 
Up to 2 
samples in 
totalab 
1 sample 
collected 
Pre-Dose 7b. 
Pre-Dose 8c 
sample 
(optional). 
Up to 2 
samples in 
total*b 
1 sample 
collected 
Pre-Dose 9b. 
Pre-Dose 
10c sample 
(optional). 
Up to 2 
samples in 
total*b 
+40-48h 
Post 
Dose 
10 
1 Sample 
1 Sample 
Part C subjects discharged prior to Dosing Visit 3: 
C 
-2 h to 0 h 
pre-dose 
(1 
sample) 
12 h Post 
Dose 1 
(pre-dose 
2)b,c 
(optional) 
NA 
NA 
1 samplea,b 
collected prior 
to either Dose 
3 or 4. 
1 sampleb,d,e 
collected prior 
to either Dose 
5 or 6 
1 sampleb,e 
collected 
prior to 
either Dose 
7 or 8 
1 sampleb,e 
collected 
prior to 
either Dose 
9 or 10 
+40-48h 
Post 
Dose 
10 (1 
sample) 
1 Sample 
1 Sample 
Footnotes appear on next page. 


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Abbreviations: h = hours; IMP = investigational medicinal product; NA = not applicable 
Notes: 
All procedures and assessments are presented against the Dosing Visit at which they should be conducted. The actual day(s) on which the visit falls is 
dependent upon the time that investigational medicinal product (IMP) is administered during Dosing Visit 1. The Follow-up +40-48 h Post-Dose 10 on 
Visit Day 7 could therefore occur on Study Day 7 or 8, depending on when the subject received his or her first dose of IMP. 
a If the subject is discharged from hospital, a nasopharyngeal swab sample should be obtained prior to discharge. Note: This sample is not required if the 
previous sample was taken less than 12 hours before the subject is discharged. 
b Nasopharyngeal swab sampling window is 60 minutes. 
c Pre-dose 2, 4, 8 and 10 are optional nasopharyngeal swab samples in study Part B. 
d If the subject is discharged prior to completion of Dosing Visit 3 it may be necessary to move the Pre-Dose 6 nasopharyngeal swab sample relative to Dose 7 
e Samples taken post-discharge at Dosing Visits 2, 3, 4 and 5 are to be spaced evenly such that the nasopharyngeal swab samples are taken daily at a similar time 
each day. For instance, the samples should either be taken Pre-Dose 3, Pre-Dose 5, Pre-Dose 7 and Pre-Dose 9, OR Pre-Dose 4, Pre-Dose 6, Pre-Dose 8 and 
Pre-Dose 10. 
 
* Procedure to be done if subject is in the hospital. 
CCI 


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Table 5. 
PK Sampling Schedule for the Study 
 
Part 
Treatment Phase 
Post Treatment Phase Total Number of 
Samples 
Dosing 
Visit 1 
Dosing 
Visit 2 
Dosing 
Visit 3 
Dosing 
Visit 4 
Dosing 
Visit 5 
Visit Day 7 
NA 
A: Single 
Dose 
1-2 h, 4-5 h, 
6-8 h, 
12 ha, 18-24 h 
NA 
NA 
NA 
NA 
NA 
5 
B*: Multiple 
Dose 
1-2 h or 4-5 h or 6-8 h 
Post-Dose 1, 
12 ha Post-Dose 1 
(Pre-Dose 2) 
NA 
Pre-Dose 6, 
1-2 h or 4-5 h or 6- 
8 h 
Post-Dose 6. 
12 ha Post-Dose 6 
(Pre-Dose 7) 
NA 
40-48 h Post-Dose 10 
6 
C**: Multiple 
Dose 
4-5 h Post-Dose 1c, 
12 ha Post-Dose 1 
(Pre-Dose 2) 
NA 
Pre-Dose 6bc 
4-5 h 
Post-Dose 6 bc 
12 ha Post-Dose 6 
(Pre-Dose 7) 
NA 
40-48 h Post-Dose 10 b 
3 or 6b 
Part C subjects discharged prior to Dosing Visit 3: 
C**: Multiple 
Dose 
4-5 h Post-Dose 1c, 
12 ha Post-Dose 1 
(Pre-Dose 2) 
NA 
(Pre-Dose 6b,c,d) 
(4-5 h Post-Dose 6 b,c,d) 
(12 ha,d Post-Dose 6/Pre-Dose 7) 
OR 
(Pre-Dose 7b,c,d) 
(4-5 h Post-Dose 7 b,c,d) 
(12 ha,d Post-Dose 7/Pre-Dose 8) 
NA 
40-48 h Post-Dose 10 b 
3 or 6b 
Footnotes appear on next page. 


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Abbreviations: h = hours; IMP = investigational medicinal product; NA = not applicable; PK = pharmacokinetic. 
Notes: All procedures and assessments are presented against the Dosing Visit at which they should be conducted. The actual day(s) on which the visit 
falls is dependent upon the time that investigational medicinal product (IMP) is administered during Dosing Visit 1. The Follow-up +40-48 h 
Post-Dose 10 on Visit Day 7 could therefore occur on Study Day 7 or 8, depending on when the subject received his or her first dose of IMP. 
* For PK Part B: After the review of PK analysis from Part A, it will be decided if the PK sample after the First Dose will be taken 1-2 h, 4-5 h Post Dose 1 or 6- 
8 h Post-Dose 1. The same time point will be taken on Dosing Visit 3 (either 1-2 h, 4-5 h or 6-8 h Post-Dose 6). Based on the Part A PK analysis, it will be 
decided if the Samples planned relative to Dose 6 should stay as planned or shifted relative to Dose 10 with the same time structure. In case the PK samples are 
shifted relative to Dose 10, then an additional PK sample 18-24 h Post-Dose 10 will be taken. 
** For PK Part C: The same PK time point Post-Dose 6 will be taken as in Part B, at 4-5 h Post-Dose 6. 
a 
The 12-hour PK sampling window is 30 minutes. 
b 
If the PK profile for a dose to be evaluated in Part C was evaluated in Part B, only 3 PK samples will be drawn: Pre-Dose 6, 4-5 h Post Dose 6 sample and 
Visit Day 7. If the PK profile was not evaluated in Part B, a total of six PK samples will be drawn as detailed in the table above. 
c 
The timing of the Post-Dose PK samples and assessments in Part C will be 4-5 h Post-Dose. 
d 
If the subject is discharged after completion of Dosing Visit 1 it may be necessary to move the Pre-Dose 6 and 4-5 h Post-Dose 6 PK sampling relative to 
Dose 7. If the PK Tmax sampling is moved relative to Dose 7 then the Pre-Dose 7 PK sample will be moved to Pre-Dose 8 
( ) Denote samples and assessments that can be taken on either Dosing Visit 


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8.2 
Overall Study Design and Plan: Description 
 
The clinical study consists of 3 parts: 
• Part A is an open-label, multicentre, single dose study in infants hospitalised with RSV 
LRTI 
• Part B is a randomised, double-blind, placebo-controlled, multicentre multiple dose study 
in infants hospitalised with RSV LRTI 
• Part C is a randomised 1:1:1, double-blind, placebo-controlled, multicentre, multiple- 
dose study comparing two dose levels of RV521 to matching placebo in infants ≥1 
months and ≤36 months hospitalised with RSV LRTI 
 
The number of subjects enrolled in Parts A and B of the study will depend on the safety and PK 
data from the group of subjects enrolled in specified cohorts and the subsequent recommendation 
of the Data Safety Monitoring Committee (DSMC). The DSMC will review all available safety 
and PK data collected from the first 3 subjects and subsequent 3 subjects in Cohort 1 and 
determine the starting dose for subjects in Cohort 2 (either 2 mg/kg or an adjusted dose based on 
Cohort 1 safety and PK data). The DSMC may recommend a dose adjustment (either a reduction 
or an escalation) and/or regimen adjustment (Part B only) for subsequent subjects because of the 
observation of an unexpected safety/tolerability profile and/or differences between the observed 
and predicted exposure resulting from a specified dose of RV521. 
 
Part A 
Part A of the study will be conducted across 2 cohorts and will comprise 2 age groups: 
• Cohort 1: subjects ≥ 6 months to ≤ 36 months 
• Cohort 2: subjects ≥ 1 month to < 6 months 
 
The proposed starting doses of RV521 of 2.5 mg/kg for subjects ≥ 6 months to ≤ 36 months of 
age (Cohort 1) and 2 mg/kg for subjects ≥ 1 month to < 6 months of age (Cohort 2) are expected 
to deliver a specified group mean exposure (1× EC90 at trough concentration) based on PK 
modelling and simulation using existing clinical data in healthy adult subjects (CCI 
and 
CCI 
) and nonclinical data. Pharmacokinetic data from groups of 3 subjects 
in Cohort 1 and Cohort 2 will be reviewed to identify any differences between the observed and 
predicted exposure resulting from a specified dose of RV521. Safety data will be sent to the 
DSMC for review prior to any dose adjustment. 
 
Enrolment into Part A of the study will commence with the older subjects (Cohort 1). 
Any adjustment(s) of dose level that are required within a cohort will occur in a sequential 
manner. A maximum of 2 dose adjustments per cohort are planned. Thus, a minimum of 
12 subjects (6 per cohort) and a maximum of 24 subjects (12 per cohort) may be enrolled in 
Part A. 


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Part B 
Part B will be conducted across 3 cohorts (Cohorts 3, 4, and 5) comprising the following age 
groups: 
Cohort 3: ≥ 6 months to ≤ 36 months 
Cohort 4: ≥ 1 month to < 6 months 
Cohort 5 
≥ 1 month to ≤ 36 months 
 
After review of the safety and PK data from a specific age group enrolled in Part A, the DSMC 
will determine the dosage and dosing regimen to be used in that age group in Part B, such that 
the target group mean trough concentration is approximately equivalent to 3× EC90, and approve 
the start of enrolment in that specified age group, ie, Cohort 3 can start after Cohort 1 (Part A) 
has been finalised and Cohort 4 can start after Cohort 2 (Part A) has been finalised. It is 
anticipated that subjects enrolled in Part B of the study will receive RV521 or placebo BID, 
12 hours apart, for a period of 5 consecutive days (total of 10 doses). However, the dosing 
regimen may be adjusted depending on the DSMC recommendations. 
 
Groups of 4 subjects will be randomised to receive RV521 or placebo (3:1) in Cohort 3 and 
Cohort 4, with enrolment occurring in parallel. It is envisioned that data from a group of 
4 subjects will be sufficient to confirm the dose exposure relationship for RV521 administered 
according to a multiple dosing regimen and therefore the DSMC will review all available safety 
and PK data collected from the first group of 4 subjects in each cohort. 
In order to identify the optimum dosage and dosing regimen in each age group, a maximum of 
2 dosage/dosing regimen adjustments is assumed in either or both of the Cohorts 3 and 
4. Subjects ≥ 6 months to ≤ 36 months of age can be enrolled in Cohort 5 after the completion of 
Cohort 3 and subjects ≥ 1 month and < 6 months can be enrolled in Cohort 5 after the completion 
of Cohort 4. Cohort 5 will be opened when either Cohort 3 or Cohort 4 is complete. Enrolment in 
Cohort 5 will continue until 24 evaluable subjects have received RV521 or placebo (2:1). The 
4 subjects in the dose group that received the specified dose from each of Cohorts 3 and/or 4 will 
contribute to this overall total. Thus a minimum of 24 subjects and a maximum of 40 subjects 
(assuming 2 adjustments per age group) may be enrolled in Part B. 
 
Part C 
 
Based on the analysis of the safety, PK, and antiviral data following the completion of Part B, 
Part C will commence to confirm the antiviral effects of the two dose levels of RV521 vs. 
placebo. The dose levels will be selected based on the paediatric PK model, and will target 
equivalent RV521 exposure levels between the two age groups (≥ 1 month to < 6 months and ≥ 6 
months to ≤ 36 months). The DSMC will evaluate safety data at intervals specified in the DSMC 
Charter. 
 
Part C will evaluate 111 subjects total (37 per treatment arm) aged ≥ 1 month to ≤ 36 months 
with an aim to have at least 34 evaluable subjects per treatment group. The primary endpoint 
will be the time-weighted average change from Baseline to Day 7 in RSV viral load measured in 
nasopharyngeal swabs by RT-qPCR comparing two dose levels of RV521 vs. placebo. 


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Secondary endpoints will assess the safety, and efficacy of two dose levels of RV521 vs. 
placebo. Dose levels in Part C will be selected following the analysis of PK data, tolerability and 
safety from Part B. Two doses (RV521 age group specific high dose and RV521 age group 
specific low dose) will be selected for inclusion in Part C. The high dose will be selected for 
each age group to target approximately 90% of subjects achieving the target trough concentration 
for efficacy (3x EC90), while not exceeding the upper safety limit, based on the paediatric PK 
model. The low dose will be selected such that the target trough level of 3xEC90 is achieved in 
approximately 75% of the subjects. The high dose may be the highest tolerated dose from Part 
B, or a higher twice daily dose of RV521, depending on the safety, tolerability and PK data from 
Part B. 
 
Subjects in Part C will be stratified by age (≥1 to < 6 months of age vs. ≥ 6 months to 
≤ 36 months of age) and randomised in a 1:1:1 ratio. Both age strata will be enrolled in parallel. 
To maintain the double-blind, subjects randomised to placebo will be allocated to low volume (to 
match the volume associated with the lowest tested dose of RV521) or the higher volume (to 
match the highest tested dose of RV521). 
The DSMC will periodically review the safety, tolerability, and PK in Part C in accordance with 
the DSMC Charter, and may make recommendations about study continuance or dose 
termination. In the event that a higher dose is selected for evaluation in Part C than was 
evaluated in Part B, the safety and PK results of the first 9 subjects in each age stratum 
(3 subjects per arm) will be reviewed in an unblinded manner by the DSMC. The primary focus 
of this DSMC review will be on the safety and PK profile of the subjects receiving the new 
higher dose. In the absence of any safety signals in the first 9 subjects in each age stratum, the 
Safety Physician may determine that continued randomisation of additional subjects is warranted 
during the DSMC review period. In the event that there is a safety signal of concern, the Safety 
Physician will make the determination that all randomisation will be halted until the DSMC has 
completed their review and has recommended that further randomisation may continue. An 
earlier meeting of the DSMC can be convened, as warranted, and based on the results of the 
DSMC review, the DSMC may recommend to the Sponsor that a dose of RV521 be terminated. 
The Sponsor will make the final decision. 
 
Duration of Hospitalisation 
Part A: All study visits should be conducted in the hospital setting, with the exception of the 
Telephone Follow-Up. Day 7 visit following the single dose (subject follow up), if the subject 
has been discharged home, will be by telephone. 
Part B: Subjects should remain in the hospital for at least 3 dosing days, and through the sample 
collection of Dosing Visit 3 to the 12 hours Post-Dose 6 PK sample (pre-Dose 7). Evaluations 
listed at Dosing Visit 4 and Dosing Visit 5 (see Table 2) should be done in the event that the 
subject remains in hospital. The last evaluation will be conducted 40 to 48 hours after the last 
dose of IMP is administered. This may be conducted in hospital, or in the event the subject has 
been discharged, in an outpatient setting. 
Part C: Subjects should ideally remain in the hospital for at least 48 hours post randomisation to 
accommodate taking the first 4 doses of IMP and collection of the assessments scheduled for 
Dosing Visit 1 and Dosing Visit 2. If the subject remains in hospital, the assessments for Dosing 


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Visit 3, Dosing Visit 4 and Dosing Visit 5 should be conducted as specified (see Table 3a). In the 
event that a subject is to be discharged after Dosing Visit 3 and the 12 hours Post-Dose 6 PK 
sample (pre-Dose 7) is required, this sample should be taken prior to discharge. 
If the subject has met the criteria for early discharge prior to Dosing Visit 3 and is being seen as 
an outpatient the required assessments should still be completed and are listed in Section 9.4 and 
Table 3b. In this circumstance upon discharge, the subject should return to the clinic or 
outpatient facility for the required assessments for the remaining Dosing Visits (e.g Dosing 
Visits 2, 3, 4 and 5) (see Table 3b). If this is not possible, an appropriately trained healthcare 
professional (such as home health nurse or equivalent) will conduct home visits. The timing of 
the clinic or home visits should be arranged to ensure that the post-dose ECG is performed and 
the pre- and post-dose PK samples are collected before and after either Dose 6 or Dose 7, 
depending on the time of day of these doses. This is to ensure that these parameters are evaluated 
at steady state. It is envisaged that the follow up evaluations, and Visit Day 7 (40-48 h Post-Dose 
10), Visit Day 14, and Visit Day 35, will be conducted in outpatient clinics, but home visits can 
be conducted if this is not possible. 
 
When a subject is discharged from hospital and IMP will be administered at home (Parts B and 
C), the parent/legal guardian (and/or another caregiver, if required) will be trained in the storage, 
preparation, and administration of IMP at home and will be issued with a Patient Booklet to 
record the relevant details of IMP administration. The parent/legal guardian will be instructed 
how to complete the Patient Booklet accurately and these instructions may be reinforced with 
phone calls during outpatient dosing to parents and/or caregivers. 
8.3 
Discussion of Study Design 
 
8.3.1 Study Design 
This is a multicentre, 3-part study to evaluate safety, tolerability, PK, PD, and antiviral effect of 
single and multiple dosing of RV521 in infants hospitalised due to RSV LRTI. Due to the 
adaptive study design, the number of enrolled subjects may vary depending on the obtained PK 
and safety profiles. 


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Figure 1.  Study Design 
 
 
 
Abbreviation: DSMC = Data Safety Monitoring Committee. 
 
 
The selection of the starting doses was estimated using a population PK approach according to 
the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) 
requirements (FDA CDER/CBER Guidance for Industry page; EMEA/CHMP Guideline page). 
Pharmacokinetic data from healthy adult subjects administered RV521 in clinical studies 
CCI 
 and CCI 
 (Section 6.4) was used to build a population PK model using Phoenix 
NLME software. The model was verified using standard checks, such as Visual Predictive Check 
plots, bootstrap analysis, and goodness of fit plots (EMA, 2007), which compare the predicted 
concentration values to actual observed concentrations as well as show the residual differences 
between predicted and actual concentrations as an assessment of model validity. The terms for 
allometric scaling and maturation factor in an infant population, depending on post-natal age and 
body weight were added to the model to simulate PK profiles and resulting exposure in infants. 
The model was informed with the available demographics covariates to allow the incorporation 
of a non-linear dose effect, formulation and/or food effect, and available body weight and age 
data to support extrapolation to infants. 


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CCI 
The simulated exposure was restricted by the lower bound for efficacy, using the EC90 for RSV 
inhibition, applied to the unbound concentration after the first dose (Dose 1) at the end of the 
dosing interval of 12 hours (Cmin). This equated to a total RV521 concentration of 
(converted from unbound) (Figure 2). 
 
To assess where the upper limit of the exposure may be set, the Cmax and AUCtau for the last dose 
(Dose 10) of the BID dosing regimen in adult subjects dosed at 350 mg of RV521 (Clinical 
Study 
were used as a guideline and are presented in a separate report 
(Syneos Health, 2018). Therefore the upper limit for dose levels will be selected such that the 
peak plasma exposure levels do not exceed the group mean values observed in Clinical Study 
(Cmax of 294 ng/mL) and total exposure, as measured by AUCtau in the same study, 
will not exceed 2500 ng × h/mL. 
The resulting proposed starting doses are 2 mg/kg for infants ≥ 1 to < 6 months of age and 
2.5 mg/kg for infants ≥ 6 to ≤ 36 months of age (Table 6 and Table 7, respectively). 
 
Table 6. 
Expected Exposure for Infants ≥ 1 to < 6 Months of Age after Administration of 
2 mg/kg RV521 
 
Age, 
years 
Boys 
Girls 
Parameter 
Median 
10th 
Percentile 
90th 
Percentile 
Median 
10th 
Percentile 
90th 
Percentile 
Cmin Dose 1 
CCI 
 
 
 
 
 
 
ng/mL 
CCI 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cmax Dose 10 
CCI 
 
 
 
 
 
 
ng/mL 
CCI 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AUCtau Dose 10 
CCI 
 
 
 
 
 
 
h × ng/mL 
CCI 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cmin Dose 10 
CCI 
 
 
 
 
 
 
ng/mL 
CCI 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abbreviations: AUCtau = area under the plasma concentration-time curve from zero to the end of last dosing interval; 
Cmax = maximum observed plasma concentration; Cmin = minimum observed plasma concentration. 
CCI 
CCI 


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Table 7. 
Expected Exposure for Infants ≥ 6 to ≤ 36 Months of Age after Administration 
of 2.5 mg/kg RV521 
 
Age, 
years 
Boys 
Girls 
Parameter 
Median 
10th 
Percentile 
90th 
Percentile 
Median 
10th 
Percentile 
90th 
Percentile 
Cmin Dose 1 
CCI 
 
 
 
 
 
 
ng/mL 
CCI 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cmax Dose 10 
CCI 
 
 
 
 
 
 
ng/mL 
CCI 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AUCtau Dose 10 
CCI 
 
 
 
 
 
 
h × ng/mL 
CCI 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cmin Dose 10 
CCI 
 
 
 
 
 
 
ng/mL 
CCI 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abbreviations: AUCtau = area under the plasma concentration-time curve from zero to the end of last dosing interval; 
Cmax = maximum observed plasma concentration; Cmin = minimum observed plasma concentration. 


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Figure 2. Trough Concentrations for Dose 1 and Dose 10 of BID Dosing vs Body Weight 
Adjusted Dose in Infants of Different Age Groups 
For the first administration of RV521 in infant subjects, an initial single-dose design is 
considered appropriate to assess the safety profile of the drug in a way that minimises subject 
risk. Furthermore, the planned doses are expected to produce quantifiable RV521 concentrations 
that will support the refinement of the population PK model. Three subjects in the older age 
group will initially receive a single dose of RV521. Following review of the PK data, a second 
group of 3 subjects in the older age group will receive a single dose of RV521 either at the same 
dose level or at an adjusted dose based on the PK data. The DSMC will review all available 
safety and PK data collected from the first 3 subjects and subsequent 3 subjects in Cohort 1 and 
determine the starting dose for subjects in Cohort 2 (either 2 mg/kg or an adjusted dose based on 
Cohort 1 safety and PK data). Pharmacokinetic data from 3 subjects in Cohort 1 and Cohort 2 
will be reviewed to identify any differences between the observed and predicted exposure 
resulting from a specified dose of RV521. The data will be used for verification and refinement 
of the population PK model currently based on the extrapolation of adult data to the paediatric 
population. The resulting refined population PK model, in addition to the safety data, will guide 
further dosing decisions. 
 
The actual number of subjects enrolled in Parts A and B of the study is dependent upon the 
recommendation of the DSMC, who will review safety and PK data from subjects enrolled in the 
CCI 
CCI 


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specified cohorts (Section 8.2). The DSMC may recommend a dose adjustment (either a 
reduction or an escalation, Part A and Part B) and/or a regimen adjustment (Part B only) for 
subsequent subjects due to the observation of an unexpected safety/tolerability profile and/or 
differences between the observed and predicted exposure resulting from a specified dose of 
RV521. 
 
This study provides an opportunity to explore CCI 
 in a number of subjects 
considered sufficient to adequately determine dose levels that are safe and pharmacologically 
active, thereby informing the selection of doses and dosing regimens to be evaluated in future 
studies. 
In Part B and Part C of the study, the double-blind placebo-controlled design ensures that 
Investigators and the subject’s parent(s)/legal guardian(s) will be blinded to whether the subject 
receives RV521 (active drug) or placebo, so as to minimise any bias when the safety and 
tolerability assessments are performed. Furthermore, limited numbers of placebo subjects are 
included in the study to allow for a more robust interpretation of the data. 
 
8.3.2 Quality Management and Risk Evaluation 
This protocol has been evaluated to identify those processes and data that are critical to assure 
human subject protection and the reliability of study results. 
Predefined quality tolerance limits have been established and documented in the functional 
plans, which take into consideration the medical and statistical characteristics of the variables as 
well as the statistical design of the study, thereby identifying systematic issues that could impact 
subject safety or data integrity. Detection of deviations from the predefined quality tolerance 
limits will trigger an evaluation to determine if action is needed. Any important deviations from 
the predefined quality tolerance limits and remedial actions taken will be described in the clinical 
study report. 
 
Risk control measures will be periodically reviewed to ascertain whether the implemented 
quality management activities remain effective and relevant, taking into account emerging 
knowledge and experience. 
 
8.4 
Selection of Study Population 
 
8.4.1 Number of Planned Subjects 
Approximately 175 subjects (24 subjects in Part A, 40 subjects in Part B, and approximately 
111 subjects in Part C) will be evaluated. Eligible subjects ranging in age from ≥ 1 month to 
≤ 36 months who are hospitalised because of RSV LRTI will be enrolled in the study. It is 
anticipated that 102 to 126 subjects will receive RV521 (12 to 24 subjects in Part A, 16 to 28 in 
Part B, and approximately 74 in Part C), and 45 to 49 subjects will receive placebo (8 to 
12 subjects in Part B and approximately 37 in Part C). The total number of subjects to finally be 
enrolled will depend on the number of DSMC-recommended dosage/dosing regimen adjustments 
in Parts A and B and whether the DSMC recommend dropping any doses from Part C following 
their review. 


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The final number of subjects enrolled in Part C will be dependent upon the number of evaluable 
subjects and may include any eligible subjects who are in the final stages of screening when the 
target of 110 enrolled subjects is attained. 
 
8.4.2 Inclusion Criteria 
 
To be eligible for study entry subjects must satisfy all of the following criteria at the Screening 
Visit: 
1. Male or female ≥ 1 month and ≤ 36 months of age. 
2. Weigh ≥ 3.5 kg (Parts A, B, and C) but ≤ 18 kg (Part C only). 
3. Clinical diagnosis of LRTI defined by 
a. Evidence of respiratory infection by one or both of the following with or without fever 
i. Rhinitis/coryza 
ii. Cough 
AND 
b. Evidence of LRTI by the presence of one or more of the following: 
i. Increased respiratory rate PLUS other evidence of lower respiratory tract 
disease (eg, laboratory or radiographic evidence) 
ii. Increased respiratory effort as evidenced by one or more of the following: 
1. Grunting with expiration 
2. Nasal flaring 
3. Retraction: intercostal or subcostal 
iii. Wheezing: audible or on chest auscultation 
4. A positive RSV diagnostic test (RSV infection confirmed either according to routine site 
practice [polymerase chain reaction or diagnostic quick test], or using a [Sponsor-provided] 
commercial kit). 
5. Hospitalised because of RSV LRTI (bronchiolitis or bronchopneumonia). 
6. For Part B, symptoms of LRTI must be present for no more than 1 week before the Screening 
Visit, with the first day of symptoms counting as Day 1. 
7. For Part C, symptoms of LRTI must be present for no more than 5 days prior to Screening 
Visit, with the first day of symptoms counting as Day 1. 
8. Expected to remain in the hospital for minimum of 3 days (administration of 6 doses) for 
Part B only. 
9. The parent(s)/legal guardian(s) of the subject have provided written informed consent for the 
subject to participate. 


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10. The parent(s)/legal guardian(s) are able and willing to comply with the study protocol. 
 
8.4.3 Exclusion Criteria 
 
Subjects will be excluded from the study if 1 or more of the following criteria are applicable at 
the Screening Visit: 
Premature (gestational age less than 37 weeks) AND < 1 year of post-natal age. 
Known to have significant comorbidities, including genetic disorders (eg, trisomy 21); 
cardiopulmonary diseases (eg, haemodynamically significant congenital heart disease); 
significant pulmonary disease (eg, bronchopulmonary dysplasia, cystic fibrosis); history of 
surgery for diaphragmatic hernia; any hereditary or acquired metabolic diseases, 
haematological or other malignancy; or is known to be HIV positive; or has evidence of 
severe neurologic impairment or developmental delay that would limit the ability to 
administer study drug or evaluate the safety or clinical response to IMP. 
Current respiratory insufficiency likely to require imminent invasive mechanical ventilation 
(Part C only). 
Malformation of the gastrointestinal tract including unresolved pyloric stenosis, history of 
necrotising enterocolitis, short bowel, or other significant condition that would alter drug 
absorption or increase the risk of diarrhoea. 
Any clinically significant electrocardiogram (ECG) abnormalities. 
Known to be immunocompromised. 
High probability of asthma (per GINA Guidance 2020) with all of the following: 
a. Symptoms (cough, wheeze, heavy breathing) for > 10 days during previous upper 
respiratory infections 
b. History of > 3 episodes per year or severe episodes and/or night worsening 
c. Between episodes, child has cough, wheeze, or heavy breathing during play or when 
laughing 
d. Allergic sensitisation, atopic dermatitis, food allergy, or family history of asthma 
Suspected of having a clinically significant bacterial infection, as indicated by symptoms or 
laboratory findings consistent with a bacterial infection, including but not limited to: elevated 
white blood cell count, elevated C-reactive protein, chest X-ray consistent with bacterial 
pneumonia, unstable vital signs, hypotension, or evidence of shock or poor perfusion. 
Has significant oral and/or maxillofacial malformations that would limit the ability to 
administer IMP. 
History of renal failure including renal anomalies likely to be associated with renal 
insufficiency (eg, clinical conditions of renal dysplasia, polycystic renal disease, renal 
agenesis). 
Clinical evidence of hepatic decompensation (eg, hepatic disorder with associated 
coagulopathy or associated encephalopathy) or significantly elevated liver enzymes 


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(aspartate aminotransferase [AST] and/or alanine aminotransferase [ALT] > 3 × the upper 
limit of normal). 
History of epilepsy or seizures. Subjects with a history of febrile seizures will be permitted 
to enrol. 
Allergy to test medication or constituents. 
Known to be concurrently infected with COVID-19 virus (SARS-CoV-2). 
Requires any prohibited medication/therapy during the course of the study: 
a. Requires inhaled, oral, or IV corticosteroids therapy during the dosing period of the 
study. 
b. Has taken within 21 days before dosing, or requires during the dosing period of the 
study, any drug that could impact on the PK of the investigational product including 
potent inhibitors or potent and moderate inducers of CYP P450s (as listed in 
Appendix 17.3). 
c. Has taken within 21 days before dosing, or requires during the dosing period of the 
study, any prescription medications, over-the-counter (OTC) medications, herbal 
remedies or dietary supplements containing CCI 
 or the consumption of 
CCI 
-containing products CCI 
 
. 
d. Requires the use of Heliox, leukotriene receptor antagonist (eg, montelukast), 
exogenous surfactant, or mucolytics during the dosing period of the study. 
Has received 1 or more doses of palivizumab at any time before Screening or received 
treatment with antiviral therapy for RSV (eg, ribavirin or intravenous [IV] immunoglobulin) 
within 3 months before the Screening Visit. Note: Subjects eligible for palivizumab 
treatment or other RSV prophylaxis cannot be included in the study. 
The subject’s parent(s) or legal guardian(s) is a study team member (ie, has direct 
involvement in this study or other studies under the direction of the Investigator or the study 
centre) or is a family member of either the Investigator or other team members. 
Currently participating in any investigational study or at the time of screening, has received 
an investigational product within 3 months or within 5 half-lives of the investigational product, 
whichever is longer. 
Any other reason which in the opinion of the Investigator makes the participant unsuitable 
for a clinical trial. 
8.4.4 Removal of Subjects from Therapy or Assessments 
 
Subjects may be withdrawn from the study for any of the following reasons: 
• Parent/legal guardian request 
• Use of prohibited concomitant medication/therapy 


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• Non-compliance with the protocol 
• Lost to follow-up 
• Occurrence of AEs that are not compatible with the continuation of the subject in the 
study, in the Investigator’s opinion, or that make it unacceptable to the subject’s 
parent/legal guardian for them to continue 
• Investigator request 
• Intercurrent illness 
• Sponsor request 
• Becoming critically ill with respiratory insufficiency leading to the requirement for 
mechanical ventilation/positive airway pressure (PAP)/high-flow oxygen 
• Randomisation code broken prematurely (Parts B and C) 
Parents/legal guardians are free to withdraw their children from the study at any time without 
providing reason(s) for withdrawal and without prejudice for receiving further treatment. The 
reason(s) for withdrawal will be documented in the case report form (CRF). Parents/legal 
guardians who choose to withdraw their child from the study will be encouraged to allow their 
child to complete the same final evaluations as subjects completing the study according to the 
protocol, particularly safety evaluations. 
All reasonable efforts should be made to contact the parent/legal guardian of a subject who is lost 
to follow-up. These efforts must be documented in the subject’s file. 
8.4.5 Interruption of Dosing or Enrolment 
 
Parts A, B and C 
 
• The study will be halted if RV521 systemic exposures observed in an individual subject 
at a dose level, or projected for a subsequent dose level, which are equal or exceed those 
values observed in Clinical Trial Study CCI 
: Cmax of 294 ng/mL and total 
exposure AUCtau of 2500 ng.h./mL. 
 
If this dosing stopping criterion is fulfilled, further dosing at the assessed dose level or higher 
dose level will be halted. Restart of dosing will only be possible if agreed by the DSMC (and 
after local regulatory authority approval, if required). 
 
Parts A and B 
 
Adverse events, singularly or cumulatively, may interrupt further dosing or enrolment until an 
evaluation can be made and a determination made as to the safety of proceeding. The following 
events will result in such an interruption, pending an evaluation by the DSMC. 
• Any death of a subject during participation in the study 
• An SAE deemed related to IMP by the Investigator 


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• Two or more SAEs of a similar type irrespective of attributability by the Investigator(s) 
• Any accumulation of AEs of Grade 3 or higher, including laboratory abnormalities that, 
in the opinion of the DSMC, Medical Monitor, or ReViral Medical Expert, represent an 
unacceptable risk to subjects enrolled in the trial. 
 
Part C: 
The study will be paused immediately and a DSMC meeting will be convened to review the 
available safety data if either of the following criteria are met: 
• At any point in the study, two or more subjects experience the same or a similar SAE that 
is rated by the Investigator as possibly, probably, or definitely related to RV521 
• At any point in the study, two or more subjects experience the same or a similar AE that 
is Grade 3 or higher using the CTCAE scale, including laboratory abnormalities that, in 
the opinion of the DSMC, Medical Monitor, or ReViral Medical Expert, represent an 
unacceptable risk to subjects enrolled in the trial. 
If any of the above stopping/pausing criteria are fulfilled in any study part, restart of dosing will 
only be possible if agreed by the DSMC (and after local regulatory authority approval, if 
required). 
Should a clear non-IMP cause for any of the above be identified, or if the subjects(s) are not 
receiving RV521 (ie, in the placebo group), the study may continue. 
If the study is terminated, the Investigators will be informed of the reason for study termination. 
Unless the study is stopped in accordance with the stopping guidelines, a subject enrolled in 
Part A who is withdrawn from the study before they have been administered IMP will be 
replaced. In addition, subjects enrolled in Part A will be replaced if emesis occurs within 
30 minutes post-dosing, although these subjects should remain in the study such that all planned 
study assessments can be conducted. In Part A subjects may also be replaced if they do not ingest 
all of the administered dose. In Part B, subjects will be replaced if emesis occurs within 
30 minutes of administration of Dose 6 (or Dose 3 if dosing is according to a once-daily 
regimen). These subjects should remain in the study such that all planned study assessments can 
be conducted. In Part B and Part C, a subject may be replaced if they have not been administered 
IMP or have not ingested/completed at least 6 doses of IMP (or 3 doses by once-daily regimen). 
8.5 
Investigational Medicinal Products 
 
8.5.1 Investigational Medicinal Products Administered 
Administration of IMP should occur within 12 hours of randomisation for all subjects across all 
cohorts, in accordance with their assigned dosage and dosing regimen. 
The times of completion of feeding prior to dosing and commencement of the first feeding after 
dosing should be recorded in the subject’s source notes. 
IMP administration will be by oral route, either via syringe or nasogastric tube. 


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Part A: 
A single oral dose of RV521will be administered in Part A. The proposed starting doses 
are: 2.5 mg/kg for subjects in Cohort 1 (≥ 6 months to ≤ 36 months of age) and 2 mg/kg for 
subjects in Cohort 2 (≥ 1 month to < 6 months of age). These dose levels are anticipated to 
achieve a target exposure equivalent to 1× EC90 at trough concentration in each age group. A 
maximum of 2 dose adjustments will be allowed for each cohort. 
 
Part B: 
Part B will be conducted across 3 cohorts (Cohorts 3, 4, and 5) comprising the following age 
groups: 
Cohort 3: ≥ 6 months to ≤ 36 months 
Cohort 4: ≥ 1 month to < 6 months 
Cohort 5: ≥ 1 month to ≤ 36 months 
 
Following review of the safety and PK data from a specific age group enrolled in Part A, the 
DSMC will determine the dosage and dosing regimen to be used in that age group in Part B, such 
that the target group mean trough concentration is approximately equivalent to 3× EC90, and 
approve the start of enrolment in that specified age group, ie, Cohort 3 can start after Cohort 1 
(Part A) has been finalised and Cohort 4 can start after Cohort 2 (Part A) has been finalised. It is 
anticipated that subjects enrolled in Part B of the study will receive RV521 or placebo BID, 
12 hours apart, for a period of 5 consecutive days (total of 10 doses). However, the dosing 
regimen may be adjusted depending on the DSMC recommendations. 
 
Groups of 4 subjects will be randomised to receive RV521 or placebo (3:1) in Cohort 3 and 
Cohort 4, with enrolment occurring in parallel. It is envisioned that data from a group of 
4 subjects will be sufficient to confirm the dose exposure relationship for RV521 administered 
according to a multiple dosing regimen and therefore the DSMC will review all available safety 
and PK data collected from the first group of 4 subjects in each cohort. In order to identify the 
optimum dosage and dosing regimen in each age group, a maximum of 2 dosage/dosing regimen 
adjustments is assumed in either or both of the Cohorts 3 and 4. Subjects ≥ 6 months to 
≤ 36 months of age can be enrolled in Cohort 5 after the completion of Cohort 3 and subjects 
≥ 1 month and < 6 months can be enrolled in Cohort 5 after the completion of Cohort 4. Cohort 5 
will be opened when either Cohort 3 or Cohort 4 is complete. Enrolment in Cohort 5 will 
continue until 24 evaluable subjects have received RV521 or placebo (2:1). The 4 subjects in the 
dose group that received the specified dose from each of Cohorts 3 and/or 4 will contribute to 
this overall total. Thus a minimum of 24 subjects and a maximum of 40 subjects (assuming 
2 adjustments per age group) may be enrolled in Part B. 
 
Part C: 
Part C will be conducted in a single cohort (Cohorts 6) in subjects ≥ 1 month to < 36 months of 
age. Subjects will be stratified by age and randomised 1:1:1 to receive one of two dose levels of 
RV521 or placebo, according to the dose and regimen specified for their age group following 


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completion of Part B (Cohort 5 subjects) and review of safety/tolerability and pharmacokinetic 
results from Part B by the DSMC and other selected local regulatory authorities, as required. 
 
8.5.2 Identity of Investigational Products 
RV521, a potent small molecule inhibitor of RSV fusion protein mediated cell-cell fusion, and of 
RSV infection, is formulated as a dry powder blend of RV521 drug substance with mannitol as 
excipient. The matching placebo is formulated as a dry blend of mannitol and microcrystalline 
cellulose. The dry blends are filled into hydroxypropyl methylcellulose (hypromellose) capsules. 
The RV521 dry powder blend is supplied in 10 mg, 20 mg, and 50 mg RV521 dose strength 
capsules, expressed as the free base. The composition of the products is stated in Table 8. 
Table 8. 
Composition of RV521 Capsules 
 
Ingredient 
RV521 Capsules 
10 mg 
RV521 Capsules 
20 mg 
RV521 Capsules 
50 mg 
Function 
Grade 
%w/w 
mg/unit 
%w/w 
mg/unit 
%w/w 
mg/unit 
RV521 drug 
substance1 
6.68 
10.82 
14.72 
21.64 
15.24 
54.10 
Active 
substance 
In-house 
Mannitol 
93.32 
151.18 
85.28 
125.36 
84.76 
300.80 
Diluent, taste 
agent 
Ph. Eur. / USP / 
JP 
TOTAL 
100 
162.0 
100 
147.0 
100 
354.9 
- 
- 
White, 
opaque, 
size 3 
HPMC 
capsule 
- 
1 per 
dosage 
unit 
- 
1 per 
dosage 
unit 
- 
- 
Encapsulation 
of powder for 
dispersion 
Manufacturer’s 
specification2 
White, 
opaque, size 
0 HPMC 
capsule 
- 
- 
- 
- 
- 
1 per 
dosage 
unit 
Encapsulation 
of powder for 
dispersion 
Manufacturer’s 
specification2 
Abbreviations: HPMC = hydroxypropylmethylcellulose, Ph. Eur. = European Pharmacopoeia, USP = United States Pharmacopeia, 
Ph. JP. = Japanese Pharmacopoeia. 
Notes: 
1. 
RV521 drug substance is the hydrochloride salt. The drug product strength is expressed in terms of the free base active 
moiety. 1.082 g of the hydrochloride salt of RV521 is equivalent to 1.0 g of RV521 free base. 
2. 
HPMC capsules consist of hypromellose of European Commission Regulation (EU) 231/2012, United States 21 Code of 
Federal Regulations, European Pharmacopoeia (Ph. Eur.), Japanese Pharmacopeia (JP), United States Pharmacopeia 
(USP)/National Formulary (NF) grade as the structural component and titanium dioxide of EU 231/2012, Ph. Eur., JP, 
USP/NF grade as an opacifier. 
 
The placebo capsules contain mannitol (85% w/w) and microcrystalline cellulose (15% w/w) of 
European Pharmacopoeia/United States Pharmacopeia/Japanese Pharmacopeia grade, with 
overall fill weights for the capsules of 159 mg for the placebo to match 10 mg and 20 mg 
capsules, and 396 mg for the placebo to match 50 mg capsules. 
Capsule shells are white, opaque hydroxypropyl methylcellulose, size 3 for the 10 mg and 20 mg 
strengths (and matching placebo) and size 0 for the 50 mg strength (and matching placebo). 


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For the preparation of the dose, the capsules must be opened, and their contents dispersed in a 
defined volume of permitted suspending diluent prior to oral administration on a mg/kg basis; the 
capsule shells must not be dispersed into the suspending diluent. Regardless of the suspending 
diluent to be used for preparing the dose for oral administration, the same process for preparation will 
be followed. Different dose levels will be attained by using the appropriate combination of 
capsule strengths, dispersing the contents of the capsules in the correct volume of suspending 
diluent, then administering the required volume of the resultant dispersion according to the 
prescribed dose required. Instructions for opening the capsule(s), and dispersing the contents in a 
fixed volume of suspending diluent prior to administration will be provided in the Pharmacy 
Manual. Guidance on the permitted suspending diluents will be provided in the Pharmacy Manual. 
 
The IMP will be provided as unblinded kits (RV521) for Part A and blinded kits (RV521 or 
placebo in accordance with the randomisation schedule) for Parts B and C. A subject will be 
administered the volume required for the age-range specified dose. In Parts B and C, depending 
on the weight of the subject, multiple kits of IMP might be assigned to the same subject. 
 
The IMP will be stored under ambient conditions between 15°C and 25°C. 
 
The IMP will be manufactured and imported according to the relevant regulatory requirements. 
 
8.5.3 Packaging and Labeling 
All packaging and labeling operations will be performed according to Good Manufacturing 
Practice (GMP) for Medicinal Products and the relevant regulatory requirements. 
8.5.4 Method of Assigning Subjects to Treatment Groups 
Part A: 
Part A of the study is open-label and all subjects will receive RV521. The dose to be received by 
a given subject will be the dose currently being investigated, at the time the subject is enrolled, in 
the applicable cohort, as described in Section 8. 
Part B and Part C: 
In Parts B and C, subjects will be randomised to treatment according to a central randomised list 
for each cohort. To protect the blind, the list will be produced by an unblinded biostatistician at 
Syneos Health who will be independent of the blinded statistician. 
 
For Part B, subjects in Cohorts 3 and 4 will be randomised to RV521 or placebo (3:1). The 
randomisation list for Cohort 5 will be designed to ensure that the subjects who contribute to the 
final recruitment total of 24 are randomised to receive RV521 or placebo (2:1). The dose to be 
received by a given subject will be the dose currently being investigated at the time the subject is 
enrolled, in the applicable cohort, as described in Section 8.1. 
 
For Part C Cohort 6, the randomisation list will be designed such that the total of approximately 
111 subjects (37 subjects per treatment group) will be randomised with an aim to have at least 
34 evaluable subjects included in the analysis of viral load. Randomisation will be stratified by age 


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group (≥ 1month to < 6 months vs. ≥ 6 months to ≤ 36 months) to ensure balance across the 
treatment groups, but there is no specified number of subjects that will be required in each stratum. 
Subjects will receive RV521 (age group specific low or high dose level) or placebo in a 1:1:1 ratio. 
Subjects randomised to placebo will be allocated randomly to either a low dose volume or a high 
dose volume to maintain the integrity of the double-blind design. 
 
At the time of randomisation, a subject will be sequentially assigned to the next available 
treatment from the randomisation list for that cohort and stratum. Randomisation will be 
performed using an interactive web response system (IWRS). A blinded treatment kit (or > 1 kit, 
if required, in Part B and Part C), corresponding to the randomised treatment, will be allocated to 
each subject. 
 
8.5.5 Blinding 
 
Part A of the study is open-label assignment to RV521. 
 
Parts B and C of the study are double-blind. All subjects’ parents/guardians, Investigators and 
their designees, and all study personnel involved in the conduct of the study, including data 
management and biostatistics, will be blinded to treatment assignment. 
No blinded team member will have access to the randomisation list before official unblinding of 
study treatment. The randomisation schedule may be shared with other groups outside of the 
Syneos Health study team (eg, the pharmacovigilance department, and the laboratory analysing 
the PK samples). 
Data and Listings together with the randomisation list will be provided to DSMC for review for 
Part B. An unblinded, independent biostatistician will be assigned by Syneos Health to prepare 
unblinded tables, figures, and listings related to Part C of the study for the DSMC. The unblinded 
statistician will not otherwise participate in study procedures. Note: this could be the same 
independent biostatistician who produces the randomisation schedule. 
 
Unblinding is discouraged but will be permitted in a medical emergency that requires immediate 
knowledge of the subject’s assigned treatment. Emergency unblinding will only be acceptable if 
it affects the medical management. If this is the case, it will be done within the IVRS. 
 
8.5.6 Prior and Concomitant Therapy 
 
All prior medication taken within 14 days prior to the study and all concomitant medication 
taken during the study must be documented in the CRF. The information must include trade and 
international non-proprietary name of medication, indication, daily dose, route of administration, 
and start and end date of administration, if applicable, to support accurate coding in accordance 
with the World Health Organisation (WHO) Drug dictionary. 


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8.5.6.1 
Permitted Medication/Therapy 
RV521 is a weak inhibitor of MATE-1. Metformin should be used with caution and glucose 
levels should be closely monitored. 
Medications that are CCI 
 substrates with a narrow therapeutic range (See Appendix 17.3) 
such as fentanyl that are required, e.g. in patients requiring procedures or ventilation, will be 
permitted provided that the subjects are appropriately monitored by the investigator who should 
be aware that the active investigational product (sisunatovir) may compete for the metabolism of 
such products, resulting in higher drug levels of these medications. 
 
8.5.6.2 
Prohibited Medication/Therapy 
The following medications/therapy will not be permitted during the study: 
 
• Palivizumab or treatment with any antiviral therapy for RSV (eg, ribavirin or IV 
immunoglobulin) 
• Corticosteroids (oral, IV, or inhaled) 
• Heliox 
• Leukotriene receptor antagonists (eg, montelukast) 
• Exogenous surfactant 
• Mucolytics 
• Any drug, which could impact on the PK of the investigational product including potent 
inhibitors or moderate or potent inducers of CYP P450s (for details see Appendix 17.3). 
• Herbal preparations/medications are not allowed throughout the study. These herbal 
medications include, but are not limited to CCI 
, kava, ephedra (ma huang), 
gingko biloba, dehydroepiandrosterone (DHEA), yohimbe, saw palmetto, and ginseng. 
• Consumption of CCI 
 -containing products are 
not allowed throughout the study,CCI 
. 
Subjects who need to start treatment with prohibited medications during the study will be 
required to discontinue study treatment, but must remain in the study according to the post-study 
drug treatment period specified in the Schedule of Assessments, and should also attend the 
follow-up visit. After the end of their participation in the study, each subject will be treated 
according to standard clinical practice. 
 
 
8.5.6.3 
Rescue Medication 
Not applicable. 


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8.5.7 Treatment Compliance 
Investigational medicinal product will be administered by an appropriately qualified person at 
the study site. Administration will be documented on the drug accountability sheet, in the 
subject’s medical record, and in the CRF. 
 
When a subject is discharged from hospital and IMP will be administered at home (Parts B and 
C), the parent/legal guardian (and/or another caregiver, if required) will be trained in the storage, 
preparation, and administration of IMP at home and will be issued a treatment diary card to 
record the relevant details of IMP administration. The parent/legal guardian will be instructed 
how to complete the treatment diary card accurately. Where possible, prior to each dose, a site 
representative will contact the parent/legal guardian to ensure compliance with the IMP 
administration procedure. 


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9 
TIMING OF STUDY PROCEDURES 
The parent(s) or legal guardian(s) will provide written informed consent before any study-related 
procedures are performed. 
The planned study assessments are presented in the relevant table in Section 8.1. 
 
9.1 
Pre-treatment 
 
9.1.1 Screening Visit: Part A, Part B, and Part C (-24 Hours to First Dose) 
 
Ensure the appropriate Informed Consent Form (ICF) was properly executed: 
• Written informed consent 
• RSV Rapid Diagnostic Test 
• Inclusion and exclusion criteria 
• Demographics 
• Medical history 
• Prior medication review 
• Physical examination (including a symptom-directed examination, general condition, 
lung auscultation, and respiratory muscles retractions) 
• Evaluation of hydration status 
• Body weight/length/head circumference 
• Vital signs (body temperature, systolic and diastolic BP, HR, RR) 
• Record the use of supplemental oxygen, method of delivery (eg, nasal cannula), percent 
O2/flow rate supplied (Part A only) 
• Pulse oximetry on room air (if deemed safe by PI or health care provider) (Part A only) 
• 12-Lead ECG 
• Record RSV-related signs and symptoms (every 12 hours), date of onset and severity (if 
indicated), including: temperature, cough, coryza, grunting with expiration, nasal flaring, 
retractions, and wheezing (Parts B and C only) 
• ReSVinet Scale for Clinicians (Part C only, Appendix 17.6) 
• RSV Clinical Scoring System (Part A and B only; Appendix 17.1) 
• Safety laboratory tests (clinical chemistry and haematology) 
• Urinalysis 
• Adapted ReSVinet scale for parental use (Part B and C only, Appendix 17.2) 
• Concomitant medication review 
• Adverse event review 
 
Note: All the screening assessments (except the RSV Rapid Diagnostic Test) should be 
completed within 24 hours before Dose 1. A positive RSV Rapid Diagnostic Test result is 
required on a sample collected within 48 hours before Dose 1. 


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9.2 
Treatment Period Part A 
9.2.1 Dosing (Part A) 
Dosing Visit 1: 
Pre-Dose (Within 2 Hours of Study Drug Administration): 
• Reassess for eligibility against the inclusion and exclusion criteria 
• Physical examination (symptom-directed examination, general condition, lung 
auscultation, and respiratory muscles retractions) 
• Evaluation of hydration status 
• Vital signs (body temperature systolic and diastolic BP, HR, RR) 
• Record the use of supplemental oxygen, method of delivery (eg, nasal cannula) and 
percent O2/flow rate supplied 
• Pulse oximetry on room air (if deemed safe by PI or health care provider) 
• 12-Lead ECG 
• RSV Clinical Scoring System (Appendix 17.1) 
• Nasopharyngeal swab according to the sampling schedule in Table 4 
• Concomitant medication review 
• Adverse event review 
 
Dosing (0 Hours): 
• Study medication administration 
• Concomitant medication review 
• Adverse event review 
 
1-2 Hours Post-Dose: 
 
• PK blood sample according to the sampling schedule in Table 5 
 
4-5 Hours Post-Dose: 
• Vital signs (body temperature, systolic and diastolic BP, HR, RR) 
• 12-Lead ECG 
• PK blood sample according to the sampling schedule in Table 5 
• Concomitant medication review 
• Adverse event review 
 
6-8 Hours Post-Dose: 
 
• PK blood sample according to the sampling schedule in Table 5 
• Concomitant medication review 
• Adverse event review 


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12 Hours Post-Dose: 
• Vital signs (body temperature, systolic and diastolic BP, HR, RR) 
• Pulse oximetry on room air (if deemed safe by PI or health care provider) 
• Record the use of supplemental oxygen, method of delivery (eg, nasal cannula), percent 
O2/flow rate supplied 
• PK blood sample according to the sampling schedule in Table 5 
• Optional Nasopharyngeal swab according to the sampling schedule in Table 4 
• Concomitant medication review 
• Adverse event review 
 
18-24 Hours Post-Dose: 
• Physical examination (symptom-directed examination, general condition, lung 
auscultation, and respiratory muscles retractions) 
• Evaluation of hydration status 
• Vital signs (body temperature, systolic and diastolic BP, HR, RR) 
• Record the use of supplemental oxygen, method of delivery (eg, nasal cannula), percent 
O2/flow rate supplied 
• Pulse oximetry on room air (if deemed safe by PI or health care provider) 
• 12-Lead ECG 
• RSV Clinical Scoring System (Appendix 17.1) 
• PK blood sample according to sampling schedule in Table 5 
• Nasopharyngeal swab according to the sampling schedule in Table 4 
• Concomitant medication review 
• Adverse event review 
 
9.2.2 Post-Treatment (Part A) 
 
Post Dosing Visit 2 (36 Hours Post-Dose): 
• 
Optional Nasopharyngeal swab according to sampling schedule in Table 4 
 
Post Dosing Visit 2 (48 Hours Post-Dose): 
• Physical examination (symptom-directed examination, general condition, lung 
auscultation, and respiratory muscles retractions) 
• Hydration status 
• Body weight/length/head circumference 
• Vital signs (body temperature, systolic and diastolic BP, HR, RR) 
• Record the use of supplemental oxygen, method of delivery (eg, nasal cannula), percent 
O2/flow rate supplied 
• Pulse oximetry on room air (if deemed safe by PI or health care provider) 
• 12-Lead ECG 
• RSV Clinical Scoring System (Appendix 17.1) 
• Safety laboratory tests (clinical chemistry and haematology) 


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• Urinalysis 
• Nasopharyngeal swab according to sampling schedule in Table 4 
• Concomitant medication review 
• Adverse event review 
 
Telephone Follow-Up (Day 7) 
• Concomitant medication 
• Adverse event review 
 
9.3 
Treatment Period Part B 
 
9.3.1 Dosing Visit 1 (Part B) 
 
-2 Hours to 0 Hours Pre-Dose 1: 
• Reassess for eligibility against the inclusion and exclusion criteria 
• Physical examination (symptom-directed examination, general condition, lung 
auscultation, and respiratory muscles retractions) 
• Evaluation of hydration status 
• Vital signs (body temperature, systolic and diastolic BP, HR, RR) 
• Record the use of supplemental oxygen, method of delivery (eg, nasal cannula), percent 
O2/flow rate supplied 
• Pulse oximetry on room air (if deemed safe by PI or health care provider) 
• RSV Clinical Scoring System (Appendix 17.1) 
• Record RSV-related signs and symptoms and severity every 12 hours (if indicated), 
including: temperature, cough, coryza, grunting with expiration, nasal flaring, retractions, 
and wheezing. 
• Nasopharyngeal swab according to sampling schedule in Table 4 
• Concomitant medication review 
• Adverse event review 
• Randomisation for eligible subjects 
Note: If any of the assessments above were carried out within 2h Pre-Dose 1 for screening 
purposes, it is not necessary to repeat that assessment for the -2h to 0h Pre-Dose 1 timepoint. 
However, if the assessment was carried out >2 h prior to Dose 1 for screening purposes (i.e. 
within the first 22 hours of the screening window), the assessment must be repeated between-2h 
to 0h Pre-Dose 1. 
 
Dosing (0 Hours): 
• Vital signs (body temperature, systolic and diastolic BP, HR, RR) 
• Study medication administration 
• The times of the prior feeding and first feeding after dosing should be recorded. 
• Adverse event review 
• Concomitant medication review 


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1-2 Hours or 4-5 Hours or 6-8 Hours Post-Dose 1: 
The following assessments will be carried out at either 1 to 2 hours, 4 to 5 hours or 6 to 
8 hours Post-Dose 1. The time point chosen (1-2, 4-5 or 6-8 hours) will be defined after 
PK analysis of Part A. 
 
• Vital signs (body temperature, systolic and diastolic BP, HR, RR) 
• 12-Lead ECG 
• PK blood sample according to sampling schedule in Table 5 
• Concomitant medication review 
• Adverse event review 
 
12 Hours Post-Dose 1 (Pre-Dose 2): 
• Vital signs (body temperature, systolic and diastolic BP, HR, RR) 
• Pulse oximetry on room air (if deemed safe by PI or health care provider) 
• Record the use of supplemental oxygen, method of delivery (eg, nasal cannula), percent 
O2/flow rate supplied 
• Record RSV-related signs and symptoms, and severity every 12 hours (if indicated), 
including: temperature, cough, coryza, grunting with expiration, nasal flaring, retractions, 
and wheezing 
• PK blood sample according to sampling schedule in Table 5. 
• Optional Nasopharyngeal swab according to sampling schedule in Table 4 
• Concomitant medication review 
• Adverse event review 
• Study medication administration (Dose 2) 
• The times of the prior feeding and first feeding after dosing should be recorded. 
 
9.3.2 Dosing Visit 2 (Part B) 
 
Doses 3 and 4: 
 
Pre-Dose 3 and 4: 
• Evaluation of hydration status (prior to Dose 3 only) 
• Vital signs (body temperature, systolic and diastolic BP, HR, RR) 
• 12-Lead ECG (prior to Dose 3 only) 
• Record the use of supplemental oxygen, method of delivery (eg, nasal cannula), percent 
O2/flow rate supplied 
• Pulse oximetry on room air (if deemed safe by PI or health care provider) 
• RSV Clinical Scoring System every 24 hours (prior to Dose 3 only) (Appendix 17.1) 
• Record RSV-related signs and symptoms, and severity every 12 hours (if indicated), 
including: temperature, cough, coryza, grunting with expiration, nasal flaring, retractions, 
and wheezing 
• Nasopharyngeal swab according to sampling schedule in Table 4 (Pre-Dose 4 sample is 
optional) 
• Concomitant medication review 


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• Adverse event review 
• Study medication administration (Dose 3 and Dose 4) 
• The times of the prior feeding and first feeding after dosing should be recorded. 
 
9.3.3 Dosing Visit 3 (Part B) 
 
Dose 5: 
Pre-Dose 5: 
• Evaluation of hydration status 
• Vital signs (body temperature, systolic and diastolic BP, HR, RR) 
• 12-Lead ECG 
• Record the use of supplemental oxygen, method of delivery (eg, nasal cannula), percent 
O2/flow rate supplied 
• Pulse oximetry on room air (if deemed safe by PI or health care provider) 
• Record RSV-related signs and symptoms, and severity every 12 hours (if subject remains 
hospitalised), including: temperature, cough, coryza, grunting with expiration, nasal 
flaring, retractions, and wheezing 
• RSV Clinical Scoring System performed every 24 hours (Appendix 17.1) 
• Nasopharyngeal swab according to sampling schedule in Table 4 
• Concomitant medication review 
• Adverse event review 
• Study medication administration (Dose 5) 
• The times of the prior feeding and first feeding after dosing should be recorded. 
Dose 6: 
Pre-Dose to 0 Hours: 
• Vital signs (body temperature, systolic and diastolic BP, HR, RR) 
• Record the use of supplemental oxygen, method of delivery (eg, nasal cannula), percent 
O2/flow rate supplied 
• Pulse oximetry on room air (if deemed safe by PI or health care provider) 
• Record RSV-related signs and symptoms, and severity every 12 hours (if indicated), 
including: temperature, cough, coryza, grunting with expiration, nasal flaring, retractions, 
and wheezing 
• PK blood sample according to sampling schedule in Table 5 
• Nasopharyngeal swab according to the sampling schedule in Table 4 
• Concomitant medication review 
• Adverse event review 
• Study Medication administration (Dose 6) 
o The times of the prior feeding and first feeding after dosing should be recorded. 
 
1-2 Hours OR 4-5 Hours OR 6-8 Hours Post-Dose 6: 
The following assessments will be carried out at either 1 to 2 hours, 4 to 5 hours or 6 to 8 
hours Post-Dose 6. The time point chosen (1-2, 4-5 or 6-8 hours) will be defined after PK 


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analysis of Part A and sites will be notified of the chosen time point in the Dosing 
Guidance letter. 
• Vital signs (body temperature, systolic and diastolic BP, HR, RR) 
• 12-Lead ECG 
• PK blood sample according to sampling schedule in Table 5 
• Concomitant medication review 
• Adverse event review 
If a subject is discharged: 
The parent/legal guardian (and another caregiver, if required) must be trained on the storage, 
preparation, and administration of the IMP at home. The parent/legal guardian will be issued 
with the IMP kit(s) for their child and adequate supplies for preparation and administration of the 
remaining doses of IMP will be provided. A Treatment Diary Card will be issued that explains 
how the IMP should be stored and prepared and the parent/legal guardian will be asked to record 
relevant details of the administration of IMP at home (including date and time). Instructions 
should also be given on when to return to the clinic for Study Visits. 
9.3.4 Dosing Visits 4 and 5 (Part B) 
 
(Doses 7 to 10): 
If in-patient: 
Pre-Dose 7 to 10: 
• Evaluation of hydration status (prior to Doses 7 and 9) 
• Vital signs (body temperature, systolic and diastolic BP, HR, RR) 
• 12-Lead ECG (prior to Doses 8 and 10) 
• RSV Clinical Scoring System performed every 24 hours (prior to Doses 7 and 9) 
• Record RSV-related signs and symptoms, and severity every 12 hours (if indicated), 
including: temperature, cough, coryza, grunting with expiration, nasal flaring, retractions, 
and wheezing (prior to each dose) 
• Record the use of supplemental oxygen, method of delivery (eg, nasal cannula), percent 
O2/flow rate supplied (prior to each dose) 
• Pulse oximetry on room air (if deemed safe) by PI or health care provider (prior to each 
dose) 
• PK blood sample 12 hours Post-Dose 6 (pre-Dose 7 only) according to sampling schedule 
in Table 5 
• Nasopharyngeal swab (prior to each dose) according to sampling schedule in Table 4. 
Pre-Dose 8 and 10 Nasopharyngeal swab samples are optional. 
• Concomitant medication review 
• Adverse event review 
• Study medication administration (Doses 7 to Dose 10) 
o The times of the prior feeding and first feeding after dosing should be recorded. 
• In case of discharge: provide parent/legal guardian with treatment diary, patient leaflet, 
and clear instructions how to administer IMP. An additional nasopharyngeal swab sample 


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should be taken according to Table 4 if the last nasopharyngeal swab sample was taken > 
12 hours prior to the discharge. 
 
9.3.5 Post-Treatment (Part B) 
 
Visit Day 7 (40-48 Hours Post-Dose 10) Follow-Up: 
Note: Visit Day 7 may occur on Study Days 7 or 8 depending on when the subject received 
their first Dose of IMP. 
• Physical examination (symptom-directed examination, general condition, lung 
auscultation, and respiratory muscles retractions) 
• Evaluation of hydration status 
• Body weight/length/head circumference 
• Vital signs (body temperature, systolic and diastolic BP, HR, RR) 
• 12-Lead ECG 
• Pulse oximetry on room air (if deemed safe by PI or health care provider) 
• RSV Clinical Scoring System 
• Record RSV-related signs and symptoms, and severity every 12 hours (if indicated), 
including: temperature, cough, coryza, grunting with expiration, nasal flaring, retractions, 
and wheezing 
• Adapted ReSVinet scale for parental use 
• Safety laboratory tests (clinical chemistry and haematology) 
• Urinalysis 
• PK blood sample according to sampling schedule in Table 5 
• Nasopharyngeal swab according to sampling schedule in Table 4 
• Concomitant medication review 
• Adverse event review 
 
Telephone Follow-Up (Day 12): 
• Concomitant medication review 
• Adverse event review 
 
9.4 
Treatment Part C 
Ideally all subjects in Part C should remain hospitalised for at least 48 hours post-randomisation 
to accommodate taking the first 4 doses of IMP and collection of all the assessments scheduled 
for Dosing Visit 1 and Dosing Visit 2 (Table 3a) 
 
A subject may be discharged from hospital prior to Dosing Visit 3 and be seen as an outpatient 
provided all of the following requirements are met: 
 
1. The subject is judged by the Investigator or other healthcare provider to be doing well 
clinically and to warrant hospital discharge, 
2. The parent/caregiver can comply with the dosing at home, 


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3. Adequate provisions are in place for the subject to be seen in an outpatient setting to 
complete the study procedures and assessments, either at the hospital/clinic as an 
outpatient or at home (ie, visited by a home health nurse or equivalent). For both 
outpatient settings, the following assessments and sample collections are required for key 
study endpoints: 
a. Administer one dose per Dosing visit or observe parent caregiver doing the same 
b. Obtain at least one nasopharyngeal swab sample each day (Pre-Dose at Dosing Visits 
2, 3 and 4 and 5) 
c. Obtain PK samples Pre-Dose 6, and at 4-5 hours Post-Dose for either Dose 6 or Dose 
7 (depending on the time of day for the doses) 
d. Obtain an ECG at Post-Dose 6. Depending on the time of day Dose 6 falls the 
assessments can be moved relative to Dose 7 
e. Assess the following at each of Dosing Visits 2, 3, 4 and 5 
• Adverse events 
• Concomitant medication review 
• Vital signs 
• Hydration status 
• ReSVinet Score for Clinicians 
• RSV signs and symptoms 
• Supplementary Oxygen 
• Pulse oximetry on room air 
Following the outpatient visits on Dosing Visit 3, the parent/caregiver must continue to complete 
all home dosing and the Adapted ReSVinet scale for parental use assessments on Dosing Visits 4 
and 5 as outlined in Table 3b and must return for Visit Day 7 40-48 hours after the last dose 
(Dose 10), Visit Day 14 and Visit Day 34. The parent/caregiver will record in the Patient Booklet 
for doses given at home whether any concomitant medications have been administered and also 
their assessment of how the child is feeling. 
9.4.1 Dosing Visit 1 (Part C) 
 
-2 Hours to 0 Hours Pre-Dose 1: 
• Reassess for eligibility against the inclusion and exclusion criteria 
• Physical examination 
• Evaluation of hydration status 
• Vital signs (body temperature, systolic and diastolic BP, HR, RR) 
• ReSVinet Scale for Clinicians (Appendix 17.6) 
• Record RSV-related signs and symptoms, and severity every 12 hours (if indicated), 
including: temperature, cough, coryza, grunting with expiration, nasal flaring, retractions, 
and wheezing 


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• Record the use of supplemental oxygen, method of delivery (eg, nasal cannula), Percent 
O2/Flow rate supplied 
• Pulse oximetry on room air (if deemed safe by PI or health care provider) 
• Randomisation for Eligible Subjects (stratified by age group) 
• Nasopharyngeal swab 
• Concomitant medication review 
• Adverse Events 
 
Note: If any of the assessments above were carried out within 2 h Pre-Dose 1 for screening 
purposes, it is not necessary to repeat that assessment for the -2 h to 0 h Pre-Dose 1 
timepoint. However, if the assessment was carried out >2 h prior to Dose 1 for screening 
purposes (i.e. within the first 22 hours of the screening window), the assessment must be 
repeated between-2 h to 0 h Pre-Dose 1. 
 
Dosing (0 Hours): 
• Concomitant medication review 
• Adverse event review 
• Study medication administration (Dose 1) 
o The times of the prior feeding and first feeding after dosing should be recorded. 
+4-5 Hours Post-Dose 1: 
The following assessments will be carried out at 4 to 5 hours Post-Dose 1. 
• Vital signs (body temperature, systolic and diastolic BP, HR, RR) 
• 12-Lead ECG 
• Concomitant medication review 
• Adverse event review 
• PK blood sample according to sampling schedule in Table 5. Note: This sample will only 
be required if the dose level was not previously evaluated in Part B. 
 
 
12 Hours Post-Dose 1 (Pre-Dose 2): 
• Vital signs (body temperature, systolic and diastolic BP, HR, RR) 
• Record RSV-related signs and symptoms, and severity every 12 hours (if indicated), 
including: temperature, cough, coryza, grunting with expiration, nasal flaring, retractions, 
and wheezing 
• Record the use of supplemental oxygen, method of delivery (eg, nasal cannula), Percent 
O2/Flow rate supplied 
• Pulse oximetry on room air (if deemed safe by PI or health care provider) 
• Optional Nasopharyngeal swab according to sampling schedule in Table 4 
• Concomitant medication review 
• Adverse event review 
• PK blood sample according to sampling schedule in Table 5. NOTE: This sample will 
only be required if the dose level was not previously evaluated in Part B. 
• Study Medication Administration (Dose 2) 


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o 
The times of the prior feeding and first feeding after dosing should be recorded. 
9.4.2 Dosing Visit 2 (Part C) 
 
Procedures and assessments scheduled for Dosing Visit 2 in Part C are required if the 
subject is currently hospitalised. If the subject has met the criteria for early discharge prior 
to Dosing Visit 2 and is being seen as an outpatient the required assessments should still be 
completed and are listed in Section 9.4 and Table 3b. In case of early discharge, provide 
parent with Patient Booklet, video access link and clear instructions how to administer 
IMP. An additional nasopharyngeal swab sample should be taken according to Table 4 if 
the last nasopharyngeal swab sample was taken > 12 hours prior to discharge. 
 
Pre-Dose 3: 
• Evaluation of hydration status 
• Vital signs (body temperature, systolic and diastolic BP, HR, RR) 
• 12-Lead ECG 
• ReSVinet scale for clinicians (Part C only, Appendix 17.6) 
• Adapted ReSVinet scale for parental use (Appendix 17.2) 
• Record RSV-related signs and symptoms, and severity every 12 hours (if indicated), 
including: temperature, cough, coryza, grunting with expiration, nasal flaring, retractions, 
and wheezing 
• Record the use of supplemental oxygen, method of delivery (eg, nasal cannula), Percent 
O2/Flow rate supplied 
• Pulse oximetry on room air (if deemed safe by PI or health care provider) 
• Nasopharyngeal swab according to sampling schedule in Table 4 
• Concomitant medication review 
• Adverse event review 
• Study Medication Administration (Dose 3) 
o 
The times of the prior feeding and first feeding after dosing should be recorded. 
Pre-Dose 4: 
• Vital signs (body temperature, systolic and diastolic BP, HR, RR) 
• Record RSV-related signs and symptoms, and severity every 12 hours (if indicated), 
including: temperature, cough, coryza, grunting with expiration, nasal flaring, retractions, 
and wheezing 
• Record the use of supplemental oxygen, method of delivery (eg nasal cannula), Percent 
O2/Flow rate supplied 
• Pulse oximetry on room air (if deemed safe by PI or health care provider) 
• Optional Nasopharyngeal swab according to sampling schedule in Table 4 
• Concomitant medication review 
• Adverse event review 
• Study Medication Administration (Dose 4) 
o The times of the prior feeding and first feeding after dosing should be recorded. 


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9.4.3 Dosing Visit 3 (Part C) 
Procedures and assessments scheduled for Dosing Visit 3 in Part C are required if the 
subject is currently hospitalised. If the subject has met the criteria for early discharge and is 
being seen as an outpatient the required assessments are listed in Section 9.4 and Table 3b. 
In case of early discharge, provide parent with Patient Booklet, video access link and clear 
instructions how to administer IMP. An additional nasopharyngeal swab sample should be 
taken according to Table 4 if the last nasopharyngeal swab sample was taken > 12 hours 
prior to discharge. 
 
Pre-Dose 5 (All of the assessments to be completed if still an in-patient): 
• Evaluation of hydration status 
• Vital signs (body temperature, systolic and diastolic BP, HR, RR) 
• 12-Lead ECG 
• ReSVinet scale for clinicians (Appendix 17.6) 
• Adapted ReSVinet scale for parental use (Appendix 17.2) 
• Record RSV-related signs and symptoms, and severity every 12 hours (if indicated), 
including: temperature, cough, coryza, grunting with expiration, nasal flaring, retractions, 
and wheezing 
• Record the use of supplemental oxygen, method of delivery (eg, nasal cannula), Percent 
O2/Flow rate supplied 
• Pulse oximetry on room air (if deemed safe by PI or health care provider) 
• Nasopharyngeal swab according to sampling schedule in Table 4 
• Concomitant medication review 
• Adverse event review 
• Study Medication Administration (Dose 5) 
o The times of the prior feeding and first feeding after dosing should be recorded. 
Dose 6 (All of the assessments to be completed if still an in-patient) 
Pre-Dose to 0 Hour: 
• Vital signs (body temperature, systolic and diastolic BP, HR, RR) 
• Record RSV-related signs and symptoms, and severity every 12 hours (if indicated), 
including: temperature, cough, coryza, grunting with expiration, nasal flaring, retractions, 
and wheezing 
• Record the use of supplemental oxygen, method of delivery (eg, nasal cannula), Percent 
O2/Flow rate supplied 
• Pulse oximetry on room air (if deemed safe by PI or health care provider) 
• PK blood sample according to sampling schedule in Table 5 
• Nasopharyngeal swab according to sampling schedule in Table 4 
• Concomitant medication review 
• Adverse event review 
• Study Medication Administration (Dose 6) 
o The times of the prior feeding and first feeding after dosing should be recorded. 


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+4-5 Hour Post-Dose 6: 
The following assessments will be carried out at 4 to 5 hours Post-Dose 6. 
• Vital signs (body temperature, systolic and diastolic BP, HR, RR) 
• 12-Lead ECG 
• PK blood sample according to sampling schedule in Table 5 
• Concomitant medication review 
• Adverse event review 
If a subject is discharged: 
The parent/legal guardian (and another caregiver, if required) must be trained on the 
storage, preparation, and administration of the IMP at home. The parent/legal guardian will 
be issued with the IMP kit(s) for their child and adequate supplies for preparation and 
administration of the remaining doses of IMP will be provided. A Patient Booklet and 
video access link will be issued that explains how the IMP should be stored and prepared 
and the parent/legal guardian will be asked to record relevant details of the administration 
of IMP at home (including date and time). Instructions should also be given on when to 
return to the clinic for Study Visits. 
 
See Section 9.4 and Table 3b for details of assessments required in subjects who are 
outpatients. 
 
9.4.4 Dosing Visits 4 and 5 (Part C) 
 
(Doses 7 to 10) - All of the assessments to be completed if still an in-patient: 
• Evaluation of hydration status (Doses 7 and 9) 
• Vital signs (body temperature, systolic and diastolic BP, HR, RR) (prior to each dose) 
• 12-Lead ECG (prior to Doses 8 and 10) 
• ReSVinet scale for clinicians every 24 hours (Doses 7 and 9) (Appendix 17.6) 
• Adapted ReSVinet scale for parental use (Appendix 17.2). Note: To be completed 
whether hospitalised or discharged. 
• Record RSV-related signs and symptoms and severity every 12 hours (if indicated), 
including: temperature, cough, coryza, grunting with expiration, nasal flaring, retractions, 
and wheezing (prior to each dose) 
• Record the use of supplemental oxygen , method of delivery (eg, nasal cannula), percent 
O2/flow rate supplied (prior to each dose) 
• Pulse oximetry on room air (if deemed safe by PI or health care provider (prior to each 
dose) 
• Nasopharyngeal swab according to sampling schedule in Table 4. Pre-Dose 8 and 10 
Nasopharyngeal swab samples are optional. 
• Concomitant medication review 
• Adverse event review 
• PK blood sample according to sampling scheduled in Table 5. Note: This sample will 
only be required if the dose level was not previously evaluated in Part B. 
• Study medication administration (Dose 7 to Dose 10), whether hospitalised or discharged 
o 
The times of the prior feeding and first feeding after dosing should be recorded. 


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• In case of discharge: provide parent with Patient Booklet, video access link, and clear 
instructions how to administer IMP. An additional nasopharyngeal swab sample should 
be taken according to Table 4 if the last nasopharyngeal swab sample was taken 
> 12 hours prior to discharge. 
 
9.4.5 Post Treatment (Part C) 
Visit Day 7 (40 – 48 Hours Post-Dose 10) Follow-up: 
Note: Visit Day 7 may occur on Study Days 7 or 8 depending on when the subject received 
his or her first dose of IMP. 
• Physical examination 
• Evaluation of hydration status 
• Body weight/length/head circumference 
• Vital signs (body temperature, systolic and diastolic BP, HR, RR) 
• 12-Lead ECG 
• Record RSV-related signs and symptoms, and severity (if indicated), including: 
temperature, cough, coryza, grunting with expiration, nasal flaring, retractions, and 
wheezing 
• ReSVinet scale for clinicians (Appendix 17.6) 
• Adapted ReSVinet Scale for Parental use (Appendix 17.2) 
• Safety laboratory tests (clinical chemistry and haematology) 
• Urinalysis 
• PK blood sample according to sampling schedule in Table 5 
• Nasopharyngeal swab 
• Concomitant medication review 
• Adverse event review 
Visit Day 14 Follow-up: 
• Vital signs 
• Body weight/length/head circumference 
• Record RSV-related signs and symptoms, and severity (if indicated), including: 
temperature, cough, coryza, grunting with expiration, nasal flaring, retractions, and 
wheezing 
• ReSVinet scale for clinicians (Appendix 17.6) 
• Adapted ReSVinet scale for parental use (Appendix 17.2) 
• Nasopharyngeal swab 
• Concomitant medication review 
• Adverse event review 
Visit Day 34 Follow-up: 
• Vital signs 
• Body weight/length/head circumference 
• Record RSV-related signs and symptoms, and severity (if indicated), including: 
temperature, cough, coryza, grunting with expiration, nasal flaring, retractions, and 
wheezing 


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• ReSVinet scale for clinicians (Appendix 17.6) 
• Adapted ReSVinet scale for parental use (Appendix 17.2) 
• Nasopharyngeal swab 
• Concomitant medication review 
• Adverse event review 
Early Withdrawal (or Discontinuation) Visit 
Parents/legal guardians who withdraw their child from the study will be encouraged to 
allow their child to complete the same final evaluations as subjects completing the study 
according to this protocol (ie, at the relevant post-treatment visit), particularly safety 
evaluations. 
9.5 
Duration of Treatment 
Part A: 
Subjects will participate for up to 8 days. A single oral dose of RV521 will be administered in 
Part A, and the visit schedule will include: 
 
• Screening Visit (-24 hours) 
• Dosing Visit 1 (-2 pre-dose to 18-24 hours post-dose) 
• Post-dosing Visit 2 (48 hours post-dose) 
• Telephone Follow-up (Day 7) 
Part B: 
Subjects will participate for up to 13 days. The proposed dosing regimen for Part B is RV521 or 
placebo administered BID, 12 hours apart, for a period of 5 consecutive days (for a total of 
10 doses), and the visit schedule will include: 
 
• Screening Visit (-24 hours) 
• Dosing Visit 1 (-2 to 18-24 hours post-dose) 
• Dosing Visit 2 
• Dosing Visit 3 
• Dosing Visit 4 
• Dosing Visit 5 
• Follow-Up Visit Day 7 (+40-48 Hours Post-Dose 10) 
• Telephone Follow-Up (Day 12) 
 
Note: The actual day of each Dosing Visit will be dependent upon the time that the subject 
receives their first dose of IMP on Visit 1. Follow-Up Visit Day 7 may therefore fall on Study 
Days 7 or Day 8 depending upon the time the subject received his or her first dose of IMP on 
Dosing Visit 1. 
Part C: 
Subjects will participate for up to 35 days, and the visit schedule will include: Screening 
(24 hours to first dose), Dosing Visits 1 to 5 (5 days), and follow-up 40-48h Post-Dose 10 (Study 


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Days 7 or 8) and at Study Days 14 and 34. Inpatient duration will be determined clinically by the 
PI or other health care provider and by ability to complete study procedures and assessments on 
an outpatient basis (Section 9.4). Follow-up days are expected to be on an outpatient basis. 


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10 PHARMACOKINETICS, EFFICACY AND SAFETY VARIABLES 
 
The planned Schedule of Assessments is in Section 8.1. 
 
The intended volume of blood to be withdrawn for each of the assessments is based on the 
minimal, reasonably required volume for each of the respective analyses and is below those 
allowed per the WHO and European and United States guidance. 
In order to limit the volume of blood to be collected, the normal protocol-driven tests will only 
be performed within the indicated time frame as part of the standard of care. 
For safety tests (haematology and chemistry), a total of 4.2 mL of blood will be drawn, per 
protocol (all study parts). 
For PK analysis, 0.2 mL of whole blood is required at each sampling time point. Thus, for a 
maximum of 6 PK samples (Part B), 1.2 mL of whole blood will be required. 
The maximum amount of blood that will be taken for the study will be 5.4 mL. 
 
Collection schedules may switch between the cannulation and heel prick methods dependent 
upon the presence and availability of a patent IV cannula as well as the sample purpose 
(PK versus safety evaluations). 
Complete instructions for collection, processing, handling, and shipment of all safety laboratory 
tests, PK, and nasopharyngeal swab samples will be provided in the Laboratory Manual. 
10.1 Pharmacokinetics, Efficacy, and Safety Assessments 
 
10.1.1 Pharmacokinetic Assessments 
Blood samples for measurement of serum concentrations of RV521 will be drawn at time points 
specified in the Schedule of Assessments in Section 8.1. The actual date and time (24-hour clock 
time) of each sampling will be recorded in the subject’s source document at the site. The 
sampling window for each time point is identified in Table 1, Table 2, and Table 5. Plasma 
samples for determination of RV521 concentrations will be analysed by a central laboratory 
using a validated assay method. Full details of the analytical methods used will be described in a 
separate bioanalytical report. Deviations from planned sampling windows will be assessed before 
database lock for the impact on PK analyses and may be excluded from time point summaries of 
PK concentrations. Actual time will be used for derivation of PK parameters. 
 
If a subject experiences an AE Grade 3 or higher or meets SAE criteria, a blood sample for the 
measurement of serum concentrations of RV521 should be collected (if less than 24 hours have 
elapsed since the last dose of IMP and more than 24 hours since the last PK sample), if possible. 
The sample will be recorded as an unscheduled time point and may be also used in PK 
parameters derivation using actual time. 


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10.1.2 Efficacy Assessments 
 
10.1.2.1 
Viral Load Assessments 
A single nasopharyngeal swab sample for the measurement of RSV viral load will be taken at 
each time point identified in the Schedule of Assessments for Part A (Table 1), Part B (Table 2), 
and Part C (Table 3a inpatients and Table 3b outpatients) in Section 8.1. The actual date and time 
(24-hour clock time) of each sampling will be recorded in the subject’s source document at the 
site. Deviations from planned sampling windows will be assessed before database lock for the 
impact on PD analyses. Actual time will be used for derivation of PD parameters. 
 
 
 
10.1.2.2 
Clinical Response Assessments 
Clinical response will be measured by evaluation of the RSV signs and symptoms list (all Parts), 
RSV Clinical Scoring System (Parts A and B), the ReSVinet Score for Clinicians (Part C), and 
the adapted version of ReSVinet scale for parental use (Parts B and C). In addition, CCI 
 
and time to normalisation of respiratory rate will be analysed in Part C. 
Details of how the clinical efficacy endpoints will be analysed, and by which scales, is briefly 
described in Section 11.1.5 and will be outlined in the Statistical Analysis Plan. 
 
10.1.3 Safety Assessments 
 
Safety assessments will consist of AEs, haematology, clinical chemistry, urinalysis, vital signs, 
physical examination, and ECGs. 
 
10.1.3.1 
Adverse Events 
Adverse Event Definition 
 
An AE is defined as any untoward medical occurrence in a clinical study subject administered a 
medicinal product which does not necessarily have a causal relationship with this treatment. 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) 
product, whether or not it is related to the medicinal (investigational) product. This includes an 
exacerbation of pre-existing conditions or events, intercurrent illnesses, drug interaction or the 
significant worsening of the indication under investigation that is not recorded elsewhere in the 
Cell-based infectivity assay and RT-qPCR assay will be used to quantify RSV viral load in 
nasopharyngeal swab samples. CCI 


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CRF under specific efficacy assessments. Anticipated fluctuations of pre-existing conditions, 
including the disease under study that does not represent a clinically significant exacerbation or 
worsening need not be considered AEs. 
It is the responsibility of the Investigator to document all AEs that occur during the study from 
the time the ICF is signed. AEs and SAEs should be followed until resolution or until the event 
is stable. An AE should be reported on the appropriate page of the CRF. 
 
Each separate AE episode must be recorded. For example, if an AE resolves completely or 
resolves to baseline and then recurs or worsens again, this must be recorded as a separate AE. 
For AEs to be considered intermittent, the events must be of similar nature and severity. 
 
Adverse Reaction Definition 
An adverse reaction is any untoward and unintended response that is related to the administration 
of the IMP at any dose. 
 
Onset Date, End Date 
If an AE starts during the study but did not end before the final closing (follow-up) visit, the 
Investigator must make a reasonable effort to establish the outcome and the end date of the AE. 
If this is not possible (eg, because the AE is still ongoing) or the subject is lost to follow-up, 
there will be no end date for the AE. 
For all AEs that resolve, resolve with sequelae, or have a fatal outcome, an end date must be 
provided. 
If an AE stops and restarts later, all occurrences have to be recorded separately. 
 
Assessment of Severity 
Severity of AEs will be assessed by the Investigator using NCI CTCAE v5.0, 27 November 2017 
(CTCAE v5.0). Grades of the NCI CTCAE refer to the severity of the AE as follows: 
• Grade 1 Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated. 
• Grade 2 Moderate; minimal, local or non-invasive intervention indicated; limiting age- 
appropriate instrumental Activities of Daily Living (ADL). 
• Grade 3 Severe or medically significant but not immediately life-threatening; 
hospitalisation or prolongation of hospitalisation indicated; disabling; limiting self-care 
ADL. 
• Grade 4 Life-threatening consequences; urgent intervention indicated. 
• Grade 5 Death related to AE. 


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If there is a change in severity of an AE, every episode of the AE will be captured separately and 
all required information for every episode will be provided separately. 
 
Assessment of Causality 
Every effort will be made by the Investigator to assess the relationship of the AE, if any, to the 
IMP. Causality should be assessed using the categories presented in the following table: 
 
Unrelated: 
Clinical event with an incompatible time relationship to IMP 
administration, and that could be explained by underlying disease or 
other drugs or chemicals or is incontrovertibly not related to the IMP. 
Unlikely: 
Clinical event whose time relationship to IMP makes a causal 
connection improbable, but that could plausibly be explained by 
underlying disease or other drugs or chemicals. 
Possibly: 
Clinical event with a reasonable time relationship to IMP, but that 
could also be explained by concurrent disease or other drugs or 
chemicals. 
Probably: 
Clinical event with a reasonable time relationship to IMP, and is 
unlikely to be attributed to concurrent disease or other drugs or 
chemicals. 
Definitely: 
Clinical event with plausible time relationship to IMP, and that cannot 
be explained by concurrent disease or other drugs or chemicals. 
 
Action Taken with IMP 
 
The Investigator will describe the action taken in the appropriate section of the CRF, as follows: 
 
• None (no action taken) 
• Unknown 
• IMP temporarily interrupted – only for Part B and Part C (date, time and reason to be 
provided) 
• IMP permanently discontinued (date and reason to be provided) 
• Other (to be specified) 
Outcome of Adverse Event 
 
The final outcome of the AE will be documented in the appropriate section of the eCRF, as 
follows: 


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• Recovered 
• Recovered with Sequelae 
• Ongoing 
• Unknown 
• Death 
Follow-up of Adverse Events 
 
All Investigators should follow up subjects with AEs or SAEs until the event is resolved or until, 
in the opinion of the Investigator, the event is stabilised or determined to be chronic. Details of 
AE or SAE resolution must be documented in the CRF. 
Subjects should be followed up to the last follow-up visit, (ie, Day 7 after receiving the last dose 
of IMP in Part A, Day 12 in Part B, and Day 34 in Part C) and any AEs that occur during this 
time should be reported according to the procedures outlined above. 
 
For all SAEs, where important or relevant information is missing, active follow-up should be 
undertaken. 
 
A follow-up report must be completed when an SAE resolves, is unlikely to change, or when 
additional information becomes available. In case the SAE is a suspected unexpected serious 
adverse reaction (SUSAR), follow-up information must be provided within the timelines as 
requested by Syneos Health Safety & Pharmacovigilance. 
 
If new or amended information on a reported SAE becomes available, the Investigator can report 
this on a new SAE form using the completion guidelines. If using the original form to notify 
further information, all new or amended information need to be initialled and dated in order all 
changes are clearly identified. 
 
Documentation and Reporting of Adverse Events 
An AE should be reported and documented in accordance with the procedures outlined below. 
All AEs occurring during the study must be documented on the relevant CRF pages. 
The following data should be documented for each AE: 


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• Diagnosis, if not available, symptoms 
• Classification of ‘serious’ or ‘not serious’ 
• Severity 
• Date and time of first occurrence and date and time of resolution (if applicable) 
• Action taken with the IMP 
• Causal relationship 
• Outcome of event (unknown, recovered, ongoing, recovered with sequelae, death [with 
date, time, and cause reported]) 
 
10.1.3.2 
Serious Adverse Events 
Serious Adverse Event Definition 
An SAE is any untoward medical occurrence or effect that, at any dose, 
 
• Results in death 
• Is life-threatening (an AE is life-threatening if the subject was at immediate risk of death 
from the event as it occurred, ie, it does not include a reaction that might have caused 
death if it had occurred in a more serious form) 
• Requires or prolongs inpatient hospitalisation. (Complications occurring during 
hospitalisation are AEs and are SAEs if they cause prolongation of the current 
hospitalisation. Hospitalisation / Prolonged hospitalisation for elective treatment of a pre- 
existing non-worsening condition is not, however, considered an AE. The details of such 
hospitalisations must be recorded on the medical history or physical examination page of 
the CRF) 
• Results in persistent or significant disability/incapacity. (An AE is incapacitating or 
disabling if it results in a substantial and/or permanent disruption of the subject’s ability 
to carry out normal life functions) 
In addition, medical and scientific judgement is required to decide if prompt notification is 
required in situations other than those defined for SAEs above. This may include any event that 
the Investigator regards as serious that did not strictly meet the criteria above but may have 
jeopardised the subject or required intervention to prevent 1 of the outcomes listed above, or that 
would suggest any significant hazard, contraindication, side effect, or precaution that may be 
associated with the use of the investigational product. 
Reporting of Serious Adverse Events 
 
Any SAE must be reported by the Investigator if it occurs during the clinical study from 
signature of Informed Consent through to the last scheduled Study Visit, whether or not the SAE 
is considered to be related to the IMP. If an AE becomes an SAE, the start date of the SAE is the 
date that the AE fulfils any seriousness criterion. The stop date of an SAE is the date that the 
event resolves or no longer fulfills the seriousness criterion. 


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An SAE report consists of the SAE form. SAE reports should be sent within 24 hours by e-mail 
to the Syneos Health Safety and Pharmacovigilance department: 
 
SafetyReporting@SyneosHealth.com 
 
The Investigator will be requested to supply as much detailed information regarding the event 
that is available at the time of the initial report (examinations carried out, laboratory results etc.). 
The Investigator is also required to submit follow-up reports as soon as possible, and within 
24 hours of becoming aware of any additional information such as diagnosis, outcome, causality 
assessment, results of specific investigations and any new significant information that has not 
been previously reported. 
The Investigator should not wait to receive additional information to document fully the event 
before notification of an SAE, although additional information may be requested by the Syneos 
Health pharmacovigilance department. Where applicable, information from relevant laboratory 
results, hospital case records, and autopsy reports should be obtained. 
Instances of death, or an event that is of such clinical concern as to influence the overall 
assessment of safety, if brought to the attention of the Investigator at any time after cessation of 
IMP administration and linked by the Investigator to this study, should be reported to the study 
monitor. 
Syneos Health, on behalf of the Sponsor will promptly notify all relevant Investigators and the 
regulatory authorities of findings that could adversely affect the safety of subjects, impact on the 
conduct of the study or alter the independent ethics committee (IEC)/institutional review board 
(IRB) approval/favourable opinion of the study. In addition, Syneos Health, on behalf of the 
Sponsor, will expedite the reporting to all concerned Investigators, to the IECs/IRBs, where 
required, and to the regulatory authorities of all adverse reactions that are both serious and 
unexpected according to local safety reporting requirements. 
 
10.1.3.3 
Unexpected Adverse Reactions 
Unexpected Adverse Reaction Definition 
 
An unexpected adverse reaction is any untoward and unintended response that is related to the 
administration of the IMP at any dose that is not consistent with the applicable RSI (eg, [IB] for 
an unauthorised IMP or summary of product characteristics for an authorised product). The 
expectedness of an adverse reaction is determined by the Sponsor in the RSI. 
 
For this protocol, the RSI for the assessment of expectedness is included in the most recent fully 
approved version of the IB for RV521. 
 
All SUSARs will be the subject of expedited reporting. Syneos Health shall ensure that all 
relevant information about a SUSAR that is fatal or life-threatening is reported to the relevant 
competent authorities and IEC/IRB, within 7 days after knowledge by the Sponsor of such a case 
and that relevant follow-up information is communicated within an additional 8 days and/or 
according to local safety reporting requirements. All other SUSARs will be reported to the 


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relevant competent authorities and IEC/IRB within 15 days after knowledge by the Sponsor of 
such a case and/or according to local safety reporting requirements. All Investigators should 
follow up SUSARs until the event is resolved or until, in the opinion of the Investigator, the 
event is stabilised or determined to be chronic. Post-study SUSARs that occur after the subject 
has completed the clinical study must be reported by the Investigator to the Sponsor. 
 
Warnings and Precautions 
 
Please refer to the IB for RV521 (summary of data, reference safety information, and guidance 
for the Investigator). 
 
10.1.3.4 
Clinical Laboratory Assessments 
The following laboratory safety tests will be performed according to the relevant Schedule of 
Assessments for Part A (Table 1), Part B (Table 2), and Part C (Table 3a inpatients and Table 3b 
outpatients) in Section 8.1. Clinically significantly abnormal laboratory finding should be 
followed up until resolution or until the analyte is stable. If the post-treatment data is reported as 
invalid, an unscheduled visit should be performed to repeat the laboratory safety tests within 
2 weeks after Dose 10. 
 
Haematology 
 
Haemoglobin, haematocrit, white blood cell count (total and differential), red blood cell count, 
platelet count, mean cell volume (MCV), mean cell haemoglobin (MCH), and MCH 
concentration (MCHC). 
 
Clinical Chemistry 
 
Creatinine, urea (or blood urea nitrogen), AST, ALT, gamma glutamyltransferase, alkaline 
phosphatase, lactate dehydrogenase, total bilirubin, albumin, total protein, sodium, potassium, 
chloride, glucose, and calcium. 
Note: for the Screening Visit ONLY, AST and ALT analysis can also be conducted at the local 
laboratory, although a blood sample must also be sent to the Central laboratory for analysis. 
Urinalysis 
 
pH, glucose, ketones, blood, protein, and microscopy. 
 
10.1.3.5 
Clinical Laboratory Evaluation 
The haematology and clinical chemistry safety laboratory analyses will be performed at the 
following laboratory: 
 
Eurofins Central Laboratory Lancaster 
2430 New Holland Pike 
Lancaster, PA 17601 
USA 
Tel +1 717 556 7350 
Fax +1 717 556 3888 


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For those analyses that are subcontracted to other laboratories (plasma PK and nasopharyngeal 
swab samples), the test results will be reported directly to Syneos Health. 
 
Reference ranges will be supplied by Eurofins and used by the Investigator to assess the safety 
laboratory data for clinical significance and pathological changes. 
 
10.1.3.6 
Other Laboratory Variables 
Not applicable 
 
10.1.3.7 
Vital Signs 
Vital signs (body temperature, systolic and diastolic BP, oxygen saturation, HR, RR, and pulse 
oximetry) will be recorded at the time points specified in the relevant Schedule of Assessments 
for Part A (Table 1), Part B (Table 2) and Part C (Table 3a inpatients and Table 3b outpatients). 
 
In Part C, collected vital signs and SpO2 levels will be analyzed as normal, mild, moderate, or 
severe according to the following definitions: 
• Temperature: 
o Normal (no fever): <38°C 
o Mild: 38-39°C 
o Moderate: >39-40°C 
o Severe: >40°C 
• Respiratory rate (breaths/min): 
o Normal: ≤30 
o Mild: 31-45 
o Moderate: 46-60 
o Severe: >60 
• SpO2 on Room Air (Oxygen Saturation) 
o Normal: >94% 
o Mild: >92-94% 
o Moderate: 90-92% 
o Severe: <90% 
 
10.1.3.8 
Physical Examination 
A full body physical examination will be performed at the time points specified in the relevant 
Schedule of Assessments for Part A (Table 1), Part B (Table 2) and Part C (Table 3a inpatients 
and Table 3b outpatients) in Section 8.1 and will include lung auscultation (wheezing during 
expiration/inspiration, crackles/crepitations), retraction of respiratory muscles, and general 
condition. Any changes from baseline will be recorded. 
 
10.1.3.9 
Electrocardiograms 
A 12-lead ECG will be performed at Screening. Additional 12 lead ECGs will be performed at 
scheduled time points as indicated in the relevant Schedule of Assessments for Part A (Table 1), 
Part B (Table 2), and Part C (Table 3a inpatients and Table 3b outpatients) in Section 8.1. 


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10.1.3.10 Other Evaluations 
Pulse Oximetry: Pulse Oximetry should be measured for all subjects without oxygen supply if 
deemed safe. When the SpO2 is measured, always record the method of O2 delivery, even if the 
SpO2 is measured on room air. Any changes from baseline will be recorded. 
 
Hydration Status: An evaluation of signs of dehydration according to the judgement of the 
Investigator should be performed (Appendix 17.5 is to be used for reference) and recorded. 
 
10.2 Data Safety Monitoring Committee 
The DSMC will consist of medical advisers/monitors, pharmacokineticists, and biostatisticians. 
The DSMC will only include independent reviewers. 
The DSMC will review all available safety and PK data collected 
 
The specific responsibilities, composition of the DSMC, and the details of outputs provided for 
the review meeting are outlined in the DSMC Charter. 
 
10.3 Appropriateness of Measurements 
Assessments of the safety, efficacy, and PK measures planned for this study are widely used and 
generally recognised as reliable, accurate, and relevant to the disease condition. 


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11 STATISTICAL METHODS 
 
11.1 Statistical and Analytical Plans 
 
A statistical analysis plan (SAP) will be prepared by Syneos Health as a separate document. The 
SAP will include a more detailed description of the planned statistical methodologies for each 
part of the study. The SAP will be finalised before the closure of Part A. Any subsequent SAP 
amendments applicable to Parts B or C will be signed off prior to database lock and unblinding 
of the respective parts. 
 
11.1.1 Datasets or Populations Analysed 
 
The study populations include the Safety Population, PK Population, PD Population, and 
Efficacy Population. 
 
Safety Population: defined as all subjects who received a single dose (Part A) or any part of any 
multiple dosing regimens (Parts B and C) of IMP (RV521 or placebo). The Safety Population is 
the primary population for the analysis of safety data. Analysis will be according to actual 
treatment received. 
 
PK Population: defined as all subjects who receive IMP and have at least 1 post-dose PK 
concentration measured. The PK Population is the primary population for the analysis of PK 
data. Analysis will be according to actual treatment received. 
 
Modified Intent-to-Treat (mITT) Population 
 
The mITT Population is the primary population for the analysis of efficacy and PD data. Subjects 
will be analysed according to the randomised treatment. The mITT Population is defined as 
follows: 
• In Part A, the mITT is defined as all subjects enrolled in the study who have an RT-qPCR 
viral load measurement and/or CBIA, if available, for at least 1 time point including 
baseline: pre-dose at Dosing Visit 1. 
• In Part B, the mITT Population will include all subjects who received at least one dose of 
IMP (RV521 or placebo) and have a pre-treatment positive RSV nasopharyngeal swab 
confirmed by the central laboratory and agreed by the project team during the blind data 
review meeting. Potential inclusion of subjects who have not completed at least 6 doses of 
IMP will be decided by the project team during the blind data review meeting. Subjects 
will be analysed according to the randomised treatment. 
• In Part C, the mITT Population will include all subjects who received at least one dose of 
IMP and have a pre-treatment positive RSV confirmed by the central laboratory. 
 
Demographic and Other Baseline Characteristics: Demographic and baseline characteristics 
will be summarised descriptively by treatment. Quantitative variables will be summarised using 
the statistics n (number of observations), mean, standard deviation, median, minimum and 


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maximum. Qualitative variables will be summarised using n (number of subjects), absolute 
numbers and relative frequencies (%) per class. 
 
11.1.2 Pharmacokinetic Variables 
The PK characteristics of RV521 to be assessed will be: Cmax, AUC0-12, AUC0-t, t1/2, AUC0-∞, 
CL/F), V/F and C12 (data permitting), and in addition for Part B: accumulation ratio, percent 
fluctuation, AUCtau, Cave, Cmin (Ctrough) as well as any other relevant parameters. 
 
Pharmacokinetic analysis will include listings and summaries of PK concentrations by time 
point, derived PK, parameters and analysis of relationship with dose and body weight. 
 
Data regarding exposure after accumulation will be compared to parameters observed in adult 
subjects (Cmax, AUCtau, C12 [data permitting]) with the application of a possible safety factor. 
 
11.1.3 Pharmacodynamic Variables 
Pharmacodynamic variables include individual viral loads (by RT-qPCR) and/or CBIA if 
available at each sampling time point, percent change from baseline for 60 and 156 hours after 
first dose as well as other additional PD parameters may be also considered as PD endpoints. 
 
For Parts B and C, the DAVG statistic (time-weighted average change in RSV viral load), for both 
total RSV viral load by RT-qPCR and RSV viral load by CBIA, will be calculated as: 
 
DAVG = 
𝑏𝑏 
𝑖𝑖=𝑎𝑎 0.5 (𝑌𝑌𝑖𝑖+𝑌𝑌𝑖𝑖+1) (𝑡𝑡𝑖𝑖+1−𝑡𝑡𝑖𝑖 ) 
𝑡𝑡𝑏𝑏− 𝑡𝑡𝑎𝑎 
 
Where Yi is the change from baseline in log10 RSV viral load at time point i, t is the actual time 
at the specified time point, a is the baseline assessment at Dosing Visit 1, and b is the last 
assessment on Follow up Day 7. 
Pharmacodynamic parameters, including the viral load, AUC, and any other PD parameters 
which are derived, will be summarised by treatment (dose level). For Parts B and C, comparisons 
will be made between RV521 and placebo using analysis of covariance models. Data will be log 
transformed as appropriate. 
 
The primary analysis in Part C will be the time-weighted average change in nasopharyngeal RSV 
viral load which will be calculated from baseline (Day of Randomisation) to Day 7 and 
compared across treatment groups. An analysis of the RSV viral load in the presence and 
absence of other known respiratory pathogens will be performed. This analysis will be outlined 
in the SAP. 
 
Secondary virology endpoints derived from the RSV viral load as measured in nasopharyngeal 
swabs will include but are not limited to: 
• Change from baseline in viral load (RT-qPCR and CBIA) at each time point 
• Time to below viral load quantification limit (RT-qPCR and CBIA) 
∑


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• Proportion of subjects with viral load below quantification limit (RT-qPCR and CBIA) at 
each timepoint throughout the study 
 
 
 
Note: the key analysis will pool subjects with both RSV A and RSV B. However, selected 
analyses will be repeated for the RSV A and RSV B subgroups separately. 
Further details of the analyses will be provided in the SAP. 
 
11.1.4 CCI 
 
 
 
 
 
 
11.1.5 Clinical Response Variables 
 
Two scales of clinical response will be considered, the RSV Clinical Scoring System and the 
ReSViNet scale. In Parts A and B, clinicians will complete the RSV Clinical Scoring System, 
which gives a score from 0 to 12. In Part C, the ReSVinet scale for clinicians, which gives a 
score from 0 to 20 will be completed. For parental assessment of clinical response, the Adapted 
Version of ReSVinet Scale for Parental Use, which gives a score from 0 to 20 will be analysed. 
 
Both the RSV Clinical Scoring System and the ReSViNet scale for clinicians will be summarised 
by treatment (dose level) and time point. In addition, for post-dose assessments, change from 
baseline will also be summarised, where baseline is the last non-missing score prior to the first 
dose of study drug. For Parts B and C, comparisons will be made between RV521 and placebo 
using analysis of covariance models. 
 
In addition the score for the RSV Clinical Scoring System will be categorised as: 
CCI 


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• Mild – scores ≤ 5 
• Moderate – scores > 5 and < 9 
• Severe – scores ≥ 9 
The number and percent of subjects with mild, moderate and severe assessments will be 
summarised by treatment (dose level and time point). 
The Adapted Version of ReSVinet Scale for Parental Use score will be summarised by treatment 
(dose level) and time point. In addition, for post-dose assessments, change from baseline will 
also be summarised, where baseline is the last non-missing score prior to the first dose of study 
drug. For Part B and Part C, comparisons will be made between RV521 and placebo using 
analysis of covariance models. 
 
Individual RSV-related signs and symptoms (Appendix 17.4) at each visit will be summarised by 
treatment (dose level). Quantitative variables will be summarised using the statistics number of 
observations (n), mean, SD, median, minimum and maximum values. In addition, change from 
baseline will also be summarised for post-baseline visits. Baseline will be defined as the last non- 
missing result before the first dose of study medication. Qualitative variables will be summarised 
using n (number of subjects), absolute numbers and relative frequencies (%) per class. 
 
Time to improvement will be calculated for RSV-related signs and symptoms that are classified 
as moderate or severe during the course of the study and will be defined as the time from 
randomisation until no longer present (absent) or mild. 
The Overall Time to Improvement will be defined as the time from randomisation to the time 
that all RSV-related signs and symptoms are mild or absent. The overall time to improvement 
will be summarised for each treatment group by mean, median, SD, minimum and maximum and 
95% confidence intervals. 
Overall Time to Resolution of RSV-related signs and symptoms will be calculated from the time 
of randomisation to the time that they are no longer present (absent), and will be summarised and 
analysed as for Time to Improvement. 
Treatment groups will be compared for differences in overall severity assessed by the composite 
symptom score on each day whilst hospitalised and at follow-up visits. 
For Part C, time to resolution of symptoms will be compared between each dose level of RV521 
and Placebo using a generalised Wilcoxon Rank test. Details of the analysis will be provided in 
the SAP. 
 
11.1.6 Safety Variables 
 
Adverse events will be coded according to the current version of MedDRA. Summary tables of 
AEs will be based on TEAEs, defined as events starting, or worsening, after the first dose of 
IMP. Summaries, by MedDRA SOC and Preferred Term, will be provided for all TEAEs, all 
treatment-related TEAEs (with causality assessed as possibly, probably or definitively related to 
IMP), all serious TEAEs and all AEs leading to early discontinuation from the study. Summary 
tables by maximum severity and maximum relationship, and by intensity per CTCAE will be 
presented. 


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For laboratory tests, ECG measures and vital signs parameters, baseline will be defined as the 
last non-missing result prior to the first dose of IMP. Results at each visit will be summarised 
using the statistics: n (number of observations), mean, SD, median, minimum and maximum. In 
addition, change from baseline from all safety parameters will also be summarised by post- 
baseline visits. 
 
11.1.7 Interim Analyses 
 
No formal interim analyses will be conducted. Each of Parts A, B and C will be reported 
separately and no pooling of Parts will occur. 
 
Following review of Part B, a decision will be made regarding the dose levels to be investigated 
in Part C. 
 
Note: Part C data will be analysed separately to the Part B data. Data will not be combined 
across Parts B and C, and therefore, the analysis of Part B has no impact on the type I error. 
 
 
11.2 Determination of Sample Size 
 
Because of the exploratory nature of the study, a formal sample size calculation has not been 
performed for Parts A and B. Twenty-four subjects enrolled in Part B and receiving RV521 or 
placebo (2:1) at the same dose level and according to the same dosing regimen for their specified 
age range group are expected to be sufficient to assess safety, PK, and antiviral data. 
 
For an anti-viral effect (Part B), measured as a difference in viral load at a specific time point, 
and using data from the human challenge model (Study CCI 
), 24 subjects split 16/8 would 
have 69% power to identify a difference of 2 log units, 87% power for a difference of 2.5 log 
units and 96% power for a difference of 3 log units. 
Estimates for total enrolment into Part C are based on the report by Cunningham et al (2021); an 
assumed time-weighted average change in RSV log10 viral load from baseline to day 7 in the 
placebo group of -1.5 log10 vp/ml, with a standard deviation of 1.25. A sample size of 34 per 
group will provide 90% power to detect at least 1 log10 decrease in RV521 groups using a 
2-sided significance level of 0.05. To account for potential drop outs, an additional 10% will be 
added to give group size of 37 (total 111 subjects randomised 1:1:1; 2 dose levels of RV-521 vs. 
placebo). 
11.3 Protocol Deviations 
Protocol deviations will be listed only. Protocol deviations will be identified through a review of 
derivations captured by the Syneos Health site monitors and through programmatic checks on the 
database. 


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Protocol deviations include: 
 
• Subjects not meeting eligibility criteria. 
• Subjects who have been unblinded. 
• Subjects taking prohibited concomitant medications during the study. 
Further details will be given in the SAP. 
12 
QUALITY ASSURANCE AND QUALITY CONTROL 
 
12.1 Audit and Inspection 
Study centres and study documentation may be subject to Quality Assurance audit during the 
course of the study by the Sponsor or its nominated representative. In addition, inspections may 
be conducted by regulatory authorities at their discretion. 
12.2 Monitoring 
Data for each subject will be recorded on a CRF. Data collection must be completed for each 
subject who signs an ICF and is administered IMP. 
In accordance with current GCP and ICH guidelines, the study monitor will carry out source 
document verification at regular intervals to ensure that the data collected in the CRF are 
accurate and reliable. Appropriate modifications to study conduct, including monitoring and 
source document verification procedures will be observed, consistent with the FDA Guidance on 
Conduct of Clinical Trials of Medical Products during the COVID-19 Pandemic; March 2020; 
the EMA Guidance on the Management of Clinical Trials During the COVID-19 
(CORONAVIRUS) Pandemic; Version 4 (04/02/2021); and other local guidance in place at the 
time of study conduct. 
The Investigator must permit the monitor, the IEC/IRB, the Sponsor’s internal auditors, and 
representatives from regulatory authorities direct access to all study-related documents and 
pertinent hospital or medical records for confirmation of data contained within the CRFs. 
12.3 Data Management and Coding 
Syneos Health will be responsible for activities associated with the data management of this 
study. This will include setting up a relevant database and data transfer mechanisms, along with 
appropriate validation of data and resolution of queries. Data generated within this clinical study 
will be handled according to the relevant standard operating procedures of the data management 
and biostatistics departments of Syneos Health. 
Study centres will enter data directly into an electronic data capture (EDC) system by completing 
the CRF via a secure internet connection. Data entered into the electronic case report form 
(eCRF) must be verifiable against source documents at the study centre. Data to be recorded 
directly on the eCRF will be identified and the eCRF will be considered the source document. 
Any changes to the data entered into the EDC system will be recorded in the audit trail and will 
be FDA CFR 21 Part 11 compliant. 


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Medical coding will use MedDRA for prior and concomitant diseases, and AEs, and WHODrug 
for medications. 
 
Missing or inconsistent data will be noted within the EDC system and queried with the 
Investigator for clarification. Subsequent modifications to the database will be documented. 
12.4 Quality Management and Risk Evaluation 
 
Details are provided in Section 8.3.2. 
 
13 RECORDS AND SUPPLIES 
 
13.1 Drug Accountability 
 
On receipt of the IMP, the Investigator (or designee) will conduct an inventory and verify that 
IMP supplies have been received intact and in the correct amounts before completing the 
supplies receipt. The Investigator will retain a copy of this receipt at the study centre and send 
the original receipt to the study monitor. The monitor may check the study supplies at each study 
centre at any time during the study. 
 
It is the responsibility of the study monitor to ensure that the Investigator (or designee) has 
correctly documented the amount of the IMP received, dispensed, and returned on the dispensing 
log that will be provided. A full drug accountability log will be maintained at the study centre at 
all times. The study monitor will arrange collection of unused IMP returned by the subject’s 
parents/legal guardians. The study monitor will also perform an inventory of IMP at the close- 
out visit to the study centre. All discrepancies must be accounted for and documented. 
13.2 Financing and Insurance 
 
Financing and insurance of this study will be outlined in a separate agreement between Syneos 
Health and the Sponsor. 


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14 ETHICS 
 
14.1 Independent Ethics Committee or Institutional Review Board 
 
Before initiation of the study at each study centre, the protocol, the ICF, other written material 
given to the subject’s parent (legal guardian), and any other relevant study documentation will be 
submitted to the appropriate IEC/IRB. Written approval of the study and all relevant study 
information must be obtained before the study centre can be initiated or the IMP is released to 
the Investigator. Any necessary extensions or renewals of IEC/IRB approval must be obtained 
for changes to the study such as amendments to the protocol, the ICF or other study 
documentation. The written approval of the IEC/IRB together with the approved ICF must be 
filed in the study files. 
 
The Investigator will report promptly to the IEC/IRB any new information that may adversely 
affect the safety of the subjects or the conduct of the study. The Investigator will submit written 
summaries of the study status to the IEC/IRB as required. On completion of the study, the 
IEC/IRB will be notified that the study has ended. 
 
14.2 Regulatory Authorities 
Relevant study documentation will be submitted to the regulatory authorities of the participating 
countries, according to local/national requirements, for review and approval before the beginning 
of the study. On completion of the study, the regulatory authorities will be notified that the study 
has ended. 
 
14.3 Ethical Conduct of the Study 
 
The Investigator(s) and all parties involved in this study should conduct the study in adherence to 
the ethical principles based on the Declaration of Helsinki, GCP, ICH guidelines, and the 
applicable national and local laws and regulatory requirements. 
 
14.4 Informed Consent 
 
The process of obtaining informed consent must be in accordance with applicable regulatory 
requirement(s) and must adhere to GCP. 
 
The Investigator is responsible for ensuring that no subject undergoes any study-related 
examination or activity before the parent(s)/legal guardian(s) have given written informed 
consent for their child to participate in the study. 
The Investigator or designated personnel will inform the parent(s)/legal guardian(s) of the 
objectives, methods, anticipated benefits and potential risks and inconveniences of the study. The 
parent(s)/legal guardian(s) should be given every opportunity to ask for clarification of any 
points s/he does not understand and, if necessary, ask for more information. At the end of the 
interview, the parent(s)/legal guardian(s) will be given ample time to consider the study. The 
parent(s)/legal guardian(s) will be required to sign and date the ICF. After signatures are 
obtained, the ICF will be kept and archived by the Investigator in the Investigator’s study file. A 


REVC003 
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v. 6.0_31 JAN 2022 
 
signed and dated copy of the subject ICF will be provided to the subject’s authorised 
representative. 
 
It should be emphasised that the parent(s)/legal guardian(s) may refuse permission for their child 
to enter the study or may withdraw their child from the study at any time, without consequences 
for their further care or penalty or loss of benefits to which the subject is otherwise entitled. 
Children of parents(s)/legal guardian(s) who refuse to give or who withdraw written informed 
consent should not be included or continue in the study. 
If new information becomes available that may be relevant to the willingness of the subject’s 
parent(s)/legal guardian(s) to allow continuation of their child’s participation in the study, a new 
ICF will be approved by the IEC(s)/IRB(s) (and regulatory authorities, if required). The 
parent(s)/legal guardian(s) of the study subjects will be informed about this new information and 
reconsent will be obtained. 
 
14.5 Subject Confidentiality 
 
Monitors, auditors, and other authorised agents of the Sponsor and/or its designee, the 
IEC(s)/IRB(s) approving this research, as well as that of any other applicable agency, will be 
granted direct access to the study subjects’ original medical records for verification of clinical 
study procedures and/or data, without violating the confidentiality of the subjects to the extent 
permitted by the law and regulations. In any presentations of the results of this study or in 
publications, the subjects’ identity will remain confidential. 


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15 REPORTING AND PUBLICATION, INCLUDING ARCHIVING 
Essential documents are those documents that individually and collectively permit evaluation of 
the study and quality of the data produced. After completion of the study (end of study is defined 
as the date of the last visit of the last subject), all documents and data relating to the study will be 
kept in an orderly manner by the Investigator in a secure study file. This file will be available for 
inspection by the Sponsor or its representatives. Essential documents should be retained for 
2 years after the final marketing approval in an ICH region or for at least 2 years since the 
discontinuation of clinical development of the investigational product. It is the responsibility of 
the Sponsor or its representatives to inform the study centre when these documents no longer 
need to be retained. The Investigator must contact the Sponsor before destroying any study- 
related documentation. In addition, all subject medical records and other source documentation 
will be kept for the maximum time permitted by the hospital, institution, or medical practice. 
 
The Sponsor must review and approve any results of the study or abstracts for professional 
meetings prepared by the Investigator(s). Published data must not compromise the objectives of 
the study. Data from individual study centres in multicentre studies must not be published 
separately. 


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16 REFERENCES 
Collins PL and Karron RA. Respiratory Syncytial Virus and Metapneumonia Virus. Fields 
Virology. Eds. Knipe DM and Howley P. Walters Kluwer, Netherlands 2013. 
Cunningham S, Piedra PA, Martinon-Torres F, et al. Nebulised ALX-0171 for respiratory 
syncytial virus lower respiratory tract infection in hospitalised children: a double-blind, 
randomised, placebo-controlled, phase 2b trial. Lancet Respir Med. 2021 Jan;9(1):21-32. doi: 
10.1016/S2213-2600(20)30320-9. Epub 2020 Sep 28. PMID: 33002427 
DeVincenzo JP, El Saleeby CM, Bush AJ. Respiratory syncytial virus load predicts disease 
severity in previously healthy infants. J Infect Dis. 2005;191:1861-1868. 
El Saleeby CM, Bush AJ, Harrison LM, et al Respiratory syncytial virus load, viral dynamics, 
and disease severity in previously healthy naturally infected children. J Infect Dis. 2011;204:996- 
1002. 
 
European Medicines Agency. Guideline on reporting the results of population pharmacokinetic 
analyses. London, 21 June 2007. Doc. Ref. CHMP/EWP/185990/06 
http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500 
003067.pdf 
 
European Medicines Agency. Guidance on the Management of Clinical Trials During the 
COVID-19 CORONAVIRUS) Pandemic; Version 4 (04/02/2021) 
 
Global Strategy for Asthma Management and Prevention (2020 Update), Global Initiative for 
Asthma. 
 
Guidance for Industry, Investigators, and Insititutional Review Boards. FDA Guidance on 
Conduct of Clinical Trials of Medical Products during COVID-19 Pandemic. March 2020. 
https://www.fda.gov/regulatory-information/search-fda-guidance-documents/fda-guidance- 
conduct-clinical-trials-medical-products-during-covid-19-public-health-emergency 
 
Guidance for Industry. General Considerations for Pediatric Pharmacokinetic Studies for Drugs 
and Biological Products. U.S. Department of Health and Human Services. Food and Drug 
Administration. Center for Drug Evaluation and Research (CDER). Center for Biologics 
Evaluation and Research (CBER). November 1998. 
 
Guideline on the role of pharmacokinetics in the development of medicinal products in the 
paediatric population. European Medicines Agency. Committee For Medicinal Products For 
Human Use (CHMP). London, 28 June 2006. Doc. Ref. EMEA/CHMP/EWP/147013/2004. 
Hall CB, Weinberg GA, Iwane MK, et al. The burden of respiratory syncytial virus infection in 
young children. N Engl J Med. 2009;360:588-598. 
National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) v5.0. 
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm 


REVC003 
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v. 6.0_31 JAN 2022 
 
Population PK Modelling Report. Population Pharmacokinetics and Dose Simulation for 
Pediatric Studies for RV521. Syneos Health 12 February 2018. 
 
Regnier SA and Huels J. Association between respiratory syncytial virus hospitalizations in 
infants and respiratory sequelae: systematic review and meta-analysis. Pediatr Infect Dis J. 
2013;32:820-826. 
Scheltema NM, Gentile A, Lucien F, et al. Global respiratory syncytial virus-associated mortality 
in young children (RSV GOLD): a retrospective case series. Lancet Glob Health. 2017;5:e984- 
991. 
 
Shi T, McAllister DA, O’Brien KL, et al. Global, regional, and national disease burden estimates 
of acute lower respiratory infections due to respiratory syncytial virus in young children in 2015: 
a systemic review and modelling study. Lancet. 2017;390:946-958. 
Simões EAF, DeVincenzo JP, Michael Boeckh M. Challenges and opportunities in developing 
respiratory syncytial virus therapeutics. J Infect Dis. 2015;211(S1):S1-S20. 
Taylor S, Taylor RJ, Lustig RL, et al. Modelling estimates of the burden of respiratory syncytial 
virus infection in children in the UK. BMJ. 2016;Open 6:e009337. 
Vega RM, Avva U. Pediatric dehydration. Treasure Island, FL: StatPearls Publishing [Internet]. 
Last update: February 3, 2019. https://www.ncbi.nlm.nih.gov/books/NBK436022/ 
Wang EE, Milner RA, Navas L, Maj H. Observer agreement for respiratory signs and oximetry 
in infants hospitalized with lower respiratory infections. Am Rev Respir Dis. 1992;145(1):106- 
109. 


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17 APPENDICES 
17.1 RSV Clinical Scoring System for Infants with RSV Infection ≥ 1 Month of Age (Parts 
A and B) 
 
Score 
Respiratory 
Rate 
(breaths/min) 
Wheezing 
Retraction of 
Respiratory 
Muscles 
General 
Condition 
0 
< 30 
Nonea 
None 
Normal 
1 
31-45 
Terminal expiration or 
only with stethoscope 
Intercostal only 
- 
2 
46-60 
Entire expiration or 
audible on expiration 
without stethoscope 
Tracheosternal 
- 
3 
> 60 
Expiration and 
inspiration audible 
without stethoscope 
Severe with nasal 
flaring 
Irritable, lethargic, 
poor feeding 
a If no wheezing is audible due to minimal air entry, score 3. 
 
Severity Grading 
≤ 5 
Mild 
> 5 but < 9 
Moderate 
≥ 9 
Severe 
 
Reference 
Wang EE, 1992 


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17.2 ReSVinet Scale for Parental Use 
 
Item 
0 points 
1 points 
2 points 
3 points 
1 
Feeding 
intolerance 
No 
Mild Decreased appetite (the child did 
not eat the same as normally) and/or 
presented isolated vomits with or 
without cough. 
Partial Frequent vomits with cough, but 
the child does not vomit with every 
intake. Feeding exhausts the child. 
Total Child is unable to feed him/herself. The 
use of a nasogastric tube or parenteral nutrition 
was required. 
2 
Medical 
intervention 
No 
Basic The child’s respiratory 
secretions required removal, he or she 
was explored by a physician or 
received sporadically nebulised 
medication. Antipyretics were 
administered. 
Intermediate The child required oxygen 
therapy, underwent a chest X-ray 
exploration, or a blood sample was 
extracted. Treatment with nebulised 
drugs was given regularly. 
High The child required respiratory support 
with a machine. Respiratory support was given 
through a special mask applied on the nose or 
mouth or resting on the child’s face, or through 
an endotracheal tube. 
3 
Respiratory 
difficulty 
No 
Mild The child was not breathing 
normally, but he/she does not seem to 
have any difficulty when drawing air. 
Moderate The child made an effort for 
breathing. Respiratory noises can be 
heard without the need of a stethoscope 
(just approaching the ear to his or her 
chest). 
Severe Respiratory effort was obvious. The 
child made important movement of his/her 
chest, the chest even collapses with every 
movement, and muscles of neck and belly were 
used. A lot of respiratory noise was heard 
without approaching the ear to the child’s chest. 
4 
Respiratory 
frequency 
Normal 
Mild or occasional tachypnoea The 
child breathed more rapidly, but the 
situation was well tolerated, or the 
respiratory frequency was normalised 
after removing secretions from 
respiratory airways or administering 
nebulised medication. 
Prolonged or recurrent tachypnoea 
The child breathed more rapidly in a 
more persistent manner, even after 
receiving nebulised medication or 
removing secretions from respiratory 
tract. 
Severe alteration The child breathed quickly 
and superficially, or really deeply. The child 
was agitated or drowsy. 
5 
Apnoea 
No 
Yes The child stopped breathing. It may have 
been necessary to stimulate him/her in order to 
regain normal breathing rate. 
6 
General 
Condition 
Normal 
Mild Child did not seem the same as 
always, but there did not seem to be 
anything to worry about. 
Moderate Child looked ill, and medical 
examination was required, but it did not 
feel like a life-threatening situation. 
Severe Child was agitated, apathetic, and/or 
lethargic. He/she required urgent medical 
attention. There was no need to be a doctor to 
see that the clinical situation of the child is 
worrying. 
7 
Fever 
No 
Yes, mild rectal or tympanic 
temperature < 38.5°C, or axillar 
temperature < 38°C 
Yes, moderate rectal or tympanic 
temperature > 38.5°C, or axillar 
temperature > 38°C 


REVC003 
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CCI 
CCI 
CCI 
17.3 List of Drugs Affecting CCI 
 and CCI  
 
Guidance regarding potential interactions with concomitant medications 
E1. Concomitant Medications Relevant to RSV521 
A clinical DDI study (REVC004) studied the effect of RV521 on the exposure of an index 
CYP3A4 substrate, midazolam, and the effects of a CYP3A4 inhibitor, itraconazole, a PGP 
inhibitor, verapamil and a CYP3A4 inducer, rifampicin on the exposure of RV521. The study 
has completed. The study suggests that RV521 can CCI 
 the exposure (Cmax and AUC0-12) 
of CCI 
 
 by approximately 
CCI and CCI fold, respectively. The study also demonstrated that 
the CCI 
 
 
, CCI 
 the exposure (Cmax and AUC0-12) of 
RV521 by approximately 
CCI and CCI fold, respectively and the  
 
, similarly 
CCI 
 the exposure ( both Cmax and AUC0-12) of RV521 by approximately CCI  . 
Additionally, the CCI 
 
 
 
 the exposure (Cmax and 
AUC0-12) of RV521 by approximately CCI and CCIfold, respectively. 
Therefore, it is anticipated that the exposure of RSV521 may be affected by drugs that CCI 
 or 
CCI 
. Table E1 provides a list of CCI .    Table    E2    provides    a 
list of CCI 
 
. Patients receiving CCI  
 
or 
within days before the first dose are 
excluded from enrolment in the study. If patients require any of these medications during the 
dosing period of the study then they should be withdrawn from the study. 
It is also anticipated that RV521 will affect the exposure of some CCI 
 substrates that have a 
narrow therapeutic range as RV521 is shown to be a CCI 
 
. Table E3 
provides a list of CCI 
 substrates. Patients receiving drugs which are known to be 
CCI 
 
 substrates within 2 weeks before the first dose of study 
treatment are excluded from enrolment in the study. 
These lists are not intended to be exhaustive, and similar restrictions will apply to other agents 
that are known to CCI 
 activity or may be affected by CCI 
 
. If required, please refer to full prescribing information for all drugs prior to co- 
administration with RSV521. 
Table E1 CCI 
 which may increase exposure to 
RV521 and are prohibited in the study 
 
 
CCI 
 


REVC003 
Page 107 of 111 
v. 6.0_31 JAN 2022 
 
Table E2 CCI 
 which may decrease exporsure to 
RV521 and are prohibited in the study 
 
 
 
Table E3 CCI 
 substrates that are permitted during the study at the 
investigator’s discretion and with close monitoring 
 
 
CCI 
 
CCI 
 


REVC003 
Page 108 of 111 
v. 6.0_31 JAN 2022 
 
17.4 RSV-related Signs and Symptoms to be Collected 
Temperature 
enter 
 
Respiratory Rate 
enter 
 
 
Coryza 
Cough 
None ☐ 
None ☐ 
Mild ☐ 
Moderate ☐ 
Mild ☐ 
Moderate ☐ 
Severe☐ 
Severe☐ 
Grunting with expiration 
None ☐ 
Present 
☐ 
Nasal flaring 
None ☐ 
Present 
☐ 
Retractions 
None ☐ 
Mild ☐ 
Moderate ☐ 
Severe☐ 
Wheezing 
SpO2 on room air 
None ☐ 
Mild ☐ 
enter 
 
Moderate ☐ 
Severe☐ 


REVC003 
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17.5 Dehydration Evaluation – Part of Physical Examination 
 
Dehydration: 
None ☐ 
Mild 3-5% ☐ 
Moderate 6-10% ☐ 
Severe > 10%☐ 
 
Dehydration% 
Mild 3% to 5% 
Moderate 6% to 
10% 
Severe > 10% 
Mental status 
Normal 
Listless, irritable 
Lethargy, altered 
mental status 
Heart rate 
Normal 
Increased 
Increased 
Quality of Pulses 
Normal 
Normal to decreased 
Decreased to thready 
Capillary refill 
Normal 
Prolonged 
Prolonged 
Blood pressure 
Normal 
Normal 
Normal to decreased 
Respirations 
Normal 
Tachypnea 
Tachypnea, deep 
Eyes 
Normal 
Slightly sunken, 
decreased tears 
Sunken, cries without 
tears 
Fontanelle 
Normal 
Sunken 
Sunken 
Urine output 
Normal to decreased 
Decreased 
Oliguric or anuric 
Source: Vega RM, 2019 
 
Note: This is a guide for the investigator. Just enter category, DO NOT enter each factor. 


REVC003 
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v. 6.0_31 JAN 2022 
 
17.6 ReSVinet Scale for Clinicians 
 


REVC003 
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SAP_001.pdf: 
This document is confidential. 
SAP Version: 2.0, 14-Jun-2021 
Page 1 of 87 
 
 
 
Statistical Analysis Plan for Interventional Studies 
 
 
Sponsor Name: ReViral Ltd 
 
Protocol Number: REVC003 
 
Protocol Title: A Phase 2a Open-Label Study in Infants with REspiratory Syncytial VIRus Lower 
RespirAtory Tract Infection, Followed by a DoubLe-blind, Placebo-controlled Part, to Evaluate the Safety, 
Tolerability, Pharmacokinetics and Antiviral Effect of RV521 (REVIRAL 1) 
 
Protocol Version and Date: 
Version 1.0, 30 July 2018 
Version 2.0, 02 October 2018 
Version 3.0, 13 May 2019 
Version 4.0, 15 January 2020 
Version 4.2 Spain, 15 April 2020 
CCI 
 
Authors: 
 
 
 
 
 
 
Notice of Confidential and Proprietary Information: 
The information contained in this document is confidential belonging to ReViral Ltd. Acceptance of this 
document constitutes agreement by the recipient that no information contained herein will be published or 
disclosed without prior written authorization from an official of ReViral Ltd. However, this document may 
be disclosed to appropriate Institutional Review Board and Ethics Committees or duly authorized 
representatives of a national regulatory authority under the condition that they are requested to keep it 
confidential. In the event of an actual or suspected breach of this obligation, Syneos Health should be 
notified promptly. 
PPD 


Statistical Analysis Plan for Interventional Studies 
Sponsor: ReViral Ltd; Protocol No.: REVC003 
This document is confidential. 
SAP Version: 2.0, 14-Jun-2021 
Page 2 of 87 
 
 
 
Revision History 
 
Version # 
Date 
(DD-Mmm-YYYY) 
Document Owner 
Revision Summary 
1.0 
09-Oct-2020 
PPD 
 
Initial Release Version 
2.0 
14-Jun-2021 
PPD 
 
Clarifications and updates prior to Part A analysis 


Statistical Analysis Plan for Interventional Studies 
Sponsor: ReViral Ltd; Protocol No.: REVC003 
This document is confidential. 
SAP Version: 2.0, 14-Jun-2021 
Page 3 of 87 
 
 
 
 


Statistical Analysis Plan for Interventional Studies 
Sponsor: ReViral Ltd; Protocol No.: REVC003 
This document is confidential. 
SAP Version: 2.0, 14-Jun-2021 
Page 4 of 87 
 
 
 
Table of Contents 
Revision History .......................................................................................................................... 2 
Approvals .................................................................................................................................. 3 
Glossary of Abbreviations ................................................................................................... 8 
Purpose ............................................................................................................................ 10 
  Study Objectives ................................................................................................................ 11 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Endpoints ......................................................................................................................... 33 
 
 
 
 
Analysis Populations ......................................................................................................... 36 
 
 
 


Statistical Analysis Plan for Interventional Studies 
Sponsor: ReViral Ltd; Protocol No.: REVC003 
This document is confidential. 
SAP Version: 2.0, 14-Jun-2021 
Page 5 of 87 
 
 
 
 
 
 
  General Aspects for Statistical Analysis ............................................................................ 37 
 
 
 
 
 
 
Demographic, Other Baseline Characteristics and Medication .......................................... 39 
 
 
 
 
 
 
 
  Clinical Efficacy .................................................................................................................. 41 
 
 
 
 
 
 
  Analysis Of Pharmacokinetics (PK) ................................................................................... 44 
 
 
 
 
 
 
 


Statistical Analysis Plan for Interventional Studies 
Sponsor: ReViral Ltd; Protocol No.: REVC003 
This document is confidential. 
SAP Version: 2.0, 14-Jun-2021 
Page 6 of 87 
 
 
 
 
 
 
 
  Analysis Of Pharmacodynamics (PD) ............................................................................... 49 
 
 
 
 
 
CCI 
53 
CCI 
 
CCI 
 
Safety ............................................................................................................................... 54 
 
 
 
 
 
 
 
  Interim Analyses ................................................................................................................ 58 
Changes from Analysis Planned in Protocol ...................................................................... 59 
  Changes from Version 1.0 of the SAP .............................................................................. 60 
  Reference List ................................................................................................................... 61 
Programming Considerations ............................................................................................ 62 
 
 
 
 
 
 
 


Statistical Analysis Plan for Interventional Studies 
Sponsor: ReViral Ltd; Protocol No.: REVC003 
This document is confidential. 
SAP Version: 2.0, 14-Jun-2021 
Page 7 of 87 
 
 
 
 
 
 
  Quality Control ................................................................................................................... 67 
  Index of Tables................................................................................................................. 68 
  Index of Figures ............................................................................................................... 81 
Index of Listings ................................................................................................................ 85 
Appendices ....................................................................................................................... 87 


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Glossary of Abbreviations 
 
Abbreviation 
Description 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
ANCOVA 
Analysis of Covariance 
AST 
Aspartate Aminotransferase 
AUC 
Area Under the Curve 
AUC0-12 
Area Under the Plasma Concentration–Time Curve from Zero to 
12 Hours 
AUC0-∞ 
Area Under the Plasma Concentration-Time Curve from Zero to 
Infinity 
AUC0-t 
Area Under the Plasma Concentration-Time Curve from Zero to the 
Last Measurable Concentration 
AUC0-tau 
Area Under the Plasma Concentration-Time Curve from Zero to the 
End of Last Dosing Interval 
BMI 
Body Mass index 
C12 
Trough Concentration at the End of 1st Dosing Interval 
Cave 
Average Plasma Concentration over Dosing Interval 
CBIA 
Cell-based Infectivity Assay 
CL/F 
Apparent total body clearance 
Cmax 
Maximum Observed Plasma Concentration 
Cmin 
Minimum Observed Plasma Concentration 
CRF 
Case Report Form 
CTCAE 
Common Terminology Criteria for Adverse Events (AEs) 
Ctrough 
Plasma Trough Concentration 
CV 
Coefficient of Variation 
DSMC 
Data Safety Monitoring Committee 
EC90 
90% of the effective concentration 
ECG 
Electrocardiogram 
ICH 
International Conference on Harmonisation 
IV 
Intravenous 
LLoQ 
Lower Limit of Quantification 
LoD 
Limit of Detection 


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Abbreviation 
Description 
LRTI 
Lower Respiratory Tract Infection 
lsmean 
Least Square Mean 
Max 
Maximum 
MedDRA 
Medical Dictionary for Regulatory Activities 
Min 
Minimum 
mITT 
Modified Intent-to-Treat 
N/A 
Not Applicable 
NA 
Not Applicable 
NCI 
National Cancer Institute 
PD 
Pharmacodynamics 
PK 
Pharmacokinetics 
PT 
Preferred Term 
Q1 
First Quartile 
Q3 
Third Quartile 
RSV 
Respiratory Syncytial Virus 
RT-qPCR 
Reverse Transcriptase Quantitative Polymerase Chain Reaction 
SAE 
Serious AE 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
t1/2 
Terminal Half-life 
TEAE 
Treatment Emergent AE 
tmax 
Time to Maximum Plasma Concentration 
TFL 
Tables, Figures and Listings 
V/F 
Apparent Volume of Distribution of the Drug after Extravascular 
Administration 
WHO 
World Health Organisation 


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Purpose 
 
The purpose of this statistical analysis plan (SAP) is to ensure that the data listings, summary tables and 
figures which will be produced, and the statistical methodologies that will be used, are complete and 
appropriate to allow valid conclusions regarding the study objectives. 
 
Responsibilities 
Syneos Health will perform the statistical analyses and are responsible for the production and quality 
control of all tables, figures and listings (TFLs). 
 
Timings of Analyses 
The primary analysis of safety, tolerability, pharmacokinetics (PK) and antiviral effect of RV521 for 
Parts A, B and C are planned after all subjects from the respective study part complete the final study visit 
or terminate early from the study. The data will therefore be reported in 3 separate parts. 
 
Interim data summaries will be provided to the independent Data Safety Monitoring Committee (DSMC) 
according to the DSMC Charter or as requested by the DSMC to allow performance of their duties to 
monitor the safety of the subjects enrolled in the study. 


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Study Objectives 
 
 
Primary Objectives 
To evaluate the safety and tolerability of single (Part A) and multiple (Part B) oral doses of RV521 in infants 
hospitalised with respiratory syncytial virus (RSV) lower respiratory tract infection (LRTI). 
 
 
Secondary Objectives 
• 
To characterise the PK of single (Part A) and multiple (Part B) oral doses of RV521 in infants 
hospitalised with RSV LRTI. Note that in Spain, this was promoted to a primary objective. 
 
• 
Part B: To evaluate the antiviral effects of RV521 in infants hospitalised with RSV LRTI. 
 
• 
Part B: To evaluate the effect of RV521 compared to placebo on the clinical course of RSV 
infection. 
 
 
Exploratory Objectives 
• 
 
 
 
 
Objectives for Part C 
• 
Primary Objective: To evaluate the effect of RV521, compared to placebo, on the clinical course 
of RSV LRTI. 
 
• 
Secondary Objectives: 
 
o 
Evaluate the safety of RV521 given as a multiple dose regimen. 
 
o 
Effect of RV521, compared to placebo, on nasopharyngeal shedding (viral load) of RSV. 
 
o CCI 
 
o CCI 
 
 
 
 
Brief Description 
The clinical study consists of 3 parts, the third part (Part C) is optional: 
 
• 
Part A is an open-label, multicentre, single-dose study in infants hospitalised with RSV LRTI. 
 
• 
Part B is a randomised, double-blind, placebo-controlled, multicentre multiple dose study in 
infants hospitalised with RSV LRTI. 
 
• 
Part C is a randomised 1:1, double-blind, placebo-controlled, multicentre, multiple-dose study in 
infants hospitalised with RSV LRTI. 
CCI 


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The number of subjects enrolled in Parts A and B of the study will depend on the safety and PK data from 
the group of subjects enrolled in specified cohorts and the subsequent recommendation of the DSMC. 
 
The DSMC may recommend a dose adjustment (either a reduction or an escalation) and/or regimen 
adjustment (Part B only) for subsequent subjects because of the observation of an unexpected 
safety/tolerability profile and/or differences between the observed and predicted exposure resulting from a 
specified dose of RV521. 
Part A 
 
Part A of the study will be conducted across 2 cohorts and will comprise 2 age groups: 
 
• 
Cohort 1: subjects ≥ 6 months to ≤ 36 months 
 
• 
Cohort 2: subjects ≥ 1 month to < 6 months 
 
The proposed starting doses of RV521 of 2.5 mg/kg for subjects ≥ 6 months to ≤ 36 months of age 
(Cohort 1) and 2 mg/kg for subjects ≥ 1 month to < 6 months of age (Cohort 2) are expected to deliver a 
specified group mean exposure (1× 90% of the effective concentration [EC90 ] at trough concentration) 
based on PK modelling and simulation using existing clinical data in healthy adult subjects (CCI 
 
and CCI 
) and nonclinical data. PK data from groups of 3 subjects in Cohort 1 and Cohort 2 will be 
reviewed to identify any differences between the observed and predicted exposure resulting from a 
specified dose of RV521. Safety data will be sent to the DSMC for review prior to any dose adjustment. 
 
Enrolment into Part A of the study will commence with the older subjects (Cohort 1). 
 
Any adjustment(s) of dose level that are required within a cohort will occur in a sequential manner. A 
maximum of 2 dose adjustments per cohort are planned. Thus, a minimum of 12 subjects (6 per cohort) 
and a maximum of 24 subjects (12 per cohort) may be enrolled in Part A. 
 
Subjects will participate for up to 8 days, and the visit schedule will include: 
Screening Visit (-24 hours to first dose), Dosing Visit 1 (-2 hours pre-dose to 18-24 hours post-dose), 
Post-dosing Visit 2 (48 hours post-dose), and a Telephone Follow-Up (Day 7). 
 
Part B 
 
Part B will be conducted across 3 cohorts (Cohorts 3, 4, and 5) comprising the following age groups: 
 
• 
Cohort 3: ≥ 6 months to ≤ 36 months 
 
• 
Cohort 4: ≥ 1 month to < 6 months 
 
• 
Cohort 5: ≥ 1 month to ≤ 36 months 
 
After review of the safety and PK data from a specific age group enrolled in Part A, the DSMC will 
determine the dosage and dosing regimen to be used in that age group in Part B, such that the target 
group mean trough concentration is approximately equivalent to 3× EC90 , and approve the start of 
enrolment in that specified age group, i.e., Cohort 3 can start after Cohort 1 (Part A) has been finalised 
and Cohort 4 can start after Cohort 2 (Part A) has been finalised. It is anticipated that subjects enrolled in 
Part B of the study will receive RV521 or placebo twice daily (BID), 12 hours apart, for a period of 


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5 consecutive days (total of 10 doses). However, the dosing regimen may be adjusted depending on the 
DSMC recommendations. 
 
Groups of 4 subjects will be randomised to receive RV521 or placebo (3:1) in Cohort 3 and Cohort 4, with 
enrolment occurring in parallel. It is envisioned that data from a group of 4 subjects will be sufficient to 
confirm the dose exposure relationship for RV521 administered according to a multiple dosing regimen 
and therefore the DSMC will review all available safety and PK data collected from the first group of 
4 subjects in each cohort. In order to identify the optimum dosage and dosing regimen in each age group, 
a maximum of 2 dosage/dosing regimen adjustments is assumed in either or both of the Cohorts 3 and 4. 
Subjects ≥ 6 months to ≤ 36 months of age can be enrolled in Cohort 5 after the completion of Cohort 3 
and subjects ≥ 1 month and < 6 months can be enrolled after the completion of Cohort 4. Enrolment in 
Cohort 5 will continue until 24 evaluable subjects have received RV521 or placebo (2:1) at the dosage 
and dosing regimen specified for each age group (4 subjects from each of Cohorts 3 and 4 will contribute 
to this overall total). Thus a minimum of 24 subjects and a maximum of 40 subjects (assuming 
2 adjustments per age group) may be enrolled in Part B. 
 
Based on the results/conclusions of the interim analysis of the safety, PK, and antiviral data following the 
completion of Part B, there will be an option to enrol up to 120 subjects in Part C if the following 
conditions are met: 
 
1. A dose has been identified that fulfils the target PK profile. 
 
2. Following review by the DSMC, safety at the selected dose is considered acceptable. 
 
3. Sufficient antiviral effect has been identified to support the probability of an effect on the clinical 
manifestations of RSV infection. 
Subjects will participate up to 13 days, and the visit schedule will include: 
Screening Visit (-24 hours to first dose), Dosing Visit 1, Dosing Visit 2, Dosing Visit 3, Dosing Visit 4, 
Dosing Visit 5, Follow-Up 40-48 hours Post-Dose 10 (Visit Day 7) and a Telephone Follow-Up (Day 12). 
Part C 
 
Part C is a double-blind and placebo-controlled study, enrolling 1 cohort (Cohort 6) of approximately 
120 subjects (≥ 1 month to ≤ 36 months of age). After a parent/legal guardian provides informed consent, 
and conditional to satisfactory fulfilment of all inclusion criteria and none of the exclusion criteria (as for 
Parts A and B), subjects will be randomised 1:1 to receive RV521 or matching placebo. RV521 or placebo 
will be administered according to the dose and regimen specified for the age group following completion 
of Part B/ Cohort 5 subjects. Subjects will be followed for safety and tolerability. Clinical findings related to 
RSV infection will be monitored. The DSMC will evaluate safety data at intervals specified in the DSMC 
Charter. Nasopharyngeal swabs will be obtained over the course of the study period to evaluate viral 
load, presence of other respiratory pathogens and CCI 
 
. 
 
Subjects will participate for 29 days, and the visit schedule will include: 
Screening (-24 hours to first dose), Dosing (5 days), and Follow-Up 40-48 hours Post-Dose 10 
(Visit Day 7) and Study Days 14, and 28. Inpatient duration will be a minimum of 3 days, with duration 
determined clinically by the PI or other health care provider. Follow-Up days are expected to be on an 
outpatient basis. 


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Subject Selection 
 
Number of Planned Subjects 
Approximately 184 subjects (24 subjects in Part A, 40 subjects in Part B, and approximately 120 subjects 
in Part C) ranging in age from ≥ 1 month to ≤ 36 months who are hospitalised because of RSV LRTI will 
be enrolled in the study. It is anticipated that 88 to 112 subjects will receive RV521 (12-24 subjects in 
Part A, 16-28 in Part B, and approximately 60 in Part C), and 68 to 72 subjects will receive placebo 
(8-12 subjects in Part B and approximately 60 in Part C). The actual total number of subjects will be 
dependent upon the number of DSMC-recommended dosage/dosing regimen adjustments in Parts A 
and B. The actual number of subjects enrolled in Part C is dependent upon the number of evaluable 
subjects and may include any eligible subjects who are in the final stages of screening when the target of 
120 enrolled subjects is attained. 
 
 
Inclusion Criteria 
To be eligible for study entry subjects must satisfy all of the following criteria at the Screening Visit: 
 
1. Male or female ≥ 1 month and ≤ 36 months of age 
 
2. Weigh ≥ 3.5 kg 
 
3. Clinical diagnosis of LRTI defined by 
 
a. Evidence of respiratory infection by one or both of the following with or without fever: 
 
i. Rhinitis/coryza 
 
ii. Cough 
AND 
 
b. Evidence of LRTI by the presence of one or more of the following: 
 
i. Increased respiratory rate PLUS other evidence of lower respiratory tract 
disease (e.g., laboratory or radiographic evidence) 
 
ii. Increased respiratory effort as evidenced by one or more of the following: 
 
1. Grunting with expiration 
 
2. Nasal flaring 
 
3. Retraction: intercostal or subcostal 
 
iii. Wheezing: audible or on chest auscultation 
 
4. A positive RSV diagnostic test (RSV infection confirmed either according to routine site practice 
[polymerase chain reaction or diagnostic quick test], or using a [Sponsor-provided] commercial 
kit) 
 
5. Hospitalised because of RSV LRTI (bronchiolitis or bronchopneumonia). 


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6. For Part B, symptoms of LRTI must be present for no more than 1 week before the Screening 
Visit, with the first day of symptoms counting as Day 1. 
 
7. For Part C, symptoms of LRTI must be present for no more than 5 days prior to the Screening 
Visit, with the first day of symptoms counting as Day 1. 
 
8. Expected to remain in hospital for a minimum of 3 days (administration of 6 doses for both 
Parts B and C) 
 
9. The parent(s)/legal guardian(s) of the subject have provided written informed consent for the 
subject to participate 
 
10. The parent(s)/legal guardian(s) are able and willing to comply with the study protocol 
 
 
Exclusion Criteria 
Subjects will be excluded from the study if 1 or more of the following criteria are applicable at the 
Screening Visit: 
 
1. Premature (gestational age less than 37 weeks) AND <1 year of post-natal age 
 
2. Known to have significant comorbidities, including genetic disorders (e.g., trisomy 21); 
cardiopulmonary diseases (e.g., haemodynamically significant congenital heart disease); 
pulmonary disease (e.g., bronchopulmonary dysplasia, cystic fibrosis); history of surgery for 
diaphragmatic hernia; any hereditary or acquired metabolic diseases, haematological or other 
malignancy; or is known to be HIV positive; or has evidence of severe neurologic impairment or 
developmental delay that would limit the ability to administer study drug or evaluate the safety or 
clinical response to IMP 
 
3. Malformation of the gastrointestinal tract including unresolved pyloric stenosis, history of 
necrotising enterocolitis, short bowel, or other significant condition that would alter drug 
absorption or increase the risk of diarrhoea 
 
4. Any clinically significant electrocardiogram (ECG) abnormalities 
 
5. Known to be immunocompromised 
 
6. High risk of having developing asthma. Features that indicate a high likelihood of asthma in a 
young child include: 
 
a. Symptoms (cough, wheeze, heavy breathing) for > 10 days during upper respiratory 
infections 
 
b. > 3 wheezing episodes per year (during the previous 12 months) or severe episodes 
and/or night wheezing 
 
c. Between episodes, child has cough, wheeze, or heavy breathing during play or when 
laughing 
 
d. Atopy or family history of asthma in a first degree relative 


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7. Suspected of having a clinically significant bacterial infection as indicated by symptoms or 
laboratory findings consistent with a bacterial infection including but not limited to: elevated white 
blood cell count, elevated C-reactive protein, chest X-ray consistent with bacterial pneumonia, 
unstable vital signs, hypotension, or evidence of shock or poor perfusion 
 
8. Has significant oral and/or maxillofacial malformations that would limit the ability to administer 
IMP 
 
9. History of renal failure including renal anomalies likely to be associated with renal insufficiency 
(e.g., clinical conditions of renal dysplasia, polycystic renal disease, renal agenesis) 
 
10. Clinical evidence of hepatic decompensation (e.g., hepatic disorder with associated 
coagulopathy or associated encephalopathy) or significantly elevated liver enzymes (aspartate 
aminotransferase [AST] and/or alanine aminotransferase [ALT] >3 × the upper limit of normal) 
 
11. History of epilepsy or seizures, including febrile seizures 
 
12. Allergy to test medication or constituents 
 
13. Requires any prohibited medication/therapy as listed in the body of the protocol 
 
e. Receiving treatment with inhaled, oral, or intravenous (IV) corticosteroids and requires 
continued corticosteroid therapy 
 
f. 
Has taken within 21 days before dosing, any drug that could impact by any mechanism 
of action on the PK of the investigational product including any CCI 
 
; or the use of prescription 
medications, over-the-counter (OTC) medications, herbal remedies or dietary 
supplements containing CCI 
, or the consumption of drugs or other 
substances CCI 
 
 
g. Requires the use of Heliox, Leukotriene receptor antagonist (e.g., Montelukast, 
exogenous surfactant, mucolytics or Hypertonic saline [allowed in the Part A of the 
study]) 
 
14. Has received 1 or more doses of palivizumab at any time before Screening or received treatment 
with antiviral therapy for RSV (e.g., ribavirin or IV immunoglobulin) within 3 months before the 
Screening Visit. NOTE: Subjects eligible for palivizumab treatment or other RSV prophylaxis 
cannot be included in the study. 
 
15. The subject’s parent(s) or legal guardian(s) is a study team member (i.e., has direct involvement 
in this study or other studies under the direction of the Investigator or the study centre) or is a 
family member of either the Investigator or other team members 
 
16. Currently participating in any investigational study or has participated in an investigational study 
within 3 months before the Screening Visit 
 
17. Any other reason which in the opinion of the Investigator makes the participant unsuitable for a 


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clinical trial 
 
 
Determination of Sample Size 
Because of the exploratory nature of the study, a formal sample size calculation has not been performed. 
Twenty-four subjects enrolled in Part B and receiving RV521 or placebo (2:1) at the same dose level and 
according to the same dosing regimen for their specified age range group are expected to be sufficient to 
assess safety, PK, and antiviral data. 
 
For an anti-viral effect (Part B), measured as a difference in viral load at a specific time point, and using 
data from the human challenge model (Study CCI 
), 24 subjects split 16/8 would have 69% power to 
identify a difference of 2 log units, 87% power for a difference of 2.5 log units and 96% power for a 
difference of 3 log units. 
 
Estimates for total enrolment into Part C are based on a median time to resolution of symptoms (defined 
as the interval from day randomisation to the day on which all symptoms of RSV are recorded as absent 
[severity = 0]) of 15 days with inter-quartile range = 9 days (Petruzella et al, 2010). A total sample size of 
120 subjects randomised 1:1 (RV521:placebo) yields a power of 80% to detect a reduction in median time 
to resolution of symptoms of 30% by Generalised Wilcoxon analysis and assuming a drop-out rate of 
15%. Median time to improvement is defined as the interval from day randomisation to the day on which 
symptoms of RSV present at study entry are recorded as mild or absent (severity =0) and is estimated to 
be 4 days (IQR = 3 to 7.5 days) (Mansbach et al, 2015). 
 
 
Treatment Assignment & Blinding 
 
Treatment Assignment 
Part A: 
 
Part A of the study is open-label and all subjects will receive RV521. The dose to be received by a given 
subject will be the dose currently being investigated, at the time the subject is enrolled, in the applicable 
cohort, as described in Protocol Section 8. 
 
Part B and Part C: 
 
In Parts B and C, subjects will be randomised to treatment according to a central randomised list for each 
cohort. To protect the blind, the list will be produced by an unblinded biostatistician at Syneos Health who 
will be independent of the blinded statistician. 
 
For Part B, subjects in Cohorts 3 and 4 will be randomised to RV521 or placebo (3:1). The randomisation 
list for Cohort 5 will be designed to ensure that the subjects who contribute to the final recruitment total of 
24 are randomised to receive RV521 or placebo (2:1). The dose to be received by a given subject will be 
the dose currently being investigated at the time the subject is enrolled, in the applicable cohort, as 
described in Protocol Section 8.1. 
 
For Part C Cohort 6, the randomisation list will be designed such that the total of approximately 
120 subjects are randomised to receive RV521 or placebo (1:1). 


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Randomisation in Part C will be stratified by: 
 
1. Duration of symptoms defined as the time first symptom reported by parent until randomisation, 
< 4 days or ≥ 4 days 
 
2. Severity of illness, defined by the RSV Scoring <9 (mild-moderate) or ≥9 (severe) 
 
At the time of randomisation, a subject will be sequentially assigned to the next available treatment from 
the randomisation list for that cohort. Randomisation will be performed using an interactive web response 
system. A blinded treatment kit (or > 1 kit, if required, in Part B), corresponding to the randomised 
treatment, will be allocated to each subject. 
 
 
Blinding 
Part A of the study is open-label assignment to RV521. 
 
Parts B and C of the study are double-blind. All subjects’ parents/guardians, Investigators and their 
designees, and all study personnel involved in the conduct of the study, including data management and 
biostatistics, will be blinded to treatment assignment. 
 
No blinded team member will have access to the randomisation list before official unblinding of study 
drug. The randomisation schedule may be shared with other groups outside of the Syneos Health study 
team (e.g., the pharmacovigilance department, and the laboratory analysing the PK samples). 
 
Data and Listings together with the randomisation list will be provided to DSMC for review for Part B. An 
unblinded, independent biostatistician will be assigned by Syneos Health to prepare unblinded TFLs 
related to Part C of the study for the DSMC. The unblinded statistician will not otherwise participate in 
study procedures. Note: this could be the same independent biostatistician who produces the 
randomisation schedule. 
 
 
Administration of Study Medication 
RV521, a potent small molecule inhibitor of RSV fusion protein mediated cell-cell fusion, and of RSV 
infection, is formulated as a dry powder blend of RV521 drug substance with mannitol as excipient. The 
RV521 dry powder blend will be supplied in capsules containing 10, 20, or 50 mg RV521. The placebo 
capsules will contain mannitol and microcrystalline cellulose. The IMP will be dispersed in a defined 
volume of water or other suspending diluent prior to oral administration on a mg/kg basis. 
 
Administration of IMP should occur within 12 hours of randomisation for all subjects across all cohorts, in 
accordance with their assigned dosage and dosing regimen. 
The times of completion of feeding prior to dosing and commencement of the first feeding after dosing 
should be recorded in the subject’s source notes. 
IMP administration will be by oral route, predominantly via syringe, dosing via nasogastric tube is 
permitted when the Principal Investigator, in their medical opinion deems this appropriate. 
 
Part A: 
 
A single oral dose of RV521 will be administered in Part A. The proposed starting doses are: 2.5 mg/kg 
for subjects in Cohort 1 (≥ 6 months to ≤ 36 months of age) and 2 mg/kg for subjects in Cohort 2 
(≥ 1 month to < 6 months of age). These dose levels are anticipated to achieve a target exposure 


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equivalent to 1× EC90 at trough concentration in each age group. A maximum of 2 dose adjustments will 
be allowed for each cohort. 
 
Part B: 
 
Part B will be conducted across 3 cohorts (Cohorts 3, 4, and 5) comprising the following age groups: 
 
Cohort 3: 
≥ 6 months to ≤ 36 months 
Cohort 4: 
≥ 1 month to < 6 months 
Cohort 5: 
≥ 1 month to ≤ 36 months 
 
Following review of the safety and PK data from a specific age group enrolled in Part A, the DSMC will 
determine the dosage and dosing regimen to be used in that age group in Part B, such that the target 
group mean trough concentration is approximately equivalent to 3× EC90 , and approve the start of 
enrolment in that specified age group, i.e., Cohort 3 can start after Cohort 1 (Part A) has been finalised 
and Cohort 4 can start after Cohort 2 (Part A) has been finalised. It is anticipated that subjects enrolled in 
Part B of the study will receive RV521 or placebo BID, 12 hours apart, for a period of 5 consecutive days 
(total of 10 doses). However, the dosing regimen may be adjusted depending on the DSMC 
recommendations. 
 
Groups of 4 subjects will be randomised to receive RV521 or placebo (3:1) in Cohort 3 and Cohort 4, with 
enrolment occurring in parallel. It is envisioned that data from a group of 4 subjects will be sufficient to 
confirm the dose exposure relationship for RV521 administered according to a multiple dosing regimen 
and therefore the DSMC will review the PK and safety data from the first group of 4 subjects in each 
cohort. In order to identify the optimum dosage and dosing regimen in each age group, a maximum of 
2 dosage/dosing regimen adjustments is assumed in either or both of the Cohorts 3 and 4. 
Subjects ≥ 6 months to ≤ 36 months of age can be enrolled in Cohort 5 after the completion of Cohort 3 
and subjects ≥ 1 month and < 6 months can be enrolled after the completion of Cohort 4. Enrolment in 
Cohort 5 will continue until 24 evaluable subjects have received RV521 or placebo (2:1) at the dosage 
and dosing regimen specified for each age group (4 subjects from each of Cohorts 3 and 4 will contribute 
to this overall total). Thus a minimum of 24 subjects and a maximum of 40 subjects (assuming 
2 adjustments per age group) may be enrolled in Part B. 
 
Part C: 
 
Part C will be conducted in a single cohort (Cohorts 6) in subjects ≥ 1 month to ≤ 36 months of age. 
Subjects will be randomised 1:1 to receive RV521 or placebo, according to the dose and regimen 
specified for their age group following completion of Part B (Cohort 5 subjects). 
 
 
Study Procedures and Flowchart 
The schedule of planned study assessments for Part A is shown in Table 1, in Table 2 for Part B, and in 
Table 3 for Part C. The nasopharyngeal swab sampling schedule is shown in Table 4, and the PK 
sampling schedule is shown in Table 5. 
 
Note: For Parts B and C, if the DSMC recommends a regimen adjustment, e.g., once-daily dosing rather 
than twice-daily dosing, all study assessments, including nasopharyngeal swab and PK sampling 
schedules will occur as shown in Table 4 and Table 5. However, all references to PK and nasopharyngeal 
swab time points pre- and post-Dose 6 will now refer to Dose 3; Dose 5 would be the final dose in the 
dosing regimen. 


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Table 1. 
Schedule of Assessments for Part A, Open-Label Part of the Study 
 
Assessment 
Screening 
Treatment Phase 
Post Treatment Phase 
Screening 
Visit 
 
Dosing Visit 1 
Post-Dosing Visit 2 
Telephone 
Follow-Up 
Visit 
Time Relative to Dose 
-24 h to First 
Dose 
-2 h 
Pre-Dose 
0 h 
Dose 
4-5 h 
Post- 
Dose 
6-8 h 
Post- 
Dose 
12 h 
Post- 
Dose 
18-24 
h 
Post- 
Dose 
36 h 
Post- 
Dose 
48 h 
Post- 
Dose 
Day 7 
Post-Dose 
Written Informed Consenta 
X 
RSV Rapid Diagnostic Test 
X 
Inclusion / Exclusion Criteria 
X 
X 
Demographicsb 
X 
Medical History 
X 
Prior Medication Review 
X 
Physical Examinationc 
X 
X 
X 
X 
Hydration Statusd 
X 
X 
X 
X 
Body Weight / Length / Head 
Circumference 
X 
X 
Vital Signse 
X 
X 
X 
X 
X 
X 
Pulse Oximetry on room airf 
X 
X 
X 
X 
X 
Record Supplemental O2 useg 
X 
X 
X 
X 
X 
12-Lead ECGh 
X 
Xi 
X 
X 
X 
RSV Clinical Scoring Systemj 
X 
X 
X 
X 
Safety Laboratory Tests (Clinical 
Chemistry and Haematology)k 
X 
X 
Urinalysis 
X 
X 
PK Blood Samplel 
X 
X 
Xm 
X 
X 
Study Medication Administrationn 
X 
Nasopharyngeal Swabo 
X 
X 
X 
X 
X 
Concomitant Medication Review 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AEs Review 
X 
X 
X 
X 
X 
X 
X 
X 
X 


Statistical Analysis Plan for Interventional Studies 
Sponsor: ReViral Ltd; Protocol No.: REVC003 
This document is confidential. 
SAP Version: 2.0, 14-Jun-2021 
Page 21 of 87 
 
 
Abbreviations: ALT = alanine aminotransferase; AST = aspartate aminotransferase; ECG = electrocardiogram; h = hours; IMP = investigational 
medicinal product; PK = pharmacokinetic; RSV = respiratory syncytial virus. 
Note: All procedures and assessments are presented with the Dosing Visit at which they should be conducted. The actual day(s) on 
which the Dosing Visit falls is dependent upon the time that investigational medicinal product (IMP) is administered during Dosing 
Visit 1. 
a 
Written informed consent includes the consent for participating in Part A of the study and the written informed consent for the optional 
Sponsor-provided commercial RSV test. 
b 
Demographic data to be collected: date of birth, gender, race and ethnicity. 
c 
Physical examination may also include a symptom-directed examination, general condition, lung auscultation, and respiratory muscles 
retractions.(Protocol Section 10.1.3.8). 
d 
Refer to Protocol Appendix 17.5 for the Dehydration Status Evaluation. 
e 
Vital signs include body temperature, systolic and diastolic blood pressure, respiratory rate, heart rate, and should be conducted before PK 
and nasopharyngeal swab samples for the respective time points are taken. 
f 
Pulse oximetry to be recorded on room air (if deemed safe by PI or health care provider) 
g 
Record supplemental oxygen use 
h 
12-Lead ECG to be performed using the centrally provided ECG machine and before PK and nasopharyngeal swab samples are taken. 
i 
The 12-Lead ECG should only be performed using the centrally provided ECG machine at -2 h Pre-Dose, if the Centrally provided ECG 
machine was not used at Screening. 
j 
Refer to Protocol Appendix 17.1 for the RSV Clinical Scoring System. 
k 
At Screening, the AST/ALT values should be obtained from the local laboratory. A blood sample will still need to be sent to the Central 
laboratory. 
l 
The actual day for taking each PK sample is dependent on the time when IMP is administered on Dosing Visit 1 (Day 1) (morning versus 
afternoon versus evening); e.g., if the subject received their first dose of IMP at 22:00 on Day 1, the post-dose samples due to be taken at 
4-5 h, 6-8 h, 12 h, and 18-24 h would be taken on Day 2 from 02:00 to 03:00, 04:00 to 06:00, 10:00, and 16:00 to 22:00, respectively (Table 5). 
m 
The 12 hour PK sampling window is 30 minutes (Table 5). 
n 
The times of the prior feeding and first feeding after dosing should be recorded. 
o 
See Table 4 for nasopharyngeal swab sample schedule. 


Statistical Analysis Plan for Interventional Studies 
Sponsor: ReViral Ltd; Protocol No.: REVC003 
This document is confidential. 
SAP Version: 2.0, 14-Jun-2021 
Page 22 of 87 
 
 
Table 2. 
Schedule of Assessments for Part B, Double-Blind, Placebo-Controlled Part of the Study 
 
Assessment 
Screening 
Treatment Phase 
Post- 
Treatment 
Phase 
Screening 
Visit 
Dosing Visit 1 
Dosing Visit 
2 
Dosing Visit 3 
Dosing Visit 4 
Dosing Visit 5 
Follow-Up 
Dose 1 
Dose 
2 
Dose 
3 
Dose 
4 
Dose 
5 
Dose 6 
Dose 
7 
Dose 
8 
Dose 
9 
Dose 
10 
Visit 
Day 7 
TFU 
Time Relative to 
Dose 
-24 to 
first dose 
- 
2h 
to 
0 
0 
h 
+4- 
5h 
Or 
+6- 
8h 
0 
h 
+4-5 
h 
or 
+6- 
8h 
Last 
Dose 
+40- 
48h 
Post- 
Dose 
10 
Day 
12 
Written Informed 
Consenta 
X 
RSV Rapid 
Diagnostic Test 
X 
Inclusion / 
Exclusion Criteria 
X 
X 
Demographicsb 
X 
Medical History 
X 
Prior Medication 
Review 
X 
Physical 
Examinationc 
X 
X 
X 
Hydration Statusd 
X 
X 
X 
X 
X* 
X* 
X 
Body Weight / 
Length / Head 
Circumference 
X 
X 
Vital Signse 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X* 
X* 
X* 
X* 
X 


Statistical Analysis Plan for Interventional Studies 
Sponsor: ReViral Ltd; Protocol No.: REVC003 
This document is confidential. 
SAP Version: 2.0, 14-Jun-2021 
Page 23 of 87 
 
 
 
Assessment 
Screening 
Treatment Phase 
Post- 
Treatment 
Phase 
Screening 
Visit 
Dosing Visit 1 
Dosing Visit 
2 
Dosing Visit 3 
Dosing Visit 4 
Dosing Visit 5 
Follow-Up 
Dose 1 
Dose 
2 
Dose 
3 
Dose 
4 
Dose 
5 
Dose 6 
Dose 
7 
Dose 
8 
Dose 
9 
Dose 
10 
Visit 
Day 7 
TFU 
Time Relative to 
Dose 
-24 to 
first dose 
- 
2h 
to 
0 
0 
h 
+4- 
5h 
Or 
+6- 
8h 
0 
h 
+4-5 
h 
or 
+6- 
8h 
Last 
Dose 
+40- 
48h 
Post- 
Dose 
10 
Day 
12 
12-Lead ECGf 
X 
X 
X 
X 
X 
X* 
X* 
X 
RSV Clinical 
Scoring Systemg 
X 
X 
X 
X 
X* 
X* 
X 
Record RSV Signs 
and Symptomsh 
X 
X 
X 
X 
X 
X 
X 
X* 
X* 
X* 
X* 
X 
Record 
Supplemental O2 
X 
X 
X 
X 
X 
X 
X* 
X* 
X* 
X* 
Pulse Oximetry on 
Room Air 
X 
X 
X 
X 
X 
X 
X* 
X* 
X* 
X* 
X 
Adapted ReSVinet 
Scale for Parental 
Usei 
X 
X 
Safety Laboratory 
Tests (Clinical 
Chemistry and 
Haematology) j 
X 
X 
Urinalysis 
X 
X 
Randomisation for 
Eligible Subjects 
X 


Statistical Analysis Plan for Interventional Studies 
Sponsor: ReViral Ltd; Protocol No.: REVC003 
This document is confidential. 
SAP Version: 2.0, 14-Jun-2021 
Page 24 of 87 
 
 
 
Assessment 
Screening 
Treatment Phase 
Post- 
Treatment 
Phase 
Screening 
Visit 
Dosing Visit 1 
Dosing Visit 
2 
Dosing Visit 3 
Dosing Visit 4 
Dosing Visit 5 
Follow-Up 
Dose 1 
Dose 
2 
Dose 
3 
Dose 
4 
Dose 
5 
Dose 6 
Dose 
7 
Dose 
8 
Dose 
9 
Dose 
10 
Visit 
Day 7 
TFU 
Time Relative to 
Dose 
-24 to 
first dose 
- 
2h 
to 
0 
0 
h 
+4- 
5h 
Or 
+6- 
8h 
0 
h 
+4-5 
h 
or 
+6- 
8h 
Last 
Dose 
+40- 
48h 
Post- 
Dose 
10 
Day 
12 
PK Blood Samplek 
Xl 
Xm 
X 
Xl 
Xm 
X 
Nasopharyngeal 
Swabn 
X 
X 
X 
X 
X 
X 
X*o 
X* 
X* 
X* 
X 
Concomitant 
Medication Review 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AEs Review 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Study Medication 
Administrationp 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Abbreviations: ECG = electrocardiogram; h = hours; PK = pharmacokinetic; RSV = respiratory syncytial virus; TFU = Telephone Follow-up Visit. 
Notes: All procedures and assessments are presented against the Dosing Visit at which they should be conducted. The actual day(s) on 
which the visit falls is dependent upon the time that investigational medicinal product (IMP) is administered during Dosing Visit 1. The 
Follow-up +40-48h Post-Dose 10 on Visit Day 7 could therefore occur on Study Day 7 or 8, depending on when the subject received his 
or her first Dose of IMP. Observations (SpO2, viral signs, inspection of RSV symptoms) should precede any procedures that manipulate 
the subject (physical examination, nasopharyngeal swabs, PK sampling). For the physical examination, listen to the lungs first. In any 
event, the order should be consistent for all the assessment days. 
a Written informed consent includes the consent for participating in Part B of the study and the written informed consent for the optional Sponsor- 
provided commercial RSV test. 
b Demographic data to be collected: date of birth, gender, race and ethnicity. 


Statistical Analysis Plan for Interventional Studies 
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This document is confidential. 
SAP Version: 2.0, 14-Jun-2021 
Page 25 of 87 
 
 
c Physical examination may also include a symptom-directed examination, general condition, lung auscultation, and respiratory muscles 
retractions (Protocol Section 10.1.3.8). For days when IMP is administered, physical examination should be conducted before a dose of IMP is 
administered. 
d Refer to Protocol Appendix 17.5 for the Dehydration Status Evaluation. 
e Vital signs include body temperature, systolic and diastolic blood pressure, respiratory rate, heart rate and should be conducted before PK and 
nasopharyngeal swab samples, for the respective time points, are taken. For the days without PK and nasopharyngeal swab samples, vital signs 
should be taken before a dose of IMP is administered. 
f 12-Lead ECG to be performed using the centrally provided ECG machine and before PK and nasopharyngeal swab samples are taken. For 
days when IMP is administered ECG should be performed before a dose of IMP is administered 
g Refer to Protocol Appendix 17.1 for the RSV Clinical Scoring System. Note: this assessment is to be done only when subject is hospitalised. 
h Refer to Protocol Appendix 17.4 for RSV signs and Symptoms 
i  Refer to Protocol Appendix 17.2 for the Adapted version of ReSVinet scale for parental use. 
j At Screening, the AST/ALT values should be obtained from the local laboratory. A blood sample will still need to be sent to the Central laboratory. 
k The actual day for taking each PK sample is dependent on the time when IMP is administered on Visit 1 (Day 1) (morning versus afternoon 
versus evening); e.g., if the subject received their first dose of IMP at 22:00 on Day 1, the post-dose samples due to be taken at 4-5 h, 6-8 h, 
12 h, and 18-24 h would be taken on Day 2 from 02:00 to 03:00, 04:00 to 06:00, 10:00, and 16:00 to 22:00, respectively (Table 5). 
l These PK samples will be defined after PK Analysis of Part A. One of those two samples will be requested, the other one will not be required 
(Table 5). 
m The 12 hour PK sampling window is 30 minutes (Table 5). 
n See Table 4 for nasopharyngeal swab sample schedule. 
o If the subject is discharged from hospital, a nasopharyngeal swab sample should be obtained prior to discharge if the parents/legal guardians 
are unlikely to return for the next visit. Note: this sample is not required if the previous sample was taken less than 12 hours before the subject is 
discharged (Table 4). 
p The times of the prior feeding and first feeding after dosing should be recorded. IMP should be administered every 12 hours or as dosing 
regimen recommended by the DSMC with a time window of ± 30 minutes. 
* 
Procedure to be done if subject is in the hospital. 


Statistical Analysis Plan for Interventional Studies 
Sponsor: ReViral Ltd; Protocol No.: REVC003 
This document is confidential. 
SAP Version: 2.0, 14-Jun-2021 
Page 26 of 87 
 
 
Table 3. 
Schedule of Assessments for Part C 
 
Assessment 
Screening 
Treatment Phase 
Post-Treatment 
Phase 
Screening 
Visit 
Dosing Visit 1 
Dosing 
Visit 2 
Dosing 
Visit 3 
Dosing 
Visit 4 
Dosing 
Visit 5 
Follow-Up 
Dose 1 
Dose 
2 
Dose 
3 
Dose 
4 
Dose 
5 
Dose 6 
Dose 
7 
Dose 
8 
Dose 
9 
Dose 
10 
Visit 
Day 7 
Visit 
Day 
14 
Visit 
Day 
28 
Time Relative to 
Dose 
-24 to first 
dose 
-2 
to 
0 
h 
0 
h 
+4- 
5 h 
Or 
+6- 
8 h 
0 h 4-5 
h 
Or 
+6- 
8 h 
Last 
Dose 
+40-48 
h Post- 
Dose 
10 
Day 
14 
Day 
28 
Written Informed 
Consenta 
X 
Inclusion / Exclusion 
Criteria 
X 
X 
RSV Rapid 
Diagnostic Test 
X 
Demographicsb 
X 
Medical History 
X 
Prior Medication 
Review 
X 
Physical 
Examinationc 
X 
X 
X 
Hydration Statusd 
X 
X 
X 
X 
X* 
X* 
X 
Body Weight / 
Length / Head 
Circumference 
X 
X 
X 
X 
Vital Signse 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X* 
X* 
X* 
X* 
X 
X 
X 


Statistical Analysis Plan for Interventional Studies 
Sponsor: ReViral Ltd; Protocol No.: REVC003 
This document is confidential. 
SAP Version: 2.0, 14-Jun-2021 
Page 27 of 87 
 
 
 
Assessment 
Screening 
Treatment Phase 
Post-Treatment 
Phase 
Screening 
Visit 
Dosing Visit 1 
Dosing 
Visit 2 
Dosing 
Visit 3 
Dosing 
Visit 4 
Dosing 
Visit 5 
Follow-Up 
Dose 1 
Dose 
2 
Dose 
3 
Dose 
4 
Dose 
5 
Dose 6 
Dose 
7 
Dose 
8 
Dose 
9 
Dose 
10 
Visit 
Day 7 
Visit 
Day 
14 
Visit 
Day 
28 
Time Relative to 
Dose 
-24 to first 
dose 
-2 
to 
0 
h 
0 
h 
+4- 
5 h 
Or 
+6- 
8 h 
0 h 4-5 
h 
Or 
+6- 
8 h 
Last 
Dose 
+40-48 
h Post- 
Dose 
10 
Day 
14 
Day 
28 
12-Lead ECGf 
X 
X 
X 
X 
X 
X* 
X* 
X 
RSV Clinical Scoring 
Systemg 
X 
X 
X 
X 
X* 
X* 
X 
X 
X 
Record RSV Signs 
and Symptomsh 
X 
X 
X 
X 
X 
X 
X 
X* 
X* 
X* 
X* 
X 
X 
X 
Record 
Supplemental O2 
X 
X 
X 
X 
X 
X 
X* 
X* 
X* 
X* 
Pulse Oximetry on 
Room Air 
X 
X 
X 
X 
X 
X 
X* 
X* 
X* 
X* 
Adapted ReSVinet 
Scale for Parental 
Usei 
X 
X 
Safety Laboratory 
Tests (Clinical 
Chemistry, and 
Haematology)j 
X 
X 
Urinalysis 
X 
X 
Randomisation for 
Eligible Subjects 
X 


Statistical Analysis Plan for Interventional Studies 
Sponsor: ReViral Ltd; Protocol No.: REVC003 
This document is confidential. 
SAP Version: 2.0, 14-Jun-2021 
Page 28 of 87 
 
 
 
Assessment 
Screening 
Treatment Phase 
Post-Treatment 
Phase 
Screening 
Visit 
Dosing Visit 1 
Dosing 
Visit 2 
Dosing 
Visit 3 
Dosing 
Visit 4 
Dosing 
Visit 5 
Follow-Up 
Dose 1 
Dose 
2 
Dose 
3 
Dose 
4 
Dose 
5 
Dose 6 
Dose 
7 
Dose 
8 
Dose 
9 
Dose 
10 
Visit 
Day 7 
Visit 
Day 
14 
Visit 
Day 
28 
Time Relative to 
Dose 
-24 to first 
dose 
-2 
to 
0 
h 
0 
h 
+4- 
5 h 
Or 
+6- 
8 h 
0 h 4-5 
h 
Or 
+6- 
8 h 
Last 
Dose 
+40-48 
h Post- 
Dose 
10 
Day 
14 
Day 
28 
PK Blood Samplek 
X 
Xl 
X 
Nasopharyngeal 
Swabm 
X 
X 
X 
X 
X 
X 
Xn* 
X* 
X* 
X* 
X 
X 
X 
Concomitant 
Medication Review 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X* 
X* 
X* 
X* 
X 
X 
X 
AEs Review 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Study Medication 
Administrationo 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Footnotes appear on next page. 


Statistical Analysis Plan for Interventional Studies 
Sponsor: ReViral Ltd; Protocol No.: REVC003 
This document is confidential. 
SAP Version: 2.0, 14-Jun-2021 
Page 29 of 87 
 
 
Abbreviations: ECG = electrocardiogram; h = hours; PK = pharmacokinetic; RSV = respiratory syncytial virus. 
Notes: All procedures and assessments are presented against the Dosing Visit at which they should be conducted. The actual day(s) on 
which the visit falls is dependent upon the time that investigational medicinal product (IMP) is administered during Dosing Visit 1. The 
Follow-p +40-48h Post-Dose 10 on Visit Day 7 could therefore occur on Study Day 7 or 8, depending on when the subject received his or 
her first Dose of IMP. 
a 
Written informed consent includes the consent for participating in Part C of the study and the written informed consent for the optional 
Sponsor-provided commercial RSV test. 
b 
Demographic data to be collected: date of birth, gender, race and ethnicity. 
c 
Physical examination may also include a symptom-directed examination, general condition, lung auscultation, and respiratory muscles 
retractions (Protocol Section 10.1.3.8). For days when IMP is administered, physical examination should be conducted before a dose of IMP is 
administered. 
d 
Refer to Protocol Appendix 17.5 for the Dehydration Status Evaluation. 
e 
Vital signs include body temperature, systolic and diastolic blood pressure, respiratory rate, heart rate and should be conducted before PK and 
nasopharyngeal swab samples, for the respective time points, are taken. For the days without PK and nasopharyngeal swab samples, vital 
signs should be taken before a dose of IMP is administered. 
f 
12-Lead ECG to be performed using the centrally provided ECG machine and before PK and nasopharyngeal swab samples are taken. For 
days when IMP is administered ECG should be performed before a dose of IMP is administered 
g 
Refer to Protocol Appendix 17.1 for the RSV Clinical Scoring System. Note: this assessment is to be done only when subject is hospitalised. 
h 
Refer to Protocol Appendix 17.4 for RSV signs and Symptoms 
i 
Refer to Protocol Appendix 17.2 for the Adapted version of ReSVinet scale for parental use. 
j 
At Screening, the AST/ALT values should be obtained from the local laboratory. A blood sample will still need to be sent to the Central 
laboratory. 
k 
The actual day for taking each PK sample is dependent on the time when IMP is administered on Visit 1 (Day 1) (morning versus afternoon 
versus evening); e.g., if the subject received their first dose of IMP at 22:00 on Day 1, the post-dose samples due to be taken at 4-5 h, 6-8 h, 
12 h, and 18-24 h would be taken on Day 2 from 02:00 to 03:00, 04:00 to 06:00, 10:00, and 16:00 to 22:00, respectively (Table 5). 
l 
These PK samples will be defined after PK Analysis of Part A. One of those two samples will be requested, the other one will not be required 
(Table 5). 
m 
See Table 4 for nasopharyngeal swab sample schedule. 
n 
If the subject is discharged from hospital, a nasopharyngeal swab sample should be obtained prior to discharge if the parents/legal guardians 
are unlikely to return for the next visit. Note: this sample is not required if the previous sample was taken less than 12 hours before the subject 
is discharged (Table 4). 
o 
The times of the prior feeding and first feeding after dosing should be recorded. IMP should be administered every 12 hours or as dosing 
regimen recommended by the DSMC with a time window of ± 30 minutes. 
* 
Procedure to be done if subject is in the hospital. 


Statistical Analysis Plan for Interventional Studies 
Sponsor: ReViral Ltd; Protocol No.: REVC003 
This document is confidential. 
SAP Version: 2.0, 14-Jun-2021 
Page 30 of 87 
 
 
Table 4. 
Nasopharyngeal Sampling Schedule for the Study 
 
Part 
Dosing Visit 1 
Dosing 
Visit 2 
Dosing 
Visit 3 
Dosing 
Visit 4 
Dosing 
Visit 5 
Visit 
Day 7 
Visit 
Day 14 
Visit 
Day 28 
A 
-2 h to 
0 
Pre- 
Dose 
12 h Post 
Dose 1 
1 sample 
collected 
24 h 
post- 
dose 
2 samples: 
1 collected 
at 36 and 1 
at 48 h 
Post Dose 
1 
NA 
NA 
NA 
NA 
NA 
NA 
NA 
B 
-2 h to 
0 h 
Pre- 
Dose 
12 h Post 
Dose 1 
(pre-dose 
2) 
NA 
NA 
1 sample 
collected 
prior to 
each 
dose; 2 
samples 
in totalb 
1 sample 
collected 
prior to 
each 
dose; 2 
samples 
in totalab 
1 sample 
collected 
prior to each 
dose; 2 
samples in 
total*b 
1 sample 
collected prior 
to each dose; 
2 samples in 
total*b 
+40-48 h 
post-Dose 
10 
NA 
NA 
C 
-2h to 
0 pre- 
doseb 
12 h Post 
Dose 1 
(pre-dose 
2) b 
NA 
NA 
1 sample 
collected 
prior to 
each 
dose; 2 
samples 
in totalb 
1 sample 
collected 
prior to 
each 
dose; 2 
samples 
in totalab 
1 sample 
collected 
prior to each 
dose; 2 
samples in 
total*b 
1 sample 
collected prior 
to each dose; 
2 samples in 
total*b 
+40-48h 
post Dose 
10 
1 Sample 
1 Sample 
Abbreviations: h = hours; IMP = investigational medicinal product; NA = not applicable. 


Statistical Analysis Plan for Interventional Studies 
Sponsor: ReViral Ltd; Protocol No.: REVC003 
This document is confidential. 
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Page 31 of 87 
 
 
Notes: 
- 
All procedures and assessments are presented against the Dosing Visit at which they should be conducted. The actual day(s) on which 
the visit falls is dependent upon the time that investigational medicinal product (IMP) is administered during Dosing Visit 1. The Follow- 
up +40-48h Post-Dose 10 on Visit Day 7 could therefore occur on Study Day 7 or 8, depending on when the subject received his or her 
first Dose of IMP. 
- 
 
a If the subject is discharged from hospital, a nasopharyngeal swab sample should be obtained prior to discharge if the parents/legal guardians are 
unlikely to return for the next visit. Note: This sample is not required if the previous sample was taken less than 12 hours before the subject is 
discharged. 
b Nasopharyngeal swab sampling window is 60 minutes. 
* Procedure to be done if subject is in the hospital 
CCI 


Statistical Analysis Plan for Interventional Studies 
Sponsor: ReViral Ltd; Protocol No.: REVC003 
This document is confidential. 
SAP Version: 2.0, 14-Jun-2021 
Page 32 of 87 
 
 
Table 5. 
PK Sampling Schedule for the Study 
 
Part 
Treatment Phase 
Post Treatment Phase 
Total 
Number of 
Samples 
Dosing Visit 1 
Dosing 
Visit 2 
Dosing Visit 3 
Dosing Visit 4 
Dosing Visit 
5 
Visit Day 7 
NA 
A: Single 
Dose 
4-5h, 
6-8h, 
12ha,18-24h, 
48h 
NA 
NA 
NA 
NA 
NA 
5 
B*: Multiple 
Dose 
4-5h or 6-8 h 
Post-Dose 1, 
12ha Post-Dose 1 
(Pre-Dose 2) 
NA 
Pre-Dose 6, 
4-5h or 6-8h 
Post-Dose 6. 
12ha Post-Dose 6 
(Pre-Dose 7) 
NA 
40-48h Post-Dose 10 
6 
C**: Multiple 
Dose 
NA 
Pre-Dose 6 
4-5h or 6-8h 
Post-Dose 6 
NA 
NA 
40-48h Post-Dose 10 
3 
Abbreviations: h = hours; IMP = investigational medicinal product; NA = not applicable; PK = pharmacokinetic. 
Notes: All procedures and assessments are presented against the Dosing Visit at which they should be conducted. The actual day(s) on 
which the visit falls is dependent upon the time that investigational medicinal product (IMP) is administered during Dosing Visit 1. The 
Follow-up +40-48h Post-Dose 10 on Visit Day 7 could therefore occur on Study Day 7 or 8, depending on when the subject received his 
or her first Dose of IMP. 
*For PK Part B: After the review of PK analysis from Part A, it will be decided if the PK sample after the First Dose will be taken 4-5h Post Dose 1 
or 6-8h Post-Dose 1. The same time point will be taken on Dosing Visit 3 (either 4-5h or 6-8h Post-Dose 6). Based on the Part A PK analysis, it 
will be decided if the Samples planned relative to Dose 6 should stay as planned or shifted relative to Dose 10 with the same time structure. In 
case the PK samples are shifted relative to Dose 10, then an additional PK sample 18-24h Post Dose 10 will be taken. 
** For PK Part C: The same PK time point Post-Dose 6 will be taken as in Part B, either 4-5h or 6-8h Post-Dose 6. Based on the Part A PK 
analysis, it will be decided if the samples planned relative to Dose 6 should stay as planned or shifted relative to Dose 10 with the same time 
structure. In case the PK samples are shifted relative to Dose 10 then an additional PK sample 18-24h Post Dose 10 will be taken. 
a The 12-hour PK sampling window is 30 minutes. 


Statistical Analysis Plan for Interventional Studies 
Sponsor: ReViral Ltd; Protocol No.: REVC003 
This document is confidential. 
SAP Version: 2.0, 14-Jun-2021 
Page 33 of 87 
 
 
Endpoints 
 
Primary Endpoints 
Safety and tolerability parameters to be assessed for study Parts A and B will include, but are not limited 
to: 
 
• 
AEs, treatment emergent AEs (TEAEs), serious AEs (SAEs), and withdrawals due to TEAEs 
 
• 
Physical examinations 
 
• 
Vital sign parameters (i.e., systolic and diastolic blood pressure, temperature, respiratory rate, 
heart rate, and pulse oximetry), and changes from baseline in these parameters at predefined 
time points 
 
• 
Laboratory tests (haematology, chemistry, and urinalysis test results) and changes from baseline 
in these parameters, at predefined time points 
 
• 
ECG measurements and changes from baseline in these parameters at predefined time points 
 
Secondary Endpoints 
Secondary endpoints (primary endpoints in Spain) related to PK for study Parts A and B will include but 
are not limited to: 
 
• 
Time to maximum plasma concentration (tmax) 
 
• 
Maximum observed plasma concentration(Cmax) 
 
• 
Area under the plasma concentration time curve from time zero to 12 hours (AUC0-12 ) 
 
• 
Area under the plasma concentration time curve from time zero to last measurable plasma 
concentration (AUC0-t) 
 
• 
Terminal half-life (t1/2 ) 
 
• 
Area under the plasma concentration time curve from time zero to infinity (AUC0-∞ ) 
 
• 
Predicted plasma clearance 
 
• 
Apparent volume of distribution of the drug after extravascular administration (V/F) 
 
• 
Trough concentration at the end of 1st dosing interval (C12 ) (data permitting) 
In addition for Part B: 
• 
Accumulation ratio, percentage fluctuation 
 
• 
Area under the plasma concentration time curve from time zero to the end of last dosing interval 
(AUC0-tau) 
 
• 
Average plasma concentration over dosing interval (Cave ) 


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• 
Minimum observed plasma concentration (Cmin) 
 
• 
Plasma trough concentration (Ctrough) 
 
• 
Any other relevant parameters 
 
Secondary endpoints related to assessment of antiviral activity and efficacy for study Part B include but 
are not limited to: 
• 
RSV viral load measured in nasopharyngeal swabs by reverse transcriptase quantitative 
polymerase chain reaction (RT-qPCR) 
 
• 
RSV viral load measured in nasopharyngeal swabs by cell-based infectivity assay (CBIA) 
 
• 
Time to resolution of symptoms 
 
• 
Time to improvement evaluated by reduction in severity of symptoms 
 
• 
Reduction in severity of symptoms by RV521, compared to placebo, measured by a composite 
score over time 
 
 
Exploratory Endpoints 
CCI 
 
 
 
 
Endpoints for Part C 
Endpoints for study Part C include but are not limited to: 
 
Primary Endpoints for Part C 
 
• 
Time to resolution of symptoms 
 
• 
Time to improvement of symptoms 
 
• 
Reduction in severity of symptoms by RV521, compared to placebo, measured by a composite 
score over time 
 
• 
Use of supplemental oxygen, including, but not limited to, duration and maximum level of oxygen 
provided 
 
Secondary Endpoints for Part C 
 
• 
Safety of RV521 compared to placebo assessed by incidences of AEs, discontinuations due to 
AEs, SAEs, and clinically significant changes in laboratory tests 
 
• 
Comparison between RV521 and placebo for changes in viral load over time as for Part B 
 
• CCI 
 


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• 
CCI 
 


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Analysis Populations 
 
 
Safety Population 
The Safety Population will include all subjects who received at least 1 dose of IMP (RV521 or placebo). 
The Safety Population is the primary population for the analysis of safety data. Analysis will be according 
to actual treatment received. 
 
 
mITT Population 
The Modified Intent-to-Treat (mITT) Population in Part A will include all subjects enrolled in the study who 
have an RT-qPCR viral load measurement and/or CBIA, if available, for at least 1 time point including 
baseline pre-dose at Dosing Visit 1. 
 
The mITT Population in Parts B and C will include all subjects who received at least 1 dose of IMP 
(RV521 or placebo) and have a pre-treatment positive RSV nasopharyngeal swab confirmed by the 
central laboratory and agreed by the project team during blind data review meeting. Potential inclusion of 
subjects who have not completed at least 6 doses of IMP will be decided by the project team during blind 
data review meeting. 
 
Subjects will be analysed according to randomised treatment. The mITT Population is the primary 
population for the analysis of efficacy and PD data. 
 
 
PK Population 
The PK Population will include all subjects who receive IMP and have at least 1 post-dose PK 
concentration measurement. The PK Population is the primary population for the analysis of PK data. 
Analysis will be according to actual treatment received. 
 
 
Protocol Deviations 
Protocol deviations will be identified through a review of deviations captured by the Syneos Health site 
monitors and through programmatic checks on the database. 
 
Protocol deviations include: 
 
• Subjects not meeting eligibility criteria. 
 
• Subjects who have been unblinded. 
 
• Subjects taking prohibited concomitant medications during the study. 
 
All protocol deviations will be listed, including a classification of major or minor. Major protocol deviations 
will be summarised overall and by deviation category for the Safety Population. 


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General Aspects for Statistical Analysis 
 
 
General Methods 
• Unless otherwise specified, summaries for Part A will be presented by cohort, dose level and 
overall, summaries for Part B will be presented by cohort, treatment, dose level and overall, and 
summaries for Part C will be presented by treatment and overall. 
 
• Unless otherwise specified, continuous variables will be summarised using the number of 
observations (n), mean, standard deviation (SD), median, minimum, and maximum. Means and 
medians will be presented with one more decimal than the observed values. SD values will be 
presented with 2 more decimals than the observed values. 
• Unless otherwise stated, categorical variables will be summarised using number of 
observations (n), frequency and percentages of subjects. 
 
• Presentations for PK data are described separately in Section 9. Presentations for PD data are 
described in Section 10. 
 
• All relevant subject data will be included in listings. All subjects entered into the database will be 
included in subject data listings. 
 
• All statistical testing will be 2-sided with an alpha level of 0.05, with no adjustment for multiple 
comparisons. 
 
• For Part B, formal statistical testing will focus on the 24 subjects treated at the doses used in 
Cohort 5 that were identified in Cohorts 3 and 4. These 24 subjects comprise the whole of Cohort 
5, plus the 4 subjects from each of Cohorts 3 and 4 that were randomized with the selected 
dose/placebo. 
• Where there are multiple assessments at a given time point, only the results recorded on the 
scheduled time point page of the case report form (CRF) will be used for summarisation, 
unscheduled assessments will be listed only. 
 
 
Key Definitions 
Baseline will be defined as the last non-missing result before the first dose of IMP. For ECG baseline, 
only results from the central ECG machine will be considered. 
 
Study day will be defined relative to Dosing Visit 1, which should be Study Day 1. For Part A, study day 
will be calculated as date of event-date of study medication administration+1 if the event is on or after 
Dosing Visit 1 and as date of event-date of study medication administration if the event is before Dosing 
Visit 1. For Parts B and C, study day will be calculated as date of event-date of randomisation+1 if the 
event is on or after the date of randomisation and as date of event-date of randomisation if the event is 
before the date of randomisation. 
 
 
Missing Data 
Data from subjects who withdraw will be included, where possible, in all summaries and analyses. 
 
In order to classify medications documented on the Prior and Concomitant Medications CRF as prior or 
concomitant, missing and partial medication dates will be handled as in Section 7.5. 


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Missing time to improvement and time to resolution of RSV-related signs and symptoms will be handled 
as in Section 8.3. No other imputation of missing efficacy data will be done. 
 
PK concentrations before the first or single dose will be imputed as 0 to reduce the number of PK 
samples. No other imputation of missing PK data will be done. 
 
Missing PD data will be handled as in Section 10. 
 
In order to assign treatment-emergence, AEs with missing or partial dates will be handled as in 
Section 12.3. 
 
In order to summarise AEs by relationship and severity, AEs with missing relatedness or severity will be 
handled as in Section 12.3. 
 
 
Visit Windows 
Deviations from planned sampling windows will be assessed before database lock for the impact on PK 
analyses and may be excluded from time point summaries of PK concentrations. Actual time will be used 
for derivation of PK parameters. 
 
Deviations from planned sampling windows will be assessed before database lock for the impact on PD 
analyses. Actual time will be used for derivation of PD parameters. 
 
 
Pooling of Centres 
No formal pooling of centres is planned. CCI 
 
 
 
Subgroups 
For Study Part C, all tables for the primary efficacy endpoints of RSV-related signs and symptoms, RSV 
Clinical Scoring System score and supplemental oxygen use and all pharmacodynamics tables will be 
presented by the following subgroups: 
 
• 
Duration of symptoms prior to randomisation: < 4 days or ≥ 4 days. 
 
• 
Severity of illness at randomisation: RSV score < 9 (mild-moderate) or ≥ 9 (severe). 
 
• 
Baseline RSV subtype by RT-qPCR (A or B or Both.) 
 
• 
Presence or absence of other known respiratory pathogens at baseline. 
 
• 
Age group (≥ 1 month to < 6 months or ≥ 6 months to ≤ 36 months at screening.) 
 
• 
Other subgroups may also be presented. 


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Demographic, Other Baseline Characteristics and Medication 
 
No formal statistical testing will be carried out on these data. 
 
Subject Disposition and Withdrawals 
Subject randomisation details will be listed for all subjects allocated to Study Parts B and C. Subject 
disposition will be listed for all subjects in the database. 
For Part A, the number and percentage of subjects treated, completed and withdrawn, together with the 
reasons for withdrawal, will be summarised for all subjects in the database. 
 
For Parts B and C, the number and percentage of subjects randomised, replaced, treated, completed and 
withdrawn, together with the reasons for withdrawal, will be summarised for all subjects in the database. 
 
The number and percentage of subjects included, and reasons for exclusion, from each of the analysis 
populations will be summarised for each study part. 
 
Demographics 
Demographic data will be listed for all subjects. 
 
Demographic data (age, sex, race, ethnicity) will be summarised descriptively. Age at screening (months) 
will be calculated as (date of screening – date of birth)*12/365.25 and presented to 1 decimal place. 
 
Demographics will be summarised for the Safety, mITT and PK Populations. 
 
 
Medical History and Concomitant Diseases 
Relevant medical history, including surgical history, will be recorded on the CRF. The study disease (RSV 
LRTI) will not be entered as a medical history record. 
Medical coding will use Medical Dictionary for Regulatory Activities (MedDRA) Version 22.1 for prior and 
concomitant diseases. 
 
Medical history will be summarised by body system, as provided on the CRF, and preferred term (PT), as 
coded, using summary statistics for categorical data for the Safety Population, and sorted alphabetically 
by body system and PT. 
 
Medical history data will be listed for all subjects with medical history and presented by record number. 
 
Other Baseline Characteristics 
CCI 
 
 
For Parts B and C, 
the number and percentage of subjects that only have RSV and the number and percentage of subjects 
who also have other respiratory pathogens will be summarised for the Safety, mITT and PK Populations. 
 
RSV diagnostic test details and CCI 
results from the central 
laboratory will be listed for all subjects. Subjects for whom central laboratory results did not match the 
RSV diagnostic test result will be flagged in the RSV diagnostic test data listing. 


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Medication 
All prior medication taken within 14 days prior to the study and all concomitant medication taken during 
the study will be documented in the CRF. 
 
Medications will be coded using the World Health Organisation (WHO) Drug dictionary, WHODrug Global 
B3 Sept 2019. Prior and concomitant medications separately will be summarised by anatomical main 
group, therapeutic subgroup and preferred name for the Safety Population. Tables will be sorted by 
descending incidence of anatomical main group, then alphabetical within therapeutic subgroup and 
preferred name. 
 
In order to classify medications documented on the Prior and Concomitant Medications CRF as prior or 
concomitant, missing and partial medication dates will be handled as follows: 
 
Missing medication start dates likely to be after the date of first dose of IMP will be imputed as the date of 
first dose of IMP. 
 
Missing end dates will be imputed as the date of last contact. 
 
Incomplete medication start dates will be imputed using the earliest possible date implied by the portions 
of the date provided. If only the year is provided, January 1st of that year will be imputed as the start date. 
If the month and year are provided, the 1st day of the provided month/year will be imputed as the start 
date. 
 
Incomplete medication end dates will be imputed using the latest possible date implied by the portions of 
the date provided. If only the year is provided, December 31st of that year will be imputed as the end 
date. If the month and year are provided, the last day of the provided month/year will be imputed as the 
end date. If any imputed end date would be after the subject’s date of last contact, then the medication 
end date will be imputed as the date of last contact. 
 
Prior and concomitant medications will be listed together for all subjects will medications with prior and 
concomitant medications flagged. The data listing will be sorted by start date, end date, Anatomical Main 
Group, Therapeutic Subgroup, Preferred Name and Verbatim Term. 
 
 
Prior Medication 
Medications will be classified as prior if the medication stop date is before the treatment start date. 
 
 
Concomitant Medication 
Medications will be classified as concomitant if the medication start date is on or after the treatment start 
date, or if the medication start date is before the treatment start date and the medication stop date is on 
or after the treatment start date. 


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Clinical Efficacy 
 
All summaries and analyses of clinical efficacy data will be based on observed data in the mITT 
Population. No imputation of missing data will be done and there will be no adjustments for multiplicity. 
Data from subjects who withdraw will be included, where possible, in all summaries and analyses. 
 
 
RSV Clinical Scoring System Score 
The RSV Clinical Scoring System gives a score from 0 to 12. 
 
For each of Parts A, B and C, the RSV Clinical Scoring System score will be summarised at baseline and 
at each post-baseline time point. Summary statistics will be provided for the observed values and the 
corresponding changes from baseline for post-dose assessments. Plots of the mean ± SD observed and 
change from baseline RSV Clinical Scoring System score by time point (baseline and each post-baseline 
assessment) will be presented. If necessary, lower SD bars will be truncated at 0 for the observed value 
plot. 
 
For Part B, comparisons will be made between RV521 and placebo using a mixed effects analysis of 
covariance (ANCOVA) model on the change from baseline in RSV Clinical Scoring System score 
including a random effect term for subject, fixed effect terms for treatment group, age group (≥ 1 month to 
< 6 months or ≥ 6 months to ≤ 36 months at screening), visit and visit by treatment group interaction, and 
baseline RSV Clinical Scoring System score as a covariate. The model will be fitted to the 24 subjects 
treated at the final doses selected for Cohort 5 (see Section 6.1). 
 
For Part C, comparisons will be made between RV521 and placebo using a mixed effects ANCOVA 
model on the change from baseline in RSV Clinical Scoring System score including a random effect term 
for subject, fixed effect terms for treatment group, visit, visit by treatment group interaction, duration of 
symptoms prior to randomisation and severity of illness at randomisation, and baseline RSV Clinical 
Scoring System score as a covariate. 
 
For each model, a point estimate and 95% confidence interval will be calculated for the mean difference 
between RV521 and placebo. 
 
Distributional assumptions underlying the statistical analyses will be assessed by visual inspection of 
residual plots. Normality will be examined by normal probability plots, while homogeneity of variance will 
be assessed by plotting the residuals against the predicted values for the model. If the distributional 
assumptions of a normal distribution in the parametric approach are not satisfied, investigations into 
influence of outliers or non-parametric methods will be considered. 
 
In addition, for each of Parts A, B and C, the RSV Clinical Scoring System score will be categorised as: 
 
• 
Mild – scores ≤ 5. 
• 
Moderate – scores > 5 and < 9. 
• 
Severe – scores ≥ 9. 
 
The number and percentage of subjects with mild, moderate and severe assessments will be summarised 
at baseline and at each post-baseline time point. 
 
All tables for Part C, will also be presented by the subgroups defined in Section 6.6. 


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Adapted Version of ReSVinet Scale for Parental Use 
The Adapted Version of ReSVinet Scale for Parental Use is used in study Parts B and C and gives a 
score from 0 to 20. 
 
For Parts B and C, the continuous Adapted Version of ReSVinet Scale for Parental Use scores will be 
summarised and analysed as for the RSV Clinical Scoring System scores. 
 
 
RSV-related Signs and Symptoms 
RSV-related signs and symptoms (temperature, respiratory rate, coryza, cough, grunting with expiration, 
nasal flaring, retractions, wheezing and SpO2 on Room air) will be collected on the CRF at each time 
point identified in the Schedule of Assessments for Part B (Table 2), and Part C (Table 3) in Section 3.10. 
 
For study Parts B and C, assessments of individual RSV-related signs and symptoms will be summarised 
at each time point. For quantitative variables, observed values and changes from baseline will be 
summarised. In addition, highest level of severity during the study for each individual RSV-related sign 
and symptom will be summarised using summary statistics for categorical variables. 
 
Time to improvement will be calculated for RSV-related signs and symptoms that are classified as 
moderate or severe during the course of the study and will be defined as the time from randomisation 
until no longer present (absent or severity=0) or mild. If there is no improvement, then time to 
improvement will be censored as the date/time RSV-related signs and symptoms were last recorded. 
Time to improvement will be summarised (number [%] of subjects analysed, mean, median, SD, 
minimum, maximum) for Parts B and C. The overall time to improvement will be defined as the time from 
randomisation to the time that all RSV-related signs and symptoms are mild or absent. The overall time to 
improvement will be summarised for Parts B and C by n, mean, median, SD, minimum, maximum and 
95% confidence intervals for the mean. For Part C only, time to improvement of symptoms and overall 
time to improvement, will be compared between RV521 and Placebo using a Generalised Wilcoxon 
analysis, which is a weighted log-rank test, weighted by the number of subjects at risk immediately prior 
to the event, and will include duration of symptoms prior to randomisation as a covariate. Also for Part C 
only, Kaplan-Meier plots for time to improvement of symptoms and overall time to improvement will be 
presented by treatment. 
 
Time to resolution will be calculated for RSV-related signs and symptoms that are present at study start 
and will be defined as the time from randomisation until no longer present (absent or severity=0). If there 
is no resolution, then time to resolution will be censored as the date/time RSV-related signs and 
symptoms were last recorded. The overall time to resolution will be defined as the time from 
randomisation to the time that all RSV-related signs and symptoms are no longer present (absent or 
severity=0). The time to resolution and the overall time to resolution will be summarised and analysed as 
for time to improvement. 
 
Times to improvement or resolution will be presented in days to 1 decimal place. 
 
All tables for Part C, will also be presented by the subgroups defined in Section 6.6. 
 
 
Supplemental Oxygen Use 
The number and percentage of subjects with supplemental oxygen use will be presented overall, at 
baseline and at each post-baseline time point. Reason for use of supplemental oxygen use will also be 
summarised. 


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Duration of use and overall maximum flow rate of oxygen will be summarised using summary statistics for 
continuous data. Duration of supplemental oxygen use will be calculated in hours from the start time of 
first use in the study to the end time of the last use in the study, i.e. ignoring any interruptions, and 
presented to 1 decimal place. 
 
All tables for Part C, will also be presented by the subgroups defined in Section 6.6. 
 
 
Duration of Hospitalisation 
Duration of hospitalisation will be calculated in days to 1 decimal place from time of informed consent to 
time of discharge, or time of last AE review if not discharged, and summarised using summary statistics 
for continuous data. CCI 
 
 
 
Hydration Status 
For each of Parts A, B and C, dehydration will be recorded as: 
 
• 
None. 
• 
Mild 3-5%. 
• 
Moderate 6-10%. 
• 
Severe >10-15%. 
The number and percentage of subjects with none, mild, moderate and severe dehydration will be 
summarised at baseline and at each post-baseline time point. 


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Analysis Of Pharmacokinetics (PK) 
 
PK parameters will be generated using Phoenix WinNonlin version 8 (Pharsight Corporation, Mountain 
View, California, USA). 
 
 
PK Sampling Schedule 
Blood samples for measurement of plasma concentrations of RV521 will be drawn at time points specified 
in the Schedule of Assessments in Section 3.10. The actual date and time (24-hour clock time) of each 
sampling will be recorded in the subject’s source document at the site. The sampling window for each 
time point is identified in Table 1, Table 2, and Table 5. Deviations from planned sampling windows will 
be assessed before database lock for the impact on PK analyses and may be excluded from time point 
summaries of plasma concentrations of RV521. Actual time will be used for derivation of PK parameters. 
 
If a subject experiences an AE Grade 3 or higher or meets SAE criteria, a blood sample for the 
measurement of plasma concentrations of RV521 should be collected (if less than 24 hours have elapsed 
since the last dose of IMP and more than 24 hours since the last PK sample), if possible. The sample will 
be recorded as an unscheduled time point and may be also used in PK parameters derivation using 
actual time. 
 
 
Plasma PK Endpoint 
The PK characteristics of RV521 to be assessed will be: Cmax, AUC0-12 , AUC0-t , t1/2 , AUC0-∞ , CL/F, V/F 
and C12 (data permitting), and in addition for Part B: accumulation ratio, percentage fluctuation, AUC0-tau, 
Cave, Cmin (Ctrough) as well as any other relevant parameters. 
 
Data regarding exposure after accumulation will be compared to parameters observed in adult subjects 
(Cmax, AUC0-tau, C12 [data permitting]). 
 
 
Presentation of Concentration Data 
 
Handling of Missing Data 
PK concentrations before the first or single dose will be imputed as 0 to reduce the number of PK 
samples. 
The profiles for all subjects including those with incomplete sampling profiles will be used to inform the 
population PK model. The results of the model will be used to simulate profiles and estimate non- 
compartmental parameters from the simulations. This is not considered to be an imputation of missing 
data and will be performed for all subjects who receive active treatment irrespective of the number of 
available PK samples. 
 
 
Listing and Presentation of Individual PK Data 
All plasma RV521 concentration data will be listed for the PK Population. No imputed data will be 
included in the data listings. Individual subject linear plasma RV521 concentration-time plots will be 
presented on a linear scale and on a log-linear scale, using actual times relative to dose for Part A and 
using nominal times relative to dose for Parts B and C. 
 
For the calculation of summary statistics, plasma RV521 concentrations that are below the limit of 
quantification (BLQ) will be treated as 0. 


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Plasma RV521 concentration data will be summarised at each nominal time point (n, number of values 
below BLQ [nBLQ], mean, SD, coefficient of variation (CV), minimum, median, maximum, geometric 
mean, and geometric CV) for the PK Population. Reporting precision for summaries of plasma RV521 
concentration data will be the same as that for the PK Parameters in Section 9.4.1. 
 
Mean ± SD plasma RV521 concentration-time profiles will be presented on a linear scale using nominal 
times for the PK Population, lower SD bars will be truncated at 0. 
 
Mean + SD plasma RV521 concentration-time profiles will be presented on a log-linear scale using 
nominal times for the PK Population, plasma RV521 concentrations that are BLQ will be treated as the 
limit of quantification value. 
 
 
PK Parameters Derivation 
The PK parameters will be derived by non-compartmental method from estimated concentration and 
available observed concentration. Considering the sparse sampling the individual PK concentrations 
profiles will be estimated using the population PK model and post-hoc Bayesian method. 
 
The PK parameters in Table 6 will be derived for RV521. 
 
Table 6. 
PK Parameter Determination 
 
Parameter 
Definition 
Method of Determination 
Cmax 
Maximum observed concentration. 
Observed from the PK profile 
Tmax 
Time to reach Cmax. If the maximum value 
occurs at more than 1 time point, Tmax is 
defined as the first time point with this 
value. 
Observed from the PK profile 
AUC0-t 
Area under the plasma concentration-time 
curve, from time 0 to the last measurable 
concentration. 
Linear trapezoidal method 
AUC0-12 
Area under the plasma concentration-time 
curve, from time 0 to the 12-hour time 
point (using the scheduled 12-hour 
sampling time). AUC0-12 will be 
interpolated/ extrapolated if the 12-hour 
concentration is not collected at the 
scheduled time, missing or not reportable, 
as appropriate. 
Linear trapezoidal method 


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Parameter 
Definition 
Method of Determination 
AUC0-∞ 
Area under the concentration-time curve, 
from time 0 extrapolated to infinity. 
AUC0-t + Clast /Kel , where Clast is 
the concentration at the last 
measurable time point. 
Kel 
Apparent first-order terminal elimination 
rate constant. 
Estimated by linear regression 
of the terminal elimination 
phase of the log-linear drug 
concentration-time curve 
t1/2 
Apparent first-order terminal elimination 
half-life. 
ln(2)/Kel 
CL/F 
Apparent total body clearance. 
Estimated as Dose/AUC0-∞ 
V/F 
Apparent volume of distribution. 
Estimated as 
Dose/(Kel × AUC0-∞ ) 
C12 
Trough concentration at the end of 1st 
dosing interval 
Observed from the PK profile 
 
 
For Parts B and C, the PK parameters in Table 7 also be derived. 
 
Table 7. 
PK Parameter Determination – Additional Parameters for Parts B and C 
 
Parameter 
Definition 
Method of Determination 
% Fluctuation 
Percentage of fluctuation. 
Computed as 100*(Cmax- 
Cmin)/Cave , where Cmin and Cmax 
measured over dosing interval. 
Tmax 
Time to reach Cmax. If the maximum 
value occurs at more than 1 time point, 
Tmax is defined as the first time point with 
this value. 
Observed from the PK profile 
AUC0-tau 
Area under the plasma concentration- 
time curve, from time 0 to the end of last 
dosing interval. 
Linear trapezoidal method 
Cave 
Average plasma concentration over 
dosing interval. 
Estimated as AUC0-tau /tau 
Ctrough 
Plasma trough concentration 
Observed from the PK profile 


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PK Parameters Summarisation 
Individual subject PK parameters will be listed for the PK Population. 
 
PK parameters will be summarised using descriptive statistics as detailed in Table 8 for the 
PK Population. 
Table 8. 
PK Parameters – Summary Statistics 
 
Variable 
Summarised with: 
AUC, Cmax, Cave, Cmin, Ctrough, 
C12 
n, arithmetic mean, SD, CV (%) calculated as 
100%*SD/mean, minimum, first quartile (Q1), median, third 
quartile (Q3), maximum, geometric mean, and geometric 
CV, calculated as 
 
Geometric CV (%) = 100%∗ ೦𝑒𝑒𝑒𝑒𝑧𝑧𝑧𝑧2 − 1, 
where z2 is the variance of ln(xi ) 
CL/F, V/F, accumulation ratio, 
percentage fluctuation 
n, arithmetic mean, SD, CV, minimum, Q1, median, Q3, 
maximum 
T1/2 
n, arithmetic mean, SD, CV, minimum, median, maximum 
Tmax 
n, minimum, median, and maximum 
The conventions to be used for the presentation of the descriptive statistics of PK parameters and 
concentrations are detailed in Table 9. 
Table 9. 
PK Parameters – Reporting Precision 
 
Statistics 
Degree of Precision 
Minimum, Q1, Median, Q3, Maximum 
3 significant digits 
Mean (arithmetic and geometric) 
3 significant digits 
SD 
3 significant digits 
CV and Geometric CV 
1 decimal place 
 
Planned Statistical Models for PK Parameters and Concentrations 
None planned. 
 
 
Interim Analyses 
Interim PK analyses will be performed during Part A and Part B to verify if the previously developed PK 
model of RV521 adequately predicted the exposure in subjects ≥ 6 months to ≤ 24 months of age and 
subjects ≥ 1 month to < 6 months of age and report the observed exposure in the infants. The results of 
these PK analyses, in addition to the safety data, will guide further dosing decision by the DSMC. The PK 
reports to be generated are provided in the DSMC Charter. 


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Deviation from Analyses Planned in Protocol 
Currently there are no changes from the analysis planned in the protocol. 


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Analysis Of Pharmacodynamics (PD) 
 
A single nasopharyngeal swab sample for the measurement of RSV viral load will be taken at each time 
point identified in the Schedule of Assessments for Part A (Table 1), Part B (Table 2), and Part C 
(Table 3) in Section 3.10. The actual date and time (24-hour clock time) of each sampling will be 
recorded. Deviations from planned sampling windows will be assessed before database lock for the 
impact on PD analyses. Actual time will be used for derivation of PD parameters. All summaries and 
analyses of PD data will be based on observed data in the mITT Population. Data from subjects who 
withdraw will be included, where possible, in all summaries and analyses. 
 
All tables for Part C, will also be presented by the subgroups defined in Section 6.6. 
 
 
Primary PD Endpoint and Analysis 
Separate assays will be used to detect viral load of RSV A separate from RSV B by RT-qPCR. The 
primary analysis will report the viral load which has been quantified from either subtype, or in the case of 
co-infection, from the combined activity of both subtypes (total RSV viral load by RT-qPCR). The CBIA 
detects both RSV A and RSV B simultaneously. 
 
If any RT-qPCR viral load result is less than the limit of detection (LoD) then a value of ½ the LoD will be 
used in the calculation of total RSV viral load by RT-qPCR. If any RT-qPCR viral load result falls between 
the LoD and the lower limit of quantification (LLoQ) then a value midway between the LoD and the LLoQ 
will be used in the calculation of total RSV viral load by RT-qPCR. Using these imputations, the value 
from each subtype will be added together at each time point to calculate total RSV viral load by 
RT-qPCR. This method ensures that the data collected from all subjects are consistent and not weighted 
to those who have both subtypes present. Total RSV viral load by RT-qPCR is calculated before any log 
transformations are applied. 
 
If any CBIA viral load result is less than the LoD then a value of ½ the LoD will be used for analysis. For 
each assay, Table 10 shows the LoD values, LLoQ values, reported results and replacement values used 
for calculations: 
 
Table 10. 
LoD and LLoQ Replacement Values 
 
Assay 
LoD LLoQ Reported 
Result (log10) 
Replacement Value (log10) 
RT-qPCR RSV A 
2.02 2.23 
<2.23 
Replacement value for <LLoQ, log10(midway 
between unlogged LLoQ and LoD) = 2.14 
RT-qPCR RSV A 
2.02 2.23 
Negative 
Replacement value for <LoD, log10(½ of unlogged 
LoD) = 1.72 
RT-qPCR RSV B 
2.33 2.60 
<2.60 
Replacement value for <LLoQ, log10(midway 
between unlogged LLoQ and LoD) = 2.49 
RT-qPCR RSV B 
2.33 2.60 
Negative 
Replacement value for <LoD, log10(½ of unlogged 
LoD) = 2.03 
CBIA 
0.7 N/A 
<0.70 
Replacement value for <LoD, log10(½ of unlogged 
LoD) = 0.40 
 
 
For all study Parts, log10 total RSV viral load measured in nasopharyngeal swabs by RT-qPCR in viral 
particles per mL, and log10 RSV viral load measured in nasopharyngeal swabs by CBIA in 50% tissue 
culture infective dose per mL, will be listed to 2 decimal places and summarised by nominal time point 
(n, mean, SD, CV, minimum, median, maximum, geometric mean, and geometric CV), including changes 
from baseline for post-dose measurements, for the mITT Population. All summary statistics will be 
presented to 2 decimal places, except CV and geometric CV, which will be presented to 1 decimal place. 


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Plots of the mean +/- SD observed and change from baseline values by nominal time point (baseline and 
each post-baseline measurement) will be presented. 
 
For Parts B and C, log10 total RSV viral load by RT-qPCR and log10 RSV viral load by CBIA will also be 
summarised by nominal time point (n, mean, SD, CV, minimum, median, maximum, geometric mean, and 
geometric CV) and presence or absence of other known respiratory pathogens at baseline for the mITT 
Population. All summary statistics for viral load will be presented to 2 decimal places, except CV and 
geometric CV, which will be presented to 1 decimal place. 
 
 
Secondary PD Endpoint(s) and Analyses 
Secondary PD endpoints will be analysed for Study Parts B and C only. All secondary PD endpoints will 
be listed to 2 decimal places for the mITT Population. All summary statistics will be presented to 
2 decimal places, except CV and geometric CV, which will be presented to 1 decimal place. 
 
 
Area Under the RSV Viral Load Curve 
The DAVG statistic will be used to summarise the change in RSV viral load from baseline over a time 
period, standardised to a unit of time (sometimes called time weighted average change in RSV viral load), 
both for total RSV viral load by RT-qPCR and for RSV viral load by CBIA. 
 
The statistic is calculated as: DAVG = 
𝑏𝑏𝑏𝑏 
𝑖𝑖𝑖𝑖=𝑎𝑎𝑎𝑎 0.5 (𝑌𝑌𝑌𝑌𝑖𝑖𝑖𝑖+𝑌𝑌𝑌𝑌𝑖𝑖𝑖𝑖+1) (𝑡𝑡𝑡𝑡𝑖𝑖𝑖𝑖+1−𝑡𝑡𝑡𝑡𝑖𝑖𝑖𝑖 ) 
𝑡𝑡𝑡𝑡𝑏𝑏𝑏𝑏− 𝑡𝑡𝑡𝑡𝑎𝑎𝑎𝑎 
Where Yi is the change from baseline in log10 RSV viral load at time point i, t is the actual time at the 
specified time point, a is the baseline assessment at Dosing Visit 1, and b is the last assessment on 
Follow up Day 7. 
 
If subjects have missing viral load data post baseline, then the data that are available will be used to 
generate the area under the curve (AUC) and will be divided through by the corresponding time period to 
obtain the DAVG value. Any subjects with less than 1 viral load value post baseline will be excluded from 
the DAVG calculation and hence from the analysis. 
 
If baseline viral load are missing, an imputation method will be used under the assumption that the data 
are missing at random. The imputed value will be determined from an ANCOVA model with baseline viral 
load used as the dependent factor and duration of symptoms prior to randomisation, severity of illness at 
randomisation and age group (≥ 1 month to < 6 months or ≥ 6 months to ≤ 36 months at screening) as 
independent factors. The predicted value for the subject with the missing baseline value will be used as 
the imputed value. 
 
DAVG for total RSV viral load by RT-qPCR and for RSV viral load by CBIA will be summarised (n, 
arithmetic mean, SD, CV, minimum, Q1, median, Q3, maximum, geometric mean, and geometric CV) by 
presence or absence of other known respiratory pathogens at baseline and overall for the mITT 
Population. 
 
For Part B, comparisons will be made between RV521 and placebo using a mixed effects ANCOVA 
model on the DAVG including a random effect term for subject, fixed effect terms for treatment group, age 
group (≥ 1 month to < 6 months or ≥ 6 months to ≤ 36 months at screening) and presence or absence of 
other known respiratory pathogens at baseline, and baseline RSV viral load as a covariate. The model 
will be fitted to the 24 subjects treated at the final doses selected for Cohort 5 (see Section 6.1). 
 
Furthermore, the above analysis will be repeated but also including a treatment group by presence or 
absence of the other known respiratory pathogens at baseline interaction, in order to investigate the 
∑


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treatment effect given the presence or absence of the pathogens. 
 
For Part C, comparisons will be made between RV521 and placebo using a mixed effects ANCOVA 
model on the DAVG including a random effect term for subject, fixed effect terms for treatment group, 
presence or absence of other known respiratory pathogens at baseline, duration of symptoms prior to 
randomisation and severity of illness at randomisation, and baseline RSV viral load as a covariate. 
 
For each model, a point estimate and 95% confidence interval will be calculated for the mean difference 
between RV521 and placebo. Estimates will also be provided separately by presence or absence of other 
known respiratory pathogens at baseline. 
 
Distributional assumptions underlying the statistical analyses will be assessed by visual inspection of 
residual plots. Normality will be examined by normal probability plots, while homogeneity of variance will 
be assessed by plotting the residuals against the predicted values for the model. If the distributional 
assumptions of a normal distribution in the parametric approach are not satisfied, investigations into 
influence of outliers or non-parametric methods will be considered. 
 
 
Percentage Change From Baseline in RSV Viral Load 
Change in log10 viral load from baseline will be calculated to 60 hours and 156 hours after first dose, both 
for total RSV viral load by RT-qPCR and for RSV viral load by CBIA. No imputation of missing data is 
planned, but prior to unblinding a check will be made to determine the amount of missing data at 60 and 
156 hours and whether an imputation method is warranted. 
 
For Part B, comparisons will be made between RV521 and placebo using a mixed effects ANCOVA 
model on the change from baseline including a random effect term for subject, fixed effect terms for 
treatment group, age group (≥ 1 month to < 6 months or ≥ 6 months to ≤ 36 months at screening) 
andpresence or absence of other known respiratory pathogens at baseline, and baseline RSV viral load 
as a covariate. The model will be fitted to the 24 subjects treated at the final doses selected for Cohort 5 
(see Section 6.1). 
 
Furthermore, the above analysis will be repeated but also including a treatment group by presence or 
absence of the other known respiratory pathogens at baseline interaction, in order to investigate the 
treatment effect given the presence or absence of the pathogens. 
 
For Part C, comparisons will be made between RV521 and placebo using a mixed effects ANCOVA 
model on the change from baseline including a random effect term for subject, fixed effect terms for 
treatment group, presence or absence of other known respiratory pathogens at baseline, duration of 
symptoms prior to randomisation and severity of illness at randomisation, and baseline RSV viral load as 
a covariate. 
 
For both Parts B and C the change from baseline least square mean (lsmean) estimates will be presented 
for log10 viral load, along with the difference in lsmeans between RV521 and placebo and 95% 
confidence intervals. In addition the lsmean change from baseline will be back transformed and presented 
as a percentage change from baseline of the original viral load. Estimates will also be provided separately 
by presence or absence of other known respiratory pathogens at baseline. 
 
Distributional assumptions underlying the statistical analyses will be assessed by visual inspection of 
residual plots. Normality will be examined by normal probability plots, while homogeneity of variance will 
be assessed by plotting the residuals against the predicted values for the model. If the distributional 
assumptions of a normal distribution in the parametric approach are not satisfied, investigations into 
influence of outliers or non-parametric methods will be considered. 


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CCI 
 
 
 
 


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CCI 
 
 
 
 
 
 
 
 
 
 
 
CCI 
 
 
 
CCI 


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Safety 
 
The population used for safety analyses will be the Safety Population. Safety will be assessed on the 
basis of AE reports, clinical laboratory data, ECG parameters, physical examinations, and vital signs. 
 
Extent of Exposure 
For Study Part A, the number and percentage of subjects with the planned dose administered and the 
number and percentage of subjects with the planned dose not administered will be summarised for all 
analysis populations. For Study Parts B and C for all analysis populations, duration of exposure to IMP in 
days will be summarised as a continuous variable, total number of doses administered will be 
summarised as a categorical variable, and the numbers and percentages of subjects with all planned 
doses administered and at least one planned dose not administered will be summarised. For the subjects 
with at least one planned dose not administered, the number of doses where the planned dose was not 
administered will be summarised as a categorical variable. Duration of exposure will be calculated from 
first and last dose times and presented to 1 decimal place. No account will be taken of gaps in 
medication. All collected IMP administration details and calculated extent of exposure variables, including 
total volume administered in mL, will be listed for the Safety Population. 
 
Treatment Compliance 
Number of doses where planned dose not administered and number of doses missed will be presented in 
a data listing for the Safety Population to assess treatment compliance. 
 
 
Adverse Events 
The Investigator will document all AEs that occur during the study from the time the ICF is signed until the 
last follow up Visit on the appropriate page of the CRF. Each separate AE episode will be recorded. For 
example, if an AE resolves completely or resolves to baseline and then recurs or worsens again, this will 
be recorded as a separate AE. For AEs to be considered intermittent, the events must be of similar nature 
and severity. 
 
Severity of AEs will be assessed by the Investigator using the National Cancer Institute (NCI) Common 
Terminology Criteria for AEs (CTCAE) v5.0, 27 November 2017 (CTCAE v5.0). Grades of the NCI 
CTCAE refer to the severity of the AE as follows: 
 
• 
Grade 1 Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated. 
• 
Grade 2 Moderate; minimal, local or non-invasive intervention indicated; limiting age-appropriate 
instrumental Activities of Daily Living (ADL). 
• 
Grade 3 Severe or medically significant but not immediately life-threatening; hospitalisation or 
prolongation of hospitalisation indicated; disabling; limiting self-care ADL. 
• 
Grade 4 Life-threatening consequences; urgent intervention indicated. 
• 
Grade 5 Death related to AE. 
 
For purposes of this study the severity will be graded as follows: 
 
• 
Grade 1: Mild 
• 
Grade 2: Moderate 
• 
Grade 3>: Severe 


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If there is a change in severity of an AE, every episode of the AE will be captured separately and all 
required information for every episode will be provided separately. 
 
AEs will be coded according to the MedDRA dictionary Version 22.1. Summary tables of AEs will be 
based on TEAEs, defined as events starting, or worsening, after the first dose of IMP. Treatment-related 
TEAEs will be defined as TEAEs with causality assessed as possibly, probably, or definitively related to 
IMP. 
 
In order to assign treatment-emergence, AEs with missing or partial dates are considered treatment- 
emergent unless there is clear indication that the event occurred before the first dose of IMP. In general, 
only TEAEs will be included in the summary tables, but all AEs will be included in the data listings. 
 
At each level of summarisation, summaries will include the number and percentage of subjects. For 
summaries by MedDRA System Organ Class (SOC) and PT, a subject will be counted once at the SOC 
level and once at each PT within the SOC level. For summaries by SOC, PT, and severity, a subject will 
be counted once at each severity level for which the event occurred at the SOC level and at each severity 
level for which the event occurred for each unique PT within that SOC level. Therefore, subjects may 
contribute to multiple severity levels within a PT or SOC. For summaries by SOC, PT, and maximum 
severity, a subject will be counted once at the highest severity level for which the event occurred at the 
SOC level and the highest severity level for each unique PT within that SOC level. Therefore, subjects 
may only contribute once to each PT and once to each SOC level. AEs with missing severity will be 
counted as severe. Summaries by maximum relationship will be handled similarly to the summaries by 
maximum severity. AEs with missing relatedness will be counted as definitely related. 
 
Summaries presenting frequency of AEs by SOC and PT will be ordered by overall descending frequency 
of SOC and then, within a SOC, by overall descending frequency of PT. 
The following tables will be produced: 
 
• 
An overall summary of the number and percentage of subjects reporting TEAEs, serious TEAEs, 
treatment-related TEAEs, TEAEs leading to permanent discontinuation of IMP and TEAEs 
leading to death. 
 
• 
TEAEs overall and by SOC and PT. 
 
• 
TEAEs overall and by SOC, PT and severity. 
 
• 
TEAEs overall and by SOC, PT and maximum severity. 
 
• 
TEAEs overall and by SOC, PT and maximum relationship to IMP. 
 
• 
Treatment-related TEAEs overall and by SOC and PT. 
 
• 
Serious TEAEs, overall and by SOC and PT. 
 
• 
TEAEs leading to permanent discontinuation of IMP, overall and by SOC and PT. 
 
Laboratory Evaluations 
Laboratory results will be presented for haematology, chemistry and urinalysis. 


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All laboratory results will be converted to Standard International units. Results below or above the normal 
range will be indicated in the listings. 
 
In the presence of re-tests, original results will be used in the summary tables, however all re-test results 
will be included in the listings. 
 
For each of Parts A, B and C, continuous laboratory results will be summarised at baseline and at each 
scheduled post-baseline time point. Summary statistics will be provided for the observed values at each 
time point, and the corresponding change from baseline. Categorical laboratory results for urinalysis will 
be summarised at baseline and at each scheduled post-baseline time point. The number and percentage 
of subjects with laboratory measurements outside of the normal reference range will also be summarised 
at baseline and at each scheduled post-baseline time point. 
 
Laboratory results will be graded according to NCI CTCAE v5.0, for applicable parameters (haemoglobin, 
white blood cells, platelets, creatinine, AST, ALT, alkaline phosphatase, lactate dehydrogenase, total 
bilirubin). The severity will be graded as follows: 
 
• 
Grade 1: Mild 
• 
Grade 2: Moderate 
• 
Grade 3: Severe 
• 
Grade 4: Life-threatening 
 
For each applicable parameter, the number and percentage of subjects experiencing each abnormality at 
any time after first dose will be summarised by severity grade and by maximum severity grade. 
 
Shift tables of laboratory results from baseline to maximum post-dose severity grade, including 
unscheduled visits, will be presented. 
 
 
Vital Signs 
Vital signs include systolic blood pressure, diastolic blood pressure, heart rate, respiration rate, 
temperature and pulse oximetry. Temperatures captured in oF will be converted to oC using the 
conversion: 
 
Temperature (in °C) = 5/9 (Temperature [in °F]-32). 
 
For each of Parts A, B and C, vital signs will be summarised at baseline and at each post-baseline time 
point. Summary statistics will be provided for the observed values at each time point, and the 
corresponding change from baseline. In addition, the investigator’s interpretation of the vital signs are 
also captured. These data will be summarised at baseline and at each post-baseline time point. 
 
Height, weight, body mass index (BMI) and head circumference will also be collected. The following 
conversions will be used: 
 
Height or circumference (in cm) = height or circumference (in inches) * 2.54 
Weight (in kg) = weight (in lbs) * 0.4536 
BMI (kg/m2) = Weight(kg)/[Height(m)2] 
 
Following conversion, the above vital signs will be presented to 1 decimal place. 


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For Parts B and C, height, weight, BMI and head circumference will be summarised at baseline and at 
each post-baseline time point. Summary statistics will be provided for the observed values at each time 
point, and the corresponding change from baseline. 
 
 
ECG 
ECG parameters include ventricular heart rate, PR interval, QRS interval, QT interval and QTcB interval. 
 
For each of Parts A, B and C, ECG parameters will be summarised at baseline and at each post-baseline 
time point. Summary statistics will be provided for the observed values at each time point, and the 
corresponding change from baseline. 
 
In addition, the investigator’s interpretation of the ECGs are also captured. These data will be 
summarised at baseline and at each post-baseline time point. 
 
Only results from the central ECG machine will be used in the summary tables. 
 
Physical Examination 
Physical examination data will be summarised for each body system at baseline and at each post- 
baseline time point. 


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Interim Analyses 
 
No formal interim statistical analyses are planned. Interim data summaries and PK analyses will be 
provided to the DSMC according to the DSMC Charter as per Sections 2.2 and 9.6. 


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Changes from Analysis Planned in Protocol 
CCI 
 
 
Clarifications were added to the determination of sample size section. 
The definition of the Safety Population was simplified for clarity. 
The Efficacy and PD Populations have been replaced by the mITT Population. 
 
The PK Population has been expanded to include all subjects from Cohort 6 who receive IMP and have at 
least 1 post-dose PK concentration measurement. 
 
The PD variables of AUC(0-60 hours post-dose 1) and AUC(0-156 hours post-dose 1) have been replaced with an analysis 
based on DAVG. 


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Changes from Version 1.0 of the SAP 
 
The following updates from Version 1.0 of the SAP, dated 09-Oct-2020 have been made: 
 
• 
Update to definition of MITT population for Parts B and C to take into account the possibility that 
we may have subjects who do not ingest the administered doses but who do not withdraw from 
the study. The following has been added to the definition of the MITT population: ‘Inclusion of 
subjects who have not completed at least 6 doses of IMP will be agreed by the project team 
during blind data review.’ 
 
• 
For Part B, it is clarified that formal statistical analyses will focus on the 24 subjects treated at the 
final doses selected for Cohort 5. 
 
• 
To allow for a different treatment effect to be estimated at each visit, for the RSV Clinical Scoring 
System and the Adapted Version of ReSVinet Scale for Parental Use, the mixed model analyses 
will also include fixed effect terms for visit and visit by treatment group interaction. Furthermore, 
for Part B, as the analyses will focus on the 24 subjects treated at the final doses selected for 
Cohort 5, dose is no longer required to be fitted to the model as a fixed effect as this is now 
synonymous with age group. 
 
• 
For the formal statistical analyses of the PD data for Part B, as the analyses will focus on the 24 
subjects treated at the final doses selected for Cohort 5, dose is no longer required to be fitted to 
the model as a fixed effect as this is now synonymous with age group. In addition, analyses will 
be repeated with the addition of an interaction term to the model for treatment group by presence 
or absence of other known respiratory pathogens. This will enable the treatment effect given the 
presence or absence of the pathogens to be investigated. 


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Reference List 
 
Mansbach JM, Clark S, Piedra PA, et al. Hospital course and discharge criteria for children hospitalised 
with bronchiolitis. J Hosp Med. 2015;10(4):205-11. 
 
Petruzella FD, Gorelick MH. Duration of illness in infants with bronchiolitis evaluated in the emergency 
department. Pediatrics. 2010;126(2):285-290. 


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Programming Considerations 
 
All tables, figures, listings (TFLs), and statistical analyses will be generated using SAS Release 9.4 (SAS 
Institute Inc., Cary, NC, USA) or higher. Computer-generated table, listing and figure output will adhere to 
the following specifications. 
 
PK parameters will be generated using Phoenix WinNonlin version 8 (Pharsight Corporation, Mountain 
View, California, USA). 
 
 
General Considerations 
• A separate SAS program will be created for each output. 
 
• Each output will be stored in a separate file. 
 
• Output files will be delivered in Word format. 
 
• Numbering of TFLs will follow ICH E3 guidance 
 
Table, Listing, and Figure Format 
General 
• 
All TFLs will be produced in landscape format on A4 paper size, unless otherwise specified. 
 
• All TFLs will be produced using the Courier New font, size 8, which is the smallest acceptable point 
size for the Regulatory Authorities. 
 
• The data displays for all TFLs will have a minimum blank 1-inch margin on all 4 sides. 
 
• Headers and footers for figures will be in Courier New font, size 8, which is the smallest acceptable 
point size for the Regulatory Authorities. 
 
• Legends will be used for all figures with more than 1 variable, group, or item displayed. 
 
• TFLs will be in black and white (no colour), unless otherwise specified. 
 
• Specialised text styles, such as bolding, italics, borders, shading, and superscripted and 
subscripted text, will not be used in the TFLs, unless otherwise specified. On some occasions, 
superscripts 1, 2, or 3 may be used (see below). 
 
• Only standard keyboard characters will be used in the TFLs. Special characters, such as non- 
printable control characters, printer-specific, or font-specific characters, will not be used. 
Hexadecimal-derived characters will be used, where possible, if they are appropriate to help 
display math symbols (e.g., μ). Certain subscripts and superscripts (e.g., cm2, Cmax) will be 
employed on a case-by-case basis. 
• Mixed case will be used for all titles, footnotes, column headers, and programmer-supplied formats, 
as appropriate. 
 
Headers 
• All output should have the following header at the top left of each page: 


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• ReViral Ltd Protocol REVC003 
 
• All output should have Page n of N at the top or bottom right corner of each page. TFLs are 
internally paginated in relation to the total length (i.e., the page number should appear sequentially 
as page n of N, where N is the total number of pages in the table). 
 
• The date output was generated should appear along with the program name as a footer on each 
page. 
 
 
Display Titles 
• Each TFL are identified by the designation and a numeral. (i.e., Table 14.1.1). A decimal system 
(x.y and x.y.z) are used to identify TFLs with related contents. The title is centred. The analysis set 
are identified on the line immediately following the title. The title and table designation are single 
spaced. A solid line spanning the margins will separate the display titles from the 
 
• 
Column headers. There will be 1 blank line between the last title and the solid line. 
 
Table x.y.z 
First Line of Title 
Second Line of Title if Needed 
(ITT Analysis Set) 
 
 
 
Column Headers 
• Column headings are displayed immediately below the solid line described above in initial upper- 
case characters. 
 
• In the case of efficacy tables, the variable (or characteristic) column will be on the far left followed 
by the treatment group columns and total column (if applicable). P-values may be presented under 
the total column or in separate p-value column (if applicable). Within-treatment comparisons may 
have p-values presented in a row beneath the summary statistics for that treatment. 
 
• For numeric variables, include “unit” in column or row heading when appropriate. 
 
• Analysis set sizes will be presented for each treatment group in the column heading as (N=xx) (or 
in the row headings, if applicable). This is distinct from the ‘n’ used for the descriptive statistics 
representing the number of subjects in the analysis set. 
 
• The order of treatments in the tables will be Placebo first in the case of placebo controlled studies, 
followed by a total column (if applicable). 
 
 
Body of the Data Display 
17.2.5.1. 
General Conventions 
Data in columns of a table or listing are formatted as follows: 
 
• Alphanumeric values are left-justified; 
 
• Whole numbers (e.g., counts) are right-justified; and 


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• Numbers containing fractional portions are decimal aligned. 
 
17.2.5.2. 
Table Conventions 
• Units will be included where available 
 
• If the categories of a parameter are ordered, then all categories between the maximum and 
minimum category are presented in the table, even if n=0 for all treatment groups in a given 
category that is between the minimum and maximum level for that parameter. For example, the 
frequency distribution for symptom severity would appear as: 
 
Severity 
Rating 
N 
severe 
0 
moderate 
8 
mild 
3 
 
 
Where percentages are presented in these tables, zero percentages will not be presented and so counts 
of 0 will be presented as 0 and not as 0 (0%). 
• If the categories are not ordered (e.g., Medical History, Reasons for Discontinuation from the 
Study, etc.), then only those categories for which there is at least 1 subject represented in 1 or 
more groups are included. 
 
• Unless otherwise specified, the estimated mean and median for a set of values are printed out to 1 
more significant digit than the original values, and SDs are printed out to 2 more significant digits 
than the original values. The minimum and maximum should report the same significant digits as 
the original values. For example, for systolic blood pressure: 
 
N 
XX 
Mean 
XXX.X 
Std Dev 
X.XX 
Median 
XXX.X 
Minimum 
XXX 
Maximum 
XXX 
 
• P-values are output in the format: “0.xxx”, where xxx is the value rounded to 3 decimal places. 
Every p-value less than 0.001 will be presented as <0.001. If the p-value are less than 0.0001, then 
present as <0.0001. If the p-value is returned as >0.999, then present as >0.999 
 
• Percentage values are printed to one decimal place, in parentheses with no spaces, one space 
after the count (e.g., 7 (12.8%), 13 (5.4%)). Pre-determine how to display values that round down 
to 0.0. A common convention is to display as '<0.1', or as appropriate with additional decimal 
places. Unless otherwise noted, for all percentages, the number of subjects in the analysis set for 
the treatment group who have an observation will be the denominator. Percentages after zero 
counts should not be displayed and percentages equating to 100% are presented as 100%, without 
decimal places. 


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• Tabular display of data for medical history, prior/concomitant medications, and all tabular displays 
of AE data are presented by the body system, treatment class, or SOC with the highest occurrence 
in the active treatment group in decreasing order, assuming all terms are coded. Within the body 
system, drug class and SOC, medical history (by PT), drugs (by anatomical main group), and AEs 
(by PT) are displayed in decreasing order. If incidence for more than 1 term is identical, they should 
then be sorted alphabetically. Missing descriptive statistics or p-values which cannot be estimated 
are reported as “-”. 
• The percentage of subjects is normally calculated as a proportion of the number of subjects 
assessed in the relevant treatment group (or overall) for the analysis set presented. However, 
careful consideration is required in many instances due to the complicated nature of selecting the 
denominator, usually the appropriate number of subjects exposed. Describe details of this in 
footnotes or programming notes. 
• For categorical summaries (number and percentage of subjects) where a subject can be included 
in more than one category, describe in a footnote or programming note if the subject are included 
in the summary statistics for all relevant categories or just 1 category and the criteria for selecting 
the criteria. 
• Where a category with a subheading (such as SOC) has to be split over more than one page, 
output the subheading followed by “(cont)” at the top of each subsequent page. The overall 
summary statistics for the subheading should only be output on the first relevant page. 
 
17.2.5.3. 
Listing Conventions 
• Listings will be sorted for presentation in order of treatment groups as above, subject number, 
visit/collection day, and visit/collection time. 
 
• Missing data are represented on subject listings as either a hyphen (“-”) with a corresponding 
footnote (“- = unknown or not evaluated”), or as “N/A”, with the footnote “N/A = not applicable”, 
whichever is appropriate. 
 
• Dates are printed in SAS DATE9.format (“ddMMMyyyy”: 01JUL2000). Missing portions of dates are 
represented on subject listings as dashes (--JUL2000). Dates that are missing because they are 
not applicable for the subject are output as “N/A”, unless otherwise specified. 
• All observed time values are to be presented using a 24-hour clock HH:MM or HH:MM:SS format 
(e.g., 11:26:45, or 11:26). Time will only be reported if it was measured as part of the study. 
 
• Units will be included where available 
 
17.2.5.4. 
Figure Conventions 
• Unless otherwise specified, for all figures, study visits will be displayed on the X-axis and endpoint 
(e.g., treatment mean change from Baseline) values will be displayed on the Y-axis. 
 
 
Footnotes 
• A solid line spanning the margins will separate the body of the data display from the footnotes. 


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• All footnotes will be left justified with single-line spacing immediately below the solid line 
underneath the data display. 
 
• Footnotes should always begin with “Note:” if an informational footnote, or 1, 2, 3, etc. if a 
reference footnote. Each new footnote should start on a new line, where possible. 
 
• Subject specific footnotes are avoided, where possible. 
 
• Footnotes will be used sparingly and add value to the table, figure, or listing. If more than six lines 
of footnotes are planned, then a cover page is strongly recommended to be used to display 
footnotes, and only those essential to comprehension of the data will be repeated on each page. 
 
• The last line of the footnote section will be a standard source line that indicates the name of the 
program used to produce the data display, date the program was run, and the listing source (i.e., 
‘Program : myprogram.sas 
Listing source: 16.x.y.z’). 


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Quality Control 
 
SAS programs are developed to produce output such as analysis data sets, summary tables, data 
listings, figures or statistical analyses. An overview of the development of programs is detailed in Syneos 
Health standard operating procedure (SOP) Developing Statistical Programs (3907). 
 
Syneos Health SOPs Developing Statistical Programs (3907) and Conducting the Transfer of 
Biostatistical Deliverables (3908) describe the quality control procedures that are performed for all SAS 
programs and output. Quality control is defined here as the operational techniques and activities 
undertaken to verify that the SAS programs produce the output by checking for their logic, efficiency and 
commenting and by review of the produced output. 


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Index of Tables 
 
Header 
Table Number 
Name 
Analysis Population 
14. 
Tables, Figures, and Graphs 
Referred to but not Included 
in the Text 
14.1 
Demographic Data 
Summary 
Tables 
14.1.1 
Subject Disposition 
14.1.1.1 
Part A: Subject Disposition 
All Subjects 
14.1.1.2 
Part B: Subject Disposition 
All Subjects 
14.1.1.3 
Part C: Subject Disposition 
All Subjects 
14.1.2 
Protocol Deviations 
14.1.2.1.1 
Part A: Major Protocol 
Deviations 
Safety Population 
14.1.2.1.2 
Part B: Major Protocol 
Deviations 
Safety Population 
14.1.2.1.3 
Part C: Major Protocol 
Deviations 
Safety Population 
14.1.2.2.1 
Part A: Analysis Populations 
All Subjects 
14.1.2.2.2 
Part B: Analysis Populations 
All Subjects 
14.1.2.2.3 
Part C: Analysis Populations 
All Subjects 
14.1.3 
Demographic and Baseline 
Characteristics 
14.1.3.1 
Subject Demographics 
14.1.3.1.1.1 
Part A: Demographics 
Safety Population 
14.1.3.1.1.2 
Part A: Demographics 
mITT Population 
14.1.3.1.1.3 
Part A: Demographics 
PK Population 
14.1.3.1.2.1 
Part B: Demographics 
Safety Population 
14.1.3.1.2.2 
Part B: Demographics 
mITT Population 
14.1.3.1.2.3 
Part B: Demographics 
PK Population 
14.1.3.1.3.1 
Part C: Demographics 
Safety Population 
14.1.3.1.3.2 
Part C: Demographics 
mITT Population 
14.1.3.1.3.3 
Part C: Demographics 
PK Population 
14.1.3.2 
Baseline Disease 
Characteristics 
14.1.3.2.1.1 
Part B: Baseline Respiratory 
Pathogens 
Safety Population 
14.1.3.2.1.2 
Part B: Baseline Respiratory 
Pathogens 
mITT Population 
14.1.3.2.1.3 
Part B: Baseline Respiratory 
Pathogens 
PK Population 
14.1.3.2.2.1 
Part C: Baseline Respiratory 
Pathogens 
Safety Population 
14.1.3.2.2.2 
Part C: Baseline Respiratory 
Pathogens 
mITT Population 
14.1.3.2.2.3 
Part C: Baseline Respiratory 
Pathogens 
PK Population 
14.1.3.3 
Medical History 
14.1.3.3.1 
Part A: Medical History 
Safety Population 
14.1.3.3.2 
Part B: Medical History 
Safety Population 
14.1.3.3.3 
Part C: Medical History 
Safety Population 


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Header 
Table Number 
Name 
Analysis Population 
14.1.4 
Medications 
14.1.4.1.1 
Part A: Prior Medications 
Safety Population 
14.1.4.1.2 
Part B: Prior Medications 
Safety Population 
14.1.4.1.3 
Part C: Prior Medications 
Safety Population 
14.1.4.2.1 
Part A: Concomitant 
Medications 
Safety Population 
14.1.4.2.2 
Part B: Concomitant 
Medications 
Safety Population 
14.1.4.2.3 
Part C: Concomitant 
Medications 
Safety Population 
14.2 
Efficacy, Pharmacokinetic 
and Pharmacodynamic Data 
Summary Figures and 
Tables 
14.2.1 
RSV Clinical Scoring 
System Score 
14.2.1.1.1.1 
Part A: RSV Clinical Scoring 
System Score: Summary 
Statistics 
mITT Population 
14.2.1.1.2 
Part A: RSV Clinical Scoring 
System Score: Categorical 
Summary 
mITT Population 
14.2.1.2.1.1 
Part B: RSV Clinical Scoring 
System Score: Summary 
Statistics 
mITT Population 
14.2.1.2.2 
Part B: RSV Clinical Scoring 
System Score: Analysis of 
Covariance 
mITT Population 
14.2.1.2.3 
Part B: RSV Clinical Scoring 
System Score: Categorical 
Summary 
mITT Population 
14.2.1.3.1.1 
Part C: RSV Clinical Scoring 
System Score: Summary 
Statistics 
mITT Population 
14.2.1.3.2 
Part C: RSV Clinical Scoring 
System Score: Analysis of 
Covariance 
mITT Population 
14.2.1.3.3 
Part C: RSV Clinical Scoring 
System Score: Categorical 
Summary 
mITT Population 
14.2.2 
Adapted Version of 
ReSVinet Scale for Parental 
Use 
14.2.2.1.1 
Part B: Adapted Version of 
ReSVinet Scale for Parental 
Use Score: Summary 
Statistics 
mITT Population 
14.2.2.1.2 
Part B: Adapted Version of 
ReSVinet Scale for Parental 
Use Score: Analysis of 
Covariance 
mITT Population 


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Header 
Table Number 
Name 
Analysis Population 
14.2.2.2.1 
Part C: Adapted Version of 
ReSVinet Scale for Parental 
Use Score: Summary 
Statistics 
mITT Population 
14.2.2.2.2 
Part C: Adapted Version of 
ReSVinet Scale for Parental 
Use Score: Analysis of 
Covariance 
mITT Population 
14.2.3 
RSV-related Signs and 
Symptoms 
14.2.3.1.1 
Part B: RSV-related Signs 
and Symptoms: Summary 
Statistics 
mITT Population 
14.2.3.1.3 
Part B: Highest Severity of 
RSV-related Signs and 
Symptoms: Summary 
Statistics 
mITT Population 
14.2.3.1.4 
Part B: Time to 
Improvement in RSV-related 
Signs and Symptoms: 
Summary Statistics 
mITT Population 
14.2.3.1.5 
Part B: Time to Resolution 
in RSV-related Signs and 
Symptoms: Summary 
Statistics 
mITT Population 
14.2.3.2.1 
Part C: RSV-related Signs 
and Symptoms: Summary 
Statistics 
mITT Population 
14.2.3.2.3 
Part C: Highest Severity of 
RSV-related Signs and 
Symptoms: Summary 
Statistics 
mITT Population 
14.2.3.2.4.1 
Part C: Time to 
Improvement in RSV-related 
Signs and Symptoms: 
Summary Statistics and 
Generalised Wilcoxon 
Analysis 
mITT Population 
14.2.3.2.5.1 
Part C: Time to Resolution 
in RSV-related Signs and 
Symptoms: Summary 
Statistics and Generalised 
Wilcoxon Analysis 
mITT Population 
14.2.4 
Supplemental Oxygen Use 
14.2.4.1.1 
Part A: Supplemental 
Oxygen Use: Summary 
Statistics 
mITT Population 
14.2.4.1.2 
Part A: Supplemental 
Oxygen Use: Duration and 
Maximum Level : Summary 
Statistics 
mITT Population 


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Header 
Table Number 
Name 
Analysis Population 
14.2.4.2.1 
Part B: Supplemental 
Oxygen Use: Summary 
Statistics 
mITT Population 
14.2.4.2.2 
Part B: Supplemental 
Oxygen Use: Duration and 
Maximum Level : Summary 
Statistics 
mITT Population 
14.2.4.3.1 
Part C: Supplemental 
Oxygen Use: Summary 
Statistics 
mITT Population 
14.2.4.3.2 
Part C: Supplemental 
Oxygen Use: Duration and 
Maximum Level : Summary 
Statistics 
mITT Population 
14.2.5 
Duration of Hospitalisation 
14.2.5.1 
Part A: Duration of 
Hospitalisation: Summary 
Statistics 
mITT Population 
14.2.5.2 
Part B: Duration of 
Hospitalisation: Summary 
Statistics 
mITT Population 
CCI 
14.2.6 
Hydration Status 
14.2.6.1 
Part A: Hydration Status: 
Summary Statistics 
mITT Population 
14.2.6.2 
Part B: Hydration Status: 
Summary Statistics 
mITT Population 
14.2.6.3 
Part C: Hydration Status: 
Summary Statistics 
mITT Population 
14.2.7 
Pharmacokinetics 
14.2.7.1 
Plasma Concentration Data 
14.2.7.1.1.1 
Part A: Plasma RV521 
Concentrations 
PK Population 
14.2.7.1.2.1 
Part B: Plasma RV521 
Concentrations 
PK Population 
14.2.7.1.3.1 
Part C: Plasma RV521 
Concentrations 
PK Population 
14.2.7.2 
Pharmacokinetic 
Parameters 
14.2.7.2.1 
Part A: Pharmacokinetic 
Parameters 
PK Population 
14.2.7.2.2 
Part B: Pharmacokinetic 
Parameters 
PK Population 
14.2.7.2.3 
Part C: Pharmacokinetic 
Parameters 
PK Population 
14.2.8 
Pharmacodynamics 
14.2.8.1.1.1 
Part A: Log10 Total RSV 
Viral Load by RT-qPCR: 
Summary Statistics 
mITT Population 


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Header 
Table Number 
Name 
Analysis Population 
14.2.8.1.2.1 
Part A: Log10 RSV Viral 
Load by CBIA: Summary 
Statistics 
mITT Population 
CCI 
14.2.8.2.1.1.1 
Part B: Log10 Total RSV 
Viral Load by RT-qPCR: 
Summary Statistics 
mITT Population 
14.2.8.2.1.2.1 
Part B: Log10 RSV Viral 
Load by CBIA: Summary 
Statistics 
mITT Population 
14.2.8.2.2.1 
Part B: Total RSV Viral Load 
by RT-qPCR: DAVG by 
Incidence of Other Known 
Respiratory Pathogens at 
Baseline 
mITT Population 
14.2.8.2.2.2 
Part B: Total RSV Viral Load 
by RT-qPCR: DAVG Mixed 
Effects Analysis of 
Covariance 
mITT Population 
14.2.8.2.2.3 
Part B: RSV Viral Load by 
CBIA: DAVG by Incidence 
of Other Known Respiratory 
Pathogens at Baseline 
mITT Population 
14.2.8.2.2.4 
Part B: RSV Viral Load by 
CBIA: DAVG Mixed Effects 
Analysis of Covariance 
mITT Population 
14.2.8.2.3.1 
Part B: Total RSV Viral Load 
by RT-qPCR: Percentage 
Change to 60 Hours Mixed 
Effects Analysis of 
Covariance 
mITT Population 
14.2.8.2.3.2 
Part B: Total RSV Viral Load 
by RT-qPCR: Percentage 
Change to 156 Hours Mixed 
Effects Analysis of 
Covariance 
mITT Population 
14.2.8.2.3.3 
Part B: RSV Viral Load by 
CBIA: Percentage Change 
to 60 Hours Mixed Effects 
Analysis of Covariance 
mITT Population 
14.2.8.2.3.4 
Part B: RSV Viral Load by 
CBIA: Percentage Change 
to 156 Hours Mixed Effects 
Analysis of Covariance 
mITT Population 
CCI 


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Header 
Table Number 
Name 
Analysis Population 
CCI 
 
 
mITT Population 
14.2.8.3.1.1.1 
Part C: Log10 Total RSV 
Viral Load by RT-qPCR 
mITT Population 
14.2.8.3.1.2.1 
Part C: Log10 RSV Viral 
Load by CBIA 
mITT Population 
14.2.8.3.2.1 
Part C: Total RSV Viral 
Load by RT-qPCR: DAVG 
by Incidence of Other 
Known Respiratory 
Pathogens at Baseline 
mITT Population 
14.2.8.3.2.2 
Part C: Total RSV Viral 
Load by RT-qPCR: DAVG 
Mixed Effects Analysis of 
Covariance 
mITT Population 
14.2.8.3.2.3 
Part C: RSV Viral Load by 
CBIA: DAVG by Incidence 
of Other Known Respiratory 
Pathogens at Baseline 
mITT Population 
14.2.8.3.2.4 
Part C: RSV Viral Load by 
CBIA: DAVG Mixed Effects 
Analysis of Covariance 
mITT Population 
14.2.8.3.3.1 
Part C: Total RSV Viral 
Load by RT-qPCR: 
Percentage Change to 60 
Hours Mixed Effects 
Analysis of Covariance 
mITT Population 
14.2.8.3.3.2 
Part C: Total RSV Viral 
Load by RT-qPCR: 
Percentage Change to 156 
Hours Mixed Effects 
Analysis of Covariance 
mITT Population 
14.2.8.3.3.3 
Part C: RSV Viral Load by 
CBIA: Percentage Change 
to 60 Hours Mixed Effects 
Analysis of Covariance 
mITT Population 
14.2.8.3.3.4 
Part C: RSV Viral Load by 
CBIA: Percentage Change 
to 156 Hours Mixed Effects 
Analysis of Covariance 
mITT Population 
CCI 
 
CCI 
 


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Header 
Table Number 
Name 
Analysis Population 
CCI 
 
14.3 
Safety Data Summary 
Tables 
14.3.1 
Adverse Events 
14.3.1.1.1 
Part A: Treatment-Emergent 
Adverse Events – Overall 
Summary 
Safety Population 
14.3.1.1.2 
Part A: Treatment-Emergent 
Adverse Events by System 
Organ Class and Preferred 
Term 
Safety Population 
14.3.1.1.3 
Part A: Treatment-Emergent 
Adverse Events by System 
Organ Class, Preferred 
Term, and Severity 
Safety Population 
14.3.1.1.4 
Part A: Treatment-Emergent 
Adverse Events by System 
Organ Class, Preferred 
Term, and Maximum 
Severity 
Safety Population 
14.3.1.1.5 
Part A: Treatment-Emergent 
Adverse Events by System 
Organ Class, Preferred 
Term, and Maximum 
Relationship 
Safety Population 
14.3.1.1.6 
Part A: Treatment-related 
Treatment-Emergent 
Adverse Events by System 
Organ Class and Preferred 
Term 
Safety Population 
14.3.1.1.7 
Part A: Serious Treatment- 
Emergent Adverse Events 
by System Organ Class and 
Preferred Term 
Safety Population 
14.3.1.1.8 
Part A: Treatment-Emergent 
Adverse Events Leading to 
Permanent Discontinuation 
of IMP by System Organ 
Class and Preferred Term 
Safety Population 
14.3.1.2.1 
Part B: Treatment-Emergent 
Adverse Events – Overall 
Summary 
Safety Population 
14.3.1.2.2 
Part B: Treatment-Emergent 
Adverse Events by System 
Organ Class and Preferred 
Term 
Safety Population 
14.3.1.2.3 
Part B: Treatment-Emergent 
Adverse Events by System 
Organ Class, Preferred 
Term, and Severity 
Safety Population 


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Header 
Table Number 
Name 
Analysis Population 
14.3.1.2.4 
Part B: Treatment-Emergent 
Adverse Events by System 
Organ Class, Preferred 
Term, and Maximum 
Severity 
Safety Population 
14.3.1.2.5 
Part B: Treatment-Emergent 
Adverse Events by System 
Organ Class, Preferred 
Term, and Maximum 
Relationship 
Safety Population 
14.3.1.2.6 
Part B: Treatment-related 
Treatment-Emergent 
Adverse Events by System 
Organ Class and Preferred 
Term 
Safety Population 
14.3.1.2.7 
Part B: Serious Treatment- 
Emergent Adverse Events 
by System Organ Class and 
Preferred Term 
Safety Population 
14.3.1.2.8 
Part B: Treatment-Emergent 
Adverse Events Leading to 
Permanent Discontinuation 
of IMP by System Organ 
Class and Preferred Term 
Safety Population 
14.3.1.3.1 
Part C: Treatment-Emergent 
Adverse Events – Overall 
Summary 
Safety Population 
14.3.1.3.2 
Part C: Treatment-Emergent 
Adverse Events by System 
Organ Class and Preferred 
Term 
Safety Population 
14.3.1.3.3 
Part C: Treatment-Emergent 
Adverse Events by System 
Organ Class, Preferred 
Term, and Severity 
Safety Population 
14.3.1.3.4 
Part C: Treatment-Emergent 
Adverse Events by System 
Organ Class, Preferred 
Term, and Maximum 
Severity 
Safety Population 
14.3.1.3.5 
Part C: Treatment-Emergent 
Adverse Events by System 
Organ Class, Preferred 
Term, and Maximum 
Relationship 
Safety Population 
14.3.1.3.6 
Part C: Treatment-related 
Treatment-Emergent 
Adverse Events by System 
Organ Class and Preferred 
Term 
Safety Population 


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Header 
Table Number 
Name 
Analysis Population 
14.3.1.3.7 
Part C: Serious Treatment- 
Emergent Adverse Events 
by System Organ Class and 
Preferred Term 
Safety Population 
14.3.1.3.8 
Part C: Treatment-Emergent 
Adverse Events Leading to 
Permanent Discontinuation 
of IMP by System Organ 
Class and Preferred Term 
Safety Population 
14.3.2 
Listings of Deaths, Other 
Serious and Significant 
Adverse Events 
14.3.2.1 
Deaths, Listing 
All Subjects Who Died 
14.3.2.2 
Treatment-related 
Treatment-Emergent 
Adverse Events, Listing 
All Subjects With 
Treatment-related 
Treatment-Emergent 
Adverse Events 
14.3.2.3 
Serious Treatment- 
Emergent Adverse Events, 
Listing 
All Subjects With Serious 
Treatment Emergent 
Adverse Events 
14.3.2.4 
Treatment-Emergent 
Adverse Events Leading to 
Permanent Discontinuation 
of IMP, Listing 
All Subjects With 
Treatment-Emergent 
Adverse Events Leading to 
Permanent Discontinuation 
of IMP 
14.3.4 
Abnormal Laboratory Values 
(each subject) 
14.3.4.1 
Clinical Laboratory Data 
14.3.4.1.1 
Haematology Data 
14.3.4.1.1.1.1 
Part A: Haematology: 
Summary by Visit and 
Change from Baseline 
Safety Population 
14.3.4.1.1.1.2 
Part A: Haematology: 
Abnormal Results by Study 
Visit 
Safety Population 
14.3.4.1.1.1.3 
Part A: Haematology: 
Abnormal Results by 
Severity 
Safety Population 
14.3.4.1.1.1.4 
Part A: Haematology: 
Abnormal Results by 
Maximum Severity 
Safety Population 
14.3.4.1.1.1.5 
Part A: Haematology: Shift 
Table of Results From 
Baseline to Maximum Post- 
Dose Severity Grade 
Safety Population 
14.3.4.1.1.2.1 
Part B: Haematology: 
Summary by Visit and 
Change from Baseline 
Safety Population 
14.3.4.1.1.2.2 
Part B: Haematology: 
Abnormal Results by Study 
Visit 
Safety Population 


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Header 
Table Number 
Name 
Analysis Population 
14.3.4.1.1.2.3 
Part B: Haematology: 
Abnormal Results by 
Severity 
Safety Population 
14.3.4.1.1.2.4 
Part B: Haematology: 
Abnormal Results by 
Maximum Severity 
Safety Population 
14.3.4.1.1.2.5 
Part B: Haematology: Shift 
Table of Results From 
Baseline to Maximum Post- 
Dose Severity Grade 
Safety Population 
14.3.4.1.1.3.1 
Part C: Haematology: 
Summary by Visit and 
Change from Baseline 
Safety Population 
14.3.4.1.1.3.2 
Part C: Haematology: 
Abnormal Results by Study 
Visit 
Safety Population 
14.3.4.1.1.3.3 
Part C: Haematology: 
Abnormal Results by 
Severity 
Safety Population 
14.3.4.1.1.3.4 
Part C: Haematology: 
Abnormal Results by 
Maximum Severity 
Safety Population 
14.3.4.1.1.3.5 
Part C: Haematology: Shift 
Table of Results From 
Baseline to Maximum Post- 
Dose Severity Grade 
Safety Population 
14.3.4.1.1.4 
Haematology: Abnormal 
Results, Listing 
Safety Population 
14.3.4.1.2 
Clinical Chemistry Data 
14.3.4.1.2.1.1 
Part A: Clinical Chemistry: 
Summary by Visit and 
Change from Baseline 
Safety Population 
14.3.4.1.2.1.2 
Part A: Clinical Chemistry: 
Abnormal Results by Study 
Visit 
Safety Population 
14.3.4.1.2.1.3 
Part A: Clinical Chemistry: 
Abnormal Results by 
Severity 
Safety Population 
14.3.4.1.2.1.4 
Part A: Clinical Chemistry: 
Abnormal Results by 
Maximum Severity 
Safety Population 
14.3.4.1.2.1.5 
Part A: Clinical Chemistry: 
Shift Table of Results From 
Baseline to Maximum Post- 
Dose Severity Grade 
Safety Population 
14.3.4.1.2.2.1 
Part B: Clinical Chemistry: 
Summary by Visit and 
Change from Baseline 
Safety Population 
14.3.4.1.2.2.2 
Part B: Clinical Chemistry: 
Abnormal Results by Study 
Visit 
Safety Population 


Statistical Analysis Plan for Interventional Studies 
Sponsor: ReViral Ltd; Protocol No.: REVC003 
This document is confidential. 
SAP Version: 2.0, 14-Jun-2021 
Page 78 of 87 
 
 
 
Header 
Table Number 
Name 
Analysis Population 
14.3.4.1.2.2.3 
Part B: Clinical Chemistry: 
Abnormal Results by 
Severity 
Safety Population 
14.3.4.1.2.2.4 
Part B: Clinical Chemistry: 
Abnormal Results by 
Maximum Severity 
Safety Population 
14.3.4.1.2.2.5 
Part B: Clinical Chemistry: 
Shift Table of Results From 
Baseline to Maximum Post- 
Dose Severity Grade 
Safety Population 
14.3.4.1.2.3.1 
Part C: Clinical Chemistry: 
Summary by Visit and 
Change from Baseline 
Safety Population 
14.3.4.1.2.3.2 
Part C: Clinical Chemistry: 
Abnormal Results by Study 
Visit 
Safety Population 
14.3.4.1.2.3.3 
Part C: Clinical Chemistry: 
Abnormal Results by 
Severity 
Safety Population 
14.3.4.1.2.3.4 
Part C: Clinical Chemistry: 
Abnormal Results by 
Maximum Severity 
Safety Population 
14.3.4.1.2.3.5 
Part C: Clinical Chemistry: 
Shift Table of Results From 
Baseline to Maximum Post- 
Dose Severity Grade 
Safety Population 
14.3.4.1.2.4 
Clinical Chemistry: 
Abnormal Results, Listing 
Safety Population 
14.3.4.1.3 
Urinalysis Data 
14.3.4.1.3.1.1 
Part A: Urinalysis: Summary 
of Continuous Results by 
Visit and Change from 
Baseline 
Safety Population 
14.3.4.1.3.1.2 
Part A: Urinalysis: Summary 
of Categorical Results by 
Visit 
Safety Population 
14.3.4.1.3.1.3 
Part A: Urinalysis: Abnormal 
Results by Study Visit 
Safety Population 
14.3.4.1.3.2.1 
Part B: Urinalysis: Summary 
of Continuous Results by 
Visit and Change from 
Baseline 
Safety Population 
14.3.4.1.3.2.2 
Part B: Urinalysis: Summary 
of Categorical Results by 
Visit 
Safety Population 
14.3.4.1.3.2.3 
Part B: Urinalysis: Abnormal 
Results by Study Visit 
Safety Population 
14.3.4.1.3.3.1 
Part C: Urinalysis: Summary 
of Continuous Results by 
Visit and Change from 
Baseline 
Safety Population 


Statistical Analysis Plan for Interventional Studies 
Sponsor: ReViral Ltd; Protocol No.: REVC003 
This document is confidential. 
SAP Version: 2.0, 14-Jun-2021 
Page 79 of 87 
 
 
 
Header 
Table Number 
Name 
Analysis Population 
14.3.4.1.3.3.2 
Part C: Urinalysis: Summary 
of Categorical Results by 
Visit 
Safety Population 
14.3.4.1.3.3.3 
Part C: Urinalysis: Abnormal 
Results by Study Visit 
Safety Population 
14.3.4.1.3.4 
Urinalysis: Abnormal 
Results, Listing 
Safety Population 
14.3.4.2 
Vital Signs 
14.3.4.2.1.1 
Part A: Vital Signs 
Safety Population 
14.3.4.2.1.2 
Part A: Vital Signs 
Investigator Interpretation 
Safety Population 
14.3.4.2.2.1 
Part B: Vital Signs 
Safety Population 
14.3.4.2.2.2 
Part B: Vital Signs 
Investigator Interpretation 
Safety Population 
14.3.4.2.2.3 
Part B: Height, Weight, BMI 
and Head Circumference 
Safety Population 
14.3.4.2.3.1 
Part C: Vital Signs 
Safety Population 
14.3.4.2.3.2 
Part C: Vital Signs 
Investigator Interpretation 
Safety Population 
14.3.4.2.3.3 
Part C: Height, Weight, BMI 
and Head Circumference 
Safety Population 
14.3.4.3 
ECG Data 
14.3.4.3.1.1 
Part A: Summary of Overall 
ECG Interpretation 
Safety Population 
14.3.4.3.1.2 
Part A: ECG Summary by 
Time Point and Change 
from Baseline 
Safety Population 
14.3.4.3.2.1 
Part B: Summary of Overall 
ECG Interpretation 
Safety Population 
14.3.4.3.2.2 
Part B: ECG Summary by 
Time Point and Change 
from Baseline 
Safety Population 
14.3.4.3.3.1 
Part C: Summary of Overall 
ECG Interpretation 
Safety Population 
14.3.4.3.3.2 
Part C: ECG Summary by 
Time Point and Change 
from Baseline 
Safety Population 
14.3.4.4 
Physical Examination 
Results 
14.3.4.4.1 
Part A: Abnormal Physical 
Examination Results 
Safety Population 
14.3.4.4.2 
Part B: Abnormal Physical 
Examination Results 
Safety Population 
14.3.4.4.3 
Part C: Abnormal Physical 
Examination Results 
Safety Population 
14.3.4.5 
Extent of Exposure 
14.3.4.5.1.1 
Part A: Extent of Exposure 
Safety Population 
14.3.4.5.1.2 
Part A: Extent of Exposure 
mITT Population 
14.3.4.5.1.3 
Part A: Extent of Exposure 
PK Population 
14.3.4.5.2.1 
Part B: Extent of Exposure 
Safety Population 
14.3.4.5.2.2 
Part B: Extent of Exposure 
mITT Population 


Statistical Analysis Plan for Interventional Studies 
Sponsor: ReViral Ltd; Protocol No.: REVC003 
This document is confidential. 
SAP Version: 2.0, 14-Jun-2021 
Page 80 of 87 
 
 
 
Header 
Table Number 
Name 
Analysis Population 
14.3.4.5.2.3 
Part B: Extent of Exposure 
PK Population 
14.3.4.5.3.1 
Part C: Extent of Exposure 
Safety Population 
14.3.4.5.3.2 
Part C: Extent of Exposure 
mITT Population 
14.3.4.5.3.3 
Part C: Extent of Exposure 
PK Population 


Statistical Analysis Plan for Interventional Studies 
Sponsor: ReViral Ltd; Protocol No.: REVC003 
This document is confidential. 
SAP Version: 2.0, 14-Jun-2021 
Page 81 of 87 
 
 
Index of Figures 
 
Figure Number 
Name 
Analysis Population 
14.2.1.1.1.2 
Part A: Mean (+/- SD) RSV 
Clinical Scoring System 
Score by Time Point 
mITT Population 
14.2.1.1.1.3 
Part A: Mean (+/- SD) 
Change from Baseline in 
RSV Clinical Scoring 
System Score by Time Point 
mITT Population 
14.2.1.2.1.2 
Part B: Mean (+/- SD) RSV 
Clinical Scoring System 
Score by Time Point 
mITT Population 
14.2.1.2.1.3 
Part B: Mean (+/- SD) 
Change from Baseline in 
RSV Clinical Scoring 
System Score by Time Point 
mITT Population 
14.2.1.3.1.2 
Part C: Mean (+/- SD) RSV 
Clinical Scoring System 
Score by Time Point 
mITT Population 
14.2.1.3.1.3 
Part C: Mean (+/- SD) 
Change from Baseline in 
RSV Clinical Scoring 
System Score by Time Point 
mITT Population 
14.2.3.2.4.2 
Part C: Kaplan-Meier Plots 
of Time to Improvement in 
RSV-related Signs and 
Symptoms by Symptom and 
Overall 
mITT Population 
14.2.3.2.5.2 
Part C: Kaplan-Meier Plots 
of Time to Resolution in 
RSV-related Signs and 
Symptoms by Symptom and 
Overall 
mITT Population 
14.2.5.3.2 
Part C: Kaplan-Meier Plot of 
Time to Discharge from 
Hospital 
mITT Population 
16.2.5.4.2 
Part A: Individual Plasma 
RV521 Concentration-Time 
Profiles 
PK Population 
16.2.5.4.3 
Part B: Individual Plasma 
RV521 Concentration-Time 
Profiles 
PK Population 
16.2.5.4.4 
Part C: Individual Plasma 
RV521 Concentration-Time 
Profiles 
PK Population 
14.2.7.1.1.2 
Part A: Mean (+/- SD) 
Plasma RV521 
Concentration-Time Profiles 
– Linear Scale 
PK Population 
14.2.7.1.1.3 
Part A: Mean (+ SD) Plasma 
RV521 Concentration-Time 
Profiles – Log-Linear Scale 
PK Population 


Statistical Analysis Plan for Interventional Studies 
Sponsor: ReViral Ltd; Protocol No.: REVC003 
This document is confidential. 
SAP Version: 2.0, 14-Jun-2021 
Page 82 of 87 
 
 
 
Figure Number 
Name 
Analysis Population 
14.2.7.1.2.2 
Part B: Mean (+/- SD) 
Plasma RV521 
Concentration-Time Profiles 
– Linear Scale 
PK Population 
14.2.7.1.2.3 
Part B: Mean (+ SD) Plasma 
RV521 Concentration-Time 
Profiles – Log-Linear Scale 
PK Population 
14.2.7.1.3.2 
Part C: Mean (+/- SD) 
Plasma RV521 
Concentration-Time Profiles 
– Linear Scale 
PK Population 
14.2.7.1.3.3 
Part C: Mean (+ SD) Plasma 
RV521 Concentration-Time 
Profiles – Log-Linear Scale 
PK Population 
14.2.8.1.1.2 
Part A: Mean (+/- SD) Log10 
Total RSV Viral Load by RT- 
qPCR by Time Point 
mITT Population 
14.2.8.1.1.3 
Part A: Mean (+/- SD) 
Change from Baseline in 
Log10 Total RSV Viral Load 
by RT-qPCR by Time Point 
mITT Population 
14.2.8.1.2.2 
Part A: Mean (+/- SD) Log10 
RSV Viral Load by CBIA by 
Time Point 
mITT Population 
14.2.8.1.2.3 
Part A: Mean (+/- SD) 
Change from Baseline in 
Log10 RSV Viral Load by 
CBIA by Time Point 
mITT Population 
14.2.8.2.1.1.2 
Part B: Mean (+/- SD) Log10 
Total RSV Viral Load by RT- 
qPCR by Time Point 
mITT Population 
14.2.8.2.1.1.3 
Part B: Mean (+/- SD) 
Change from Baseline in 
Log10 Total RSV Viral Load 
by RT-qPCR by Time Point 
mITT Population 
14.2.8.2.1.2.2 
Part B: Mean (+/- SD) Log10 
RSV Viral Load by CBIA by 
Time Point 
mITT Population 
14.2.8.2.1.2.3 
Part B: Mean (+/- SD) 
Change from Baseline in 
Log10 RSV Viral Load by 
CBIA by Time Point 
mITT Population 
CCI 
 
14.2.8.3.1.1.2 
Part C: Mean (+/- SD) 
Log10 Total RSV Viral Load 
by RT-qPCR by Time Point 
mITT Population 


Statistical Analysis Plan for Interventional Studies 
Sponsor: ReViral Ltd; Protocol No.: REVC003 
This document is confidential. 
SAP Version: 2.0, 14-Jun-2021 
Page 83 of 87 
 
 
 
Figure Number 
Name 
Analysis Population 
14.2.8.3.1.1.3 
Part C: Mean (+/- SD) 
Change from Baseline in 
Log10 Total RSV Viral Load 
by RT-qPCR by Time Point 
mITT Population 
14.2.8.3.1.2.2 
Part C: Mean (+/- SD) 
Log10 RSV Viral Load by 
CBIA by Time Point 
mITT Population 
14.2.8.3.1.2.3 
Part C: Mean (+/- SD) 
Change from Baseline in 
Log10 RSV Viral Load by 
CBIA by Time Point 
mITT Population 
CCI 
 
CCI 
 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan for Interventional Studies 
Sponsor: ReViral Ltd; Protocol No.: REVC003 
This document is confidential. 
SAP Version: 2.0, 14-Jun-2021 
Page 84 of 87 
 
 
 
Figure Number 
Name 
Analysis Population 
CCI 
 
 
CCI 
 
 
 
 
 
 
 
 


Statistical Analysis Plan for Interventional Studies 
Sponsor: ReViral Ltd; Protocol No.: REVC003 
This document is confidential. 
SAP Version: 2.0, 14-Jun-2021 
Page 85 of 87 
 
 
Index of Listings 
 
Header 
Table Number 
Name 
Analysis Population 
16.2 
Subject Data Listings 
16.2.1 
Discontinued Subjects 
16.2.1.1 
Subject Randomisation 
All Subjects Allocated 
to Study Parts B and C 
16.2.1.2 
Subject Disposition 
All Subjects 
16.2.2 
Protocol Deviations 
16.2.2.1 
Protocol Deviations 
All Subjects with 
Protocol Deviations 
16.2.3 
Subjects Excluded from the Efficacy 
Analysis 
16.2.3.1 
Inclusion/Exclusion Criteria 
All Subjects 
16.2.3.2 
Exclusions from Analysis Populations 
All Subjects 
16.2.4 
Demographic Data 
16.2.4.1 
Demographics 
All Subjects 
16.2.4.2 
Medical History 
All Subjects With 
Medical History 
16.2.4.3 
RSV Diagnostic Test 
All Subjects 
16.2.4.4 
Prior and Concomitant Medications 
All Subjects With 
Medications 
16.2.5 
Compliance and Drug Concentration Data 
16.2.5.1 
Study Drug Administration 
Safety Population 
16.2.5.2 
Study Drug Exposure and Compliance 
Safety Population 
16.2.5.3 
Meals 
Safety Population 
16.2.5.4.1 
Plasma RV521 Concentrations 
PK Population 
16.2.5.5 
Pharmacokinetic Parameters 
PK Population 
16.2.6 
Individual Efficacy Response Data 
16.2.6.1 
RSV Clinical Scoring System 
All Subjects 
16.2.6.2 
Adapted ReSVinet Scale for Parental Use 
All Subjects Allocated 
to Study Parts B and C 
16.2.6.3 
RSV Signs and Symptoms 
All Subjects Allocated 
to Study Parts B and C 
16.2.6.4 
Supplemental Oxygen Use 
All Subjects 
16.2.6.5 
Hospitalisation 
All Subjects 
16.2.6.6 
Hydration Status 
All Subjects 
16.2.7 
Adverse Event Listings 
16.2.7.1 
Adverse Events 
All Subjects 
16.2.8 
Listing of individual laboratory 
measurements by subject 
16.2.8.1 
Clinical Laboratory Data 
16.2.8.1.1 
Haematology 
All Subjects 
16.2.8.1.2 
Clinical Chemistry 
All Subjects 
16.2.8.1.3 
Urinalysis 
All Subjects 
16.2.8.2 
Other Safety Data 
16.2.8.2.1.1 
Vital Signs 
All Subjects 
16.2.8.2.1.2 
Height, Weight, BMI and Head 
Circumference 
All Subjects 
16.2.8.2.1.3 
Pulse Oximetry on Room Air 
All Subjects 
16.2.8.2.2 
Electrocardiogram (ECG) 
All Subjects 
16.2.8.2.3 
Physical Examination 
All Subjects 
16.2.8.2.4.1 
Nasopharyngeal Swab: RSV Viral Load 
mITT Population 


Statistical Analysis Plan for Interventional Studies 
Sponsor: ReViral Ltd; Protocol No.: REVC003 
This document is confidential. 
SAP Version: 2.0, 14-Jun-2021 
Page 86 of 87 
 
 
 
Header 
Table Number 
Name 
Analysis Population 
16.2.8.2.4.2 
Nasopharyngeal Swab: Respiratory 
Pathogens at Dosing Visit 1, -2 h to 0 h 
Pre-Dose 
mITT Population 
16.2.8.2.4.3 
Pharmacodynamic Parameters 
mITT Population 


Statistical Analysis Plan for Interventional Studies 
Sponsor: ReViral Ltd; Protocol No.: REVC003 
This document is confidential. 
SAP Version: 2.0, 14-Jun-2021 
Page 87 of 87 
 
 
Appendices 
 
Not applicable.