A Randomized, Double-blind, Placebo-controlled, Multicenter Dose Ranging Study of ALX-0171 in Infants and Young Children Hospitalized for Respiratory Syncytial Virus Lower Respiratory Tract Infection
Phase: PHASE2
Conditions: Respiratory Syncytial Virus Lower Respiratory Tract Infection
Sponsor: Ablynx, a Sanofi company

 
  
CLINICAL STUDY PROTOCOL 
ALX0171-C201
 
A Randomized, Double-Blind, Placebo-Controlled, Multicenter 
Dose-Ranging Study of ALX-0171 in Infants and Young Children 
Hospitalized for Respiratory Syncytial Virus Lower Respiratory Tract 
Infection  
 
Investigational Product: 
ALX-0171 nebulizer solution 
EudraCT n°: 
2016-001651-49 
Sponsor Protocol Code: 
ALX0171-C201 
Sponsor: 
Ablynx NV  
Technologiepark 21 
9052 Zwijnaarde, Belgium 
Coordinating Investigator 
 
,  
Royal Hospital for Sick Children 
Sciennes Road, Edinburgh, Midlothian EH9 1LF, United 
Kingdom 
Clinical Operations Contract 
Research Organization: 
  
 
Phase of Development: 
Phase 2b 
Indication: 
Respiratory Syncytial Virus Lower Respiratory Tract 
Infection (RSV LRTI) 
Study Center: 
Multicenter  
Protocol Date: 
30 October 2017 
Protocol Version: 
V3.0 
Protocol Status: 
Final 
This study will be performed in compliance with the Clinical Study Protocol, the principles of 
Good Clinical Practice (GCP), and the applicable regulatory requirement(s). 

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30 October 2017 
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CONFIDENTIALITY STATEMENT 
 
The information contained in this document, especially unpublished data, is the property of 
Ablynx NV (or under its control), and therefore provided to you in confidence as an 
Investigator, potential Investigator, or consultant, for review by you, your study staff, and 
applicable Independent Ethics Committee (IEC)/Institutional Review Board (IRB), and 
Competent Authorities (CA). It is understood that this information will not be disclosed to 
others without written authorization from Ablynx NV, except to the extent necessary to 
obtain informed consent from the parent(s)/legal guardian(s) of the young children to whom 
the study drug may be administered. 
 

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APPROVAL OF CLINICAL STUDY 
PROTOCOL
 
 
The Sponsor and the Investigator(s) agree to conduct the study as outlined in this Clinical 
Study Protocol. Any modification of the Clinical Study Protocol must be agreed upon by the 
Sponsor and the Investigator(s), and must be documented in writing. 
 
 
Sponsor: 
 
Name: 
 
Function: Senior Medical Director 
 
Signature ± Date: See signature page at the end of the document 
 
 

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Investigator:
 
 
 
I have read Clinical Study Protocol ALX0171-C201 and agree to personally 
conduct or supervise the clinical study in accordance with this Clinical 
Study Protocol, with the terms of the clinical trial agreement and with any 
other study procedures and documents provided by Ablynx NV. 
 
I agree to ensure that all associates, colleagues, and employees assisting 
in the conduct of the study are informed about their obligations. 
Mechanisms are in place to ensure that site staff receives the appropriate 
information throughout the study. 
 
I confirm that the study team and I will not implement any deviations from 
this Clinical Study Protocol without agreement of Ablynx NV, except where 
necessary to eliminate an immediate hazard to the patients. 
 
I confirm that I am thoroughly familiar with the appropriate use of the 
study drug, as described in this Clinical Study Protocol and any other 
information provided by Ablynx NV. 
 
I confirm that I am aware of and will comply with ICH-GCP and all 
applicable national and regional regulations/guidelines.  
 
Hence, I agree to supply Ablynx NV with any necessary information 
regarding the ownership interest and financial ties, to promptly update this 
information if any relevant changes occur during the course of the study 
and for one year following completion of the study, and that Ablynx NV 
may disclose any available information about such ownership interest and 
financial ties to regulatory authorities. 
 
Principal Investigator Name: 
 
 
Site details/Address: 
 
 
 
Signature ± Date: 
 
 
 

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SERIOUS ADVERSE EVENT CONTACT 
INFORMATION 
 
 
Contact details of the Sponsor and third parties are available in the ³Investigator Site File´.  

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TABLE OF CONTENTS 
 
CONFIDENTIALITY STATEMENT ............................................................................. 2
APPROVAL OF CLINICAL STUDY PROTOCOL ........................................................... 3
SERIOUS ADVERSE EVENT CONTACT INFORMATION .............................................. 5
TABLE OF CONTENTS ............................................................................................. 6
LIST OF ABBREVIATIONS ...................................................................................... 9
CHANGES COMPARED TO PREVIOUS VERSION(S) ................................................ 11
PROTOCOL SYNOPSIS ......................................................................................... 14
SCHEDULE OF ASSESSMENTS .............................................................................. 27
1.
INTRODUCTION ........................................................................................... 30
1.1. TREATMENT OF RESPIRATORY SYNCYTIAL VIRUS INFECTION ................... 30
1.2. ALX-0171 .................................................................................................. 30
1.2.1.
Pharmaceutical Properties ................................................................... 31
1.2.2.
Nonclinical Studies ............................................................................. 32
1.2.3.
Effects in Humans .............................................................................. 33
1.3. SAFETY PROFILE AND RISK BENEFIT ASSESSMENT .................................... 35
1.3.1.
Nonclinical Results ............................................................................. 35
1.3.2.
Clinical Safety Results ........................................................................ 36
1.3.3.
Potential Risks ................................................................................... 36
1.3.4.
Potential Benefits ............................................................................... 39
1.3.5.
Conclusion ........................................................................................ 39
2.
OBJECTIVES ................................................................................................ 40
3.
STUDY DESIGN ............................................................................................ 41
3.1. OVERALL STUDY DESIGN ........................................................................... 41
3.1.1.
Study Overview ................................................................................. 41
3.1.2.
Study Rationale and Discussion of Study Design ..................................... 47
3.1.3.
Blinding ............................................................................................ 51
3.2. SELECTION OF STUDY POPULATION .......................................................... 53
3.2.1.
Inclusion Criteria ............................................................................... 53
3.2.2.
Exclusion Criteria ............................................................................... 54
3.2.3.
Removal of Subjects from Therapy or Assessment .................................. 55
3.3. TREATMENT OF SUBJECTS ......................................................................... 58
3.3.1.
Overview of Treatments Administered ................................................... 58
3.3.2.
Selection of Doses in the Study ............................................................ 58
3.3.3.
Randomization................................................................................... 60
3.3.4.
Identity of Study Drug ........................................................................ 61

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3.3.5.
Drug Accountability ............................................................................ 62
3.3.6.
Study Drug Handling .......................................................................... 63
3.3.7.
Study Drug Administration .................................................................. 63
3.3.8.
Concomitant Therapy ......................................................................... 67
3.3.9.
Treatment Compliance ........................................................................ 69
3.4. ASSESSMENTS ........................................................................................... 70
3.4.1.
Timing of Assessments ....................................................................... 70
3.4.2.
Baseline Characteristics ...................................................................... 73
3.4.3.
Assessment of Viral Load .................................................................... 73
3.4.4.
Assessments of Efficacy ...................................................................... 74
3.4.5.
Pharmacokinetic Assessments .............................................................. 77
3.4.6.
Pharmacodynamic Assessments ........................................................... 77
3.4.7.
Immunogenicity ................................................................................. 78
3.4.8.
Assessments of Safety ........................................................................ 79
3.4.9.
Total Blood Volume ............................................................................ 83
3.4.10.
Appropriateness and Timing of Measurements ........................................ 84
3.5. ADVERSE EVENT EVALUATION AND REPORTING ........................................ 85
3.5.1.
Adverse Events .................................................................................. 85
3.5.2.
Serious Adverse Events ...................................................................... 87
3.5.3.
Suspected Unexpected Serious Adverse Reactions .................................. 89
3.5.4.
Reporting of Adverse Events ................................................................ 90
3.5.5.
Follow-up of Adverse Events ................................................................ 90
3.5.6.
Other Reportable Information .............................................................. 90
3.6. STATISTICS ............................................................................................... 92
3.6.1.
Study Populations .............................................................................. 92
3.6.2.
Statistical and Analytical Plan .............................................................. 92
3.6.3.
Baseline Characteristics ...................................................................... 92
3.6.4.
Endpoints ......................................................................................... 93
3.6.5.
Evaluation of Virology and Clinical Efficacy Endpoints .............................. 93
3.6.6.
Evaluation of Pharmacokinetic, Pharmacodynamic, and Immunogenicity 
Parameters ....................................................................................... 94
3.6.7.
Evaluation of Safety Parameters ........................................................... 95
3.7. DATA 
QUALITY 
ASSURANCE 
AND 
DIRECT 
ACCESS 
TO 
SOURCE 
DATA/DOCUMENTS .................................................................................... 96
3.8. DATA PROTECTION .................................................................................... 96
4.
ETHICS ........................................................................................................ 97
4.1. ETHICS COMMITTEES AND COMPETENT AUTHORITIES ............................... 97
4.2. ETHICAL CONDUCT OF THE STUDY ............................................................. 97
4.3. SUBJECT INFORMATION AND CONSENT ..................................................... 98
4.4. PRIVACY ................................................................................................... 99
5.
DATA HANDLING AND RECORD KEEPING ................................................... 101

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5.1. DISTRIBUTION OF ACTIVITIES ................................................................ 101
5.2. DOCUMENTATION .................................................................................... 101
5.2.1.
Case Report Form Completion ............................................................ 101
5.2.2.
Source Documentation ...................................................................... 101
5.2.3.
Record Retention ............................................................................. 102
5.2.4.
Monitoring ...................................................................................... 103
6.
FINANCING AND INSURANCE .................................................................... 104
7.
USE OF INFORMATION AND PUBLICATION ................................................. 105
8.
REFERENCES .............................................................................................. 106
9.
APPENDICES .............................................................................................. 108
 

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LIST OF ABBREVIATIONS 
 
ADA
Anti-drug antibodies 
AE
Adverse event 
ATC 
Anatomical therapeutic chemical 
AUC 
Area under the curve 
BQL 
Below the limit of quantification 
CA 
Competent Authority 
CFR 
Code of federal regulations 
CL/F 
Apparent clearance 
cPAP 
Continuous positive airway pressure 
CRA 
Clinical research associate 
CRO 
Contract research organization 
CTD 
Clinical Trial Directive 
DAP 
Data analysis plan 
DNA 
Deoxyribonucleic acid 
ECG
Electrocardiogram 
eCRF
Electronic case report form 
EMA 
European Medicines Agency 
EOS 
End of study 
FDA 
Food & Drug Administration 
FU 
Follow-up 
GCP
Good Clinical Practice 
GLP
Good Laboratory Practice 
GS 
Glycine-serine (linker) 
HFOT 
High flow oxygen therapy 
HIV 
Human immunodeficiency virus 
IB
Investigator¶s brochure 
ICF
Informed consent form 
ICH
International Conference on Harmonization 
ICU 
Intensive care unit 
ID 
Identification 
IDMC 
Independent Data Monitoring Committee 
IEC
Independent Ethics Committee 
IMP 
Investigational Medicinal Product 
IRB 
Institutional Review Board 
ITT
Intent-to-treat 
i.v.
Intravenous 
IWRS/IVRS
Interactive web/voice response system  
KL-6 
Krebs von den Lungen 
LBA 
Ligand binding assay 
Legal guardian(s) 
Authorized representative(s) for the subject, according to local legislation 
LRTI
Lower respiratory tract infection 

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LSLV 
Last visit of the last subject 
LTRA 
leukotriene receptor antagonists 
mAb 
Monoclonal antibody 
MD 
Medical Doctor 
MedDRA
Medical Dictionary for Regulatory Activities 
mITT 
Modified intent-to-treat 
NAb 
Neutralizing anti-drug antibodies 
O2
Oxygen 
qPCR 
Quantitative polymerase chain reaction 
PD
Pharmacodynamic 
PFU 
Plaque forming unit  
PK
Pharmacokinetic 
PP 
Per-protocol 
Pre-Ab 
Pre-existing antibodies 
qRT-PCR 
Quantitative reverse transcriptase polymerase chain reaction 
RACS 
Respiratory Assessment Change Score 
RDAI
Respiratory Distress Assessment Instrument 
RNA 
Ribonucleic acid 
RSV
Respiratory syncytial virus 
SAE
Serious adverse event 
SAP
Statistical analysis plan 
SpO2
Peripheral capillary oxygen saturation 
SUSAR 
Suspected Unexpected Serious Adverse Reactions 
TE 
Treatment-emergent 
TEAE
Treatment-emergent adverse event 
VAS 
Visual Analogue Scale  
WHO 
World Health Organization 
 

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CHANGES COMPARED TO PREVIOUS 
VERSION(S)
 
Global Version 2.0 (dated 25 October 2016) compared to Global Version 1.0 (dated 20 June 2016). This 
amendment is considered substantial due to inclusion of dose-escalation stopping criteria in the study, 
an update to the instructions for dosing, and changes of in/exclusion criteria.  
Version n° and date were adapted throughout the document (including headers and footers). The Table of Contents 
was updated and the Section ³Changes Compared to Previous Version(s)´ was completed. 
Original section 
Change/Rationale 
Synopsis and Section 3.1.1. 
Figures have been updated to ensure consistency. 
Synopsis and Sections 1.3.5., 3.1.1., 3.1.2., 
3.2.3., 3.3.2. and 3.3.3. 
Criteria for stopping dose escalation during the sequential part of 
the study, as well as specifications for which doses could be used 
in the parallel part of the study, have been added. The individual 
discontinuation criteria have been updated to ensure consistency 
with the dose-escalation stopping criteria. 
Synopsis and Section 3.2.1. 
Inclusion criterion 2 has been updated to allow subjects weighing 
up to <15.0 kg to be included in the study. 
Synopsis and Section 3.2.2. 
For clarity, the exclusion criterion on HIV positivity has been 
reworded and an additional criterion was added to exclude 
subjects with a known hypersensitivity to the study drug or any 
excipient of the study drug from the study. 
Sections 3.3.2., 3.3.7. and 3.3.7.1. 
Instructions for dosing have been updated with additional weight 
bands 
and 
safety 
margin 
calculation 
has 
been 
updated 
accordingly. 
Section 3.4.1.1. 
A typographical error has been corrected. 
Section 3.4.8.1. 
More detailed guidance on early detection and treatment of the 
potential risks of airway hyperreponsiveness and immediate or 
delayed adverse drug reactions have been added. 
Section 3.5.1.3. 
The category ³not related/unlikely related´ of the causality 
assessment for AEs has been split to 2 categories; ³not related´ 
and ³unlikely related´.  
 
 
 
 
 
 
 
 
 
 
 
 
 

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Global Version 3.0 (dated 30 October 2017) compared to Global Version 2.0 (dated 25 October 2016). 
This amendment is considered substantial as the non-interventional, Follow-Up study that was 
described in the original version of the Protocol was removed. Furthermore, the method of 
randomization was corrected. The inclusion and exclusion criteria were further specified and clarified 
to ensure that a homogenous population of subjects is enrolled across the sites. To allow flexibility and 
consistency between assessments, certain time windows were adapted in the Schedule of 
Assessments. 
Version n° and date were adapted throughout the document (including headers and footers). The Table of Contents 
was updated. The section ³Changes Compared to Previous Version(s)´ was updated with the changes of the current 
amendment. Minor typographical errors were corrected throughout the document, use of abbreviations and the 
abbreviations list had minor updates stemming from the amendment changes. 
Section affected 
Change/ Rationale 
Synopsis, Section 3.1.1 
The non-interventional, Follow-up Study ALX0171 C202 was deleted, as it will not be 
conducted; following interactions between the Sponsor and the European Medicines 
Agency¶s Paediatric Committee, it was confirmed the study is not necessary at this 
stage of development. 
Synopsis 
- 
Study Design 
- 
Study Population 
Section 3.1.1  
The age range for study population was updated for consistency (age range reads: 
28 days to <2 years). 
Schedule of 
Assessments;  
Section 3.4.1.2 
The Schedule of Assessments underwent changes for clarity and easier flow in the 
assessments to be performed: 
1. On Day 1, the time window before study drug administration was extended to 
3 hours. 
2. Time windows of 0.5 hours before and after the 2-hour post-dose assessments were 
added to allow additional time for the site staff to perform the assessments. 
3. To enhance the overview, the randomization row was moved. 
4. Additional guidance was added on the footnote referring to the documentation of 
sleep disturbance due to night-time coughing. 
5. The sequence of footnotes was updated. 
Section 1.2.3  
(First-in-infant study; 
Immunogenicity) 
The reporting of the first in infant study has been completed; the main conclusions are 
included in the Protocol. A typographical error was corrected in the code of Phase 1 
safety study ALX-0171-1.2/13. 
Schedule of 
Assessments and 
Section 3.3.3 
A clarification was added that, at a minimum, the SpO2, feeding, respiratory muscle 
retractions, and respiratory rate should be evaluated on Day 1 before randomization, 
unless these assessments were already performed within the last 3 hours before 
randomization. 
Section 3.3.3 
The method of stratified randomization per cohort was corrected. 
Synopsis, Exclusion 
criteria, Section 3.3.8 
Additional guidance for the Investigators was provided on the use of forbidden 
medications. It was clarified that initiation of treatment with leukotriene receptor 
antagonists and sodium cromoglycate is forbidden. It was further clarified that topical 
corticosteroids to treat ear disorders are permitted. Inosine pranobex, xanthines and 
expectorants were added to the list of forbidden medications. 
Section 3.4.2 
An explanation was added that if the nasal swab sample collected before study drug 
administration on Day 1 was insufficient for adventitious viral screening, the sample 
collected after the Day 1 study drug administration could be used. 

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Global Version 3.0 (dated 30 October 2017) compared to Global Version 2.0 (dated 25 October 2016). 
This amendment is considered substantial as the non-interventional, Follow-Up study that was 
described in the original version of the Protocol was removed. Furthermore, the method of 
randomization was corrected. The inclusion and exclusion criteria were further specified and clarified 
to ensure that a homogenous population of subjects is enrolled across the sites. To allow flexibility and 
consistency between assessments, certain time windows were adapted in the Schedule of 
Assessments. 
Version n° and date were adapted throughout the document (including headers and footers). The Table of Contents 
was updated. The section ³Changes Compared to Previous Version(s)´ was updated with the changes of the current 
amendment. Minor typographical errors were corrected throughout the document, use of abbreviations and the 
abbreviations list had minor updates stemming from the amendment changes. 
Section affected 
Change/ Rationale 
Schedule of 
Assessments, 
Section 3.4.8.2, 
Section 3.4.9 
The following clarification was added regarding hematology and biochemistry 
assessments to be performed at screening: If all hematology and biochemistry blood 
parameters required for the study are already known from analysis done as a routine 
assessment upon arrival at the hospital, collection of screening clinical laboratory 
samples does not need to be repeated for the purpose of this study. However, the 
samples should be analyzed at the same local laboratory that will be used for the 
remainder of the study. 
Section 3.4.3.1 
The collection of nasal swabs should be performed in both nostrils using the same swab 
was added as a clarification. 
Synopsis, Section 3.2.1  
Methods of feeding support were provided as extra guidance to the Investigator. 
Inclusion Criteria: 
Synopsis and 
Section 3.2.1 
Clarifications were added on the timing study population inclusion criteria must be 
fulfilled (specified at screening and/or randomization as applicable).  
Secondary endpoints: 
Synopsis and Section 
3.6.4 
The reference timepoint in the definition of time to clinical response was updated for 
consistency with other time to event endpoint.  
Section 3.4.5.1 
The following clarification was added: The blood samples for PK assessments will be 
collected from a vein, as using capillary blood (e.g., from heel pricks) is not allowed. 
Section 3.4.7.1 
The following clarification was added: The blood samples for ADA assessments will be 
collected from a vein, as using capillary blood (e.g., from heel pricks) is not allowed. 
Schedule of 
Assessments and 
Section 3.4.1.2 
Stable oxygen saturation on room air of >92% over a period of at least 4 hours would 
be adequate to fulfill the criterion for clinical response. 
Exclusion Criteria: 
Synopsis and 
Section 3.2.2 
A sentence specifying that if any of the exclusion criteria were to be fulfilled at 
screening or randomization, the subject would be excluded. Typographical errors were 
corrected in Exclusion Criteria 5, 7, 8, and 11. 
Synopsis, 
Section 3.4.8.2 
Further details were provided for the analysis of differential white blood cell counts. 

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PROTOCOL SYNOPSIS 
 
 
Protocol title: 
 
A randomized, double-blind, placebo-controlled, multicenter dose-ranging study of 
ALX-0171 in infants and young children hospitalized for respiratory syncytial virus lower 
respiratory tract infection 
 
 
Investigational product: 
 
ALX-0171 nebulizer solution. 
 
The active pharmaceutical ingredient is ALX-0171 Nanobody, a therapeutic protein directed 
against the fusion protein of the human respiratory syncytial virus (RSV). 
 
 
EudraCT n°:  
 
2016-001651-49 
 
Sponsor protocol code: 
 
ALX0171-C201 
 
 
Sponsor: 
 
Ablynx NV  
Technologiepark 21 
9052 Zwijnaarde, Belgium 
 
 
Phase of Development: 
 
Phase 2b 
 
 
Indication: 
 
Respiratory Syncytial Virus Lower Respiratory Tract Infection (RSV LRTI) 
 
Study centers: 
 
International multicenter study 
 

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Objectives:
 
Primary objective:  
To evaluate the anti-viral effect and safety of different doses of inhaled ALX-0171 in 
subjects hospitalized for RSV LRTI.  
 
Secondary objective:
To evaluate the clinical activity, pharmacokinetic (PK) properties, pharmacodynamic (PD) 
effect and immunogenicity of different doses of inhaled ALX-0171.  
Study design: 
 
This 
is 
a 
randomized, 
double-blind, 
placebo-controlled, 
international, 
multicenter 
dose-ranging study. Study drug will be administered along with standard of care treatment, 
which will be determined by the Investigator (or his/her designee) according to institutional 
practice*.  
 
Three dose levels are planned to be evaluated: 

Dose 1: target dose of 3.0 mg/kg  

Dose 2: target dose of 6.0 mg/kg  

Dose 3: target dose of 9.0 mg/kg  
 
The dose range that will be evaluated is expected to provide a potential benefit to the 
subjects, and is selected to allow assessment of reduction in nasal viral shedding and 
improvement of clinical symptoms, to support selection of an optimal dose for future 
development. 
 
Study drug will be administered once daily for 3 consecutive days. The 3-day treatment 
period is expected to bridge the time needed for the body to mount an effective immune 
response.  
 
The study is planned to enroll approximately 180 infants and young children (aged 28 days 
to <2 years) who are diagnosed with and hospitalized for RSV LRTI. 
 
The study consists of a sequential part followed by a parallel part (Figure 1).  
 
 
                                          
*  Clinical Practice Guideline: The diagnosis, management and Prevention of Bronchiolitis as described by the 
American Academy of Pediatrics (2014) may be followed in addition to institutional practice. 

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Figure 1: Overview of study design 
 
Sequential Part 
In safety Cohorts 1 to 3, sequential dose escalation is used to enable appropriate safety 
follow-up. Each of the 3 safety cohorts consists of 12 subjects (N=36 in total) randomized 
3:1 to ALX-0171 (N=9) or placebo (N=3).  
 
In addition to the individual discontinuation criteria (see section 3.2.3), criteria for stopping 
or pausing recruitment in a safety cohort and criteria to stop dose escalation will apply in 
the sequential part of the study (see section 3.1.1). These criteria will also be used to 
decide on the doses taken forward into Cohort 4 (i.e., parallel part of the study).  
In addition to these dose stopping criteria, cumulative unblinded safety data will be 
reviewed by an IDMC consisting of an independent group of clinical experts not participating 
in the study (and an independent statistician). 
 
After each safety cohort (when the last subject in a safety cohort has completed the 
treatment period), recruitment will be paused while the IDMC reviews the available 
cumulative safety data (i.e., all data from prior visits that have been done for all included 
subjects, including preceding cohorts).  
After this comprehensive review, the IDMC will advise the Sponsor on proceeding to the 
subsequent cohort (i.e., the higher dose), and which planned dose levels can be taken 
forward into the parallel part.  
 
Throughout the study, SAE information will be communicated to the IDMC in real time, 
according to the reporting requirements. An ad-hoc meeting can be requested by the IDMC 
members. During the parallel part, an IDMC review will be done when 72 subjects 
completed treatment. 
 

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Parallel Part 
If no stopping criteria have been met during the sequential part and if the IDMC issues a 
positive recommendation after each safety cohort and the Sponsor decides to proceed, the 
remaining 144 subjects (i.e., Cohort 4) will be randomly assigned in a 1:1:1:1 ratio to one 
of following treatment groups, yielding an overall randomization ratio of 3:1 active to 
placebo. 
 
ALX-0171 dose 1 
ALX-0171 dose 2  
ALX-0171 dose 3  
Placebo 
 
In the event one or two dose groups are discontinued for safety, the remaining groups will 
enroll the number of subjects initially specified (i.e., 45 per arm). 
 
The Placebo group will serve as comparator group for the 3 ALX-0171 dose groups. To 
achieve double-blinding across the different groups, each dose will be administered as 
two serial nebulizations. These two nebulizations will consist either of two nebulizations of 
ALX-0171, or one of ALX-0171 and one of placebo, or two nebulizations of placebo 
depending on the assigned treatment group. 
 
Subjects will be screened as soon as possible after arrival to the hospital/emergency unit. 
After completion of the screening assessments and confirmation of subject¶s eligibility, 
randomization should follow as soon as possible but not more than 24 hours after arrival. 
Study drug administration should start as soon as possible after randomization with a 
maximum time interval of 3 hours following randomization. Subsequent doses of study drug 
will be administered at 24-hour intervals (± 4 hours) relative to the first dose. No 
premedication is required or recommended per protocol, but an inhaled 2-agonist may be 
administered at the discretion of the treating Investigator.  
 
On the first 2 dosing days, inpatient hospital stay is required. Provided that the clinical 
response criteria have been met (which are based on adequate oral feeding and oxygen 
saturation), discharge from the hospital can take place per protocol at the Investigator¶s 
discretion from dosing Day 2 onwards after all required assessments of the 5 hours 
(± 1 hour) post-dose time point have been completed. Subjects discharged after the second 
dose must return to the hospital for the third study drug administration (to be administered 
48 ± 4 hours after the first dose by the appropriately trained study personnel), and be 
monitored for a 2-hour pre-dose and post-dose period. Subjects who are not discharged 
from the hospital after completion or premature discontinuation of study drug enter an in-
hospital post-treatment period with assessments in the morning and evening. A Follow-Up 
(FU) visit is scheduled on Day 14 (± 2 days), and an End of Study (EOS) visit on Day 28 

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(± 2 days). For subjects prematurely withdrawn from the study, a Withdrawal visit is to be 
performed on the day of withdrawal. 
Study population: 
 
Infants and young children aged 28 days to <2 years with a gestational age of 
 33 weeks 
who are hospitalized for and diagnosed with RSV LRTI. 
Number of subjects: 
 
Approximately 180 subjects will be enrolled in the study. Subjects will be randomly assigned 
to receive ALX-0171 dose 1, ALX-0171 dose 2, ALX-0171 dose 3 or placebo (N=45 per 
treatment group), yielding an overall allocation ratio of 3:1 active to placebo. Of these, 
48 subjects (12 per dose group) will undergo more extensive PK sample analysis (3 PK 
samples per subject instead of 1 PK sample). 
 
 
Inclusion criteria: 
 
A subject will be eligible for study participation if he/she meets all of the following criteria at 
screening and randomization, unless specified otherwise. 
 
1.
Subject is a male or female infant or young child aged 28 days to <2 years with 
gestational age 
 33 weeks at screening.  
2.
Subject weighs between 
 3.0 kg and < 15.0 kg at screening. 
3.
Subject is otherwise healthy, but is hospitalized for and clinically diagnosed with RSV 
LRTI (bronchiolitis or broncho-pneumonia), i.e., showing typical clinical signs and 
symptoms such as tachypnea, wheezing, cough, crackles, use of accessory muscles 
and/or nasal flaring. 
4.
Subject has a positive RSV diagnostic test at screening. 
5.
Subject is expected to have to stay in the hospital for at least 24 hours (according to 
the Investigator¶s judgment at screening). 
6.
Symptoms likely related to RSV infection (i.e., the symptoms present need to be 
probably linked to the current RSV infection according to Investigator¶s judgment) have 
appeared within 4 days of screening and are not yet improving at screening and 
randomization. 
7.
Subject fulfils at least two of the following RSV disease severity criteria at screening and 
randomization:  

Inadequate oral feeding that requires feeding support (i.e., nasogastric tube or 
intravenous [i.v.] line)  
                                          
 RSV infection will be confirmed either according to routine site practice (PCR or diagnostic quick test), or using a 
(Sponsor-provided) commercial kit. 

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
Inadequate oxygen saturation defined as: 
-
Oxygen saturation (SpO2) 
92% on room air or 
-
Requiring oxygen supplementation to maintain oxygen saturation >90% with 
documented pre-supplementation value 
 92%  

Signs of respiratory distress defined as: 
-
Respiratory rate 
 50 per minute in infants up to 12 months of age, and 
 40 per minute in children above 12 months and/or 
-
Moderate or marked respiratory muscle retractions 
8.
Subject has normal psychomotor development. 
9.
Parent(s)/legal guardian(s) provide written informed consent in accordance with locally 
approved consent process at screening. 
10. The parent(s)/legal guardian(s) are able and willing to comply with the study protocol 
procedures. 
 
Exclusion criteria:  
 
Subjects meeting any of the following criteria at screening or randomization will not be 
eligible for study participation. 
 
1.
Subject is known to have significant comorbidities including: 
Genetic disorders (e.g., trisomy 21, cystic fibrosis),  
Hemodynamically significant congenital heart disease (e.g., needing corrective 
therapy or inotropic support),  
Bronchopulmonary dysplasia,  
Any hereditary or acquired metabolic (bone) diseases,  
Hematologic or other malignancy.  
2.
Subject is known to be human immunodeficiency virus (HIV)-positive. If the subject is 
< 6 months of age, a known HIV-positivity of the mother is also exclusionary. 
3.
Subject is known to be immunocompromised.  
4.
Subject has or is suspected to have an active, clinically relevant concurrent infection 
(e.g., bacterial pneumonia, urinary tract infection). Concurrent acute otitis media is not 
exclusionary. 
5.
Subject has significant oral and/or maxillofacial malformations that would prevent 
proper positioning of the face mask. 
6.
Subject received invasive mechanical ventilation or non-invasive respiratory support 
(i.e., continuous or bilevel positive airway pressure) in the 4 weeks prior to screening.  
7.
During the current admission, subject is initially hospitalized in an intensive care unit 
(ICU) setting and/or received invasive mechanical ventilation or non-invasive 
respiratory support (i.e., continuous or bilevel positive airway pressure). 
8.
Subject is critically ill and/or is expected to require invasive mechanical ventilation, 
non-invasive respiratory support (i.e., continuous or bilevel positive airway pressure), 
or High Flow oxygen therapy (HFOT) at levels not enabling nebulization therapy 

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according to the Investigator¶s judgment. High Flow oxygen, with a maximum flow of 
2 L/kg/min, is permitted under the following conditions:  
used as Standard of Care outside ICU setting 
can be removed for study drug administration (Note: oxygen flow at 2 L/min can be 
provided) 
9.
Subject has received 1 or more doses of palivizumab or treatment or prophylaxis with 
any RSV antiviral compound (e.g., ribavirin, i.v. immunoglobulin, or any investigational 
drug or vaccine for RSV [including subject¶s mother who has been vaccinated against 
RSV]) at any time prior to screening.  
10. Subject is required to continue or start systemic corticosteroid therapy. Subject on a 
maintenance therapy of inhaled corticosteroids will continue this treatment at the usual 
dose. Topical corticosteroids for skin or ear disorders are permitted. 
11. Subject is a child in care (i.e., a child who has been placed under the control or 
protection of an agency, organization, institution or entity by the courts, the 
government or a government body, acting in accordance with powers conferred on 
them by law or regulation). A child in care can thus include a child cared for by foster 
parents or living in a care home institution, provided that the arrangement falls within 
the definition above, but does not include a child who is adopted or has appointed legal 
representative(s). 
12. Subject is currently participating in any other study with investigational drug or has 
received an investigational drug within 4 weeks or 5 half-lives of the concerned drug 
(whichever is longer) prior to screening. 
13. Subject was previously enrolled in a clinical study of ALX-0171 (including the current 
Study ALX0171-C201). 
14. Subject has a known hypersensitivity to the study drug or any excipient of the study 
drug. 
 
Study drug: 
 
Investigational Product 

Name: ALX-0171 (nebulizer solution). 

Active substance: ALX-0171 Nanobody. 

Activity: ALX-0171 Nanobody specifically and potently binds to the RSV F protein, 
thereby inhibiting an early step in the viral replication cycle. 

Composition: 
 
 
 
Reference Product 

Name: Matching placebo (nebulizer solution). 

Active substance: None.  

Composition: 
 
 

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Device: 

Name: FOX-Flamingo inhalation system - CE marked.  

Main components: re-usable base unit (containing the electronics), single-use 
disposable inhalation set (including pediatric face mask in 2 sizes, mask adaptor, 
vibrating mesh nebulizer with reservoir). 

Description: The FOX-Flamingo inhalation system consists of a battery-operated, 
hand-held device, intended for single-patient use. The device provides an aerosol 
with particle size suitable for the intended study population. The nebulizer is always 
to be used with a flow of 2 L/min additional air or O2. 
 
Standard of care treatment 
 
The treatment and care provided to each subject are determined by the Investigator (or 
designee) according to institutional practice. The recommendations on the diagnosis, 
management, and prevention of bronchiolitis, as described by the American Academy of 
Pediatrics (2014), may be followed in addition to institutional practice.  
 
Treatment may include (but is not limited to) the following: 
O2 supplementation through nasal cannula, via face mask or headbox. The initiation, 
monitoring and weaning of oxygen supplementation will follow local practice. It should 
be removed for the nebulized study drug administration, during which air or oxygen flow 
of 2L/min is provided 
Fluid/food supplementation (i.v. or via nasogastric tube, if applicable) 
Antipyretics and/or nonsteroidal anti-inflammatory medication 
Hypertonic saline (but not within 4 hours before start or 4 hours after the end of study 
drug administration)  
Short acting 
2-agonists 
Antibiotics (in case of secondary bacterial infection) 
Epinephrine  
Anticholinergics 
 
Concomitant medications are permitted, apart from those listed under the prohibited 
therapies (see below), at the Investigator¶s discretion (based on medical need). 
 

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Forbidden medications 
 
The following treatments are prohibited up to the Follow-up visit (Day 14 ± 2 days): 
Ribavirin, i.v. immunoglobulin and palivizumab 
Inosine pranobex 
Xanthines 
Heliox 
Initiation of leukotriene receptor antagonists (LTRAs, i.e., montelukast) and/or sodium 
cromoglycate; infants who are on maintenance chronic therapy at screening are to 
continue their usual dose during the study. 
Exogenous surfactant  
Systemic corticosteroids; topical corticosteroids for treatment of a skin or ear disorder 
are permitted; initiation of inhaled corticosteroids is not permitted; infants who are on a 
maintenance therapy of inhaled corticosteroids at inclusion are to continue their usual 
dose during the study 
Mucolytic and/ or expectorant  drugs (e.g., Dornase Alpha, N-Acetylcysteine, 
Bromhexine) 
 
Subjects whose respiratory condition is deteriorating (e.g., hypercapnia with pCO2 
> 8 kPa/60mmHg, decreased consciousness) and need to start non-invasive respiratory 
support or invasive ventilation need to discontinue study drug treatment but should remain 
in the study according to the in-hospital post-treatment period as specified in the Schedule 
of Assessments, and should also attend the FU and EOS Visits. Subjects on HFOT as 
standard of care at inclusion and for whom the flow needs to be increased to levels not 
enabling study drug nebulization and/or above 2 L/kg/min also need to discontinue study 
drug treatment and be further followed up as described above. SAE reporting is required for 
these subjects with deterioration of the respiratory condition requiring above mentioned 
methods of ventilation.  
 
After the end of the subject¶s participation in the study, each subject is to be treated 
according to standard clinical practice. 
 
 
Study duration: 
 
The overall study duration is expected to be approximately 23 months. The planned study 
duration for each subject is approximately 28 days. The completion of the study is defined 
as the last visit of the last subject (LSLV) participating in the study. 
 

Screening period: Within 24 hours after arrival at hospital.  

Study drug treatment period: Subjects will receive once-daily doses of study drug on 
3 consecutive days. The first dose will be administered as soon as possible and within 
3 hours after randomization. The second dose is to be administered approximately 
24 hours (± 4 hours) after administration of the first dose, and the third dose 
approximately 48 hours (± 4 hours) after administration of the first dose. 

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
Ambulatory treatment on dosing Day 3: If the subject¶s clinical condition has improved 
sufficiently in the opinion of the Investigator to allow discharge from hospital and if the 
per protocol-defined clinical response criteria have been met, the subject may be 
discharge from the hospital after all required assessments of the 5 hours (± 1 hour) 
post-dose time point on dosing Day 2 have been completed. In this case the subject is to 
return to the investigational site in the hospital for administration of the 3rd dose of study 
drug by appropriately trained study personnel. The subject should remain in the hospital 
for a 2-hour pre-dose and post-dose monitoring period. 
In-hospital post-study drug treatment period: Additional post-treatment assessments are 
foreseen for subjects who are not discharged from the hospital after the completion or 
discontinuation of study drug treatment.  

A Follow Up visit will take place on study Day 14 (± 2 days).  

An End of Study visit will take place on study Day 28 (± 2 days).  

For subjects who are prematurely withdrawn from the study, a Withdrawal visit is to be 
performed on the day of withdrawal unless consent was withdrawn. 
 
 
 
Outcome Measures: 
 
Viral Load Outcome Measure 

Quantitative viral titers in the nasal cavity (plaque and qPCR) over time. 
 
Safety Outcome Measures 
Treatment-emergent adverse events (TEAEs), as noted by healthcare staff and/or 
reported by parents/caregivers. The Investigator (or his/her designee) will review at each 
visit whether AEs/SAEs have occurred since the last visit. 
Physical examination including heart auscultation, examination of abdomen, skin and 
ears/nose/throat.  
Lung auscultation  
Peripheral capillary O2 saturation (SpO2) 
Vital signs: body weight, body temperature, heart rate, respiratory rate 
Clinical laboratory test results: 
-
Clinical chemistry: alanine aminotransferase, aspartate aminotransferase, creatinine, 
sodium, potassium, chloride, C-reactive protein, 
-glutamyl-transferase, blood urea 
nitrogen 
-
Hematology: hemoglobin, hematocrit, red blood cell count and indices, mean 
corpuscular hemoglobin, mean corpuscular hemoglobin concentration, platelet count 
(or estimate), white blood cell count including differential (lymphocytes, neutrophils, 
monocytes, basophils, eosinophils). 
Safety lab assessments are planned two times during the study (at screening and at the FU 
visit) and will be performed by the local laboratory in order to allow timely availability of the 
results. 

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Clinical Activity Outcome MeasuresÁ 

Heart rate and SpO2  

Feeding: type of feeding support, and (time and date of) sufficient feeding to enable 
hospital discharge, in the opinion of the Investigator (with particular attention to 
hydration and breathing comfort during feeding) 

Respiratory rate measured over a 1-minute interval 

Wheezing as assessed during lung auscultation 

Cough during the night and during the day 

Respiratory muscle retractions (supraclavicular, intercostal, and subcostal) 

General appearance: activity, irritation, and responsiveness 

Body temperature 
 
Based on the Clinical Activity Outcome Measures, composite scores such as the Respiratory 
Distress Assessment Instrument (RDAI) score (based on wheezing and respiratory muscle 
retractions), Respiratory Assessment Change Score (RACS; based on RDAI and change in 
respiratory rate), and a Global Severity Score (based on respiratory parameters, medical 
interventions, feeding, general appearance and body temperature) will be calculated. 
 
The feeding and oxygen saturation outcome measures will be used to calculate Time to 
Clinical Response. Subjects will be considered to have met the Clinical Response criteria 
when both of the following criteria are fulfilled: 

Stable oxygen saturation on room air, defined as SpO2 > 92% over a period of 
 4 hours. In case of oxygen supplementation, the level of supplementation is to be 
considered for reduction at least three times per day. Provided oxygen saturation is 
stable, attempts to remove the supplementation will be done at least three times a day.  

Adequate oral feeding which is sufficient to maintain sufficient hydration, in the judgment 
of the Investigator. 
Medical Interventions Outcome Measures: 
Length of hospital stay for RSV infection 

Level, method, and duration of supplemental oxygen therapy 

Initiation of invasive or non-invasive ventilation (i.e., continuous positive airway pressure 
[cPAP] or HFOT)  

Level, method and duration of invasive or non-invasive ventilation  

Transfer to ICU and duration of stay in ICU 
 
                                          
Á The evaluation of several of these parameters will also inform on safety outcome. 

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Parent/Caregiver Outcome Measures: 
Parent(s)/Caregiver(s) assessment of the clinical condition of the child will be done by 
daily completion of a diary during the hospital stay and up to the EOS (Day 28) visit. This 
diary includes scoring of respiratory symptoms over the past 24 hours (cough, wheezing, 
trouble breathing), evaluating the general health of the child by completing a Visual 
Analogue Scale (VAS), and answering a question whether the child has returned to 
his/her normal condition from before the onset the RSV infection. For the period after 
discharge from the hospital, this diary will also allow to capture data on health care 
utilization and use of medication for respiratory symptoms. 
PK Outcome Measures 

The systemic concentration of ALX-0171 will be evaluated in serum. A subset 
(48 subjects, i.e., 12 subjects per dose group) will undergo more extensive PK sample 
analysis (3 blood samples for PK assessment). In the remainder of subjects, only 1 PK 
blood sample will be taken.  
 
PD Outcome Measures 

Quantification of the biomarker Krebs von den Lungen-6 (KL-6) in serum 
 
Immunogenicity 

Systemic presence (serum) of anti-drug antibodies (ADA)  
 
 
Endpoints: 
 
Primary Endpoint 
Anti-viral effect as measured by the time needed for the viral load to drop below the plaque 
assay quantification limit (time-to-BQL) in nasal mid-turbinate swab specimens. 
 
Secondary Endpoints 

Safety assessment (assessed by physical examination, AEs, laboratory assessments and 
vital signs) of different doses of ALX-0171 

Change from baseline in Global Severity Score 

Time to clinical response: defined as the time between first administration of study drug 
and achieving adequate oxygen saturation and oral feeding 

PK properties of ALX-0171  

Viral load profile over time in nasal swab specimens (qPCR and plaque assay) 

Evaluation of serum ADA 
 
Other Endpoints 

Evolution over time in clinical symptoms (SpO2, feeding, respiratory rate, wheezing, 
cough, respiratory muscle retractions, and general appearance) 

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
Evolution over time in RDAI, RACS 

Length of hospital stay for RSV defined as time between admission and discharge 

Duration of supplemental oxygen therapy 

Initiation of invasive and non-invasive ventilation and duration of respiratory support 

Transfer to ICU and duration of ICU stay 

Parent(s)/Caregiver(s) assessment of the clinical condition of the subject  

Evolution of serum biomarker over time  
 
 
Sample Size: 
 
With 45 subjects per arm, 85% power is achieved to detect a 50% reduction in median 
time-to-BQL using a two-sided log-rank test at significance level of 0.05. For each 
comparison of the ALX-0171 dose groups with placebo, a significance level of 0.05 is 
assumed. For multiple pairwise comparisons, the family-wise error rate is controlled at 5% 
through the closed testing principle, where the comparison of the lower dose of ALX-0171 to 
placebo is only performed if the comparison of the higher dose of ALX-0171 to placebo is 
significant. The sample size also incorporates a 15% drop-out rate. 
 
Statistical Analysis: 
 
For the primary endpoint, the anti-viral effect will be measured as the time-to-BQL in nasal 
mid-turbinate swab specimens. The median time-to-BQL will be compared between each of 
the ALX-0171 dose groups and placebo using a log-rank test. The tests will be performed in 
a sequential way to preserve the family-wise error rate at 0.05. Specifically, dose 3 of 
ALX-0171 will first be tested against placebo at the 0.05 significance level. Dose 2 of 
ALX-0171 will only be compared to placebo at the 0.05 significance level if the comparison 
of dose 3 with placebo is significant. Consequently, dose 1 of ALX-0171 will only be 
compared to placebo at the 0.05 significance level if the comparison of dose 2 of ALX-0171 
with placebo is significant. 
 
The data from the secondary endpoints will be analyzed by descriptive statistics as 
applicable. For selected secondary endpoints, comparisons of active dose groups with 
placebo may be performed through appropriate inferential tests. No correction for multiple 
testing is foreseen for secondary endpoints, and p-values reported for the analyses are to 
be interpreted accordingly. 
 
Analysis of all parameters will be described in a Statistical Analysis Plan (SAP) or a Data 
Analysis Plan (DAP; for PK analysis), which will be finalized prior to database lock, and will 
comprise all methods and tests applied for analysis of the corresponding data.  

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SCHEDULE OF ASSESSMENTS 
Period 
Screeninga, b
Study Drug Treatment Periodc
In-hospital 
Post-
Treatment 
Period d
FU visit 
(Day 14±2) 
or Withdrawal 
visite
EOSe
(Day 28±2) 
Hospitalized Dosing 
Hospitalized or 
Ambulatory Dosing
Visit 
Day 1
Day 2 
Day 3
Morning and 
evening 
Approximate time/ 
Study procedure  
-24h to 
randomization 
-3h to 
dose 
Dose
2h 
(±0.5h)
5h 
(±1h)
-2h to 
dose 
Dose 
2h 
(±0.5h) 
5h 
(±1h) 
-2h to 
dose 
Dose 
2h 
(±0.5h)
Informed consent
X
 
Inclusion/exclusion criteria 
X
 
RSV diagnosis f 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics and medical history 
X
 
Hospitalization information/Clinical 
response information g 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study drug administration h 
  
X 
 
 
X 
 
 
 
X 
 
 
 
Nasal mid-turbinate swab i 
  
X 
 
X 
X 
 
 
X 
X 
 
X 
Xj 
X 
Physical examination k 
X 
X 
 
 
X 
X 
 
 
X 
X 
 
X 
X 
X 
X 
Body weight 
X
 
X
X
Body height 
X
 
Body temperature
X
X
X
X
X 
X
X
X
X
General appearance
X
X
X
X
X 
X
X
X
X
Lung auscultationn 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
X
Heart rate 
X
X
X
X
X
X
X 
X
X
X
X
SpO2 l
X
X
X
X
X
X
X 
X
X
X
Feeding m 
X 
X 
 
 
X 
X 
 
 
X 
X 
 
X 
X 
X 
(Respiratory muscle) retractions 
X
X
X
X
X
X
X 
X
X
X
X
Respiratory rate
X
X
X
X
X
X
X 
X
X
X
X
Randomization b
X
 
Daytime coughing
X
X
X
X
X
X
X 
X
X
X
X
X
(Sleep disturbance from) night-time 
coughing o 
Xo 
Xo 
 
 
 
Xo 
 
 
 
Xo 
 
 
Xo 
Xo 
X 
Parent/caregiver assessment p 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pharmacokinetics (single sample) 
 
 
 
 
 
 
 
q 
 
 
 
  
Pharmacokinetics
(more extensive sampling) 
 
 
 
 
 
Xr 
r
r 
 
 
 
 
 
Clinical laboratory (hematology and 
clinical biochemistry) 
Xs, t 
 
 
 
 
 
 
 
 
 
 
 
 
Xu 
Immunogenicity  
Xs 
 
 
 
 
 
 
 
 
 
 
 
 
Xu 
 
Previous and concomitant 
medication 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse events v
 
h = hour; FU = Follow-up; EOS = End of Study.  
Timing of assessments: post-dose time points relate to the end of the 2nd of the 2 nebulizations of study drug administration. Pre-dose time points relate to 
the start of the 1st of the 2 nebulizations of study drug administration. Throughout the study, study personnel should make every reasonable effort to follow the 
timing in the schedule of assessments for each subject.  

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a.
If the Day 1 pre-dose assessments will be performed within 3 hours after the screening assessments have been performed, the assessments already done 
at screening do not need to be repeated and only the additional assessments to be performed on Day 1, pre-dose will need to be performed. 
b.
At the time of randomization, subjects should be eligible for study participation as defined in the inclusion/exclusion criteria. Therefore, at a minimum, the 
SpO2, feeding, respiratory muscle retractions, and respiratory rate should be evaluated on Day 1 before randomization, unless these assessments were 
already performed within the last 3 hours before randomization. 
c.
Study drug administration should take place within 24 hour intervals (± 4 hours) relative to the start of the 1st nebulization of the 1st dose. Provided that 
the clinical response criteria have been met, discharge from the hospital can take place per protocol at the Investigator¶s discretion from dosing Day 2 
onwards after all required assessments of the 5 hours (± 1 hour) post-dose time point have been completed. Subjects who started study drug dosing but 
were discontinued prematurely from study drug treatment, should be further monitored according to the in-hospital post treatment period (if applicable) and 
should attend the FU and EOS visits. 
d. The in-hospital post-treatment assessments are to be performed for subjects who are not discharged from the hospital after the completion or 
discontinuation of study drug treatment. 
e.
For subjects who discontinue the study before Day 28, the Withdrawal visit will be conducted on the day of withdrawal as long as there has been no 
withdrawal of consent. If the Withdrawal visit assessments are performed within 6 hours after the Day 1, Day 2, Day 3, or in-hospital post-treatment Day 
assessments have been performed, the assessments already done at the prior time point do not need to be repeated and only the additional assessments to 
be performed on the Withdrawal Visit will need to be performed. No EOS visit needs to be performed after the Withdrawal Visit. In case subjects are 
hospitalized beyond the Day 14 FU visit, the additional assessments (in addition to the in-hospital post treatment period assessments) of the Day 14 FU visit 
need to be done on Day 14.  
f. RSV infection will be confirmed either according to routine site practice (PCR or diagnostic quick test), or using a (Sponsor-provided) commercial kit. 
g. Hospitalization information will include occurrence of ICU transfer, apnea episodes, initiation and type of ventilation and hospital/ICU discharge information. 
Assessment of Clinical Response will be done with collection of date and time of adequate oral feeding to enable discharge as well as adequate stable oxygen 
saturation on room air of >92% over a period of at least 4 hours. 
h. Study drug will be administered via nebulization using the study-specific device. One dose consists of 2 serial nebulizations.  
i. A mid-turbinal nasal swab should be taken using provided kits and following specific instructions in case the subject is re-hospitalized or consults the 
Investigator for a respiratory condition after hospital discharge. 
j. A nasal swab should only be collected during the in-hospital post-treatment period on the day of hospital discharge.  
k. Physical examination includes examination of abdomen and skin and ears/nose/throat. Lung auscultation is listed separately as it is to be assessed more 
frequently. 
l. Continuous monitoring of SpO2 needs to be done until the clinical response criterion for oxygen has been met and/or in case saturation monitoring is to be 
continued according to the Investigator¶s judgment.  
m.Type of feeding support, if any, and feasibility of oral feeding. 
n. To assess wheezing, crackles/crepitation and other abnormalities in lung auscultation. 
o. Sleep disturbance from night-time coughing to be documented pre-dose the next day or in the morning during the in-hospital post-treatment period, or at the 
FU visit, EOS or Withdrawal visit, based on feedback from the nursing staff. In case there is no night between screening and study drug administration on 
Day 1, the Day 1 assessment should not be performed. 
p. The parent/caregiver assessment should be done every evening from screening until the EOS visit by completing a diary. 
q. Blood draw for PK assessments on Day 2 or Day 3, at any time between 0.5 hours post second dose and start of the third dose. If sufficient serum remains 
after PK assessment, exploratory biomarker (KL-6) may also be evaluated.  

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r. 48 subjects will undergo more extensive PK analysis (3 PK samples per subject instead of the 1 sample), i.e., blood draws on Days 2-3 1) pre second dose, 2) 
at any time between 0.5 hours and 3 hours post second dose, and 3) at any time between 3 hours and 6 hours post second dose (and at least 1 hour apart 
from the previous sampling); If sufficient serum remains after PK assessment, exploratory biomarker (KL-6) may also be evaluated. 
s. Blood draw at screening for clinical laboratory (hematology and clinical biochemistry) and immunogenicity. If sufficient serum remains after immunogenicity 
assessment, exploratory biomarker (KL-6) may also be evaluated. In case the blood sample for immunogenicity was not taken at screening, the sample 
should be collected at the Day 1 pre-dose timepoint, as far as possible. 
t. If all hematology and biochemistry blood parameters required for the study are already known from analysis done as a routine assessment upon arrival at the 
hospital, collection of screening clinical laboratory samples does not need to be repeated for the purpose of this study. However, the samples should be 
analyzed at the same local laboratory that will be used for the remainder of the study. 
u. Blood draw on Day 14 for clinical laboratory (hematology and clinical biochemistry) and immunogenicity. If sufficient serum remains after immunogenicity 
assessment, exploratory biomarker (KL-6) may also be evaluated. No blood sample needs to be taken in case of premature withdrawal from the study for 
subjects who did not receive any study drug. In case the blood sample for immunogenicity was not taken on Day 14, the sample should be collected at the 
EOS (Day 28) visit, as far as possible. 
v. In case of a severe and/or serious hypersensitivity reaction, an additional serum sample should be collected (if reasonably feasible) as soon as possible after 
the start of the event. 
 
 

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1.
INTRODUCTION
 
Respiratory syncytial virus (RSV) lower respiratory tract infection (LRTI) is a leading cause 
of bronchiolitis in infants and results in over 3 million hospitalizations worldwide per year.
ALX-0171 is a therapeutic protein (Nanobody) that is currently being developed for the 
treatment of RSV LRTI. 
The antiviral effect of ALX-0171 is expected to provide rapid control of the infection, thereby 
reducing the intensity and duration of severe disease. The favorable in vitro potency of 
ALX-0171 Nanobody and the in vivo results obtained in nonclinical studies indicate that 
ALX-0171 may provide an opportunity for therapeutic intervention in established 
RSV infection. This is also supported by an initial clinical study in children hospitalized for 
RSV lower respiratory tract infection, where treatment with inhaled ALX-0171 had an 
immediate impact on viral replication and reduced viral load compared to placebo. 
 
1.1.
TREATMENT OF RESPIRATORY 
SYNCYTIAL VIRUS INFECTION 
 
Nearly all infants are infected with RSV in the first years of life. RSV LRTI is associated with 
significant morbidity and mortality [1, 2]. RSV infection imposes a significant burden on 
health care infrastructure and there is a high unmet medical need for treatment options. 
Evidence-based guidelines indicate that there are no treatments that shorten the course of 
bronchiolitis or hasten the resolution of symptoms; supportive care remains the cornerstone 
of clinical management (hydration and oxygen saturation) [1, 3, 4]. 
  
1.2.
ALX-0171
 
Nanobodies are a novel class of therapeutic proteins, and are based on the smallest 
functional fragments of single-chain antibodies that occur naturally in the Camelidae family. 
ALX-0171 Nanobody is directed towards the RSV fusion (F) protein, and is intended to 
interfere with viral entry into host cells. ALX-0171 is a trivalent Nanobody, formed by three 
identical building blocks connected via two linkers (Figure 2). All three moieties are capable 
of binding to the homotrimeric RSV F protein. 

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Figure 2: Schematic representation of ALX-0171 Nanobody 
The amino acid (15-GS) linkers connect the C-terminus of the first building block with the N-terminus of the 
second one, and the C-terminus of the second building block with the N-terminus of the third one. The three 
building blocks (designated RSVNMP1A4) are identical, with the only exception of the E1D mutation in the first 
building block, which has been introduced to avoid pyroglutamate formation. 
 
 
The F protein is highly conserved between RSV serotypes, and is therefore considered the 
main target for development of viral entry inhibitors. Following activation, the RSV F protein 
causes the membranes of the host cell and the virion to come into close vicinity and fuse 
together, allowing further infection and viral replication. Glycoprotein F also induces fusion 
of infected cells with adjacent, uninfected cells (epithelial cell syncytia), which allow for 
cell-to-cell transmission of the replicated viral RNA and confer additional protection against 
host immune responses [5]. 
 
ALX-0171 Nanobody binds to a well-conserved epitope in antigenic site II of the RSV F 
protein, close to or overlapping with the epitope of the clinical benchmark palivizumab 
(trade name Synagis®, MedImmune/AstraZeneca). The latter is a humanized monoclonal 
antibody (mAb) indicated for the prevention of serious lower respiratory tract disease in 
high risk children, and is prophylactically administered by monthly intramuscular injections 
throughout the RSV season.  
 
1.2.1. PHARMACEUTICAL PROPERTIES 
 
Since direct delivery and deposition in the respiratory tract is desirable, inhalation was 
considered the preferred route of administration. ALX-0171 was therefore developed as a 
solution for nebulization, containing 50 mg/mL ALX-0171 Nanobody dissolved in a 
formulation buffer suitable for inhalation.  

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ALX-0171 solution for nebulization is administered using the handheld FOX-Flamingo 
inhalation system. The FOX-Flamingo is intended for professional use in a clinical 
environment, in spontaneously-breathing subjects from birth up to 3 years. 
 
1.2.2. NONCLINICAL STUDIES 
 
Pharmacological properties:
 
ALX-0171 was characterized using in vitro systems, including assessment of affinity, 
biological activity and specificity. Different cellular systems of RSV replication were used, 
with cell-line adapted virus strains as well as viruses isolated from clinical cases. 
In vivo efficacy was demonstrated in the RSV infection cotton rat model, a standard 
model used in the field. Intranasal and intratracheal administration and nebulization were 
used to reflect the clinical route of administration.  
Efficacy and safety were further confirmed in the neonatal lamb model of RSV infection, a 
disease model that allows the assessment of clinical symptoms, histopathology and viral 
titres, and more closely mimics the clinical situation in infants. 
 
Safety pharmacology: 
 
Specific GLP-compliant in vivo studies were designed for the evaluation of ALX-0171 effects 
on respiratory and cardiovascular system, in rats and dogs respectively. 
 
Pharmacokinetics: 
 
The objective of the pharmacokinetic (PK) program was the characterization of plasma and 
local (lung) kinetics of ALX-0171 in nonclinical toxicity studies. Additionally, the impact of 
anti-drug antibodies (ADA) on the PK of ALX-0171 was evaluated. PK parameters were also 
derived from a study in juvenile rats after single or repeated dose inhalation (starting from 
post-natal dose 4), as well as from an efficacy study in neonatal lambs. The latter includes 
information from infected animals.  
 
Toxicology: 
 
Two 14-day repeat-dose toxicity studies in rats, after once-daily administration via 
inhalation and via intravenous (i.v.) administration respectively, showed no treatment-
related effects on local tolerance, clinical signs, body weight, food consumption, 
ophthalmic examination, hematology and coagulation, clinical chemistry, urine analysis, 
macropathology, histopathology, or organ weights. 
Safety evaluations were included in the studies involving RSV-infected cotton rats and 
neonatal lambs.  

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The risk of accidental exposure of the face, and particularly of the eyes, during 
nebulization via a face mask, was assessed nonclinically. No local irritant effects of 
ALX-0171 on bovine cornea were observed. Likewise, in a repeated dose PK study in 
juvenile rats after inhalation, no clinical signs indicative of eye irritation or histopathology 
findings were reported. 
 
1.2.3. EFFECTS IN HUMANS 
 
At present, three Phase 1 clinical trials have been conducted in adults, to obtain initial 
safety and PK data. Following completion of the adult studies, a first-in-infant clinical study 
was recently completed. Please refer to the Investigator¶s Brochure (IB) for a detailed 
overview of each of the individual studies. 
 
First-in-man Phase 1 study ALX-0171-1.1/11 (N=60) evaluated the safety, tolerability 
and pharmacokinetics of ALX-0171, administered by inhalation, in healthy male 
volunteers. 
Phase 1 study ALX-0171-1.3/13 (N=44) was performed to obtain additional information 
on local and systemic PK of ALX-0171 in healthy male volunteers.  
Phase 1 safety study ALX-0171-1.2/13 (N=24) evaluated the potential occurrence, 
reversibility and prevention of bronchoconstriction upon inhalation of ALX-0171 by adults 
with sensitive (hyperresponsive) airways. 
Study ALX0171-C104 (N=53) was a Phase 1/2a multicenter study in infants and toddlers 
hospitalized for RSV lower respiratory tract infection, to provide an initial evaluation of 
the safety, tolerability, anti-viral and clinical activity of ALX-0171. A summary of the 
main conclusions is described below. 
 
Clinical Safety: 
 
The clinical studies in adults showed that inhalation of ALX-0171 was well-tolerated at all 
doses evaluated.  
 

Treatment-emergent adverse events (TEAEs) resolved quickly without further treatment, 
and were generally of mild to moderate intensity. The most common study drug-related 
TEAEs reported in the Phase 1 studies in adults included cough, headache, oropharyngeal 
pain, rhinitis, nasopharyngitis and diarrhea, generally of mild intensity.  

No study drug-related TEAEs leading to withdrawal were reported. Similarly, no study 
drug-related, clinically significant findings were observed with respect to clinical 
laboratory parameters, vital signs, electrocardiogram (ECG), physical examinations, or 
lung auscultations.  

In the studies in healthy volunteers, no meaningful trends in spirometry parameters were 
observed. The study in adults with hyperresponsive airways demonstrated the 

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reversibility of bronchoconstriction with bronchodilator treatment ( 2-agonist) and 
prevention with prophylactic use of bronchodilator thereof. 
 
ALX-0171 also found to be well-tolerated in infants and young children hospitalized for RSV 
LRTI.  
 

In line with the underlying disease, the most frequent TEAEs were respiratory, thoracic 
and mediastinal disorders and infections and infestations. Possibly-related TEAEs 
occurred in 3 subjects (8.6%) in the ALX-0171 group. These were cough, rhinorrhea, and 
pyrexia. All were mild and resolved.  

There were no treatment-related serious adverse events (SAEs) in this study. Five SAEs 
were reported in 4 subjects in the ALX-0171 group. These were hyporesponsiveness and 
hypotonia (both in 1 subject), pneumonia (2 subjects), and atelectasis. All resolved.  

Two subjects were prematurely discontinued from study treatment (due to SAEs 
hypotonia and hyporesponsiveness and pneumonia). As noted above, all of these SAEs 
resolved. 
 
Clinical Pharmacokinetics: 
 
In adults, the local (epithelial lining fluid) and systemic exposure levels were above the 
target for infants and young children, with good tolerability.  
Consistent with lung exposure, inhaled ALX-0171 was quantifiable in the serum of most 
of the infants and young children in Study ALX0171-C104.  
 
Clinical Activity and Pharmacodynamics: 
 
Study ALX0171-C104 provided a first indication of anti-viral and clinical activity in a relevant 
clinical setting, i.e., hospitalized infants with RSV LRTI. 
 
Data on nasal viral load indicates that ALX-0171 treatment rapidly and sustainably 
reduces cultivatable virus titers to below the quantification limit.   
Post-hoc analysis of a composite of clinical parameters, the Global Severity Score, led to 
an encouraging initial indication of a therapeutic effect for infants treated with ALX-0171. 
 

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Immunogenicity 
 
In adults, pre-existing antibodies (pre-Ab§) were found in 7 to 18% of the subjects. In 
the Phase 1 studies ALX-0171-1.1/11 and ALX-0171-1.3/13, no treatment-emergent 
(TE) ADA responses were detected, whereas in the Phase 1 safety study ALX-0171-
1.2/13, TE ADA were observed in 33% of the subjects (population of subjects with 
hyperresponsive airways). 
 
In Study ALX-0171-C104, pre-Ab were found in 45% of the subjects, while TE ADA was 
detected in 22.9% of the infants. Pre-Ab detected in those children may reflect maternal 
antibodies transferred to the infant via the transplacental route during gestation or 
during breastfeeding. As the assay cannot discriminate pre-Ab from drug induced TE 
ADA, it is not clear to what extent the TE ADA detected may represent fluctuating levels 
of pre-Ab. Currently it is not known to what extent pre-Ab can fluctuate within the short 
study period (14 days). No effect of ADA on PK was observed. 
 
TE ADA is not expected to have an impact on PK or efficacy given the short treatment 
duration, as TE ADA do not emerge to considerable amounts within the first 7 days after 
initial drug administration. 
 
1.3.
SAFETY PROFILE AND RISK 
BENEFIT ASSESSMENT 
 
The potential benefits and risks for administration of ALX-0171 are assessed from the 
available nonclinical data and the results of the completed Phase 1 clinical studies in adults 
and a Phase 1/2a trial in children hospitalized for RSV LRTI.  
 
1.3.1. NONCLINICAL RESULTS 
 
Detailed nonclinical assessment of systemic toxicity as well as local tolerability and 
respiratory safety revealed no clinically meaningful risks for administration of ALX-0171 to 
pediatric subjects. The results were consistent across the different nonclinical safety and 
toxicology studies.  
                                          
§ Pre-existing antibodies, i.e., ADA present in samples from treatment-naïve subjects, have been commonly 
observed during immunogenicity assessments for various therapeutic proteins. 

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1.3.2. CLINICAL SAFETY RESULTS 
 
At present, three Phase 1 clinical studies have been conducted in adults. In addition, a 
Phase 1/2a study in children aged 1 month to < 2 years hospitalized for RSV LRTI was 
recently completed. ALX-0171 was generally well tolerated in all clinical studies.   
 
1.3.3. POTENTIAL RISKS 
 
ALX-0171 has no endogenous target and no secondary pharmacology was noted throughout 
the pre-clinical development program; potential risks related to the pharmacology or to the 
mechanism of action of the compound are therefore considered unlikely.  
 
More general risks, inherent to administration of inhalation products or therapeutic proteins, 
cannot be excluded. A continuous further evaluation is included during clinical development 
to assess if these potential effects would constitute clinically meaningful risks for 
administration of ALX-0171.  
 
Airway Hyperresponsiveness 
Viral respiratory infections are known to transiently increase bronchial reactivity, potentially 
leading to airway hyperresponsiveness (i.e., an abnormal airway narrowing of the bronchi, 
triggered by various chemical or physical stimuli).  
 
The occurrence, treatment and prevention of potential bronchoconstriction subsequent to 
ALX-0171 inhalation was evaluated in a dedicated Phase 1 study in adults with 
hyperresponsive airways (Study ALX-0171-1.2/13). In total, 24 subjects participated in the 
study. In this population with bronchial hyperreactivity, 10 subjects (42%) experienced a 
mild to moderate bronchoconstriction either during the escalating dose or repeated dose 
part of the study. All events were treated successfully with ß2-agonist (salbutamol). The 
results of this study demonstrated the immediate reversibility of bronchoconstriction with 
bronchodilator 
treatment 
( 2-agonist) 
and 
prevention 
with 
prophylactic 
use 
of 
bronchodilator thereof. 
 
In the first-in-infant Study ALX0171-C104, as a precaution and in order to standardize 
treatment across the sites an inhaled dose of the short-acting 2-agonist salbutamol was 
administered before each administration of study drug. A review of the safety data and 
respiratory 
parameters 
collected 
in 
the 
first-in-infant 
study 
did 
not 
reveal 
a 
bronchoconstrictive risk after study drug inhalation. Therefore, the requirement for 
prophylactic administration of a 2-agonist will not be implemented in the current protocol. 
The use of bronchodilator treatment will be permitted at the Investigator¶s discretion.   
 

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The potential risks of airway hyperresponsiveness and bronchoconstriction will be closely 
monitored in each of the safety cohorts and the overall study. Independent Data Monitoring 
Committee (IDMC) review is planned before each increment in dose and on a regular basis 
thereafter. 
Immediate or Delayed Adverse Drug Reactions 
 
All therapeutic proteins have the potential to elicit antibody or other immune- or 
non-immune-mediated responses, potentially resulting in hypersensitivity or allergic 
reactions such as rash, urticaria, angioedema, serum sickness and anaphylactoid or 
anaphylactic reactions. These responses are complex and could occur following initial or only 
after repeated exposure, and are very difficult to predict.  
 
Within the context of the planned clinical study, immunogenicity-related AEs as a 
consequence of TE ADA are not expected, as TE ADA typically do not emerge to 
considerable amounts earlier than 7 days after first administration of study drug, at times 
where study drug is expected to be cleared, given the short treatment period of 3 days. 
 
While pre-Ab and TE ADA have been reported in clinical studies with ALX-0171, no obvious 
correlation with potential immune-related AEs has been established thus far, neither in 
adults nor in RSV-infected children. No immune response-related toxicological findings were 
reported during the nonclinical studies.  
During Study ALX-0171-1.3/13, a possible mild hypersensitivity reaction (unilateral eyelid 
oedema) was noticed in one subject approximately 1 hour after 1 single i.v. dose. No pre-Ab 
nor TE ADA were detected in this subject.  
During Study ALX-0171-C104, no correlation between immunogenicity (both pre-Ab or TE 
ADA) and safety was seen. One subject with a history of acute urticaria presented with a 
mild exanthema of abdomen, trunk, back and retroauricular area, about 5 hours after the 
second drug administration. The event resolved without medication and was considered 
unlikely/not related to the study drug by the Investigator. This subject was pre-Ab positive 
and TE ADA positive. A possible correlation with immunogenicity (pre-Ab and/or TE ADA) 
cannot be excluded for this subject.  
 
In line with regulatory and scientific guidance, an immunogenicity risk assessment [6] was 
prepared for administration of ALX-0171, in support of the currently proposed study [7-9]. 
This assessment comprised evaluation of the immunogenic potential of ALX-0171 through 
determination of product-specific, patient- and/or disease-related factors affecting 
immunogenicity. In addition, the available nonclinical and clinical immunogenicity results 
were evaluated to come to an appraisal on the potential consequences on safety, PK and 
efficacy in case immunogenicity would occur in the current pediatric study. The overall risk 
assessment led to a ³lower risk class´ designation (the lowest category for a therapeutic 
protein) [8], with favorable risk/benefit balance for the current pediatric study. Of note, the 

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immunogenicity risk assessment is a dynamic process, with further evaluations and updates 
scheduled as data become available [6]. 
 
Unintentional Contact 
 
To ensure correct administration of ALX-0171 and handling of the device, detailed 
instructions for use will be provided. During administration by nebulization, caregivers or 
other persons close to the nebulizer may nevertheless come into contact with ALX-0171. 
This may for instance occur due to aerosol escaping through the outlet valves of the 
facemask, or via particles exhaled by the subject. This is not considered to pose a safety 
risk. ALX-0171 is highly specific towards the RSV F protein, and lacks an endogenous 
human target. The in vivo safety pharmacology and toxicology studies revealed no 
meaningful safety risks. As described above, the clinical studies conducted so far showed 
that ALX-0171 was well tolerated at all dose levels and dosing regimens evaluated. In 
addition, no teratogenic or oncogenic properties are expected. As ALX-0171 is a protein 
drug, it is not expected to enter cells and interfere directly with DNA or nuclear proteins.  
 
Furthermore, Investigators, clinical staff, parents, family members or other children in the 
vicinity would only come in contact with ALX-0171 at a negligible dose**. Potential 
deposition of aerosol particles onto surfaces, or unintentional contact by means other than 
inhalation, is not of concern. Similar to other proteins or macromolecules, standard hospital 
or household hygiene procedures are considered sufficient for cleaning of surfaces. There is 
no added risk for contact with skin, since ALX-0171 does not cause irritation, and is not 
prone to transdermal delivery (similar to other macromolecules). Exposure to mucosal 
tissues may be more relevant, but there are no indications that this would be associated 
with additional safety concerns, systemic uptake, or irritative effects. Finally, in case of 
accidental oral intake, ALX-0171 would be rapidly degraded in the digestive tract, similar to 
other proteins.  
 
Routine hygiene conditions and cleaning procedures in the hospital are therefore sufficient 
for administration of ALX-0171. In view of the above, potential risks associated with 
unintentional contact are considered negligible. It should also be noted that, while not 
considered necessary, a standard facemask would be sufficient to further limit unintentional 
contact with ALX-0171 for the person administering study drug.  
 
                                          
** Calculated ³worst case´ scenarios (e.g., 1-hour stay after administration of ALX-0171 in an examination room of 
5 m2 with poor ventilation, and assuming that the entire dose filled into the nebulizer is dissipated into the room) 
indicate that inhalation of dissipating aerosol by any person (adult or infant) other than the intended subject 
would result in an ALX-0171 dose at least 100-fold below the nebulized dose. Of note, in case only incomplete or 
inefficient administration is achieved (e.g., because of poor fitting of the face mask, or because of intense crying 
of the subject), nebulization is to be stopped, thereby avoiding unwanted loss of study drug into the room. 

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1.3.4. POTENTIAL BENEFITS 
 
As a respiratory virus, RSV may present as an upper respiratory tract infection (including 
rhinitis, otitis media and pharyngitis), or, as is more often the case in infants and young 
children, as a LRTI, (including acute bronchiolitis and/or broncho-pneumonia). RSV LRTI 
results in hospitalization of about 3% of RSV-infected infants less than 1 year old, and about 
0.5% of RSV-infected children aged between 1 and 2 years [1, 2]. Since there are no 
adequate medications available for treatment of RSV infection, the standard of care for 
hospitalized infants is mostly supportive (e.g., fluid/feed supplementation, observation, and 
respiratory support as needed) [1, 3, 4].  
 
ALX-0171 is an antiviral treatment and is intended to neutralize RSV (thereby inhibiting viral 
infectivity). ALX-0171 was shown to be highly effective in nonclinical in vitro and in vivo 
model systems, including RSV-infected cotton rats and neonatal lambs. Results from these 
studies demonstrate a beneficial effect with regard to viral load, inflammatory signs, and/or 
symptoms and signs of RSV infection. The studies in RSV-infected neonatal lambs provided 
proof-of-concept for therapeutic intervention with a 3-day treatment course of ALX-0171.    
 
In the first pediatric study, inhaled ALX-0171 demonstrated pharmacological effect in a 
relevant clinical setting by an immediate impact on viral titers in nasal swab specimen. 
Analysis of a composite of clinical parameters, the Global Severity Score, led to an 
encouraging initial indication of a therapeutic effect for infants treated with ALX-0171 and 
warrants further assessment of this potential clinical benefit in a larger study.  
 
1.3.5. CONCLUSION
 
The nonclinical and clinical studies performed so far did not reveal clinically meaningful risks 
for administration of ALX-0171 to pediatric subjects. The results in representative 
nonclinical models, together with those obtained in first-in-infant Study ALX0171-C104, 
indicate that ALX-0171 may provide an opportunity for therapeutic intervention in 
established RSV LRTI. The current benefit/risk assessment is therefore considered favorable 
and supportive of further clinical development.  
 
The doses that will be administered to subjects in Study ALX0171-C201 are estimated to 
achieve concentrations at which antiviral and clinical activity can be expected while 
appropriate safety margins are respected. Regular review of clinical data by the IDMC, 
including during the pauses in recruitment after enrollment of each safety cohort, together 
with the predefined stopping criteria defined in section 3.1.1 will enable adequate safety 
follow-up throughout the study. The clinical study protocol foresees close monitoring of all 
subjects, and is considered to provide a suitable setting for evaluation of ALX-0171 in 
infants and young children. 
 

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2.
OBJECTIVES
 
Primary objective:  

To evaluate the anti-viral effect and safety of different doses of inhaled ALX-0171 in 
subjects hospitalized for RSV LRTI. 
 
Secondary objective:

To evaluate the clinical activity, PK properties, pharmacodynamic (PD) effect and 
immunogenicity of different doses of inhaled ALX-0171.  
 
 

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3.
STUDY DESIGN 
 
3.1.
OVERALL STUDY DESIGN
 
3.1.1. STUDY OVERVIEW 
 
This 
is 
a 
randomized, 
double-blind, 
placebo-controlled, 
international, 
multicenter 
dose-ranging study (Figure 3). Study drug will be administered along with standard of care 
treatment, which will be determined by the Investigator (or his/her designee) according to 
institutional practice.  
 
 
 
 
Figure 3: Overview of study design 
 
Three dose levels are planned to be evaluated: 

Dose 1:  
target dose of 3.0 mg/kg  

Dose 2:  
target dose of 6.0 mg/kg  

Dose 3:  
target dose of 9.0 mg/kg  
 
The dose range that will be evaluated is expected to provide a potential benefit to the 
subjects, and is selected to allow assessment of reduction in nasal viral shedding and 
improvement of clinical symptoms, to support selection of an optimal dose for future 
development. 
 
                                          
  Clinical Practice Guideline: The diagnosis, management and Prevention of Bronchiolitis as described by the 
American Academy of Pediatrics (2014) may be followed in addition to institutional practice. 

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Study drug will be administered once daily for 3 consecutive days. The 3-day treatment 
period is expected to bridge the time needed for the body to mount an effective immune 
response.  
 
The study is planned to enroll approximately 180 infants and young children (aged 28 days 
to <2 years) who are diagnosed with and hospitalized for RSV LRTI. 
 
The study consists of a sequential part followed by a parallel part (Figure 3).  
 
Sequential Part 
In safety Cohorts 1 to 3, sequential dose escalation is used to enable appropriate safety 
follow-up. Each of the 3 safety cohorts consists of 12 subjects (N=36 in total) randomized 
3:1 to ALX-0171 (N=9) or placebo (N=3).  
 
In addition to the individual discontinuation criteria (see section 3.2.3), the following criteria 
apply to stopping or pausing recruitment in a safety cohort (sequential part of the study): 
 
1. Should an SAE indicative of acute respiratory distress or an acute systemic 
hypersensitivity reaction be considered by the Investigator to be related to administration 
of ALX-0171, recruitment in that cohort will be stopped and no further dose escalation 
will be done. This dose will not be taken forward into the parallel part of the study.  
2. The reporting of any other SAE considered by the Investigator to be related to 
administration of ALX-0171 will trigger a pause in recruitment and an immediate review 
by the IDMC. Confirmation of the causality between the administration of ALX-0171 and 
the serious adverse reaction by the IDMC will result in the stopping of recruitment in that 
cohort and no further dose escalation will be done. This dose will not be taken forward 
into the parallel part of the study.  
3. In case 2 SAEs considered by the Investigator to be possibly related to administration of 
ALX-0171 occur in the same safety cohort, recruitment in that cohort will be paused to 
allow further investigation by the IDMC. This includes assessment of the index events as 
well as review of any prior similar events, after which the IDMC will issue a 
recommendation regarding continuation or stopping of the paused cohort. 
 
The following criteria apply to stopping dose escalation, and will be used to decide on the 
doses taken forward into Cohort 4 (parallel part of the study): 
 
1. In case recruitment of a safety cohort is stopped due to a related SAE (criteria 1 and 2 
above), no further dose escalation will be done and this dose will not be taken forward 
into the parallel part of the study.  
2. In case recruitment is paused due to 2 possibly-related SAEs (criterion 3 above) but 
reinitiated based on the IDMC recommendation, the assessment for further dose 
escalation and whether or not the dose is taken forward to Cohort 4, will be performed by 

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the IDMC during the planned pause after completing the cohort, when the cumulative 
dataset is available (see below). 
3. If 2 severe AEs indicative of acute respiratory distress or an acute systemic 
hypersensitivity reaction would occur in a particular safety cohort and are considered by 
the Investigator to be related to administration of ALX-0171, no further dose escalation 
will be done. This dose will not be taken forward into the parallel part of the study. 
 
In addition to these stopping criteria, cumulative unblinded safety data will be reviewed by 
an IDMC consisting of an independent group of clinical experts not participating in the study 
(and an independent statistician). 
 
After each safety cohort (when the last subject in a safety cohort has completed the 
treatment period), recruitment will be paused while the IDMC reviews the available 
cumulative safety data (i.e., all data from prior visits that have been done for all included 
subjects, including preceding cohorts). 
After this comprehensive review, the IDMC will advise the Sponsor on proceeding to the 
subsequent cohort (i.e., higher dose) and which planned dose levels can be taken 
forward into the parallel part.  
 
Please see below for additional information with regard to the IDMC. 
 
Concentrations of ALX-0171 in serum from subjects participating in the safety cohorts will 
be analyzed after completion of the cohorts to assess if there is a relationship between dose 
and concentration. The analysis will be performed by an independent statistical analysis 
team, separate from the statistics and programming staff assigned to the study, and a 
recommendation will be provided to the Sponsor.   
 
Parallel Part 
If no stopping criteria have been met during the sequential part and if the IDMC issues a 
positive recommendation after each safety cohort and the Sponsor decides to proceed, the 
remaining 144 subjects (i.e., Cohort 4) will be randomly assigned in a 1:1:1:1 ratio to one 
of following treatment groups, yielding an overall randomization ratio of 3:1 active to 
placebo. 
 
ALX-0171 dose 1 
ALX-0171 dose 2  
ALX-0171 dose 3  
Placebo 
 
In the event one or two dose groups are discontinued for safety, the remaining groups will 
enroll the number of subjects initially specified (i.e., 45 per arm). 
 

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The Placebo group will serve as comparator group for the 3 ALX-0171 dose groups. To 
achieve double-blinding across the different groups, each dose will be administered as 
two serial nebulizations. These two nebulizations will consist either of two nebulizations of 
ALX-0171, or one of ALX-0171 and one of placebo, or two nebulizations of placebo 
depending on the assigned treatment group (also see section 3.3.7). 
An overview of the study flow is provided in Figure 4. 
 
 
 
 
 
Figure 4: Overview of study flow 
 
Subjects will be screened as soon as possible after arrival to the hospital/emergency unit. 
After completion of the screening assessments and confirmation of subject¶s eligibility, 
randomization should follow as soon as possible but not more than 24 hours after arrival. 
Study drug administration should start as soon as possible after randomization with a 
maximum time interval of 3 hours following randomization. Subsequent doses of study drug 
will be administered at 24-hour intervals (± 4 hours) relative to the first dose. No 
premedication is required or recommended per protocol, but an inhaled 2-agonist may be 
administered at the discretion of the treating Investigator. 
 
On the first 2 dosing days, inpatient hospital stay is required. Provided that the clinical 
response criteria have been met (which are based on adequate oral feeding and oxygen 
saturation), discharge from the hospital can take place per protocol at the Investigator¶s 
discretion from dosing Day 2 onwards after all required assessments of the 5 hours 
(± 1 hour) post-dose time point have been completed. Subjects discharged after the second 
dose must return to the hospital for the third study drug administration (to be administered 
48 ± 4 hours after the first dose by the appropriately trained study personnel), and be 
monitored for a 2-hour pre-dose and post-dose period. Subjects who are not discharged 

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from the hospital after completion or premature discontinuation of study drug enter an in-
hospital post-treatment period with assessments in the morning and evening. A Follow-Up 
(FU) visit is scheduled on Day 14 (± 2 days), and an End of Study (EOS) visit on Day 28 
(± 2 days). For subjects prematurely withdrawn from the study, a Withdrawal visit is to be 
performed on the day of withdrawal. 
 
The primary endpoint in this study is the evaluation of viral load in samples obtained via 
nasal mid-turbinate swabs. In particular, the time needed for the viral load (as assessed by 
plaque assay) to drop below the quantification limit (BQL) is calculated (time-to-BQL). 
 
Secondary endpoints include: 

Safety will be assessed through AE collection, measurements of vital signs, peripheral 
capillary oxygen saturation (SpO2), physical examination and laboratory parameters. 
Safety lab assessments are planned two times during the study (at screening and at the 
FU visit) and will be performed by the local laboratory in order to allow timely availability 
of the results. Furthermore, an IDMC will be involved in the regular review of the 
available safety data.   

Clinical activity of ALX-0171: assessed through evaluation of clinical symptoms over time 
(SpO2, feeding, respiratory rate, wheezing, cough, respiratory muscle retractions, and 
general appearance) and further calculation of composite clinical scores such as Global 
Severity Score, Respiratory Assessment Change Score (RACS) and Respiratory Distress 
Assessment Instrument (RDAI).  

Time to clinical response, utilizing the criteria of adequate oxygen saturation and oral 
feeding (see below). 
 
Subjects will be considered to have met the Clinical Response criteria when both of the 
following criteria are fulfilled: 
Stable oxygen saturation on room air, defined as SpO2 > 92% over a period of 
 4 hours. In case of oxygen supplementation, the level of supplementation is to be 
considered for reduction at least three times per day. Provided oxygen saturation is 
stable, attempts to remove the supplementation will be done at least three times a day.    
Adequate oral feeding which is sufficient to maintain sufficient hydration, in the judgment 
of the Investigator. 
 
In addition, data on medical interventions will be captured in order to assess the impact of 
ALX-0171 on duration of hospitalization and the need for ventilation or transfer to an 
intensive care unit (ICU) setting.  
 
Parent(s)/Caregiver(s) assessment of the clinical condition of the child will be done by daily 
completion of a diary during the hospital stay and up to the EOS (Day 28) visit. This diary 
includes scoring of respiratory symptoms over the past 24 hours (cough, wheezing, trouble 
breathing), evaluating the general health of the child by making a mark on a Visual 

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Analogue Scale (VAS) to indicate the child¶s health, and answering a question whether the 
child has returned to his/her normal condition from before the onset the RSV infection. For 
the period after discharge from the hospital, this diary will also allow to capture data on 
health care utilization and use of medication for respiratory symptoms.  
 
The study will also evaluate pharmacokinetics, pharmacodynamics and immunogenicity: 
The systemic concentration of ALX-0171 will be evaluated in serum, as a surrogate for 
evaluating local (lung) concentration. A subset (48 subjects, i.e., 12 subjects per dose 
group) will undergo more extensive PK sample analysis (3 blood samples for PK 
assessment). The extensive sampling scheme might become mandatory during the study 
in order to achieve the predefined sample size. Replacement of subjects who are part of 
the extensive PK sampling will be done for those for whom not all 3 PK samples could be 
collected successfully and/or who have not completed study drug administration on 
dosing Day 1 or dosing Day 2. Subjects part of the extensive PK sampling who have not 
successfully received study drug on Day 1 or Day 2 do not need to undergo the full PK 
sampling schedule. In the remainder of subjects, only 1 PK blood sample will be taken. 
The number of subjects undergoing the more extensive PK sample analysis was 
determined to obtain sufficient precision on the PK parameters as described by Wang et 
al. [10].  

In addition, PD biomarker (Krebs von den Lungen [KL-6]) will be assessed (serum). 

Potential immunogenicity will also be assessed systemically (serum).  
 
For determination of sample size, please refer to section 3.1.2. 
 
Estimated Study Duration 
The overall study duration is expected to be around 23 months. The planned study duration 
for each subject is approximately 28 days. 
The completion of the study is defined as the last visit of the last subject (LSLV) 
participating in the study. 
 
 
Independent Data Monitoring Committee  
In line with applicable guidelines, an IDMC is assigned to monitor the study. The IDMC 
consists of an independent group of clinical experts not participating in the study and an 
independent statistician.  
After each safety cohort (when the last subject in a safety cohort has completed treatment 
period), recruitment will be paused while the IDMC reviews the available cumulative safety 
data (i.e., all data from prior visits that have been done for all included subjects, including 
preceding cohorts).  
After this comprehensive review of safety data, the IDMC will advise the Sponsor on 
proceeding to the subsequent cohort (i.e., the higher dose) and which planned dose levels 

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can be taken forward into the parallel part. This recommendation will complement the 
above-described predefined stopping criteria. 
During the parallel part of the study, an IDMC review is planned after 72 subjects completed 
treatment. 
 
Throughout the study, SAE information will be communicated in real time according to the 
reporting requirements. An ad-hoc meeting can be requested by the IDMC members. 
 
The composition, objectives, and roles and responsibilities of the IDMC will be described in 
an IDMC charter, agreed with the IDMC members and Sponsor. The IDMC charter will also 
define and document the content of the safety summaries, and general procedures 
(including communications). The first version of the charter will be available prior to the 
initiation of the study. 
 
3.1.2. STUDY RATIONALE AND DISCUSSION OF 
STUDY DESIGN 
 
Safety and tolerability of ALX-0171 have been evaluated in 3 Phase 1 studies in adults, and 
in a Phase 1/2a study in infants and young children hospitalized for RSV LRTI. Study 
ALX0171-C201 will include a similar population and aims primarily to evaluate the anti-viral 
effect of three doses of inhaled ALX-0171, as well as to assess the safety and clinical 
activity (see section 3.3.2 for dose selection rationale). The outcome of this dose ranging 
study will support the selection of the optimal dose and the most relevant endpoints for 
further clinical development. 
 
Study ALX0171-C201 will start with a stepwise assessment of cohorts of 12 subjects, each 
being randomized in a 3:1 ratio to increasing doses of ALX-0171 or placebo (i.e., 9 subjects 
receiving ALX-0171 and 3 receiving placebo in each cohort). To guide dose escalation, 
stopping criteria have been included in the protocol (section 3.1.1). In addition, after each 
of these 3 sequential cohorts, recruitment will be paused in order to allow the IDMC to 
evaluate available cumulative safety data and recommend whether the subsequent cohort 
can be initiated and which planned dose levels can be taken forward into the parallel part. 
When these initial cohorts have been completed and safety has been confirmed, the study 
will continue with a parallel allocation to ALX-0171 or placebo. 144 eligible subjects will be 
randomly assigned in a 1:1:1:1 ratio to 1 of the 4 treatment groups (3 active groups and 
1 placebo group).  
 
The design of Study ALX0171-C201 allows an approach with a placebo-controlled group as 
representative comparison for the three active dose levels. The total volume and 
corresponding inhalation times of study drug per weight category is similar in all dosing 
groups, by using a combination of placebo and ALX-0171 (if applicable), administered via 

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2 serial nebulizations. This ensures blinding across the treatment groups (also see 
section 3.3.7).  
 
The primary objective of the study is evaluation of the anti-viral effect of ALX-0171 
compared to placebo.  
 
As pharmacologically active doses will be used, clinical activity of ALX-0171 will be 
evaluated in order to assess if the pharmacological effect translates in clinical benefit to the 
subject. Other objectives include evaluation of pharmacokinetics, pharmacodynamics 
(biomarker), and immunogenicity.  
 
Viral load will be assessed in samples obtained via nasal swabs collecting a mid-turbinate 
specimen. Based on the results of Study ALX0171-C104, the anti-viral effect of ALX-0171 
will be mainly determined by the time to drop BQL in plaque cultures, which is the 
parameter that best reflects the inhibition of viral replication. Quantification of viral load by 
RT-qPCR will also be assessed as it is a more sensitive method than culture assay and has a 
good dynamic range. However, as the mode of action of ALX-0171 is to inhibit viral entry 
into the target cell, modest effects of ALX-0171 treatment on viral RNA are expected as 
complete viral particles that are unable to replicate, partially assembled virions, and whole 
and fragmented viral genome will be quantified by RT-qPCR in addition to fully replication-
competent virus.   
 
The clinical impact of treatment by ALX-0171 in infants and young children will be evaluated 
by changes in clinical symptoms and subsequent calculation of composite scores, the time 
needed to enable adequate feeding and oxygen saturation, need for medical interventions 
and length of hospital stay. Based on the clinical activity parameters measured during the 
study, composite scores that reflect the clinical status of the subject suffering from RSV will 
be calculated, including the Global Severity Score, RDAI score, and RACS. The Global 
Severity Score is based on a recent clinical score that allows categorisation of infants with 
respiratory infections on 7 different parameters: feeding intolerance, medical intervention, 
respiratory difficulty, respiratory frequency, apnea, general condition and fever [11, 12]. It 
takes into account all clinically relevant aspects of an RSV infected subject. The RDAI is a 
scoring system based on the presence and severity of wheezing and respiratory muscle 
retractions. The RACS is based on the RDAI and adds a standardized score for the change in 
respiratory rate.   
 
Given the importance of timing of the administration of this anti-viral compound in the time 
course of the RSV infection, details on the time elapsed between onset of first clinical 
symptoms and start of treatment with study drug will be collected and analyzed. The need 
for medical interventions will be documented through collection of data on the need for and 
level of oxygen supplementation or respiratory support, need for transfer to ICU, duration of 
stay in ICU and overall hospital stay. 

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In addition to the assessments performed by healthcare professionals, the study will also 
collect information on how parents or caregivers perceive the clinical condition of the child 
through daily completion of a diary. This diary includes scoring of respiratory symptoms 
over the past 24 hours (cough, wheezing, trouble breathing), evaluating the general health 
of the child by making a mark on a VAS, and answering to a question if the child has 
returned to his/her normal condition from before the onset the RSV infection. For the period 
after discharge from the hospital, this diary will also capture data on health care utilization 
and use of medication for respiratory symptoms. The diary will be completed during hospital 
stay and daily thereafter up to the EOS (Day 28) visit as RSV induced bronchiolitis is often 
associated with continuing respiratory symptoms following hospitalization. 
 
The systemic concentration of ALX-0171 will be evaluated in serum, as a surrogate for local 
(lung) concentrations. Potential immunogenicity will also be assessed systemically (serum), 
both pre-dose and post-dose (14 days post initial drug administration) and results will be 
correlated with PK, PD and safety findings.  
Systemic levels of the serum biomarker KL-6 will be determined in left-over serum samples. 
Serum KL-6 was shown to indicate disease activity in various interstitial lung diseases and is 
believed to reflect the presence of alveolar damage [13, 14]. High serum KL-6 levels in 
RSV±infected infants correlate with low SpO2 and need for O2 administration [15]. These 
findings suggest that serum KL-6 is associated with the severity of RSV bronchiolitis, and 
that it may provide additional insight on potential treatment benefits.  
 
The intended volume of blood to be withdrawn for each of the assessments is based on the 
minimum required volume for each of the respective analyses, and is in line with the 
volumes allowed per applicable guidelines [16-20].  
 
Rationale for Sample Size 
The sample size calculation is based on statistical considerations for the analysis of the 
primary endpoint. With 45 subjects per arm, 85% power is achieved to detect a 50% 
reduction in median time-to-BQL (0.5 day with ALX-0171 versus 1 day with placebo) for the 
plaque assay using a two-sided log-rank test at significance level of 0.05. For each 
comparison of the ALX-0171 dose groups with placebo, a significance level of 0.05 is 
assumed. For multiple pairwise comparisons, the family-wise error rate is controlled at 5% 
through the closed testing principle, where the comparison of the lower dose of ALX-0171 to 
placebo is only performed if the comparison of the higher dose of ALX-0171 to placebo is 
significant. The sample size calculation also assumes a drop-out rate of 15% to account for 
subjects dropping out prior to reaching the primary endpoint, or due to a false positive RSV 
test. 
 
Change from baseline in Global Severity Score is a secondary endpoint of interest in this 
study. With this sample size, a power of 80% is achieved to detect a difference of 2 points 

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in the mean change from baseline (to Day 2 post-dose) on the Global Severity Score for 
each of the ALX-0171 dose groups to placebo. This is based on a two-sided t-test with a 
significance level of 0.05 and assuming a common standard deviation of 3.2 in each group. 
Dosing Rationale 
The study drug will be administered along with standard of care treatment, which will be 
determined by the Investigator (or his/her designee) according to institutional practice. 
Study drug will be administered once-daily for 3 consecutive days, similar to the treatment 
schedule in Study ALX0171-C104. This 3-day treatment period is expected to bridge the 
time needed for the body to mount an effective immune response. In order to assess a dose 
response in Study ALX0171-C201, three doses (target dose of 3 mg/kg, 6 mg/kg and 
9 mg/kg) will be investigated. This dose range will provide information on the PK, PD and 
clinical outcomes across a relevant range, is expected to provide a potential benefit to the 
subjects, and is intended to determine the most optimal dose of ALX-0171 for further 
clinical development.  
 
Please refer to section 3.3.2 for more information on the dose selection. 
 
All doses of study drug will be administered in the hospital setting. Subjects may be 
discharged from hospital starting from dosing Day 2 onwards, after all required assessments 
of the 5 hours (± 1 hour) post-dose time point have been completed. The decision to 
discharge is up to the Investigator but can only occur per protocol if the protocol-defined 
clinical response criteria have been met. Hence, an ambulatory visit will be permitted for the 
3rd study drug administration (i.e., subjects need to return to the hospital for the 
administration of the 3rd dose by the appropriately trained personnel and have their 2 hour 
pre- and post-dose monitoring period). 
 
Study drug will be administered via inhalation, using a dedicated vibrating mesh nebulizer.  
 

Vibrating mesh type nebulizers are considered the most appropriate technology for 
nebulization of a therapeutic protein such as ALX-0171 Nanobody.  

The FOX-Flamingo nebulizer (Vectura GmbH, Germany) was developed concurrently with 
the study drug. The nebulizer is a battery-operated, hand-held device, intended for 
single-patient use. The device provides an aerosol with particle size suitable for the 
intended study population (~3 µm).  

The nebulizer is always to be used with a flow of 2 L/min additional air or O2 (to be 
decided by the Investigator based on oxygen need of the subject).   
The formulation of ALX-0171 (and matching placebo) was developed specifically as a liquid 
solution for inhalation, to ensure rapid delivery of the study drug to the site of RSV 
infection, and to maintain product quality and stability in combination with the nebulization 
protocol.  
 

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
The formulation buffer is comparable to a normal 0.9% saline solution with respect to 
salt content but has additional buffering capacity. The osmolality and ion concentration of 
the (isotonic) solution were chosen to be within the physiological range. The phosphate 
buffer system helps to maintain a constant pH, and therefore, to guarantee the stability 
of the drug.  

All excipients comply with the European Pharmacopoeia and the United States 
Pharmacopeia.  

The formulation contains no antimicrobial preservatives or tension active agents 
(surfactants), and no coloring agents, flavors, or sugars/sweeteners are present. 
Correspondingly, the nebulizer solution does not have a specific taste or odor. 
 
The use of formulation buffer as placebo is considered appropriate, taking into account that 
formulation buffer is the most representative control for the active study drug, while the 
minute amounts of phosphate present in the buffer would not be expected to result in 
effects different from saline. Throughout the clinical studies conducted with ALX-0171 and 
placebo, there were no consistent findings that would suggest a direct effect of the 
formulation buffer on respiratory parameters. 
 
Details on initiation, interruptions and completion of study drug administration, will be 
collected in the electronic case report form (eCRF), as will the acceptability of the face mask 
and nebulizer and whether or not correct administration was achieved (also see 
section 3.3.7). 
 
3.1.3. BLINDING 
 
To ensure blinding across dose groups, study drug will be administered via inhalation using 
2 serial nebulizations. These two nebulizations will consist either of two nebulizations of 
ALX-0171, or one of ALX-0171 and one of placebo, or two nebulizations of placebo 
depending on the assigned treatment group (see section 3.3.7). 
 
In order to protect the integrity of the data, treatment assignment will be kept blinded for 
investigative sites, subjects, subject¶s parent(s)/legal guardian(s) and caregiver(s), site 
monitors, and other members of the study team, until after the final database lock (i.e., 
after the last subject has completed the final [EOS] visit and all data is considered clean).  
Identification of Sponsor and contract research organization (CRO) personnel who will have 
access to unblinded data (e.g., PK sample analysis team) during the course of the study will 
be documented prior to unblinding. The number of Sponsor personnel having access to the 
data will be limited. 
 

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Emergency unblinding procedure 
Code-breaking and unblinding in the event of medical emergencies can be done by the 
Investigator via the Interactive web/voice response system (IWRS/IVRS), which will be 
accessible 24 hours per day/7 days per week. 
 
Unblinding by the Investigator should occur only in the event of an AE for which it is 
necessary to know the study treatment to determine an appropriate course of therapy for 
the subject. The Investigator should first discuss options with the Medical Monitor if possible 
with due consideration of the safety of the subject. If the Investigator must identify the 
treatment assignment of an individual subject, the Principal Investigator/Sub-investigator is 
to contact the IWRS/IVRS.  
 
Subjects for whom the code has been broken by the Investigator will have to discontinue 
study drug treatment and subjects will be followed up according to the in-hospital 
post-treatment period (if applicable), FU visit and EOS visit. 

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3.2.
SELECTION OF STUDY POPULATION 
 
Infants and young children of both genders, diagnosed with and hospitalized for RSV LRTI 
but otherwise healthy, are eligible for this study. Approximately 180 subjects are planned to 
be enrolled in the study. 
 
3.2.1. INCLUSION CRITERIA 
 
A subject will be eligible for study participation if he/she meets all of the following criteria at 
screening and randomization, unless specified otherwise: 
 
1.
Subject is a male or female infant or young child aged 28 days to <2 years with 
gestational age 
 33 weeks at screening.  
2.
Subject weighs between 
 3.0 kg and < 15.0 kg at screening. 
3.
Subject is otherwise healthy, but is hospitalized for and clinically diagnosed with RSV 
LRTI (bronchiolitis or broncho-pneumonia), i.e., showing typical clinical signs and 
symptoms such as tachypnea, wheezing, cough, crackles, use of accessory muscles 
and/or nasal flaring. 
4.
Subject has a positive RSV diagnostic test at screening.ÁÁ 
5.
Subject is expected to have to stay in the hospital for at least 24 hours (according to 
the Investigator¶s judgment at screening). 
6.
Symptoms likely related to RSV infection (i.e., the symptoms present need to be 
probably linked to the current RSV infection according to Investigator¶s judgment) have 
appeared within 4 days of screening and are not yet improving at screening and 
randomization. 
7.
Subject fulfils at least two of the following RSV disease severity criteria at screening and 
randomization:  

Inadequate oral feeding that requires feeding support (i.e., nasogastric tube or i.v. 
line)  

Inadequate oxygen saturation defined as: 
-
Oxygen saturation (SpO2) 
92% on room air or 
-
Requiring oxygen supplementation to maintain oxygen saturation >90% with 
documented pre-supplementation value 
 92%  

Signs of respiratory distress defined as: 
-
Respiratory rate 
 50 per minute in infants up to 12 months of age, and 
 40 per minute in children above 12 months and/ or 
-
Moderate or marked respiratory muscle retractions 
                                          
ÁÁ RSV infection will be confirmed either according to routine site practice (PCR or diagnostic quick test), or using a 
(Sponsor-provided) commercial kit. 

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8.
Subject has normal psychomotor development. 
9.
Parent(s)/legal guardian(s) provide written informed consent in accordance with locally 
approved consent process at screening. 
10. The parent(s)/legal guardian(s) are able and willing to comply with the study protocol 
procedures. 
 
3.2.2. EXCLUSION CRITERIA 
 
Subjects meeting any of the following criteria at screening or randomization will not be 
eligible for study participation: 
 
1.
Subject is known to have significant comorbidities including: 
Genetic disorders (e.g., trisomy 21, cystic fibrosis),  
Hemodynamically significant congenital heart disease (e.g., needing corrective 
therapy or inotropic support),  
Bronchopulmonary dysplasia,  
Any hereditary or acquired metabolic (bone) diseases,  
Hematologic or other malignancy.  
2.
Subject is known to be human immunodeficiency virus (HIV)-positive. If the subject is 
< 6 months of age, a known HIV-positivity of the mother is also exclusionary. 
3.
Subject is known to be immunocompromised.  
4.
Subject has or is suspected to have an active, clinically relevant concurrent infection 
(e.g., bacterial pneumonia, urinary tract infection). Concurrent acute otitis media is not 
exclusionary. 
5.
Subject has significant oral and/or maxillofacial malformations that would prevent 
proper positioning of the face mask. 
6.
Subject received invasive mechanical ventilation or non-invasive respiratory support 
(i.e., continuous or bilevel positive airway pressure) in the 4 weeks prior to screening.  
7.
During the current admission, subject is initially hospitalized in an ICU setting and/or 
received invasive mechanical ventilation or non-invasive respiratory support (i.e., 
continuous or bilevel positive airway pressure). 
8.
Subject is critically ill and/or is expected to require invasive mechanical ventilation, 
non-invasive respiratory support (i.e., continuous or bilevel positive airway pressure), 
or High Flow oxygen therapy (HFOT) at levels not enabling nebulization therapy 
according to the Investigator¶s judgment. High Flow oxygen, with a maximum flow of 
2  L/kg/min, is permitted under the following conditions:  
used as Standard of Care outside ICU setting 
can be removed for study drug administration (Note: oxygen flow at 2 L/min can be 
provided). 
9.
Subject has received 1 or more doses of palivizumab or treatment or prophylaxis with 
any RSV antiviral compound (e.g., ribavirin, i.v. immunoglobulin, or any investigational 

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drug or vaccine for RSV [including subject¶s mother who has been vaccinated against 
RSV]) at any time prior to screening.  
10. Subject is required to continue or start systemic corticosteroid therapy. Subject on a 
maintenance therapy of inhaled corticosteroids will continue this treatment at the usual 
dose. Topical corticosteroids for skin or ear disorders are permitted. 
11. Subject is a child in care (i.e., a child who has been placed under the control or 
protection of an agency, organization, institution or entity by the courts, the 
government or a government body, acting in accordance with powers conferred on 
them by law or regulation). A child in care can thus include a child cared for by foster 
parents or living in a care home institution, provided that the arrangement falls within 
the definition above, but does not include a child who is adopted or has appointed legal 
representative(s). 
12. Subject is currently participating in any other study with investigational drug or has 
received an investigational drug within 4 weeks or 5 half-lives of the concerned drug 
(whichever is longer) prior to screening. 
13. Subject was previously enrolled in a clinical study of ALX-0171 (including the current 
Study ALX0171-C201). 
14. Subject has a known hypersensitivity to the study drug or any excipient of the study 
drug. 
 
3.2.3. REMOVAL OF SUBJECTS FROM THERAPY OR 
ASSESSMENT
 
Every reasonable attempt should be made by the Investigator (or his/her designee) to keep 
subjects in the study, however, a subject must be withdrawn from the study if: 
Study drug administration cannot be successfully initiated on Day 1 (see section 3.3.7.2). 
The Investigator considers it, for safety reasons, in the best interest of the subject. 
The parent(s)/legal guardian(s) withdraw(s) consent. 
 
A subject may be withdrawn from the study if the subject and/or parent(s)/legal 
guardian(s) fail to comply with dosing, evaluations, or other requirements of the study. 
 
Investigators (or their designees) must attempt to contact the parent(s) or legal 
guardian(s) of subjects who fail to attend scheduled visits by telephone or other means, to 
exclude the possibility of an AE being the cause of withdrawal. Should this be the cause, the 
AE must be documented, reported, and followed-up as described in section 3.5. 
 
If a subject is prematurely withdrawn from the study, the reason for withdrawal and the 
date of withdrawal will be recorded in the eCRF. Whenever possible and reasonable, a 
Withdrawal visit should be conducted at the time of withdrawal (no EOS visit).  

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A subject must be discontinued from study drug treatment if: 
The randomization code is broken prematurely by the Investigator or Sub-Investigator. 
A severe and/or serious hypersensitivity reaction occurs 
A severe and/or serious acute respiratory distress reaction induced by study drug 
administration occurs 
The subject needs to start treatment with one of the medications listed as prohibited (see 
section 3.3.8) 
The subject needs to start non-invasive respiratory support, invasive ventilation or HFOT 
at levels not enabling removal of the cannula for administration of the study drug 
nebulization and/or levels exceeding 2 L/kg/min. The event will be captured as an SAE 
and will be monitored until resolution, as described in section 3.5. 
If the investigator or the Sponsor / medical monitor deems it is in the subject¶s best 
interest 
 
A subject may be discontinued from study drug treatment if an SAE occurs (if considered 
necessary or appropriate by the Investigator). 
 
Subjects having received at least one study drug administration and remaining in the 
hospital after study drug treatment discontinuation will remain in the study according to the 
in-hospital post-treatment period specified in the Schedule of Assessments and should also 
attend the FU and EOS visits. 
 
If a subject is discontinued from the study and/or study drug, the study monitor and the 
Sponsor will be informed immediately. 
 
3.2.3.1.
REPLACEMENT OF SUBJECTS 
 
Replacement of subjects will only be done for subjects randomized to the extensive PK 
sampling schedule. Replacement will be done for those for whom not all 3 PK samples could 
be collected successfully and/or who have not completed study drug administration on 
dosing Day 1 or dosing Day 2. Subjects who have not successfully received study drug on 
Day 1 or Day 2 do not need to undergo the full PK sampling schedule.  
 
3.2.3.2.
STUDY TERMINATION
 
If the Sponsor abandons the study prior to commencement of any protocol activities, and/or 
after IEC/IRB and CA approvals have been received, the Investigator or Sponsor must notify 
the IEC/IRB and CA by letter outlining the reasons for abandonment of the study, as 
required per national regulations. 
 
At any time during the study, the Sponsor may suspend or terminate the study or part of 
the study for any reason. If the Investigator plans to suspend or terminate participation in 

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the study, the Investigator will promptly inform the Sponsor and the IEC/IRB and provide 
them with a detailed written explanation.  
 
Upon study completion, the Sponsor will provide the Investigator, IEC/IRB, and CA with 
final reports and summaries as required by regulations.  
 
In case of suspension or halt due to safety reasons, the CA and IEC/IRB will be notified 
immediately and at the latest within the number of days as specified by local regulations 
after the study is halted, clearly explaining the reasons, and describing follow-up measures, 
if any, taken for safety reasons. 
 
The IDMC, consisting of an independent group of clinical experts not participating in the 
study and an independent statistician, will review unblinded safety data. The IDMC will 
advise the sponsor concerning continuation, modification or potential early termination of 
the study after every meeting (also see section 3.1.1). 

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3.3.
TREATMENT OF SUBJECTS 
 
3.3.1.
OVERVIEW OF TREATMENTS 
ADMINISTERED
 
Eligible subjects will be randomly assigned to one of the following treatment groups.  
 
ALX-0171 dose 1: target dose of 3.0 mg/kg  
ALX-0171 dose 2: target dose of 6.0 mg/kg  
ALX-0171 dose 3: target dose of 9.0 mg/kg  
Placebo 
 
ALX-0171 or matching placebo will be administered via inhalation using the FOX-Flamingo 
inhalation system (using 2 serial nebulizations; also see section 3.3.7), once daily for 
3 consecutive days. The formulation of ALX-0171 (and matching placebo) was developed 
specifically as a liquid solution for inhalation, to ensure rapid delivery of the study drug to 
the site of RSV infection, and to maintain product quality and stability in combination with 
the nebulization protocol. 
 
The first and second study drug administrations require inpatient hospital stay. Provided 
that the clinical response criteria have been met, discharge from the hospital can take place 
per protocol at the Investigator¶s discretion from dosing Day 2 onwards after all required 
assessments of the 5 hours (± 1 hour) post-dose time point have been completed. Subjects 
must return to the hospital for the third study drug administration (to be administered by 
the appropriately trained study personnel), and be monitored for a 2-hour pre-dose and 
post-dose period. 
 
3.3.2. SELECTION OF DOSES IN THE STUDY 
 
For the first-in-infant pediatric study (Study ALX0171-C104), dose determination was based 
on a modelling approach, complemented by additional experiments that generated data 
specifically for administration of ALX-0171 with the FOX-Flamingo inhalation system. 
Physiologically-based PK modelling was considered the best approach to bridge nonclinical, 
human adult and human pediatric PK parameters, taking into account growth and 
developmental processes such as organ maturation, changes in blood flow, body 
composition, and ontogeny of elimination mechanisms [21, 22]. Based on this approach, a 
dose of 1.2 mg/kg was chosen for evaluation. The results of study ALX0171-C104 indicated 
that this dose was well tolerated in all age groups (1 to 24 months). Reductions in nasal 
viral load (obtained from nasal swabs) were noted, confirming that ALX-0171 can exert 
antiviral activity when relevant concentrations are achieved. Although the first-in-infant 

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study was not designed to demonstrate clinical effect, first assessments indicated that the 
desired level of clinical efficacy was not reached with the administered dose. This was in line 
with the observation of lower than expected serum concentrations of ALX-0171 which could 
be indicative of insufficient drug concentrations in the lung, an important site of RSV 
replication and the driver for clinical effect.  
 
In order to assess a dose response in Study ALX0171-C201, three doses (target dose of 
3 mg/kg, 6 mg/kg and 9 mg/kg) will be investigated. At the beginning of the study, 
3 sequential safety cohorts of 12 subjects each will be enrolled, with predefined stopping 
criteria and IDMC assessment before proceeding to the next higher dose. 
This dose range will provide information on the PK, PD and clinical outcomes across a 
relevant range, is expected to provide a potential benefit to the patients, and is intended to 
determine the optimal dose of ALX-0171 for further clinical development. In view of the 
favorable safety profile of ALX-0171 in nonclinical and clinical studies and the plasma drug 
concentrations in the prior study, the doses in Study ALX0171-C201 are considered 
appropriate to further explore clinical effect. Anticipated systemic concentration to 
ALX-0171 at the highest dose is estimated to be similar or lower than those obtained in 
human adult volunteer studies, and maintains at least a 10-fold safety margin compared to 
nonclinical safety studies.  
 
Safety margins were calculated based on results obtained in a pivotal toxicity study 
conducted in Sprague Dawley rats after 14 day repeated administration via inhalation (see 
IB). Supportive information from (i) a PK study in juvenile rats after single or repeated 
inhalation (see IB), and (ii) a neonatal lamb study after single dose in uninfected animals 
and after repeated dose in RSV uninfected or RSV-infected animals (see IB) did not yield 
unexpected retention of ALX-0171 in tissue or plasma. Concentrations in lung in juvenile 
rats were somewhat lower when compared to adult rats, with high variability to be 
considered in the study. No safety signals were detectable in either study in neonatal or 
juvenile animals. Based on the available information, a correction of calculations based on 
the GLP-generated data in the toxicity studies was not considered warranted. 
For calculating the safety margins, in vitro SAINT model data was used to predict the 
ALX-0171 dose that will come into contact with the infants. The inhaled dose (i.e., the 
lung dose and the dose deposited in the nasopharyngeal airways) and the dose on the 
face/oral cavity were taken into consideration and were experimentally shown to be 
29.1% of the nebulizer filling dose. This fraction of the nebulizer filling dose is assumed 
to be totally deposited in the lungs. This was assumed as ³maximally expected local 
exposure´.   
The maximally expected local exposure in pediatric subjects was compared to the highest 
lung exposure achieved in the pivotal nonclinical toxicity study (the 14-day repeated 
dose toxicity study after daily administration via inhalation in rats; see IB). In this study, 
no AEs were observed, so the highest dose administered (117 mg/kg) was considered 
safe. Assuming 10% lung deposition in rat, the highest local dose achieved was 

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11.7 mg/kg or 2.3 mg/g lung (female numbers were used as these are the lower than 
males).  
Local safety margins were calculated taking the 29.1% fraction of the nominal dose in the 
planned clinical study. With a maximal nominal dose of 10.7 mg/kg (see section 3.3.7), 
and assuming a 1.8% lung weight to body weight ratio [23], the calculated maximal 
deposited dose is 0.17 mg/g lung in the planned pediatric population. 
The corresponding safety margin was calculated as the ratio between maximal achieved 
dose in rat (2.3 mg/g lung) to maximal calculated deposited dose in patients (0.17 mg/g 
lung), which results in a safety margin of 
 13.3. 
 
3.3.3. RANDOMIZATION 
 
After obtaining written informed consent from the parent(s)/legal guardian(s) or legally 
acceptable representative(s), subjects will be screened according to the inclusion and 
exclusion criteria and will receive a unique subject identification (ID) number, assigned by 
IWRS/IVRS.  
 
At the time of randomization, subjects should be eligible for study participation as defined in 
the inclusion/exclusion criteria. Therefore, at a minimum, the SpO2, feeding, respiratory 
muscle retractions, and respiratory rate should be evaluated on Day 1 before 
randomization, unless these assessments were already performed within the last 3 hours 
before randomization. 
 
At randomization, subjects will be assigned a randomization number by IWRS/IVRS prior to 
study drug administration according to the randomization scheme.  
 
In safety Cohorts 1 to 3, sequential dose escalation is used to enable appropriate safety 
follow-up. Each of the 3 safety cohorts consists of 12 subjects (N=36 in total) that will be 
randomized in a 3:1 ratio to receive either ALX-0171 dose 1 or placebo (Cohort 1), 
ALX-0171 dose 2 or placebo (Cohort 2), or ALX-0171 dose 3 or placebo (Cohort 3).  
After each safety cohort (when the last subject in a safety cohort has completed the 
treatment period), an IDMC will review the available cumulative safety data and advise the 
Sponsor on proceeding to the subsequent cohort (i.e., the higher dose) and which planned 
dose levels can be taken forward into the parallel part. If no stopping criteria have been met 
during the sequential part and if the IDMC issues a positive recommendation after each 
safety cohort and the Sponsor decides to proceed, the remaining 144 subjects (i.e., 
Cohort 4) will be randomly assigned in a 1:1:1:1 ratio to one of the 4 treatment groups, 
yielding an overall randomization ratio of 3:1 active to placebo. In the event one or 
two dose groups are discontinued for safety, the remaining groups will enroll the number of 
subjects initially specified (i.e., 45 per arm). 
 

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A separate randomization list will be created for each cohort. A restricted randomization 
algorithm will be used in cohort 4 to maintain the balance between the different treatment 
arms overall but also in the PK substudy. 
 
3.3.4. IDENTITY OF STUDY DRUG 
 
ALX-0171 and matching placebo will be provided in sterile, preservative-free, masked 
depyrogenated single-use DIN 2R glass vials, with injection stoppers and aluminium 
crimped caps. Each vial contains 
 2 mL nebulizer solution (target fill volume: 2.2 mL).  
 
Instructions for preparation, use and handling of study medication, the appropriate volume 
to be administered and the materials to be used, are provided in a manual concerning study 
drug. Instructions for use for the FOX-Flamingo nebulizer are provided as well. 
 
ALX-0171
Formulation: nebulizer solution 
Route of administration: inhalation (to be administered via the FOX-Flamingo inhalation 
system) 
Active substance: ALX-0171 Nanobody 
Activity: ALX-0171 Nanobody specifically and potently binds to the RSV F protein, 
thereby inhibiting an early step in the viral replication cycle.  
Composition: 
 
  
 
Matching placebo  
Formulation: nebulizer solution 
Route of administration: inhalation (to be administered via the FOX-Flamingo inhalation 
system) 
Active substance: None 
Activity: None  
Composition: 
 
 
 
 
Device: 

Name: FOX-Flamingo inhalation system - CE marked (Figure 5).  

Main components: re-usable base unit (containing the electronics), disposable inhalation 
set (including pediatric face mask in 2 sizes, mask adaptor, vibrating mesh nebulizer 
reservoir). 

Description: Vibrating mesh type nebulizers are considered the most appropriate 
technology for nebulization of a therapeutic protein such as ALX-0171 Nanobody. The 
FOX-Flamingo inhalation system consists of a battery-operated, hand-held device, 
intended for single-patient use. The device provides an aerosol with particle size suitable 

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for the intended study population. The nebulizer is always to be used with a flow of 
2 L/min additional air or O2. 
 
 
Figure 5: Overview of the FOX-Flamingo inhalation system
 
3.3.5. DRUG ACCOUNTABILITY 
 
The Pharmacist, the Investigator or his/her designee is responsible for acknowledge receipt 
of each shipment of study drug/inhalation system and will verify the condition and quantity 
of the study drug and other clinical supplies related to Investigational Medicinal Product 
(IMP) administration. 
 
At study site, the study drug will be kept in a locked and secured storage facility accessible 
only to those authorized by the Investigator to dispense the study drug. 
The responsible person will keep an inventory. This will include the quantity of study 
drug/inhalation system received for the study and a record of the materials that are 
dispensed, to whom (subject number) and when. 
 
The pharmacist, the Investigator and/or designated personnel will conduct a final inventory 
of the study drug/inhalation system and will record the results of this inventory. Upon 
Sponsor approval, all study drug and clinical supplies will be returned to the depot, or will 
be destroyed locally according to local regulations and site procedures. 
 
Instructions for drug/inhalation system accountability are available in the manual 
concerning study drug. 
 

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3.3.6. STUDY DRUG HANDLING 
 
Instructions for study drug receipt, handling, storage and administration are available in the 
manuals concerning study drug and IWRS/IVRS. 
 
Packaging and Labeling 
Final packaging and labeling will comply with the regulatory requirements of each country 
where the study will be conducted.  
 
Storage
Study drug will be provided under refrigerated conditions and must be stored in a secure, 
limited-access location protected from light and under the storage conditions specified by 
the Sponsor.  
 
Study drug must be refrigerated at 2°C to 8°C (35.6 °F to 46.4 °F) and should be stored in 
the secondary packaging until administration. It should not be frozen or shaken.  
 
Site storage conditions should be monitored by the site personnel and reviewed by the 
monitor during site visits. Deviations from the storage requirements must be documented 
and reported to the Sponsor, according to the instructions provided in the manual 
concerning study drug.  
 
Dispensing 
The 
Investigator 
or 
qualified 
designee(s) 
will 
dispense 
(via 
IWRS/IVRS) 
study 
drug/inhalation system to subjects who have met the entry criteria. Clinical supplies 
(including study drug) may not be used for any purpose other than that which is stated in 
this protocol. 
 
Product Quality Complaint 
Product quality complaints have to be communicated (written or electronically) to the 
Sponsor and the manufacturer of the device if the device is concerned (as applicable).  
 
3.3.7. STUDY DRUG ADMINISTRATION 
 
Three dose levels are planned to be evaluated. The precise dose that will be administered 
depends on the subject¶s weight: the drug volume filled into the nebulizer (nominal dose 
range) is calculated per weight category range (see Table 1). 
 

Dose 1: target dose of 3.0 mg/kg (depending on the subject¶s weight category, the actual 
nominal dose is between 2.5 and 3.6 mg/kg) 

Dose 2: target dose of 6.0 mg/kg (depending on the subject¶s weight category, the actual 
nominal dose is between 5.0 and 7.1 mg/kg) 

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
Dose 3: target dose of 9.0 mg/kg (depending on the subject¶s category, the actual 
nominal dose is between 7.6 and 10.7 mg/kg) 
 
Study drug is administered via inhalation of an aerosol generated by the FOX-Flamingo 
inhalation system. Detailed instructions for study drug administration are available in the 
manual concerning study drug.  
 
Study drug administration should start within 3 hours following randomization.  
Subsequent doses of study drug will be administered at 24-hour intervals (± 4 hours) 
relative to the first dose. 
 
No premedication is required or recommended per protocol, but an inhaled 2-agonist may 
be administered at the discretion of the treating Investigator.   
 
Study drug will be administered via inhalation using 2 serial nebulizations. In the placebo 
group, subjects will receive 2 nebulizations of placebo. In the ALX-0171 dose 1 and 2 
groups, subjects will receive 1 nebulization of ALX-0171 and 1 nebulization of placebo. In 
the ALX-0171 dose 3 group, both nebulizations will contain ALX-0171.  
 
Placebo group 
Nebulization 1 with volume 1 of placebo at each dosing day. 
Nebulization 2 with volume 2 of placebo at each dosing day. 
 
Dose 1 group 
Nebulization 1 with volume 1 of ALX-0171 at each dosing day. 
Nebulization 2 with volume 2 of placebo at each dosing day. 
 
Dose 2 group 
Nebulization 1 with volume 1 of placebo at each dosing day. 
Nebulization 2 with volume 2 of ALX-0171 at each dosing day. 
 
Dose 3 group 
Nebulization 1 with volume 1 of ALX-0171 at each dosing day. 
Nebulization 2 with volume 2 of ALX-0171 at each dosing day. 
 
Per body weight category, the total volume (to be administered via the 2 serial 
nebulizations) will be the same for the 4 treatment groups ensuring blinding across the 
treatment groups. This approach allows a design with a placebo-controlled group as 
representative comparison for the 3 dose levels. 
 
For information on nebulizer fill volumes for nebulizations 1 and 2 (in order to achieve the 
desired dose) to be administered per body weight category, please see section 3.3.7.1. 

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3.3.7.1.
ADMINISTRATION PROCEDURE 
 
An overview of the appropriate volume to be filled into the nebulizer (per body weight 
category and per nebulization), is available in Table 1. In line with other inhalation products, 
the administered dose of ALX-0171 is standardized for body weight categories. This is 
supported by adequate safety margins (see section 3.3.2), and also takes into account 
feasibility of accurately measuring and filling the appropriate volume into the nebulizer with 
a graduated syringe.  
 
Table 1: Nebulizer filling volumes of study drug 
Weight category 
Fill volume  
Nebulization 1 
Nebulization 2 
3.0 to <4.0 kg 
0.20 mL 
0.40 mL 
4.0 to <5.0 kg 
0.25 mL 
0.50 mL 
5.0 to <7.0 kg  
0.35 mL 
0.70 mL 
7.0 to <10.0 kg 
0.50 mL 
1.0 mL 
10.0 to <12.0 kg 
0.65 mL 
1.3 mL 
12.0 to <15.0 kg 
0.75 mL 
1.5 mL 
 
 
The FOX-Flamingo nebulizer features a tubing connector for air or O2 supply, and is 
always to be used with a fixed 2 L/min flow of air, or if needed, O2 (to be decided by the 
Investigator based on O2 need of the subject).  
During administration, the face mask should always be in contact with the face of the 
subject: a close fit is essential for appropriate dose administration. Hence, administration 
by ³blow by´ technique (i.e., hovering the face mask in front of the child during 
administration) is not permitted. 
At the start of each study drug nebulization, the face mask (connected to the nebulizer) 
will be placed on the subject¶s face, and must be verified as being in contact with the 
face. If applicable, the subject¶s nasal cannula, face mask, or headbox will need to be 
removed immediately before administration of the study drug (air or O2 are provided 
through the nebulizer). A nasogastric tube, if used, is to remain in place.§§  
Once the subject is able to breathe comfortably in the face mask, the nebulization 
procedure should be started.  
Nebulization should proceed as long as aerosol is visible in the transparent face mask. As 
a guidance, the estimated duration of nebulization is approximately 4 minutes for a 
volume of 0.5 mL, approximately 8 minutes for a volume of 1.0 mL and approximately 
12 minutes for a volume of 1.5 mL. Note: the FOX-Flamingo inhalation system is 
                                          
§§ Presence of the nasogastric tube has a negligible influence on the inhaled dose of study drug. 

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designed to switch off automatically when the filled volume has been completely 
nebulized. 
 
3.3.7.2.
ADDITIONAL GUIDANCE  
If dosing cannot be initiated successfully (e.g., because the subject is so agitated as to 
prevent adequate contact of the face mask with the face, and/or is crying or coughing 
intensely), new attempts should be made within a maximum of 1 hour (60 minutes) of 
nebulizer filling. 
 

If on Day 1, study drug initiation (first of 2 serial nebulizations) has not been successful 
after 60 minutes, the subject will be withdrawn from the study (see section 3.2.3).  

If on Day 2 or Day 3, study drug initiation (first of 2 serial nebulizations) has not been 
successful after 60 minutes, study drug treatment should be discontinued (i.e., in case 
dose initiation was not successful on Day 2, then no dosing on Day 3 should be done). 
The subjects should remain in the study and all per protocol visits should be conducted 
according to the Schedule of Assessments. 
 
If the first of the 2 serial nebulizations is started successfully but cannot be continued 
successfully and needs to be interrupted (e.g., because the subject starts crying intensely, 
or if the face mask loses adequate contact with the subject¶s face), study drug 
administration is to be stopped and resumed as soon as possible and the nebulization 
should be completed within 2 hours (120 minutes) of nebulizer filling for this nebulization.  
The second of the 2 serial nebulizations should be initiated as soon as possible after the end 
of the first nebulization and should be completed within 2 hours (120 minutes) of nebulizer 
filling for this nebulization. In case the study drug administration was started successfully 
but could not be completed, appropriate documentation is needed in the medical file and 
eCRF but subsequent daily study drug administration should continue per protocol.  
 
The maximum time window allowed to complete both serial nebulizations is 4 hours. 
 
The exact times of study drug administration (i.e., initiation and end of each nebulization 
and number of interruptions, if any) will be recorded in the eCRF. In addition, acceptability 
of the face mask and the nebulizer after each complete or partial administration, and 
whether or not correct and complete administration could be achieved will be documented in 
the eCRF. 
 
The product-contacting parts of the nebulizer (i.e., the nebulizer mesh/head and fill 
reservoir, mask adapter, and face mask) are to be disposed of after each nebulization; only 
the base unit containing the electronics and the air/O2 tubing will be reused (per subject 
and per 3-day treatment window). After completing the study drug treatment period, the 
base unit of the nebulizer must be safely disposed in a secured environment for further 
return to the sponsor or designee (e.g., delegated CRO). 

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3.3.7.3.
MANAGEMENT OF OVERDOSE 
 
The intended dose of ALX-0171 should not be exceeded during the study. No antidote is 
available.  
 
Overdoses that occur during the study should be documented and reported to the Sponsor 
or designee whether or not it results in an AE/SAE. Overdoses with signs and symptoms 
need to be reported as an AE/SAE. For information on medication errors, please refer to 
section 3.5.6.1. 
 
3.3.8. CONCOMITANT THERAPY 
 
Any 
concomitant 
medication 
(including 
over-the-counter 
medications 
and 
herbal 
supplements) taken during the study (i.e., from signing of ICF until the subject¶s last visit), 
must be recorded in the eCRF. Items to be recorded concerning concomitant medication 
include: dose and units of dose, start and end date, administration frequency, route of 
administration, therapeutic indication, brand name (or generic name if brand name is not 
available). Of note, previous medications relevant for eligibility will also be recorded in the 
eCRF.  
 
Standard of care treatment 
The treatment and care provided to each subject are determined by the Investigator (or 
designee) according to institutional practice. The recommendations on the diagnosis,  
management, and prevention of bronchiolitis, as described by the American Academy of 
Pediatrics (2014), may be followed in addition to institutional practice.  
 
Treatment may include (but is not limited to) the following: 
O2 supplementation through nasal cannula, via face mask or headbox. The initiation, 
monitoring and weaning of oxygen supplementation will follow local practice. It should 
be removed for the nebulized study drug administration, during which air or oxygen flow 
of 2L/min is provided 
Fluid/food supplementation (i.v. or via nasogastric tube, if applicable) 
Antipyretics and/or nonsteroidal anti-inflammatory medication 
Hypertonic saline (but not within 4 hours before start or 4 hours after the end of study 
drug administration) 
Short acting 
2-agonists 
Antibiotics (in case of secondary bacterial infection) 
Epinephrine  
Anticholinergics 
 

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Concomitant medications are permitted, apart from those listed under the forbidden 
medications (see below), at the Investigator¶s discretion (based on medical need). 
 
Forbidden medication 
 
The following treatments are prohibited up to the Follow-up visit (Day 14 ± 2 days): 
Ribavirin, i.v. immunoglobulin and palivizumab 
Inosine pranobex 
Xanthines 
Heliox 
Initiation of leukotriene receptor antagonists (LTRAs, i.e., montelukast) and/ or sodium 
cromoglycate; infants who are on maintenance chronic therapy at screening are to 
continue their usual dose during the study. 
Exogenous surfactant  
Systemic corticosteroids; topical corticosteroids for treatment of a skin or ear disorder 
are permitted; initiation of inhaled corticosteroids is not permitted; infants who are on a 
maintenance therapy of inhaled corticosteroids at inclusion are to continue their usual 
dose during the study 
Mucolytic and/ or expectorant drugs (e.g., Dornase Alpha, N-Acetylcysteine, 
Bromhexine) 
 
Subjects whose respiratory condition is deteriorating (e.g., hypercapnia with pCO2 > 
8 kPa/60mmHg, decreased consciousness) and need to start non-invasive respiratory 
support or invasive ventilation need to discontinue study drug treatment but should remain 
in the study according to the in-hospital post-treatment period as specified in the Schedule 
of Assessments, and should also attend the FU and EOS Visits. Subjects on HFOT as 
standard of care at inclusion and for whom the flow needs to be increased to levels not 
enabling study drug nebulization and/or above 2 L/kg/min also need to discontinue study 
drug treatment and be further followed up as described above. SAE reporting is required for 
these subjects with deterioration of the respiratory condition requiring above mentioned 
methods of ventilation. 
 
After the end of the subject¶s participation in the study, each subject is to be treated 
according to standard clinical practice. 
 

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3.3.9. TREATMENT COMPLIANCE 
 
Study drug will be administered by a health care professional in hospital, ensuring 
treatment compliance. 
 
The exact times of study drug administration (i.e., initiation and end of each nebulization 
and number of interruptions, if any) will be recorded in the eCRF. In addition, acceptability 
of the face mask and the nebulizer after each complete or partial administration, and 
whether or not correct and complete administration could be achieved will be documented in 
the eCRF. Compliance will be further confirmed by bioanalytical assessment of ALX-0171 in 
blood samples, and could be further confirmed by electronic documentation of the 
administration on the nebulizer base unit. 

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3.4.
ASSESSMENTS 
 
3.4.1. TIMING OF ASSESSMENTS 
 
Study related procedures will be done after informed consent has been obtained, after 
which each subject will be assigned a unique subject ID number. Date of obtaining written 
informed consent will be recorded in the eCRF. 
 
AEs will be recorded from time of obtaining written informed consent to the subject¶s last 
visit. 
 
3.4.1.1.
ELIGIBILITY PROCEDURES 
 
A signed and dated ICF must be obtained from the parent(s)/legal guardian(s) or legally 
acceptable representative(s) before any study-specific procedures are performed.  
 
The screening process begins when written informed consent has been obtained and 
continues until randomization. Subjects must be randomized within 24 hours of arrival at 
the hospital/emergency unit. 
At screening, subjects will be screened according to the inclusion and exclusion criteria 
(section 3.2) and have other assessments performed as specified in the Schedule of 
Assessments. The results of the screening procedures needed to evaluate eligibility must be 
available prior to randomization.  
Note: In case the result of the RSV diagnostic test (see inclusion criterion 4) is negative, the 
other assessments of the screening visit (see Schedule of Assessments) do not need to be 
performed and only the data to be collected in case of ³screen failure´ needs to be collected 
in the eCRF.  
 
Data of all subjects screened will be collected in the eCRF in order to assess the numbers 
and demographic characteristics of the excluded subjects, and the reasons for their 
exclusion, including documentation of adverse events. In case an SAE occurs, this needs to 
be reported according to standard process (see section 3.5.2). 
 
For details with regard to randomization, refer to section 3.3.3. 
 
Assessments and procedures should be performed as outlined in the Schedule of 
Assessments. 
 
Screening and baseline (i.e., Day 1, pre-dose) can be on the same day as long as the above 
applies. 
 

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Screening  
-
Obtain informed consent 
-
Review of eligibility criteria (including RSV diagnosis) 
-
Demographics and medical history (including RSV-related signs and symptoms) 
-
Previous and concomitant medications 
-
Body weight, body height, body temperature 
-
Physical examination 
-
Heart rate and SpO2 
-
Feeding, general appearance, lung auscultation, respiratory muscle retractions, 
respiratory rate, daytime coughing, night-time coughing,  
-
Hospitalization information: ICU transfer, apnea episodes, ventilation information, 
discharge from ICU/hospital  
-
Parent(s)/caregiver(s) assessment by completion of a diary including scoring of 
respiratory symptoms and assessing the global condition of the subject 
-
Blood sample for clinical laboratory  
-
Blood sample for immunogenicity (ADA) 
 
3.4.1.2.
STUDY DRUG TREATMENT AND IN-
HOSPITAL POST-TREATMENT PERIOD 
 
During the study drug treatment period, assessments should be performed as detailed in 
the Schedule of Assessments. 
 
If the Day 1, pre-dose assessments will be performed within 3 hours after the screening 
assessments have been performed, the assessments already done at screening do not need 
to be repeated and only the additional assessments to be performed on Day 1, pre-dose will 
need to be performed. 
 
Subjects will receive once-daily administration of study drug on 3 consecutive days. The 
first dose of study drug is to be administered as soon as possible and within 3 hours after 
randomization. For all subjects, the exact date and start and end time (and number of 
interruptions, if any) of the study drug nebulizations will be collected in the eCRF. 
 
Provided that the clinical response criteria have been met, discharge from the hospital can 
take place per protocol at the Investigator¶s discretion from dosing Day 2 onwards after all 
required assessments of the 5 hours (±1 hour) post-dose time point have been completed. 
Subjects discharged after the second dose must return to the hospital for the third study 
drug administration (to be administered 48 ± 4 hours after the first dose by the 
appropriately trained study personnel), and be monitored for a 2-hour pre- and post-dose 
period. 
 

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Subjects who are still hospitalized during the post-treatment period will be followed up twice 
daily (in the morning and the evening) until the subject is discharged from hospital.  
Hospitalization information will be collected during the study drug treatment period and the 
in-hospital post-treatment period, including occurrence of ICU transfer, apnea episodes, 
initiation and type of ventilation and hospital/ICU discharge information. Assessment of 
Clinical Response will be done with collection of date and time of adequate oral feeding to 
enable discharge as well as adequate stable oxygen saturation on room air of >92% over a 
period of at least 4 hours. For subjects in the in-hospital post-treatment period, the nasal 
swab should be collected only on the day of hospital discharge.  
  
All assessments will be performed as specified in the Schedule of Assessments.  
 
Unscheduled visits may be planned to assess, confirm, and follow up on clinically relevant 
AEs or laboratory abnormalities. Findings made during these unscheduled visits should be 
reported in the designated sections of the eCRF.  
 
Missed visits: 
 
If a subject misses a study visit for any reason, the Medical Monitor should be contacted as 
soon as possible to discuss rescheduling options of the missed visit to be proposed to the 
subject¶s parent(s)/legal guardian(s). For subjects who are considered lost to follow-up, 
reasonable attempts must be made (and documented) to obtain information on the subject. 
 
3.4.1.3.
FOLLOW-UP AND END-OF-STUDY VISITS 
 
Subjects who have received at least one dose of study medication should complete a FU 
visit on Day 14 ± 2 days and an EOS visit on Day 28 ± 2 days.  
 
In case a subject is re-hospitalized or consults the Investigator for a respiratory condition 
after hospital discharge, an unscheduled visit is to be performed. At a minimum this is to 
include collection of a mid-turbinate nasal swab, lung auscultation and physical 
examination. 
 
Premature discontinuation of Study Drug  
A subject who started study drug dosing but was discontinued prematurely from study drug 
treatment, should be further monitored according to the in-hospital post-treatment period 
(if they remain hospitalized) and should attend the FU and EOS visits to undergo the 
assessments as specified in the Schedule of Assessments.  
 
Withdrawal from the Study  
In case a subject is withdrawn from the study for any reason other than lost to follow-up or 
informed consent withdrawal (including subjects randomized but not dosed), a Withdrawal 

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Visit should be conducted at the time of withdrawal. The reason for withdrawal should be 
recorded in the eCRF. 
 
No further assessments/visits will be done in case subjects terminate study participation for 
reason of informed consent withdrawal. 
 
3.4.2. BASELINE CHARACTERISTICS 
 
Demographic and medical history data (including RSV-related signs and symptoms) will be 
collected at screening. 
 
Collected data will include (but are not limited to): month and year of birth, age (with 
indication of week level), gender, race (if allowed), and ethnicity (if allowed). 
 
Data on atopy in the family, environmental exposure to tobacco, pets and breastfeeding will 
also be collected. 
 
The nasal swab sample collected on Day 1 will be used to test for concurrent viruses and 
the presence of mycoplasma in nasal swab samples. If the volume of the Day 1 pre-dose 
sample is insufficient, the sample collected after study drug administration can be used for 
adventitious viral screening. 
 
3.4.3. ASSESSMENT OF VIRAL LOAD 
 
3.4.3.1.
SAMPLE COLLECTION AND HANDLING 
 
Throughout the study, nasal swabs (mid-turbinate specimen) will be collected for analysis of 
viral load, according to the time points defined in the Schedule of Assessments.  
The swabs that will be used are anatomically-designed for the collection of respiratory 
specimens which allows improved patient comfort and efficiency in specimen collection. In 
addition, appropriate training on the nasal swabbing procedure will be provided to the 
clinical sites to enable standardization across the study. Every effort should be made to 
perform the nasal swab sampling in both nostrils using the same swab. 
 
For all subjects, the exact date and time of nasal swab sampling will be collected in the 
eCRF. 
 
Note that a mid-turbinate nasal swab should also be taken in case the subject is 
re-hospitalized or consults the Investigator for a respiratory condition after hospital 
discharge up to the EOS (Day 28) visit. This should be considered for AE reporting according 
to the Investigator¶s judgment; however in any case, in addition to the nasal swab, a lung 
auscultation and a physical examination should be performed when a subject returns to the 

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hospital or consults the Investigator for a respiratory problem. The information on health 
care utilization for a respiratory condition will be collected through the diary completed by 
the parent(s)/caregiver(s).  
If permitted by local regulations, nasal swab samples that remain after protocol-specific 
assessments have been performed may be used by the Sponsor for further exploratory work 
in the context of the development of ALX-0171 or evaluation of RSV (e.g., potential viral 
resistance monitoring). These samples may be kept for up to 5 years after the end of the 
study. No human DNA or RNA analysis will be performed. 
 
3.4.3.2.
BIOANALYSIS 
 
Viral load will be measured by plaque forming unit (PFU) assay for the primary endpoint and 
by qRT-PCR for the secondary endpoint(s). Determination of Log10 PFU/mL and Log10 viral 
copies/mL in nasal swabs will be done by validated methods at a designated analytical 
laboratory. Bioanalytical procedures will be described in a separate Bioanalytical Analysis 
plan. 
 
3.4.4. ASSESSMENTS OF EFFICACY 
 
3.4.4.1.
CLINICAL ACTIVITY OUTCOME 
MEASURES  
 
The following assessments are performed to evaluate clinical activity of ALX-0171, but may 
also provide additional safety information: 
 

Heart rate and SpO2  

Feeding: type of feeding support, and (time and date of) sufficient feeding to enable 
hospital discharge, in the opinion of the Investigator (with particular attention to 
hydration and breathing comfort during feeding) 

Respiratory rate measured over a 1-minute interval 

Wheezing as assessed during lung auscultation 

Cough during the night and during the day 

Respiratory muscle retractions (supraclavicular, intercostal, and subcostal) 

General appearance: activity, irritation, and responsiveness 

Body temperature 
 
Based on the Clinical Activity Outcome Measures, composite scores such as RDAI score, 
(based on wheezing and respiratory muscle retractions) (see Appendix 1), RACS (based on 
RDAI and change in respiratory rate, see Appendix 2), and a Global Severity Score (see 
below and Appendix 3) will be calculated. 
 

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Global Severity Score 
 
The Global Severity Score is a composite score based on the GENVIP scale that allows 
objective categorization of infants with respiratory infections based on seven different items 
(i.e., feeding intolerance, medical intervention, respiratory difficulty, respiratory frequency, 
apnea, general condition, and fever) [11, 12]. 
 
Each item is scored from 0 to 3, except for body temperature (fever) that is scored from 0 
to 2, resulting in a maximum total score of 20 points. 
 
The collection of the parameters feeding, respiratory muscle retraction, wheezing, 
respiratory rate, body temperature, apnea episodes, general appearance, information on 
oxygen supplementation and hospital information (as described in the Schedule of 
Assessments) will allow calculation of the Global Severity Score (see Appendix 3). 
 
Clinical Response 
 
Time to Clinical Response will be calculated based on the feeding and oxygen saturation 
data. Subjects will be considered to have met the Clinical Response criteria when both of 
the following criteria are fulfilled: 

Stable oxygen saturation on room air, defined as SpO2 > 92% over a period of 
 4 hours. In case of oxygen supplementation, the level of supplementation is to be 
considered for reduction at least three times per day. Provided oxygen saturation is 
stable, attempts to remove the supplementation will be done at least three times a day.    

Adequate oral feeding which is sufficient to maintain sufficient hydration, in the judgment 
of the Investigator. 
 
The assessment of the subject having reached Clinical Response will be done daily until 
achieved and date and time for each item will be documented in the eCRF.  
 
3.4.4.2.
MEDICAL INTERVENTIONS OUTCOME 
MEASURES 
 
The following data will be captured to enable evaluation of the medical interventions 
outcome measures: 
 
Length of hospital stay for RSV infection 

Level, method, and duration of supplemental oxygen therapy 

Initiation of invasive or non-invasive ventilation (i.e., continuous positive airway pressure 
[cPAP] or HFOT)  

Level, method and duration of invasive or non-invasive ventilation  

Transfer to ICU and duration of stay in ICU 

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These measures also contribute to the calculation of the concerned parameters for the 
Global Severity Score (see Appendix 3). 
 
3.4.4.3.
HEART RATE AND SPO2
 
Continuous monitoring of SpO2 needs to be done during the study drug treatment period 
and the in-hospital post-treatment period until the clinical response criterion for oxygen 
(i.e., saturation on room air was > 92 % for at least 4 hours) has been met and/or in case 
saturation monitoring is to be continued according to the Investigator¶s judgment. 
 
The values for these parameters will be regularly captured in the eCRF (together with e.g., 
oxygen flow delivered and method), according to the Schedule of Assessments. 
In addition, the date and time of achieving the clinical response criterion for oxygen will be 
collected in the eCRF (cfr clinical response information collection). 
 
Clinically significant warnings and measurements during the pulse oximetry monitoring 
period are to be captured as AEs in the eCRF. 
 
3.4.4.4.
PARENT/CAREGIVER OUTCOME 
MEASURES 
 
Parent(s)/Caregiver(s) assessment of the clinical condition of the subject will be done by 
daily completion of a diary during the hospital stay and up to the EOS (Day 28) visit. The 
diary will be used to measure three respiratory symptoms (cough, [audible] wheeze, and 
trouble breathing), to score the general health of the subject and will ask for use of health 
care utilization and medication for respiratory symptoms.  
 
The three respiratory symptoms (cough, trouble breathing and wheezing) will be scored 
from not present over very mild, mild, moderate, and severe up to very severe. 
 
The global rating of the child¶s health by the parent(s)/caregiver(s) will be captured by a 
VAS. The parent or caregiver will make a mark between 0 (´very bad´) and 100 mm 
(³perfect´) on the scale to indicate the subject¶s current health. In addition, the 
parent(s)/caregiver(s) will indicate when the child was back to his/her condition as before 
the RSV infection started. 
 

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3.4.5. PHARMACOKINETIC ASSESSMENTS 
 
3.4.5.1.
SAMPLE COLLECTION AND HANDLING 
 
Throughout the study, blood samples will be taken for analysis of ALX-0171 concentrations 
in serum, according to the time points defined in the Schedule of Assessments.  

Subjects not undergoing the more extensive blood sampling scheme will have 1 blood 
sample taken on Day 2 or 3, at any time between 0.5 hours after completion of the 
second dose and initiation of the administration of the third dose. 

Subjects undergoing the more extensive blood sampling scheme will have 3 blood 
samples taken on Days 2-3: 1) pre second dose, 2) at any time between 0.5 hours and 
3 hours after completion of the second dose, and 3) at any time between 3 hours and 6 
hours after completion of the second dose (and at least 1 hour apart from the previous 
sampling). 
 
The exact dates and times of blood sampling will be recorded. 
 
The blood samples for PK assessments will be collected from a vein, as using capillary blood 
(e.g., from heel pricks) is not allowed. Anesthetic cream or spray can be used to minimize 
the subject¶s discomfort and distress. For further details on sample collection, shipment, 
storage and processing, please refer to a separate Lab Manual. 
 
3.4.5.2.
BIOANALYSIS 
 
Determination of ALX-0171 concentrations in serum will be done by a validated Ligand 
Binding Assay (LBA)-based method at a designated analytical laboratory according to the 
bioanalytical methodology and procedures described in a separate Bioanalytical Analysis 
Plan. All PK samples (both from placebo and ALX-0171 treated subjects) will be analyzed for 
measurement of ALX-0171. 
 
3.4.6. PHARMACODYNAMIC ASSESSMENTS 
 
3.4.6.1.
SAMPLE COLLECTION AND HANDLING 
 
Exploratory analysis of KL-6 levels will be done according to the time points defined in the 
Schedule of Assessments.  
 
KL-6 will be assessed on the remainder (if any) of the blood samples obtained for PK or 
immunogenicity testing, once the appropriate volume for their intended purpose has been 
extracted. 
 

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3.4.6.2.
BIOANALYSIS 
 
Determination of KL-6 levels in serum will be done by validated methods at the Sponsor. 
Bioanalytical procedures will be described in a separate Bioanalytical Analysis plan. 
 
3.4.7. IMMUNOGENICITY
 
3.4.7.1.
SAMPLE COLLECTION AND HANDLING 
 
To assess systemic immunogenicity of ALX-0171, blood samples will be collected at the time 
points defined in the Schedule of Assessments. If ADA are present, a further evaluation of 
their neutralizing capacity will be performed.  
Note: In case no sample was taken at the screening visit, a blood sample for assessment of 
immunogenicity should be collected at the Day 1 pre-dose timepoint, as far as possible. In 
case no sample was taken at the FU (Day 14) visit, a blood sample for assessment of 
immunogenicity should be collected at the EOS (Day 28) visit, as far as possible.  
 
The exact date and time of blood sampling will be recorded. 
 
The blood samples for ADA assessments will be collected from a vein, as using capillary 
blood (e.g., from heel pricks) is not allowed. Anesthetic cream or spray can be used to 
minimize the subject¶s discomfort and distress. For further details on sample collection, 
shipment, storage and processing, please refer to a separate Lab Manual.  
 
Of note, an additional serum sample should be collected (if reasonably feasible) in case of 
serious and/or severe hypersensitivity reaction (blood volume: 1 mL and collected as soon 
as possible after the start of the event) to allow characterization of the reaction if deemed 
required (also see section 3.4.8.1). 
 
3.4.7.2.
BIOANALYSIS 
 
Determination of ADA will be done using a validated screening, confirmation and titration 
ADA bridging assay, with further characterization of ADA positive samples by a competitive 
ligand binding neutralizing antibody assay. The immunogenicity data will be processed 
according to a dedicated Bioanalytical Analysis plan.  
 
Bioanalytical procedures for the additional sample in case of serious and/or severe 
hypersensitivity reaction will be described in a separate Bioanalytical Analysis plan. 
 

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3.4.8. ASSESSMENTS OF SAFETY 
 
Safety assessments consist of AE reports (including SAEs, hypersensitivity reactions), 
clinical laboratory assessments, heart rate and SpO2, respiratory rate, body weight, body 
temperature, physical examination, and lung auscultation.  
The time points are defined in the Schedule of Assessments.  
 
At each of the time points indicated in the Schedule of Assessments, a physical examination 
should be performed, including heart auscultation, examination of abdomen, skin and 
ears/nose/throat. Lung auscultation is to be performed more frequently and is therefore 
listed separately in the Schedule of Assessment. 
 
The parent(s)/legal guardian(s) will receive a subject card, indicating the address and phone 
number of the Investigator and/or other relevant emergency contact details (including e.g., 
subject number, medication number). The subject¶s parent(s)/legal guardian(s) will be 
advised to carry this card with them throughout the study so that the appropriate actions 
can be undertaken in case of emergency. They will also be advised to contact the 
Investigator (or his/her designee) with any medical and/or safety concern. 
 
In order to appropriately document possible events after discharge from the hospital, a 
diary will be completed by the parent(s) or caregiver(s) and be brought to the site at the FU 
visit on Day 14 and EOS visit on Day 28. 
 
3.4.8.1.
ADVERSE EVENTS 
 
General information on evaluation and reporting of AEs is provided in section 3.5. 
 
It is the responsibility of the Investigator to collect all AEs (both serious and non-serious) 
resulting from spontaneous, unsolicited reports by parents/caregivers and/or by healthcare 
staff, by observation (by the Investigator and/or healthcare staff), by routine open 
questioning of the parents/caregivers by the Investigator (e.g., ³Is there anything new that 
you wish to discuss?´) and by reviewing the diary with the parent(s)/caregiver(s). 
 
All AEs occurring between the time a signed and dated ICF is obtained until completion of 
the subject¶s last visit must be documented in the source documents and the eCRF.  
 
Criteria for determining whether an abnormal objective test finding (e.g., laboratory result), 
a complication of a protocol mandated procedure (e.g., blood draw), or a change in physical 
examination findings should be reported as an AE include, but are not limited to:  
 
1.
Result/finding is associated with accompanying clinical signs and symptoms (new onset 
or aggravated in severity of frequency from baseline condition), and/or 
2.
Result/finding requires extra diagnostic testing (other than diagnostic exclusion tests) 
or medical/surgical intervention, and/or 

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3.
Result/finding would require a premature discontinuation from the study drug, 
significant additional concomitant drug treatment or other therapy, and/or 
4.
Result/finding leads to any of the outcomes included in the definition of an SAE, and/or 
5.
Result/finding is considered to be an AE by the Investigator. 
 
Any abnormal test result that is determined to be an error and merely repeating an 
abnormal test does not require reporting as an AE.   
 
Airway hyperresponsiveness and immediate or delayed adverse drug reactions should be 
managed according to the Investigator¶s clinical judgment and applicable standard of care. 
  
If airway hyperresponsiveness would occur, administration of a bronchodilator like the 
short-acting 2-agonist salbutamol may be administered (with an appropriate follow-up 
period) according to the investigator¶s assessment of the particular reaction and subject¶s 
characteristics.  
With regard to immediate or delayed hypersensitivity reactions, measures beyond basic 
supportive care are not considered necessary for subjects with purely local reactions. 
Subjects with suspected systemic hypersensitivity, however, should be admitted or 
treated and observed for a longer period, preferably in the emergency department or 
another close-observation area, depending on the severity of the reaction and its 
hemodynamic impact. 
 
In case of severe and/or serious hypersensitivity reactions, an additional serum sample 
should be collected (if reasonably feasible) as soon as possible after the start of the event 
(blood volume: 1 mL) to characterize the reaction (if deemed required). As described in 
section 3.2.3, subjects must be discontinued from study drug treatment in case of a severe 
and/or serious hypersensitivity reaction, a severe and/or serious acute respiratory distress 
reaction induced by study drug, or when a subject needs to start non-invasive respiratory 
support or ventilation. 
 
Occurrence of episodes of apnea will be captured together with the overall hospitalization 
information and should be reported as an AE. As defined by the American Academy of 
Pediatrics, apnea is ³an unexplained episode of cessation of breathing for 20 seconds or 
longer, or a shorter respiratory pause associated with bradycardia, cyanosis, pallor, and/or 
marked hypotonia.´ 
 
In addition to the events meeting the seriousness criteria mentioned in section 3.5.2 , the 
following events will trigger a SAE reporting: 
Transfer to ICU.  
Initiation of non-invasive respiratory support (including start of HFOT or increasing the 
flow above the allowed level) or invasive ventilation. 
Episodes of apnea that fulfil the seriousness criteria. 
 

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3.4.8.2.
LABORATORY ASSESSMENTS 
 
Blood samples for clinical laboratory analyses will be collected at the time points indicated in 
the Schedule of Assessments.  
 
Safety lab assessments will be performed by the local laboratory in order to allow for timely 
availability of the results. For local laboratory data, the local normal ranges and laboratory 
accreditation are to be collected/provided. 
 
If all hematology and biochemistry blood parameters required for the study are already 
known from analysis done as a routine assessment upon arrival at the hospital, collection of 
screening clinical laboratory samples does not need to be repeated for the purpose of this 
study. However, the samples should be analyzed at the same local laboratory that will be 
used for the remainder of the study. 
 
The blood samples will be collected according to the site¶s standard practice. Anesthetic 
cream or spray can be used to minimize the subject¶s discomfort and distress.  
 
The following tests will be included in the clinical laboratory analysis: 

Clinical chemistry: alanine aminotransferase, aspartate aminotransferase, creatinine, 
sodium, potassium, chloride, C-reactive protein, 
-glutamyl-transferase, blood urea 
nitrogen 

Hematology: hemoglobin, hematocrit, red blood cell count and indices, mean corpuscular 
hemoglobin, mean corpuscular hemoglobin concentration, platelet count (or estimate), 
white blood cell count including differential (lymphocytes, neutrophils, monocytes, 
basophils, eosinophils). 
 
Clinical relevance of values outside the local laboratory¶s normal range will be assessed by 
the Investigator. All clinically significant laboratory findings will be recorded as AEs in the 
eCRF (also see section 3.4.8.1). 
 
In the event of unexplained or unexpected clinical laboratory test values, the test(s) may be 
repeated and followed up until the results have returned to the normal range and/or an 
adequate explanation for the abnormality is found. 
 
3.4.8.3.
LUNG AUSCULTATION 
 
At each of the time points indicated in the Schedule of Assessments, a lung auscultation will 
be performed to assess wheezing, crackles/crepitation and other abnormalities in lung 
auscultation.  
 

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A new finding or a change of a finding that is judged as an undesirable medical event shall 
be reported as an AE. 
 
In case the subject is re-hospitalized or consults the Investigator for a respiratory condition 
after hospital discharge up to the EOS (Day 28) visit, an unscheduled visit is to be 
performed that will include a lung auscultation assessment (in addition to a physical 
examination and collection of a nasal swab) (see section 3.4.1.3). 
 
3.4.8.4.
PHYSICAL EXAMINATION 
 
At each of the time points indicated in the Schedule of Assessments, a physical examination 
should be performed, including heart auscultation, examination of abdomen, skin and 
ears/nose/throat.  
 
Physical examination will be recorded as ³normal´, ³abnormal, not clinically significant´ or 
³abnormal, clinically significant´ at every assessment. A new finding or a change of a finding 
that is judged as an undesirable medical event (including all findings recorded as ³abnormal, 
clinically significant´) shall be reported as an AE. 
 
In case the subject is re-hospitalized or consults the Investigator for a respiratory condition 
after hospital discharge up to the EOS (Day 28) visit, an unscheduled visit is to be 
performed that will include a physical examination (in addition to a lung auscultation and 
collection of a nasal swab) (see section 3.4.1.3). 
 
3.4.8.5.
HEART RATE AND SPO2
 
The collection of these parameters is described in section 3.4.4.3 as the evolution of the 
heart rate and oxygen saturation levels will also inform on clinical activity outcome.  
 
3.4.8.6.
BODY WEIGHT, HEIGHT, AND 
TEMPERATURE 
 
At the time points indicated in the Schedule of Assessments, the following parameters will 
be assessed: body height, weight, and temperature.  
 
To obtain the actual body weight, subjects must be weighed lightly clothed.  
 
Temperature is to be measured preferably rectal, oral, or tympanic (axillary method less 
preferred). For each individual subject, the same method should be used throughout the 
study as far as possible. The method will be recorded in the eCRF. 
 

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3.4.9. TOTAL BLOOD VOLUME 
 
The blood samples will be used i) for safety evaluation (clinical laboratory: hematology and 
clinical biochemistry), ii) to monitor the systemic concentration of ALX-0171 (as a surrogate 
measure of the local lung concentration), and iii) to assess potential immunogenicity 
(Table 2).  
 
If all hematology and biochemistry blood parameters required for the study are already 
known from analysis done as a routine assessment upon arrival at the hospital, collection of 
screening clinical laboratory samples does not need to be repeated for the purpose of this 
study. However, the samples should be analyzed at the same local laboratory that will be 
used for the remainder of the study. 
 
Exploratory biomarker will only be assessed on the remainder of the blood samples once the 
appropriate volume for their intended purpose has been extracted. An additional serum 
sample should be collected (if reasonably feasible) in case of serious and/or severe 
hypersensitivity reaction (volume of 1 mL). Note that no human DNA or RNA analysis will be 
performed. 
 
The precise assessments that are intended to be performed on each of the blood samples 
are arranged by priority; when insufficient volume is available (e.g., because of difficulties 
in or limits to obtaining blood), only the highest priority(ies) will be assessed (see Table 2). 
 
Of note: for subjects with a body weight below 5 kg (irrespective of whether they undergo 
the more extensive blood sampling scheme or not), the sample for analysis of 
immunogenicity at screening and on Day 14 should not be collected in case blood volume 
needed for local assessment of clinical laboratory parameters exceeds 2.5 mL (in order to 
not exceed the maximum blood volume allowed to be collected at a single time point). 
Instead and if possible, the blood sample for immunogenicity should be collected at Day 1 
pre-dose (replacing the screening sample) and at the EOS (Day 28) visit (replacing the FU 
visit sample). 
 
In the 48 subjects undergoing more extensive sampling, 5 blood samples will be taken (for 
evaluation of clinical safety, PK, and immunogenicity) with a total estimated volume of 
3.5 mL (not including volumes for local lab assessments). In the remainder of subjects, 3 
blood samples will be taken with a total estimated volume of 2.5 mL (not including volumes 
for local lab assessments). 
 
If permitted by local regulations, blood samples that remain after protocol-specific 
assessments have been performed may be used by the Sponsor for further exploratory work 
in the context of the development of ALX-0171 or evaluation of RSV. These samples may be 

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kept for up to 5 years after the end of the study. No human DNA or RNA analysis will be 
performed. 
 
Table 2: Timing, priority and estimated volume of scheduled blood draws  
Sample 
Priority
Maximal Target volume
1 blood draw at 
Screening a 
1. Clinical laboratory:  
- Hematology (whole 
blood) 
- Biochemistry (serum) 
2. Immunogenicity (serum) b 
3. Exploratory biomarker c 
-  whole blood for hematology (volume according to 
local practice) 
- whole blood to be processed into serum for 
biochemistry (volume according to local practice) 
-  1 mL whole blood, to be processed into serum for 
immunogenicity and biomarker b 
 Total: 1 mL whole blood + volume needed for 
clinical laboratory 
1 blood draw on Day 2 
or 3 OR 
3 blood draws on 
Days 2-3  
(in 48 subjects) 
1. PK (serum) 
2. Exploratory biomarker c 
-  0.5 mL whole blood, to be processed into serum for 
PK and biomarker b  
 Total: 0.5 mL whole blood in case of 1 blood 
draw or 1.5 mL whole blood in case of 3 blood 
draws 
1 blood draw during the 
Day 14 FU visit  
1. Clinical laboratory:  
- Hematology (whole 
blood) 
- Biochemistry (serum) 
2. Immunogenicity (serum) b 
3. Exploratory biomarker c  
-  whole blood for hematology (volume according to 
local practice) 
- whole blood to be processed into serum for 
biochemistry (volume according to local practice) 
- 1 mL whole blood, to be processed into serum for
immunogenicity and biomarker b 
 Total: 1 mL whole blood + volume needed for 
clinical laboratory 
a.
If all hematology and biochemistry blood parameters required for the study are already known from analysis 
done as a routine assessment upon arrival at the hospital, collection of screening clinical laboratory samples 
does not need to be repeated for the purpose of this study. However, the samples should be analyzed at the 
same local laboratory that will be used for the remainder of the study. 
b.
For subjects with a body weight below 5 kg (irrespective of whether they undergo the more extensive blood 
sampling scheme or not) and in case blood volume needed for local clinical laboratory exceeds 2.5 mL, the 
sample for analysis of immunogenicity should not be collected at screening and on Day 14 but at Day 1 pre-
dose and Day 28, as far as possible.  
c.
Only if sufficient blood volume (serum) is available after analyzing the samples obtained for PK or 
immunogenicity. 
 
3.4.10. APPROPRIATENESS AND TIMING OF 
MEASUREMENTS 
 
The assessments which will be made in this study are standard and generally recognized as 
reliable, accurate, and relevant. 
 
The timing of all assessments is detailed in the Schedule of Assessments. 
 
Throughout the study, study personnel should make every reasonable effort to follow the 
timing of assessments and procedures in the Schedule of Assessments for each subject.  

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3.5.
ADVERSE EVENT EVALUATION AND 
REPORTING 
 
3.5.1. ADVERSE EVENTS 
 
Study-specific information on evaluation and reporting of AEs is provided in section 3.4.8.1. 
 
AE definitions will be consistent with the ³Note for Guidance on clinical safety data 
management: definitions and standards for expedited reporting´ (International Conference 
on Harmonization [ICH] topic E2A). 
 
An AE is any untoward medical occurrence in a clinical study subject administered a 
medicinal (investigational or non-investigational) product. An AE does not necessarily have 
a causal relationship with the treatment. An AE can therefore be any unfavorable and 
unintended sign (including an abnormal finding), symptom, or disease temporally associated 
with the use of a medicinal (investigational or non-investigational) product, whether or not 
considered related to that medicinal (investigational or non-investigational) product. 
 
This includes any occurrence that is new in onset or aggravated in severity or frequency 
from the baseline condition, or abnormal results of diagnostic procedures, including 
laboratory test abnormalities. 
 
In differentiating between medical history and AEs, the following points will be considered: 
Conditions that started before signing of informed consent and for which no symptoms or 
treatment are present up to the timing of signing of informed consent are recorded as 
medical history (e.g., seasonal allergy without acute complaints). 
Conditions that started before signing of informed consent and for which symptoms or 
treatment are present after signing of informed consent, but with unchanged severity, 
are recorded as medical history (e.g., allergic pollinosis). 
Conditions that started or deteriorated after signing of informed consent will be 
documented as AEs. 
 
All AEs will be reported from the time a signed and dated ICF is obtained until completion of 
the subject¶s last visit. 
 
A TEAE is any AE temporally associated with the use of study drug, whether considered 
related to the study drug or not. TEAEs are recorded from the start of study drug 
administration, until completion of the subject¶s last visit. 
 

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All AEs will be assessed by the Investigator and recorded in the patient medical records and 
on the AE eCRF page. AE entry should indicate time of onset and end time and rating of the 
seriousness (see section 3.5.2), severity (see section 3.5.1.1), and outcome (see 
section 3.5.1.2) of the AEs, relationship to study drug and study procedures (see 
section 3.5.1.3), action taken regarding study drug (see section 3.5.1.4), and concomitant 
therapy taken for the AE. 
 
The Investigator will judge upon the severity of the AEs and relation to study drug and 
study procedures.  
 
3.5.1.1.
AE SEVERITY 
 
The severity of AEs will be rated on a 3-point scale:  
Mild: discomfort noticed but no disruption of normal daily activity  
Moderate: discomfort sufficient to reduce or affect normal daily activity 
Severe: incapacitating with performing normal daily activity  
 
It is emphasized that the term severe is a measure of intensity: a severe AE is not 
necessarily serious. For example, itching for several days may be rated as severe, but may 
not be clinically serious. 
 
3.5.1.2.
OUTCOME 
 
The outcome of the AE is to be documented as follows: 
Recovered/resolved 
Recovering/resolving 
Recovered/resolved with sequelae 
Not recovered/not resolved 
Fatal 
Unknown 
 
 
3.5.1.3.
RELATION TO STUDY DRUG OR STUDY 
PROCEDURES 
 
The assessment of the causal relationship between an AE and the administration of 
treatment is a clinical decision based on all available information at the time of the 
completion of the eCRF. 
 

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The assessment is based on the question whether there was a ³reasonable causal 
relationship´ to the study treatment in question. Possible answers are: 

Not related 

Unlikely related 

Possibly related 

Related 

Not applicable 
 
Note that only AEs starting after administration of study drug can be assigned a causal 
relationship between the AE and study drug administration. For AEs starting prior to study 
drug administration, causal relationship between the AE and study drug should be ³not 
applicable´. 
 
Assessment of causal relationship of any AE to protocol-required procedures can be 
completed with: 
Yes (specify) 
No 
 
3.5.1.4.
ACTION TAKEN REGARDING STUDY 
DRUG  
 
Any action taken regarding the study drug is to be documented using following categories: 
Dose not changed 
Drug interrupted 
Drug withdrawn 
Not applicable 
Unknown 
 
3.5.2. SERIOUS ADVERSE EVENTS 
 
SAE definitions will be consistent with the ³Note for Guidance on clinical safety data 
management: definitions and standards for expedited reporting´ (International Conference 
on Harmonization [ICH] topic E2A). 
 
An SAE is any untoward medical occurrence that at any dose meets any of the following 
conditions: 
Results in death. 

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Is life-threatening: the subject is at risk of death at the time of the event. It does not 
refer to an event that hypothetically might cause death if it were more severe. 
Requires 
in-patient 
hospitalization 
or 
prolongation 
of 
existing 
hospitalization; 
an AE associated with a hospitalization or prolongation of hospitalization will not be 
regarded as an SAE if at least one of the following exceptions is met: 
-
The admission results in a hospital stay of less than 12 hours. 
-
The admission is pre-planned (i.e., elective or scheduled surgery arranged prior to the 
start of the study). 
-
The admission is not associated with an AE (e.g., social hospitalization for purposes of 
respite care). 
However, it should be noted that invasive treatment during any hospitalization may fulfill 
the criterion of ³medically important´ and as such may be reportable as an SAE 
dependent on clinical judgment. In addition, where local regulatory authorities specifically 
require a more stringent definition, the local regulation takes precedence. 
Results in persistent or significant disability/incapacity. Disability means a substantial 
disruption of a person¶s ability to conduct normal life¶s functions. 
Is another medically important serious event as judged by the Investigator, or is defined 
as requiring intervention to prevent one of the outcomes listed in the definition above 
(including suspected transmission of an infectious agent by a medicinal product should be 
reported as an SAE). Other examples of such events are intensive treatment in an 
emergency room or at home for allergic bronchospasm; blood dyscrasias or convulsions 
that do not result in hospitalization; or development of drug dependency or drug abuse. 
Any AE is considered an SAE if it is associated with clinical signs or symptoms judged by 
the Investigator to have a significant clinical impact. 
 
In addition, the following events will trigger a SAE reporting: 
Transfer to ICU.  
Initiation of non-invasive respiratory support (including start of HFOT or increasing the 
flow above the allowed level) or invasive ventilation. 
Episodes of apnea that fulfill the seriousness criteria. 
 
A treatment-emergent SAE is any SAE temporally associated with the use of study drug, 
whether considered related to the study drug or not.  
 
The Investigator or clinical site personnel should notify the designated CRO of all SAEs, 
regardless of relationship to the study drug, within 24 hours of clinical site personnel 
becoming aware of the event (see Investigator Site File). The Investigator will provide the 
initial notification by sending a completed ³SAE Form´, which must include the Investigator¶s 
assessment of the relationship of the event to study drug, and must be signed by the 
Investigator.  
 

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The first report of an SAE may also be made by telephone to the Medical Monitor or local 
Clinical research Associate (CRA). At a minimum, the Reporter must provide the following 
information: reporter identification, study number, year of birth, medication code number, 
period of intake, nature of the AE, and relation to study drug. 
 
The report of an SAE by telephone must always be confirmed by a written, more detailed 
report (the SAE Form) to be completed and signed by the Investigator.   
 
Follow-up information, or new information regarding an ongoing SAE, must be provided 
promptly to the contacts provided in the Investigator Site File. 
 
The SAE should also be recorded in the eCRF. Any medications necessary for the treatment 
of the SAE must be recorded on the concomitant medication section of the eCRF. 
 
SAEs that begin after the subject¶s participation in the study is complete, but that the 
Investigator considers to be related to study drug, should be reported to the CRO/Sponsor 
at any time. 
 
3.5.3. SUSPECTED UNEXPECTED SERIOUS 
ADVERSE REACTIONS  
 
Suspected unexpected serious adverse reactions (SUSARs) are serious adverse reactions of 
which the nature or severity is not consistent with the applicable product information (as 
described in the Reference Safety Information, provided in the Investigator¶s Brochure) and 
have a reasonable suspected causal relationship (i.e., at least possibly related) to the 
medicinal product. 
 
The vendor(s) will expedite reports of the following SUSARs to the IEC/IRB on behalf of the 
Sponsor: 
SUSARs that have arisen in the current clinical study that was assessed by the IEC/IRB. 
SUSARs that have arisen in other clinical studies of the same Sponsor and with the same 
study drug and that could have consequences for the safety of the subjects involved in 
the current clinical study that was assessed by the IEC/IRB. 
 
The vendor(s) will expedite all reports of SUSARs to the relevant CA on behalf of the 
Sponsor. 
 
The Sponsor (or the CRO on behalf of the Sponsor) will also report to all concerned 
Investigators all SAEs that are unlisted (unexpected) and associated with the use of the 
drug. 
 

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The expedited reporting will occur no later than 15 calendar days after the Sponsor (or the 
CRO on behalf of the Sponsor) has first knowledge of the adverse reactions or as per local 
regulations.  
 
For fatal or life-threatening cases the term will be maximal 7 calendar days for a preliminary 
report with another 8 days for completion of the report or as per local regulations. 
 
3.5.4. REPORTING OF ADVERSE EVENTS 
 
AE reporting, including SUSARs, will be carried out in accordance with applicable local 
regulations. For reported deaths, the Investigator should supply the Sponsor and the 
IEC/IRB with any additional requested information (e.g., autopsy reports and terminal 
medical reports). 
 
After termination of the clinical study (last subject last visit in the study), any unexpected 
safety issue that changes the risk benefit analysis and is likely to have an impact on the 
subjects who have participated in the study, will be reported by the Sponsor as soon as 
possible to the competent authority(ies) concerned, together with proposed actions. 
 
3.5.5. FOLLOW-UP OF ADVERSE EVENTS 
 
AEs will be handled according to common clinical practice. If necessary, in order to obtain 
additional information to ensure safety to the subject, additional blood or other samples 
may be taken at the discretion of the Investigator. Information relative to other means of 
investigational diagnostics used in relation to the AE will also be communicated. 
 
AEs are recorded from signing the ICF until completion of the subject¶s last visit. TEAEs are 
recorded from the start of study drug administration, until the subject¶s last visit.  
 
All AEs occurring at any time during the study (including the FU period) will be followed by 
the Investigator until stable outcome.  
 
3.5.6. OTHER REPORTABLE INFORMATION 
 
3.5.6.1.
MEDICATION ERROR 
 
Medication errors include, but are not limited to, the following: 
 
Administration of the wrong dosage to the subject (i.e., different from the dose 
prescribed by the protocol). 
Administration of study drug that has not been assigned to the subject. 

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Administration of expired study drug. 
Administration by a route other than inhalation. 
Deviations to the study drug storage conditions when administered to the subject. 
Nasal cannula not removed. 
Air or oxygen tube not connected to the FOX-Flamingo inhalation system, damaged or 
kinked. 
Air or oxygen flow to the FOX-Flamingo inhalation system too low or too high. 
Re-use of inhalation set (i.e., the face mask, mask adapter, and nebulizer mesh/head 
and fill reservoir). 
  
Medication errors that occur during the study should be documented and reported to the 
Sponsor or designee whether or not it results in an AE/SAE. Medication errors with signs 
and symptoms need to be reported as an AE/SAE. 
 
For information on management of overdoses, please refer to section 3.3.7.3. 

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3.6.
STATISTICS
 
3.6.1. STUDY POPULATIONS 
 
The following populations will be considered for analysis: 

Intent-to-treat (ITT) Population: All randomized subjects. 

Modified Intent-to-treat (mITT) Population All subjects who received at least 
1 administration of study drug, as randomized (i.e., using the treatment to which the 
subject was randomized). 

Safety Population: All subjects who received at least 1 administration of study drug, as 
treated (i.e., using the treatment that the subject actually received). 

PK population: Subset of the subjects in the safety population for whom the primary PK 
data are considered to be sufficient and interpretable. For this study, this will correspond 
to all subjects in the safety population who received at least 1 administration of 
ALX-0171 and for whom at least one ALX-0171 serum concentration has been 
determined.  

Per Protocol (PP) Population: Consists of a subset of the ITT population, and excludes 
those subjects who have had a major protocol deviation.   
 
The mITT Population will be the primary study population used for the analysis of efficacy 
data, the Safety Population for the analysis of safety, PD, and immunogenicity data, and the 
PK population for analysis of PK data. 
 
3.6.2. STATISTICAL AND ANALYTICAL PLAN 
 
Analysis of parameters will be detailed in a Statistical Analysis Plan (SAP). The PK analysis 
will be described in a Data Analysis Plan (DAP). The SAP and DAP will be generated under 
responsibility of the Sponsor and will be finalized prior to database lock. Any deviation from 
the reporting and analysis plans will be reported in the section ³Changes in the planned 
analysis´ in the Clinical Study Report.  
 
3.6.3. BASELINE CHARACTERISTICS 
 
Baseline characteristics will be summarized using descriptive statistics (including number of 
observations, mean, standard deviation, median, maximum, and minimum) for continuous 
variables and counts and percentages for categorical variables. 
Prior and concomitant medications will be summarized by treatment group, by the number 
and percentage of subjects taking each medication, classified using World Health 
Organization (WHO) Drug Dictionary, anatomical therapeutic chemical (ATC) class and 
preferred term. 

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3.6.4. ENDPOINTS 
 
Primary Endpoint 
Anti-viral effect as measured by the time needed for the viral load to drop below the plaque 
assay quantification limit (time-to-BQL) in nasal mid-turbinate swab specimens. 
 
Secondary Endpoints 

Safety assessment (assessed by physical examination, AEs, laboratory assessments and 
vital signs) of different doses of ALX-0171 

Change from baseline in Global Severity Score 

Time to clinical response: defined as the time between first administration of study drug 
and achieving adequate oxygen saturation and oral feeding 

PK properties of ALX-0171  

Viral load profile over time in nasal swab specimens (qPCR and plaque assay) 

Evaluation of serum ADA  
 
Other Endpoints 

Evolution over time in clinical symptoms (SpO2, feeding, respiratory rate, wheezing, 
cough, respiratory muscle retractions, and general appearance) 

Evolution over time in RDAI, RACS 

Length of hospital stay for RSV defined as time between admission and discharge 

Duration of supplemental oxygen therapy 

Initiation of invasive and non-invasive ventilation and duration of respiratory support 

Transfer to ICU and duration of ICU stay  

Parent(s)/Caregiver(s) assessment of the clinical condition of the subject  

Evolution of serum biomarker over time 
 
3.6.5. EVALUATION OF VIROLOGY AND CLINICAL 
EFFICACY ENDPOINTS 
 
3.6.5.1.
ANALYSIS OF PRIMARY ENDPOINT 
 
For the primary endpoint, the anti-viral effect will be measured as the time-to-BQL in nasal 
mid-turbinate swab specimens. The median time-to-BQL will be compared between each of 
the ALX-0171 dose groups and the combined placebo group using a log-rank test. The tests 
will be performed in a sequential way to preserve the family-wise error rate at 0.05. 
Specifically, dose 3 of ALX-0171 will first be tested against the combined placebo group at 
the 0.05 significance level. Dose 2 of ALX-0171 will only be compared to placebo at the 0.05 
significance level if the comparison of dose 3 with placebo is significant. Consequently, 
dose 1 of ALX-0171 will only be compared to placebo at the 0.05 significance level if the 
comparison of dose 2 of ALX-0171 with placebo is significant. 

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3.6.5.2.
EVALUATION OF SECONDARY EFFICACY 
ENDPOINTS
 
The data from the secondary endpoints will be analyzed by descriptive statistics (number of 
observations, mean, standard deviation, median, minimum and maximum for most 
continuous data; frequencies and percentages for categorical data, as appropriate) as 
applicable. For selected secondary endpoints, comparisons of active dose groups with 
placebo may be performed through appropriate inferential tests. No correction for multiple 
testing is foreseen for secondary endpoints, and p-values reported for the analyses are to 
be interpreted accordingly. 
 
Based on the Clinical Activity Outcome Measures, Time to Clinical Response and scores such 
as the Global Severity Score, RDAI score and RACS will be calculated. 
 
3.6.6. EVALUATION OF PHARMACOKINETIC, 
PHARMACODYNAMIC, AND 
IMMUNOGENICITY PARAMETERS 
 
Systemic (serum) concentrations of ALX-0171 will be used as a surrogate for local (lung) 
concentrations. Individual study drug concentrations will be listed. In addition, a listing of 
the actual sampling times relative to the study drug administration times will be presented.  
If considered meaningful, geometric means and standard deviations will be added to the 
summary tables. 
A population PK model (non-linear mixed effect modeling) will be developed based on the 
ALX-0171 serum concentrations from this study. The dataset might be supplemented with 
serum concentration data from Study ALX-0171-C104 and/or data from clinical studies in 
healthy adult volunteers (or a subset to balance between pediatric and adult populations in 
the dataset) to support model structure. Individual PK parameters will be derived by means 
of empirical Bayesian estimation. The following individual PK parameters will be provided: 
apparent clearance (CL/F), area under the curve (AUC) as nominal (filling) dose divided by 
CL/F and cumulative AUC over 72 hours as an expression of the cumulated exposure during 
the course of treatment. Individual PK parameters will be summarized with sample size, 
mean, standard deviation and coefficient of variation. The modeling exercise will be 
described in a separate analysis plan and will be reported in a separate report. The main 
findings will be summarized in the Clinical Study Report. 
 
Pharmacodynamic effect will evaluate the evolution over time of (i) viral load, and (ii) 
exploratory biomarker KL-6.  
 
Analysis of the time needed for the viral load to drop below the plaque assay quantification 
limit (time-to-BQL) in nasal mid-turbinate swab specimens (i.e., the primary endpoint) will 
be analyzed as described in section 3.6.5. 

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In addition, viral load will be characterized through parameters including time-to-BQL, AUC, 
percent of subjects with undetectable RSV (from Day 1 to Day 14) and rate of decline from 
baseline in viral load.  
 
All PD data (other than the primary endpoint), will be summarized using descriptive 
statistics and will be listed. 
 
Individual immunogenicity results will be listed, and summarized using descriptive statistics. 
Subjects will be classified for presence of pre-Ab, TE ADA and neutralizing anti-drug 
antibodies (NAb). Prevalence of pre-Ab and incidence of TE ADA or NAb, as well as titer 
levels of the antibody responses, will be reported. Potential correlation between pre-existing 
antibodies, TE ADA or NAb and safety, pharmacokinetics or efficacy will be assessed. 
 
In case of severe and/or serious hypersensitivity reactions, a blood sample will be collected 
to further characterize the hypersensitivity reactions (if deemed necessary). Correlation 
between hypersensitivity reactions and immunogenicity results will be assessed. Results will 
be summarized through listing of the individual results. 
 
3.6.7. EVALUATION OF SAFETY PARAMETERS 
 
The IDMC will evaluate the cumulative safety data after completion of each safety cohort, 
and periodically during the parallel dose ranging phase of the study (see section 3.1.1). 
Further details will be provided in the IDMC charter. 
 
All safety analyses will be performed using the Safety Population.  
 
AEs will be fully described and coded according to the Medical Dictionary for regulatory 
Activities (MedDRA). A treatment-emergent analysis of AEs will be done. Frequency of 
subjects presenting with AEs, AEs leading to withdrawal, adverse drug reactions, and SAEs 
will be tabulated for each treatment group by system organ class and preferred term.  
 
For laboratory parameters, descriptive statistics (mean, median, standard deviation, 
minimum, and maximum) will be computed on the actual values and the change from 
baseline for each parameter. All laboratory values will be categorized according to their 
normal ranges as below, within or above normal.  
 
Other safety variables, including e.g., heart rate and SPO2 levels, need for O2 therapy (and 
when applicable, relevant parameters such as duration of O2 therapy needed, oxygen 
delivery mode, flow of inspired oxygen), or any significant worsening requiring immediate or 
intensive medical intervention, will be fully depicted using descriptive statistics. Where 
relevant, actual values and changes from baseline, and/or and shift tables according to 
normal ranges, will be included.  
 

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Findings in physical examinations will be listed.  
 
Body height, body weight, and body temperature results will be summarized by descriptive 
statistics. 
3.7.
DATA QUALITY ASSURANCE AND 
DIRECT ACCESS TO SOURCE 
DATA/DOCUMENTS
 
Audits may be conducted to evaluate systems, processes, and expertise for the 
subcontracted activities and to assess compliance with the contractual agreements, the 
protocol, applicable Standard Operating Procedures, and regulatory requirements. During or 
after the conduct of the study, process-related audits may be performed as well. When 
performed, an audit certificate will be provided in appendix of the final study report.  
 
The clinical research facility will be monitored by the study monitor, to ensure correct 
performance of the study procedures and to ensure that the study is conducted according to 
the relevant regulatory requirements. 
 
Regulatory authorities, the IEC/IRB, and/or the Sponsor representative may request access 
to all source documents, eCRFs and other study documentation for an on-site audit or 
inspection. Direct access to these documents must be guaranteed by the Investigator, who 
must provide support at all times for these activities. 
 
Quality control principles will be applied throughout the performance of this study. 
 
3.8.
DATA PROTECTION 
 
During this clinical study, all clinical data will be identified only through an ID number in 
order to protect the rights of the subjects to privacy and to the protection of their personal 
data in accordance with the European Data Protection Directive 95/46/EC, the Privacy Rule 
(45 CFR Parts 160 and 164), and Health Insurance Portability and Accountability Act (as 
applicable). Global principles and standards for Processing Personal Data and for meeting 
Data Transfer Obligations will be applied.  
 

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4.
ETHICS 
 
4.1.
ETHICS COMMITTEES AND 
COMPETENT AUTHORITIES 
 
The Clinical Study Protocol(s) and the ICF(s) will be submitted for review and approval by 
the IEC/IRB prior to the eligibility screening/baseline. The composition of the IEC/IRB is in 
accordance with the recommendations of the World Health Organization, the ICH E6 
Guideline for GCP, the European Union Clinical Trial Directive (CTD) (Directive 2001/20/EC) 
and/or the USA Code of Federal Regulations (CFR) (21 CFR 56), in line with local 
regulations.  
 
The Investigator/Sponsor (or CRO on behalf of the sponsor) will keep the IEC/IRB informed 
about the progress of the study. All changes in research activities and all unanticipated 
problems involving risks to human subjects will be immediately reported to the responsible 
persons. The study may be suspended pending further review by the IEC/IRB, unless 
suspension would jeopardize the subject¶s health. The Investigator will take care that all 
subject¶s parent(s)/legal guardian(s) or the legally acceptable representative(s) are kept 
informed.  
 
No substantial amendments will be implemented to the study without prior IEC/IRB 
approval and CA approval (if applicable according to local regulations), except when 
required to eliminate apparent immediate hazards to subjects. 
 
Notification of the end of the study will be sent to the CA and to the IEC/IRB, within the 
number of days as specified by local regulations after completion of follow-up for the last 
subject. In case the study is ended prematurely, the IEC/IRB and the CA will be notified 
within the number of days as specified by local regulations, including the reasons for the 
premature termination. Results will be provided to the CA and the EC/IRB according to local 
requirements for format and timing. 
 
4.2.
ETHICAL CONDUCT OF THE STUDY 
 
This study will be conducted in compliance with the Guidance for Industry ICH E6 GCP 
(including archiving of essential study documents), the Declaration of Helsinki, the 
applicable regulations of the country(ies) in which the study is conducted, and with the 
Commission Directives 2001/20/EC and 2005/28/EC. 
 

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ICH-adopted guidelines and other relevant international guidelines, recommendations, and 
requirements will be taken into account as comprehensively as possible, as long as they do 
not violate local laws. 
The Investigator will be responsible for the care of the subjects throughout the study. If the 
Investigator is not present at the study site, he/she will leave instructions for the staff and a 
telephone number where he/she can be reached. 
 
4.3.
SUBJECT INFORMATION AND 
CONSENT
 
As the potential subjects are infants or young children, subjects¶ parent(s), legal guardian(s) 
or the legally acceptable representative(s) must provide their written informed consent 
before enrolment of their child in the clinical study, and before any protocol-specified 
procedures are performed.  
 
Freely given and written informed consent must be obtained according to local requirements 
after the nature of the study has been fully explained. The consent form must be signed 
before performance of any study-related activity. The consent form that is used will be 
approved by both the Sponsor or designee and by the reviewing IEC/IRB. The informed 
consent will be in accordance with principles that originated in the Declaration of Helsinki, 
current ICH and GCP guidelines, applicable regulatory requirements, and Sponsor policy. 
 
Before undertaking any study-related procedure in the study, the Investigator or an 
authorized member of the investigational staff must explain to the subjects¶ parent(s), legal 
guardian(s) or the legally acceptable representative(s) the aims, methods, objectives, 
potential clinical benefits, and potential hazards of the study, and any discomfort 
participation in the study may entail.  
 
The subjects¶ parent(s), legal guardian(s), or the legally acceptable representative(s) will be 
informed that the participation is voluntary and that they may refuse to participate or 
withdraw from the study, at any time, without penalty or loss of benefits to which the 
subject is otherwise entitled, and that all data collected up to the point of withdrawal will be 
used and reported in an anonymized way. They will be told that the Investigator will 
maintain a subject identification register for the purposes of long-term follow-up if needed, 
and that the records may be accessed by health authorities, authorized Sponsor staff, and 
Sponsor representative without violating the confidentiality of the subject, to the extent 
permitted by the applicable law(s) or regulations. In addition, insurance coverage provided 
during the study will be explained. 
 

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By signing the ICF the subjects¶ parent(s), legal guardian(s), or the legally acceptable 
representative(s) is/are authorizing such access, and agrees to allow the study physician to 
recontact 
the 
subjects¶ 
parent(s), 
legal 
guardian(s), 
or 
the 
legally 
acceptable 
representative(s) for the purpose of obtaining consent for additional safety evaluations, if 
needed. 
 
If the subjects¶ parent(s), legal guardian(s), or the legally acceptable representative(s) 
is/are unable to read, an impartial witness must be present during the entire informed 
consent discussion. Once the written ICF (and any other written information) is read and 
explained to the subjects¶ parent(s), legal guardian(s) or the legally acceptable 
representative(s), and after the subjects¶ parent(s), legal guardian(s), or the legally 
acceptable representative(s) has orally consented to the subject¶s participation in the study, 
and, if capable of doing so, has signed and personally dated the ICF, the witness must sign 
and personally date the consent form. By signing the consent form, the witness attests that 
the information in the consent form and any other written information was accurately 
explained to, and apparently understood by, the subjects¶ parent(s), legal guardian(s) or 
the legally acceptable representative(s), and that informed consent was freely given by the 
subjects¶ parent(s), legal guardian(s) or the legally acceptable representative(s). 
 
The language used in the oral and written information about the study, including the ICF, 
will be as nontechnical as practical and should be understandable to the subjects¶ parent(s), 
legal guardian(s) or the legally acceptable representative(s). They will be given sufficient 
time to read the ICF and given the opportunity to ask questions. After this explanation and 
before entry into the study, consent will be appropriately recorded by means of the 
subjects¶ parent(s), legal guardian(s) or the legally acceptable representative(s) personally 
dated signature(s) and by the Investigator or an authorized member of the investigational 
staff who conducted the ICF discussion.  
 
After having obtained the consent, a copy of the signed ICF will be given to the subject¶s 
parent(s)/legal guardian(s) or the legally acceptable representative(s). The original of the 
ICF will be retained by the Investigator in the ³Investigator Site File´. 
 
4.4.
PRIVACY
 
The study is conducted according to the principles of ICH, including the specifications for 
privacy and data protection.  
 
The collection and processing of personal data from subjects enrolled in this study will be 
limited to those data that are necessary to investigate the safety, quality, and utility of the 
investigational study drug(s) used in this study. The collected data are adequate, and not 
excessive in relation to the purposes for which they are collected and processed. 

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The data are collected and processed with adequate precautions to ensure confidentiality 
and compliance with applicable data privacy protection laws and regulations. Appropriate 
technical and organizational measures to protect the personal data against unauthorized 
disclosures or access, accidental or unlawful destruction, or accidental loss or alteration is in 
place. The data will be kept in a form, which does not readily permit identification of the 
subject. Subjects will be identified by his/her assigned unique subject number and his/her 
year of birth. Personal data will only be collected and processed using these unique 
identification items. Only the Investigator and his/her study team keeps a list that makes it 
possible to link unique subject numbers to an individual name. Sponsor personnel whose 
responsibilities require access to personal data have to agree to keep the identity of study 
subjects confidential. 
 
The informed consent obtained from the subject¶s parent(s)/legal guardian(s) or the legally 
acceptable representative(s) includes explicit consent for the processing of personal data 
and for the Investigator to allow direct access to his/her original medical records for study-
related monitoring, audit, IEC/IRB review, and regulatory inspection. This consent also 
addresses the transfer of the data to other entities and to other countries. 
 
 

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5. DATA HANDLING AND RECORD 
KEEPING
 
5.1.
DISTRIBUTION OF ACTIVITIES 
 
Contact details of the Sponsor and third parties are available in the ³Investigator Site File´. 
 
5.2.
DOCUMENTATION 
 
Study documentation required for study start (as specified in the ICH E6 Guideline for GCP 
[CPMP/ICH/135/95]) shall be exchanged between Ablynx NV and the vendor prior to the 
administration of study drug. 
 
5.2.1. CASE REPORT FORM COMPLETION 
 
Case report forms will be completed for each subject (incl. screen failures in order to assess 
the numbers and demographic characteristics of the excluded subjects, and the reasons for 
their exclusion). 
 
The Investigator will ensure that data are recorded on the eCRF as specified in the Clinical 
Study Protocol and in accordance with the instructions in the eCRF completion guidelines. 
The Investigator will ensure the accuracy, completeness, legibility, and timeliness of the 
data recorded in the eCRF, and of the provision of answers to data queries according to the 
Clinical Study Agreement. All eCRF entries, corrections, and alterations must be made by 
the Investigator or other authorized study-site personnel. The Investigator will sign the 
completed eCRF. A copy of the completed eCRF will be archived at the study site. 
 
5.2.2. SOURCE DOCUMENTATION 
 
At a minimum, source documentation must be available for the following: informed consent 
process, medical history, subject identification, eligibility, and study identification; date of 
informed consent; dates of visits; results of all efficacy evaluations; results of safety 
parameters as required by the protocol; record of all AEs; and follow-up of AEs; prior and 
concomitant medication; study drug receipt records; study drug administration information; 
any medical notes (original documents, data and records, e.g., laboratory data); date of 
study completion, and reason for early discontinuation of study procedures or withdrawal 
from the study (and information on documented attempts to obtain information on the final 
status of the subject for those who are considered lost to follow-up), if applicable.  
 

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In addition, the author of an entry in the source documents should be identifiable. 
 
At a minimum, the type and level of detail of source data available for a study subject 
should be consistent with that commonly recorded at the site as a basis for standard 
medical care (Patient¶s Medical File). 
 
Following the ICH-GCP guidelines, direct access to source documentation (medical records) 
must be allowed. 
 
5.2.3. RECORD RETENTION 
 
In compliance with the ICH/GCP guidelines, the Investigator/Institution will maintain all 
eCRFs and all source documents that support the data collected from each subject, as well 
as all study documents as specified in ICH/GCP section 8, Essential Documents for the 
Conduct of a Clinical Study, and all study documents as specified by the applicable 
regulatory requirement(s). The Investigator/ Institution will take measures to prevent 
accidental or premature destruction of these documents. 
 
Essential documents must be retained until at least 15 years after completion of the study, 
at least 2 years after the last approval of a marketing application in an ICH region and until 
there are no pending or contemplated marketing applications in an ICH region or until at 
least 2 years have elapsed since the formal discontinuation of clinical development of the 
study drug. These documents will be retained for a longer period if required by the 
applicable regulatory requirements or by an agreement with the Sponsor. It is the 
responsibility of the Sponsor to inform the Investigator/Institution as to when these 
documents no longer need to be retained. 
 
If the responsible Investigator retires, relocates or for other reasons withdraws from the 
responsibility of keeping the study records, custody must be transferred to a person who 
will accept the responsibility. The Sponsor must be notified in writing of the name and 
address of the new custodian. Under no circumstance shall the Investigator relocate or 
dispose of any study documents before having obtained written approval from the Sponsor. 
 
If it becomes necessary for the Sponsor or the appropriate regulatory authority to review 
any documentation relating to this study, the Investigator must permit access to such 
essential documents and subject data. 
 
The Sponsor and the vendor(s) to whom the Sponsor has transferred duties and functions 
are responsible for organizing and maintaining a clear documentation of the course of the 
study. 
 

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The Trial Master File maintained during the study by the assigned vendor(s) will be sent 
back to the Sponsor at the end of the study, after final review and upon Sponsor approval. 
 
5.2.4. MONITORING 
 
The monitor will perform on-site monitoring visits as specified in a monitoring plan to 
ensure that all aspects of the protocol, contractual agreements and regulatory requirements 
are followed and that subjects¶ human rights, safety and well-being are protected. The 
monitor will record dates of monitoring in a study center visit log that will be kept at the 
site. At these visits, the monitor will perform source data verification and check the data 
entered into the eCRF for completeness and accuracy. The nature and location of all source 
documents will be identified to ensure that all sources of original data required to complete 
the eCRF are known to the Sponsor and investigational staff and are accessible for 
verification by the Sponsor site contact. If electronic records are maintained at the 
investigational site, the method of verification must be discussed with the investigational 
staff.  
 
Direct access to source documentation ([electronic] medical records) must be permitted at 
all times. Findings from this review of captured data will be discussed with the 
investigational staff. The Sponsor expects that, during on-site monitoring visits, the relevant 
investigational staff will be available, the source documentation will be accessible, and a 
suitable environment will be provided for review of study-related documents. The monitor 
will meet with the Investigator on a regular basis during the study to provide feedback on 
the study conduct. The Investigator agrees to cooperate with the monitor to ensure that any 
problems detected in the course of these monitoring visits will be resolved in a timely 
manner.
 
 

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6.
FINANCING AND INSURANCE 
 
Insurance
Ablynx NV holds and will maintain an adequate insurance policy covering damages arising 
from Ablynx-sponsored clinical research studies. 
 
Ablynx NV will indemnify the Investigator in accordance with the provisions as set in a 
separate written agreement between Ablynx NV (or a vendor on behalf of the Sponsor) and 
the relevant Investigator/clinical site. 
 
Financing 
 
The financial aspects of the study will be documented in an agreement between the Sponsor 
(or a vendor on behalf of the Sponsor) and the Investigator/Institution. 
 
Compensation for reasonable expenses made related to the study such as travel costs to 
visit the study center for assessments related to the study will be foreseen. 
 
Financial Disclosure 
Any identified Investigator or sub-investigator directly involved in the treatment or 
evaluation of research subjects will disclose for the time period during which the 
Investigator is participating in the study and for 1 year following completion of the study 
that 
he/she 
entered 
a 
financial 
arrangement 
between 
the 
Sponsor 
and 
the 
Investigator/Institution. The Investigator should promptly update this information if any 
relevant changes occur during this period. 
 

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7.
USE OF INFORMATION AND 
PUBLICATION 
 
By signing this protocol, the Investigator reaffirms to the Sponsor that he or she will 
maintain in confidence all information furnished, or resulting from this study. He/she will 
only divulge such information as may be necessary to the IEC/IRB and the members of the 
staff and the parent(s)/legal guardian(s) of subjects who are involved in this study.  
 
All data and records provided by the Sponsor or generated during the study (other than 
subject¶s medical records) and all data and inventions covered in the course of conducting 
the study, whether patentable or not, are the sole and exclusive property of the Sponsor. 
 
The Investigator and all other study team members at any service provider involved will 
keep strictly confidential all information provided by the Sponsor related to this study and 
all data and records generated in the course of the study. They will not use the information, 
data, or records for any other purpose than conducting the study without prior written 
approval of the Sponsor. 
 
Publication of any results from this study will be according to the principles of the 
Declaration of Helsinki, and will require prior review and written agreement of the Sponsor. 
 

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8.
REFERENCES 
 
1. 
Ralston, S.L., et al., Clinical practice guideline: the diagnosis, management, and 
prevention of bronchiolitis. Pediatrics, 2014. 134(5): p. e1474-502. 
2. 
National Institute for Health and Care Excellence (NICE), Guideline in development - 
Bronchiolitis: Diagnosis and Management of Bronchiolitis in Children, 2015: London. 
3. 
Meissner, H.C., Viral Bronchiolitis in Children. The New England journal of medicine, 
2016. 374(1): p. 62-72. 
4. 
Mazur, N.I., et al., Lower respiratory tract infection caused by respiratory syncytial 
virus: current management and new therapeutics. The Lancet. Respiratory medicine, 
2015. 3(11): p. 888-900. 
5. 
Black, C.P., Systematic review of the biology and medical management of respiratory 
syncytial virus infection. Respir Care, 2003. 48(3): p. 209-31; discussion 231-3. 
6. 
Ablynx Summary Report, Immunogenicity risk assessment ALX-0171. 
7. 
Chamberlain, P., Addressing immunogenicity-related risks in an integrated manner. 
Informa UK - Dossier Strategy, 2011. 
8. 
Shankar, G., C. Pendley, and K.E. Stein, A risk-based bioanalytical strategy for the 
assessment of antibody immune responses against biological drugs. Nature 
biotechnology, 2007. 25(5): p. 555-61. 
9. 
FDA, Draft guidance: guidance for industry: Immunogenicity assessment for 
therapeutic protein products. 2013. 
10. Wang, Y., et al., Clarification on precision criteria to derive sample size when designing 
pediatric pharmacokinetic studies. Journal of clinical pharmacology, 2012. 52(10): p. 
1601-6. 
11. Justicia-Grande, A., et al., Development and validation of a new clinical scale for 
infants suffering from acute respiratory infection. Leipzig: 33rd Annual Meeting of the 
European Society for Paediatric Infectious Diaseases, 2015. 
12. Cebey-Lopez, M., et al., Bacteremia in Children Hospitalized with Respiratory Syncytial 
Virus Infection. PloS one, 2016. 11(2): p. e0146599. 
13. Imai, T., et al., Serum KL-6 levels in pediatric patients: reference values for children 
and levels in pneumonia, asthma, and measles patients. Pediatric pulmonology, 
2002. 33(2): p. 135-41. 
14. Kawasaki, Y., et al., Serum KL-6 levels as a biomarker of lung injury in respiratory 
syncytial virus bronchiolitis. Journal of medical virology, 2009. 81(12): p. 2104-8. 
15. Kubota, M. and T. Haruta, The role of serum KL-6 measurement in common pediatric 
respiratory infections. Journal of infection and chemotherapy : official journal of the 
Japan Society of Chemotherapy, 2006. 12(1): p. 22-4. 
16. Howie, S.R., Blood sample volumes in child health research: review of safe limits. 
Bulletin of the World Health Organization, 2011. 89(1): p. 46-53. 
17. WHO, Paediatric clinical trials - guidance for assessors. 2011. 
18. EMA, Recommendations of the ad hoc group for the development of implementing 
guidelines for Directive 2001/20/EC relating to good clinical practice in the conduct of 
clinical trials on medicinal products for human use - Ethical considerations for clinical 
trials on medicinal products conducted with the paediatric population. 2008. 
19. FDA, 21CFR50 - Subpart D: Additional Safeguards for Children in Clinical 
Investigations. 2013. 
20. FDA, 45CFR46 - Protection of human subjects. 2013. 
21. Barrett, J.S., et al., Physiologically based pharmacokinetic (PBPK) modeling in children. 
Clinical pharmacology and therapeutics, 2012. 92(1): p. 40-9. 

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22. Khalil, F. and S. Laer, Physiologically Based Pharmacokinetic Modeling: Methodology, 
Applications, and Limitations with a Focus on Its Role in Pediatric Drug Development. 
Journal of Biomedicine and Biotechnology, 2011. 2011. 
23. De Paepe, M.E., et al., Postmortem lung weight/body weight standards for term and 
preterm infants. Pediatric pulmonology, 2005. 40(5): p. 445-8. 
 
 
 

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9.
APPENDICES
Appendix 1: RDAI scoring system 
 
RDAI is a 17-point score based on wheezing and retraction. 
Number of Points 
Variable 
0 
1 
2 
3 
4 
Maximum 
Points 
Wheezing
 
 
  Expiration 
None 
End
1-2
3-4
All 
4
  Inspiration 
None 
Part
All
NA
NA 
2
  Location 
None 
Segmental 
 2-4 
lung fields 
Diffuse 
 3-4 
lung fields 
NA 
NA 
2 
Retractions 
 
 
 
 
 
 
  Supraclavicular 
None 
Mild
Moderate
Marked
NA 
3
  Intercostal 
None 
Mild
Moderate
Marked
NA 
3
  Subcostal 
None 
Mild
Moderate
Marked
NA 
3
NA = not applicable 
 
The RDAI score is the sum of the row scores, with total range 0 to 17; higher scores 
indicate more severe disease. 
 
 
Appendix 2: RACS score 
 
The RACS score is the sum of the change in the RDAI score and a standardised score for the 
change in respiratory rate. The change in respiratory rate is assigned 1 point per each 10% 
change in the respiratory rate.  
A decrease in the RDAI or in the respiratory rate during the study period is recorded as a 
negative RACS, meaning an improvement. 
 
 

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Appendix 3: Global Severity Score 
 
The Global Severity Score is the sum of the scores of the 7 individual items as described 
below; total maximum score is 20 points; higher score indicates more severe disease. 
 
Item
Number 
of Points 
Description 
Feeding 
0 
Adequate oral feeding 
 
1 
No adequate oral feeding, occasional breaks during feeding 
 
2 
No adequate oral feeding, frequent breaks during feeding 
 
3 
No adequate oral feeding, unable to feed, feeding support 
Medical 
interventions 
0 
Not hospitalized 
1 
Hospitalization without O2 supplementation 
 
2 
Conventional oxygen supplementation 
 
3 
Non-invasive respiratory support or invasive ventilation 
Respiratory 
distress 
0 
No wheezing and no retractions 
1-2-3 
Points will be attributed uniformly across the 17 points for RDAI 
Respiratory rate 
0-1-2-3 
Points will be attributed uniformly across the respiratory rate values 
for each age range 
Apnea 
0 
No apnea episode 
 
3 
Apnea episode 
General 
appearance a 
0 
Active, playing/ content/ interactive and happy 
1 
Less active/ mildly irritable/ less interactive or responsive 
 
2 
Less active/ moderately irritable/ less interactive or responsive 
 
3 
Not active/ Severely irritable/ Not interactive or not responsive 
 
Note: In case worst item is less active and/or less interactive: if both are present: 2 points; 
if only one of both is present and the highest: 1 point 
Body 
Temperature 
0 
<37,0°C: (measured axillary); <37,5°C (measured by other method) 
1 
37,0°C but <38°C (measured axillary); 
37,5°C but <38,5°C 
(measured by other method) 
 
2 
>38°C (measured axillary); >38,5°C (measured by other method) 
a Assessed through activity, irritation and interest in environment (worst of the three items will be used for 
attributing the points) 
 
 
 

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